|
1
|
Hung LY, Alves ND, Del Colle A, Talati A, Najjar SA, Bouchard V, Gillet V, Tong Y, Huang Z, Browning KN, Hua J, Liu Y, Woodruff JO, Juarez D, Medina M, Posner J, Tonello R, Yalcinkaya N, Israelyan N, Ringel R, Yang L, Leong KW, Yang M, Sze JY, Savidge T, Gingrich J, Shulman RJ, Gershon MD, Ouellet A, Takser L, Ansorge MS, Margolis KG. Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood. Gastroenterology 2025; 168:754-768. [PMID: 39672518 DOI: 10.1053/j.gastro.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/11/2024] [Accepted: 11/15/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND & AIMS Mood disorders and disorders of gut-brain interaction (DGBI) are highly prevalent, commonly comorbid, and lack fully effective therapies. Although selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for these disorders, they may impart adverse effects, including anxiety, anhedonia, dysmotility, and, in children exposed in utero, an increased risk of cognitive, mood, and gastrointestinal disorders. SSRIs act systemically to block the serotonin reuptake transporter and enhance serotonergic signaling in the brain, intestinal epithelium, and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development. METHODS We used transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial serotonin reuptake transporter or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development. RESULTS Serotonin reuptake transporter ablation targeted to the intestinal epithelium promoted anxiolytic and antidepressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms. CONCLUSION These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation, and suggest a new link in humans between in utero SSRI exposure and DGBI development.
Collapse
Affiliation(s)
- Lin Y Hung
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Nuno D Alves
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York
| | - Andrew Del Colle
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Ardesheer Talati
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York
| | - Sarah A Najjar
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Virginie Bouchard
- Department of Pediatrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Virginie Gillet
- Department of Pediatrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Yan Tong
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Zixing Huang
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania
| | - Jialiang Hua
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York
| | - Ying Liu
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York
| | - James O Woodruff
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York
| | - Daniel Juarez
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Melissa Medina
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Jonathan Posner
- Department of Psychiatry, Duke University School of Medicine; Durham, North Carolina
| | - Raquel Tonello
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Nazli Yalcinkaya
- Department of Pathology and Department of Immunology, Baylor College of Medicine and Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas
| | - Narek Israelyan
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Roey Ringel
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Letao Yang
- Department of Biomedical Engineering, Columbia University, New York, New York
| | - Kam W Leong
- Department of Biomedical Engineering, Columbia University, New York, New York; Department of Systems Biology, Columbia University Medical Center, New York, New York
| | - Mu Yang
- Neurobehavior Core, Institute of Genomic Medicine, Columbia University Irving Medical Center, New York, New York
| | - Ji Ying Sze
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York
| | - Tor Savidge
- Department of Pathology and Department of Immunology, Baylor College of Medicine and Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas
| | - Jay Gingrich
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York
| | - Robert J Shulman
- Department of Pediatrics and USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Michael D Gershon
- Department of Pathology and Cell Biology, Columbia University, New York, New York
| | - Annie Ouellet
- Department of Obstetrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Larissa Takser
- Department of Pediatrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Mark S Ansorge
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York.
| | - Kara Gross Margolis
- NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York; Department of Cell Biology, NYU Grossman School of Medicine, New York, New York; Department of Pediatrics, NYU Grossman School of Medicine, New York, New York.
| |
Collapse
|
|
2
|
Lee MJ, Chen YL, Wu SI, Huang CW, Dewey ME, Chen VCH. Association between maternal antidepressant use during pregnancy and the risk of autism spectrum disorder and attention deficit hyperactivity disorder in offspring. Eur Child Adolesc Psychiatry 2024; 33:4273-4283. [PMID: 38762849 DOI: 10.1007/s00787-024-02460-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/29/2024] [Indexed: 05/20/2024]
Abstract
Prenatal antidepressant exposure has been reported to be associated with adverse neurodevelopmental outcomes, yet studies considering confounding factors in Asian populations are lacking. This study utilized a nationwide data base in Taiwan, enrolling all liveborn children registered in the National Health Insurance system between 2004 and 2016. Subjects were divided into two groups: antidepressant-exposed (n = 55,707)) and antidepressant-unexposed group (n = 2,245,689). The effect of antidepressant exposure during different trimesters on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) was examined. Sibling controls and parallel comparisons by paternal exposure status were treated as negative controls. Additional sensitivity analyses were conducted to examine the effects of antidepressant exposure before and after pregnancy. Prenatal antidepressant exposure was associated with increased risks of ASD and ADHD in population-wide and adjusted analysis. However when comparing antidepressant-exposed children with their unexposed siblings, no differences were found for ASD (Hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.76-1.42 in first trimester; HR: 0.96, 95% CI 0.62-1.50 in second trimester; HR: 0.69, 95% CI 0.32-1.48 in third trimester) and ADHD (HR: 0.98, 95%CI 0.84-1.15 in first trimester; HR: 0.91, 95% CI 0.73-1.14 in second trimester; HR: 0.79, 95% CI 0.54-1.16 in third trimester). Increased risks for ASD and ADHD were also noted in paternal control, before and after pregnancy analyses. These results imply that the association between prenatal antidepressant exposure and ASD and ADHD is not contributed to by an intrauterine medication effect but more likely to be accounted for by maternal depression, genetic, and potential environmental factors.
Collapse
Affiliation(s)
- Min-Jing Lee
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi County, Puzi City, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Lung Chen
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Shu-I Wu
- Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Chien-Wei Huang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Michael E Dewey
- Health Service and Population Research Department, King's College London, London, UK
| | - Vincent Chin-Hung Chen
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi County, Puzi City, Taiwan.
- School of Medicine, Chang Gung University, Taoyuan, Taiwan.
| |
Collapse
|
|
3
|
Damera SR, De Asis-Cruz J, Cook KM, Kapse K, Spoehr E, Murnick J, Basu S, Andescavage N, Limperopoulos C. Regional homogeneity as a marker of sensory cortex dysmaturity in preterm infants. iScience 2024; 27:109662. [PMID: 38665205 PMCID: PMC11043889 DOI: 10.1016/j.isci.2024.109662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 01/23/2024] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
Atypical perinatal sensory experience in preterm infants is thought to increase their risk of neurodevelopmental disabilities by altering the development of the sensory cortices. Here, we used resting-state fMRI data from preterm and term-born infants scanned between 32 and 48 weeks post-menstrual age to assess the effect of early ex-utero exposure on sensory cortex development. Specifically, we utilized a measure of local correlated-ness called regional homogeneity (ReHo). First, we demonstrated that the brain-wide distribution of ReHo mirrors the known gradient of cortical maturation. Next, we showed that preterm birth differentially reduces ReHo across the primary sensory cortices. Finally, exploratory analyses showed that the reduction of ReHo in the primary auditory cortex of preterm infants is related to increased risk of autism at 18 months. In sum, we show that local connectivity within sensory cortices has different developmental trajectories, is differentially affected by preterm birth, and may be associated with later neurodevelopment.
Collapse
Affiliation(s)
- Srikanth R. Damera
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Josepheen De Asis-Cruz
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Kevin M. Cook
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Kushal Kapse
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Emma Spoehr
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Jon Murnick
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Sudeepta Basu
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Nickie Andescavage
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| | - Catherine Limperopoulos
- Developing Brain Institute, Children’s National, 111 Michigan Avenue NW, Washington, DC 20010, USA
| |
Collapse
|
|
4
|
Koc D, Tiemeier H, Stricker BH, Muetzel RL, Hillegers M, El Marroun H. Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory. JAMA Psychiatry 2023; 80:1208-1217. [PMID: 37647036 PMCID: PMC10469300 DOI: 10.1001/jamapsychiatry.2023.3161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 06/13/2023] [Indexed: 09/01/2023]
Abstract
Importance Clinical decision-making on antidepressant treatment during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), is challenging, as both prenatal SSRI exposure and maternal depressive symptoms may be associated with negative outcomes in offspring. Objective To investigate the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring from mid-childhood to early puberty. Design, Setting, and Participants This prospective, population-based cohort study was embedded in the Generation R Study in Rotterdam, the Netherlands. All pregnant individuals with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Data were analyzed from February 1 to September 30, 2022. Exposure Maternal-reported SSRI use verified by pharmacy records. In mid-pregnancy and 2 and 6 months after delivery, participants reported depressive symptoms using the Brief Symptom Inventory and were divided into 5 groups: SSRI use during pregnancy (n = 41; 80 scans), SSRI use only before pregnancy (n = 77; 126 scans), prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans), postnatal depressive symptoms only (n = 74; 128 scans), and nonexposed control individuals (n = 2749; 4813 scans). Main Outcomes and Measures The main outcome was brain morphometry in offspring, including global and cortical brain volumes, measured at 3 magnetic resonance imaging assessments from 7 to 15 years of age. Results The study included 3198 mother-child dyads. A total of 3198 mothers (100%) identified as women; mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment from 7 to 15 years of age with 5624 total scans. Most brain gray matter volumes showed an inverted U-shaped trajectory. Compared with nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter (β [SE], -20 212.2 [7285.6] mm3; P = .006), particularly within the corticolimbic circuit, which persisted up to 15 years of age. Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala (age interaction: β [SE], 43.3 [13.4] mm3; P = .006) and fusiform gyrus (age interaction: β [SE], 168.3 [51.4] mm3; P = .003) from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform observed in childhood did not persist until early adolescence. Prenatal depression was associated with a smaller volume in the rostral anterior cingulate gyrus (β [SE], -166.3 [65.1] mm3; P = .006), and postnatal depression was associated with a reduced fusiform gyrus (β [SE], -480.5 [189.2] mm3; P = .002). No association of SSRI use before pregnancy with brain outcomes was observed. Conclusions and Relevance The results of this cohort study suggest that prenatal SSRI exposure may be associated with altered developmental trajectories of brain regions involved in emotional regulation in offspring. Further research on the functional implications of these findings is needed.
Collapse
Affiliation(s)
- Dogukan Koc
- Generation R Study Group, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | - Henning Tiemeier
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Bruno H. Stricker
- Department of Epidemiology, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | - Ryan L. Muetzel
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | - Manon Hillegers
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | - Hanan El Marroun
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
- Department of Psychology, Education and Child Studies, Erasmus School of Social and Behavioural Sciences, Erasmus University Rotterdam, Rotterdam, the Netherlands
| |
Collapse
|
|
5
|
Carkaci-Salli N, Bewley MC, Tekin I, Flanagan JM, Vrana KE. The A328 V/E (rs2887147) polymorphisms in human tryptophan hydroxylase 2 compromise enzyme activity. Biochem Biophys Rep 2023; 35:101527. [PMID: 37608910 PMCID: PMC10440358 DOI: 10.1016/j.bbrep.2023.101527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Human tryptophan hydroxylase 2 (hTPH2) is the rate-limiting enzyme for serotonin biosynthesis in the brain. A number of naturally-occurring single nucleotide polymorphisms (SNPs) have been reported for hTPH2. We investigated the activity and kinetic characteristics of the most common missense polymorphism rs2887147 (A328 V/E; 0.92% allelic frequency for the two different reported SNPs at the same site) using bacterially expressed hTPH2. The recombinant full-length enzyme A328E had no measurable enzyme activity, but A328V displayed decreased enzyme activity (Vmax). A328V also displayed substrate inhibition and decreased stability compared to the wild-type enzyme. By contrast, in constructs lacking the N-terminal 150 amino acid regulatory domain, the A328V substitution had no effect; that is, there was no substrate inhibition, enzyme stabilities (for wild-type and A328V) were dramatically increased, and Vmax values were not different (while the A328E variant remained inactive). These findings, in combination with molecular modeling, suggest that substitutions at A328 affect catalytic activity by altering the conformational freedom of the regulatory domain. The reduced activity and substrate inhibition resulting from these polymorphisms may ultimately reduce serotonin synthesis and contribute to behavioral perturbations, emotional stress, and eating disorders.
Collapse
Affiliation(s)
- Nurgul Carkaci-Salli
- Departments of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Maria C. Bewley
- Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Izel Tekin
- Departments of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - John M. Flanagan
- Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Kent E. Vrana
- Departments of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| |
Collapse
|
|
6
|
Achterberg EJM, Vanderschuren LJMJ. The neurobiology of social play behaviour: Past, present and future. Neurosci Biobehav Rev 2023; 152:105319. [PMID: 37454882 DOI: 10.1016/j.neubiorev.2023.105319] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/07/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023]
Abstract
Social play behaviour is a highly energetic and rewarding activity that is of great importance for the development of brain and behaviour. Social play is abundant during the juvenile and early adolescent phases of life, and it occurs in most mammalian species, as well as in certain birds and reptiles. To date, the majority of research into the neural mechanisms of social play behaviour has been performed in male rats. In the present review we summarize studies on the neurobiology of social play behaviour in rats, including work on pharmacological and genetic models for autism spectrum disorders, early life manipulations and environmental factors that influence play in rats. We describe several recent developments that expand the field, and highlight outstanding questions that may guide future studies.
Collapse
Affiliation(s)
- E J Marijke Achterberg
- Dept. of Population Health Sciences, Section Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM Utrecht, the Netherlands.
| | - Louk J M J Vanderschuren
- Dept. of Population Health Sciences, Section Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM Utrecht, the Netherlands.
| |
Collapse
|
|
7
|
Bonanno SL, Krantz DE. Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter. Transl Psychiatry 2023; 13:226. [PMID: 37355701 DOI: 10.1038/s41398-023-02521-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/26/2023] Open
Abstract
The transcriptional effects of SSRIs and other serotonergic drugs remain unclear, in part due to the heterogeneity of postsynaptic cells, which may respond differently to changes in serotonergic signaling. Relatively simple model systems such as Drosophila afford more tractable microcircuits in which to investigate these changes in specific cell types. Here, we focus on the mushroom body, an insect brain structure heavily innervated by serotonin and comprised of multiple different but related subtypes of Kenyon cells. We use fluorescence-activated cell sorting of Kenyon cells, followed by either bulk or single-cell RNA sequencing to explore the transcriptomic response of these cells to SERT inhibition. We compared the effects of two different Drosophila Serotonin Transporter (dSERT) mutant alleles as well as feeding the SSRI citalopram to adult flies. We find that the genetic architecture associated with one of the mutants contributed to significant artefactual changes in expression. Comparison of differential expression caused by loss of SERT during development versus aged, adult flies, suggests that changes in serotonergic signaling may have relatively stronger effects during development, consistent with behavioral studies in mice. Overall, our experiments revealed limited transcriptomic changes in Kenyon cells, but suggest that different subtypes may respond differently to SERT loss-of-function. Further work exploring the effects of SERT loss-of-function in other circuits may be used help to elucidate how SSRIs differentially affect a variety of different neuronal subtypes both during development and in adults.
Collapse
Affiliation(s)
- Shivan L Bonanno
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - David E Krantz
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
| |
Collapse
|
|
8
|
Cheng Y, Chen R, Su B, Zhang G, Sun Y, An P, Fang Y, Zhang Y, Shan Y, de Villers-Sidani É, Wang Y, Zhou X. Pairing with Enriched Sound Exposure Restores Auditory Processing Degraded by an Antidepressant. J Neurosci 2023; 43:2850-2859. [PMID: 36948582 PMCID: PMC10124948 DOI: 10.1523/jneurosci.2027-22.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 03/24/2023] Open
Abstract
Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.
Collapse
Affiliation(s)
- Yuan Cheng
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Ruru Chen
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Bowen Su
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Guimin Zhang
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Yutian Sun
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Pengying An
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Yue Fang
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Yifan Zhang
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| | - Ye Shan
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Étienne de Villers-Sidani
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec Canada
| | - Yunfeng Wang
- ENT institute and Department of Otorhinolaryngology of Eye & ENT Hospital, NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China
| | - Xiaoming Zhou
- Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, 200062, China
- New York University-East China Normal University Institute of Brain and Cognitive Science, New York University-Shanghai, Shanghai, 200062, China
| |
Collapse
|
|
9
|
Bonanno SL, Krantz DE. Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter. RESEARCH SQUARE 2023:rs.3.rs-2626506. [PMID: 36993644 PMCID: PMC10055553 DOI: 10.21203/rs.3.rs-2626506/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The transcriptional effects of SSRIs and other serotonergic drugs remain unclear, in part due to the heterogeneity of postsynaptic cells, which may respond differently to changes in serotonergic signaling. Relatively simple model systems such as Drosophila afford more tractable microcircuits in which to investigate these changes in specific cell types. Here, we focus on the mushroom body, an insect brain structure heavily innervated by serotonin and comprised of multiple different but related subtypes of Kenyon cells. We use fluorescence activated cell sorting of Kenyon cells, followed by either or bulk or single cell RNA sequencing to explore the transcriptomic response of these cells to SERT inhibition. We compared the effects of two different Drosophila Serotonin Transporter (dSERT) mutant alleles as well as feeding the SSRI citalapram to adult flies. We find that the genetic architecture associated with one of the mutants contributed to significant artefactual changes in expression. Comparison of differential expression caused by loss of SERT during development versus aged, adult flies, suggests that changes in serotonergic signaling may have relatively stronger effects during development, consistent with behavioral studies in mice. Overall, our experiments revealed limited transcriptomic changes in Kenyon cells, but suggest that different subtypes may respond differently to SERT loss-of-function. Further work exploring the effects of SERT loss-of-function in other Drosophila circuits may be used help to elucidate how SSRIs differentially affect a variety of different neuronal subtypes both during development and in adults.
Collapse
Affiliation(s)
- Shivan L. Bonanno
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - David E. Krantz
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| |
Collapse
|
|
10
|
Bezenah JC, Tejada AN, Garcia DA, Lopez K, Richie JA, Amodeo DA, Amodeo LR. Early prenatal and late prenatal escitalopram exposure differentially impacts behavioral flexibility and anxiety-related behaviors in adulthood. Pharmacol Biochem Behav 2023; 224:173534. [PMID: 36889444 DOI: 10.1016/j.pbb.2023.173534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are medications commonly used by pregnant women. While SSRIs have been considered safe during pregnancy, there is limited understanding of the long-term consequences of prenatal SSRI exposure on adult behavioral processes. Recent human studies have demonstrated prenatal exposure to some SSRIs in humans may increase susceptibility to autism spectrum disorder (ASD) and developmental delays. While escitalopram is one of the most effective antidepressants, it is also one of the newer available SSRIs, resulting in less information on its safety profile during pregnancy. The current study administered escitalopram (0 or 10 mg/kg, s.c.) to nulliparous female Long-Evans rats for the first (G1-10) or last half (G11-20) of the gestational period. Young adult male and female offspring were subsequently tested on a battery of behavioral tasks consisting of probabilistic reversal learning task, open field conflict, marble burying and social approach tasks. Results demonstrate that escitalopram exposure during the first half of pregnancy resulted in reduced anxiety-like behavior (disinhibition) on the modified open field and enhanced flexibility on the probabilistic reversal learning task. Exposure to escitalopram later in pregnancy resulted in an increase in marble burying behavior, but no differences were found with the other measures. These results suggest that exposure to escitalopram during the first half of prenatal development can have long lasting changes on adult behavior demonstrating better behavioral flexibility and lower anxiety-like behavior compared to non-exposed controls.
Collapse
Affiliation(s)
- Jessica C Bezenah
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America
| | - Alexandra N Tejada
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America
| | - Dominic A Garcia
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America
| | - Korina Lopez
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America
| | - Johnna A Richie
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America
| | - Dionisio A Amodeo
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America
| | - Leslie R Amodeo
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, United States of America.
| |
Collapse
|
|
11
|
Bravo K, González-Ortiz M, Beltrán-Castillo S, Cáceres D, Eugenín J. Development of the Placenta and Brain Are Affected by Selective Serotonin Reuptake Inhibitor Exposure During Critical Periods. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1428:179-198. [PMID: 37466774 DOI: 10.1007/978-3-031-32554-0_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are usually prescribed to treat major depression and anxiety disorders. Fetal brain development exhibits dependency on serotonin (5-hydroxytryptamine, 5-HT) from maternal, placental, and fetal brain sources. At very early fetal stages, fetal serotonin is provided by maternal and placental sources. However, in later fetal stages, brain sources are indispensable for the appropriate development of neural circuitry and the rise of emergent functions implied in behavior acquisition. Thus, susceptible serotonin-related critical periods are recognized, involving the early maternal and placental 5-HT synthesis and the later endogenous 5-HT synthesis in the fetal brain. Acute and chronic exposure to SSRIs during these critical periods may result in short- and long-term placental and brain dysfunctions affecting intrauterine and postnatal life. Maternal and fetal cells express serotonin receptors which make them susceptible to changes in serotonin levels influenced by SSRIs. SSRIs block the serotonin transporter (SERT), which is required for 5-HT reuptake from the synaptic cleft into the presynaptic neuron. Chronic SSRI administration leads to pre- and postsynaptic 5-HT receptor rearrangement. In this review, we focus on the effects of SSRIs administered during critical periods upon placentation and brain development to be considered in evaluating the risk-safety balance in the clinical use of SSRIs.
Collapse
Affiliation(s)
- Karina Bravo
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile USACH, Santiago, Chile.
- Facultad de Ingeniería, Universidad Autónoma de Chile, Santiago, Chile.
| | - Marcelo González-Ortiz
- Laboratorio de Investigación Materno-Fetal (LIMaF), Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
| | - Sebastian Beltrán-Castillo
- Centro integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile
| | - Daniela Cáceres
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile USACH, Santiago, Chile
| | - Jaime Eugenín
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile USACH, Santiago, Chile
| |
Collapse
|
|
12
|
Abstract
Many (> 40%) women discontinue antidepressants during pregnancy because of concerns about effects on the foetus, based on information from inadequately-controlled studies. The sibling-control study design provides the best control for confounding factors, notably maternal depression. The purpose of this review was to investigate the evidence from sibling-control analyses for adverse outcomes in offspring associated with antidepressant exposure during pregnancy. Fourteen sibling-control studies were identified through searches of PubMed and Embase. Outcomes included preterm birth, small for gestational age, neonatal size, birth defects, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), behavioural problems, neurodevelopmental deficits, and scholastic attainment. For the majority of these outcomes, no statistically significant associations were found when comparing exposed and unexposed siblings. Single studies reported associations with preterm birth, reduced gestational age, ADHD, anxiety at 36 months, and lower mathematics test scores, which persisted in the sibling-control analyses. However, differences were small and possibly not clinically significant. Moreover, effects of residual confounding could not be excluded. These findings provide evidence that many of the previously reported associations between prenatal antidepressant exposure and adverse outcomes in offspring are no longer statistically significant when exposed offspring are compared with unexposed siblings. The few statistically significant differences in sibling-control analyses were generally small with doubtful clinical significance. Decisions on antidepressant treatment during pregnancy should be made individually, based on evidence from properly controlled studies, not on misleading information based on studies that have not controlled adequately for confounding factors.
Collapse
Affiliation(s)
- Frank M C Besag
- East London NHS Foundation Trust, 9 Rush Court, Bedford, MK40 3JT, UK.
- University College London, London, UK.
- King's College London, London, UK.
| | | |
Collapse
|
|
13
|
Hong X, Chen R, Zhang L, Yan L, Xin J, Li J, Zha J. Long-Term Exposure to SSRI Citalopram Induces Neurotoxic Effects in Zebrafish. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022; 56:12380-12390. [PMID: 35985052 DOI: 10.1021/acs.est.2c01514] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Residual antidepressants are of increasing concern worldwide, yet critical information on their long-term neurotoxic impacts on nontarget aquatic animals is lacking. Here, we investigated the long-term effects (from 0 to 150 days postfertilization) of the selective serotonin reuptake inhibitor citalopram (0.1-100 μg/L) on motor function, learning, and memory in zebrafish over two generations and explored the reversibility of the effect in F1 larvae. Unlike F0+ larvae, we found that F1+ larvae displayed decreased sensorimotor performance when continuously exposed to citalopram at 100 μg/L. No adverse effects were found in F1- larvae after they were transferred to a clean medium. Whole-mount immunofluorescence assays suggested that the motor impairments were related to axonal projections of the spinal motor neurons (MNs). For F0+ adults, long-term citalopram exposure mainly caused male-specific declines in motor, learning, and memory performance. Analysis of serotonergic and cholinergic MNs revealed no significant changes in the male zebrafish spinal cord. In contrast, the number of glutamatergic spinal MNs decreased, likely associated with the impairment of motor function. Additionally, treatment with 100 μg/L citalopram significantly reduced the number of dopaminergic neurons, but no significant neuronal apoptosis was observed in the adult telencephalon. Overall, this study provides neurobehavioral evidence and novel insights into the neurotoxic mechanisms of long-term citalopram exposure and may facilitate the assessment of the environmental and health risks posed by citalopram-containing antidepressant drugs.
Collapse
Affiliation(s)
- Xiangsheng Hong
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Rui Chen
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Le Zhang
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liang Yan
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiajing Xin
- Department of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, China
| | - Jiasu Li
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Jinmiao Zha
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| |
Collapse
|
|
14
|
Unroe KA, Maltman JL, Shupe EA, Clinton SM. Disrupted serotonin system development via early life antidepressant exposure impairs maternal care and increases serotonin receptor expression in adult female offspring. Dev Psychobiol 2022; 64:e22292. [PMID: 35748633 DOI: 10.1002/dev.22292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 11/11/2022]
Abstract
Manipulating serotonin (5-HT) levels in the developing brain elicits a range of effects on brain function and behavior. For example, early-life exposure to selective 5-HT reuptake inhibitor (SSRI) antidepressants disrupts dorsal raphe function and triggers aberrant adult behaviors such as increased passive stress coping and anhedonia. However, much less is understood about how alterations in 5-HT signaling in early life impact outcomes in female offspring, including critical social functions such as maternal care. The present study shows that early-life SSRI exposure disrupts adult female offspring's maternal behavior. Pregnant/postpartum female Sprague-Dawley rats were treated with the SSRI citalopram in drinking water or provided regular tap water as control. Female offspring were raised to adulthood and mated with treatment-naïve males. Following parturition, we observed maternal behavior during portions of the light and dark phases of postnatal days (P)1-14. Relative to controls, dams with a history of early-life SSRI exposure exhibited decreased maternal care, including diminished arched-back nursing, reduced licking and grooming of pups, and increased behavioral inconsistency. Brains were collected from dams with and without a history of early-life SSRI exposure to measure relative mRNA expression of select 5-HT receptor transcripts (5HTR1A, -1B, -2A, -2C) in regions involved in maternal care. Early-life SSRI exposure augmented expression of 5-HTR1A in the medial preoptic area and 5-HTR1B, 5-HTR2A, and 5-HTR2C in the prefrontal cortex. These results demonstrate that early alterations to 5-HT signaling through SSRI exposure may disrupt nurturing parental behaviors and 5-HT receptor expression in affected female rat offspring.
Collapse
Affiliation(s)
- Keaton A Unroe
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.,Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Jessica L Maltman
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Elizabeth A Shupe
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.,Neuroscience Graduate Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Sarah M Clinton
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| |
Collapse
|
|
15
|
Ramsteijn AS, Verkaik-Schakel RN, Houwing DJ, Plösch T, Olivier JDA. Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats. Neuropsychopharmacology 2022; 47:1620-1632. [PMID: 35102259 PMCID: PMC9283398 DOI: 10.1038/s41386-022-01270-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 12/11/2021] [Accepted: 01/04/2022] [Indexed: 12/30/2022]
Abstract
Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
Collapse
Affiliation(s)
- Anouschka S. Ramsteijn
- grid.4830.f0000 0004 0407 1981Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands ,grid.7107.10000 0004 1936 7291Present Address: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK
| | - Rikst Nynke Verkaik-Schakel
- grid.4830.f0000 0004 0407 1981Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Danielle J. Houwing
- grid.4830.f0000 0004 0407 1981Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands ,grid.10417.330000 0004 0444 9382Present Address: Department of Cognitive Neuroscience, Center for Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Torsten Plösch
- grid.4830.f0000 0004 0407 1981Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jocelien D. A. Olivier
- grid.4830.f0000 0004 0407 1981Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| |
Collapse
|
|
16
|
An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster. Cells 2022; 11:cells11091544. [PMID: 35563850 PMCID: PMC9105628 DOI: 10.3390/cells11091544] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/24/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms and dopaminergic cell loss. A pre-symptomatic phase characterized by non-motor symptoms precedes the onset of motor alterations. Two recent PET studies in human carriers of mutations associated with familial PD demonstrate an early serotonergic commitment—alteration in SERT binding—before any dopaminergic or motor dysfunction, that is, at putative PD pre-symptomatic stages. These findings support the hypothesis that early alterations in the serotonergic system could contribute to the progression of PD, an idea difficult to be tested in humans. Here, we study some components of the serotonergic system during the pre-symptomatic phase in a well-characterized Drosophila PD model, Pink1B9 mutant flies. We detected lower brain serotonin content in Pink1B9 flies, accompanied by reduced activity of SERT before the onset of motor dysfunctions. We also explored the consequences of a brief early manipulation of the serotonergic system in the development of motor symptoms later in aged animals. Feeding young Pink1B9 flies with fluoxetine, a SERT blocker, prevents the loss of dopaminergic neurons and ameliorates motor impairment observed in aged mutant flies. Surprisingly, the same pharmacological manipulation in young control flies results in aged animals exhibiting a PD-like phenotype. Our findings support that an early dysfunction in the serotonergic system precedes and contributes to the onset of the Parkinsonian phenotype in Drosophila.
Collapse
|
|
17
|
Tokariev A, Oberlander VC, Videman M, Vanhatalo S. Cortical Cross-Frequency Coupling Is Affected by in utero Exposure to Antidepressant Medication. Front Neurosci 2022; 16:803708. [PMID: 35310093 PMCID: PMC8927083 DOI: 10.3389/fnins.2022.803708] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/27/2022] [Indexed: 11/24/2022] Open
Abstract
Up to five percent of human infants are exposed to maternal antidepressant medication by serotonin reuptake inhibitors (SRI) during pregnancy, yet the SRI effects on infants’ early neurodevelopment are not fully understood. Here, we studied how maternal SRI medication affects cortical frequency-specific and cross-frequency interactions estimated, respectively, by phase-phase correlations (PPC) and phase-amplitude coupling (PAC) in electroencephalographic (EEG) recordings. We examined the cortical activity in infants after fetal exposure to SRIs relative to a control group of infants without medical history of any kind. Our findings show that the sleep-related dynamics of PPC networks are selectively affected by in utero SRI exposure, however, those alterations do not correlate to later neurocognitive development as tested by neuropsychological evaluation at two years of age. In turn, phase-amplitude coupling was found to be suppressed in SRI infants across multiple distributed cortical regions and these effects were linked to their neurocognitive outcomes. Our results are compatible with the overall notion that in utero drug exposures may cause subtle, yet measurable changes in the brain structure and function. Our present findings are based on the measures of local and inter-areal neuronal interactions in the cortex which can be readily used across species, as well as between different scales of inspection: from the whole animals to in vitro preparations. Therefore, this work opens a framework to explore the cellular and molecular mechanisms underlying neurodevelopmental SRI effects at all translational levels.
Collapse
Affiliation(s)
- Anton Tokariev
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- *Correspondence: Anton Tokariev,
| | - Victoria C. Oberlander
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Department of Computer Science, Aalto University, Espoo, Finland
| | - Mari Videman
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Department of Pediatric Neurology, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Sampsa Vanhatalo
- Department of Clinical Neurophysiology, BABA Center, New Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- Department of Physiology, University of Helsinki, Helsinki, Finland
- Sampsa Vanhatalo,
| |
Collapse
|
|
18
|
Alcaraz AJG, Baraniuk S, Mikulášek K, Park B, Lane T, Burbridge C, Ewald J, Potěšil D, Xia J, Zdráhal Z, Schneider D, Crump D, Basu N, Hogan N, Brinkmann M, Hecker M. Comparative analysis of transcriptomic points-of-departure (tPODs) and apical responses in embryo-larval fathead minnows exposed to fluoxetine. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 295:118667. [PMID: 34896397 DOI: 10.1016/j.envpol.2021.118667] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 11/17/2021] [Accepted: 12/08/2021] [Indexed: 06/14/2023]
Abstract
Current approaches in chemical hazard assessment face significant challenges because they rely on live animal testing, which is time-consuming, expensive, and ethically questionable. These concerns serve as an impetus to develop new approach methodologies (NAMs) that do not rely on live animal tests. This study explored a molecular benchmark dose (BMD) approach using a 7-day embryo-larval fathead minnow (FHM) assay to derive transcriptomic points-of-departure (tPODs) to predict apical BMDs of fluoxetine (FLX), a highly prescribed and potent selective serotonin reuptake inhibitor frequently detected in surface waters. Fertilized FHM embryos were exposed to graded concentrations of FLX (confirmed at < LOD, 0.19, 0.74, 3.38, 10.2, 47.5 μg/L) for 32 days. Subsets of fish were subjected to omics and locomotor analyses at 7 days post-fertilization (dpf) and to histological and biometric measurements at 32 dpf. Enrichment analyses of transcriptomics and proteomics data revealed significant perturbations in gene sets associated with serotonergic and axonal functions. BMD analysis resulted in tPOD values of 0.56 μg/L (median of the 20 most sensitive gene-level BMDs), 5.0 μg/L (tenth percentile of all gene-level BMDs), 7.51 μg/L (mode of the first peak of all gene-level BMDs), and 5.66 μg/L (pathway-level BMD). These tPODs were protective of locomotor and reduced body weight effects (LOEC of 10.2 μg/L) observed in this study and were reflective of chronic apical BMDs of FLX reported in the literature. Furthermore, the distribution of gene-level BMDs followed a bimodal pattern, revealing disruption of sensitive neurotoxic pathways at low concentrations and metabolic pathway perturbations at higher concentrations. This is one of the first studies to derive protective tPODs for FLX using a short-term embryo assay at a life stage not considered to be a live animal under current legislations.
Collapse
Affiliation(s)
| | - Shaina Baraniuk
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada
| | - Kamil Mikulášek
- Central European Institute of Technology, Masaryk University, Brno, CZ-625 00, Czech Republic
| | - Bradley Park
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada
| | - Taylor Lane
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada; Department of Environment and Geography, University of York, Heslington, YO10 5NG, United Kingdom
| | - Connor Burbridge
- Global Institute for Food Security, University of Saskatchewan, Saskatoon, SK, S7N 0W9, Canada
| | - Jessica Ewald
- Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, H9X 3V9, Canada
| | - David Potěšil
- Central European Institute of Technology, Masaryk University, Brno, CZ-625 00, Czech Republic
| | - Jianguo Xia
- Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, H9X 3V9, Canada
| | - Zbyněk Zdráhal
- Central European Institute of Technology, Masaryk University, Brno, CZ-625 00, Czech Republic
| | - David Schneider
- Global Institute for Food Security, University of Saskatchewan, Saskatoon, SK, S7N 0W9, Canada; School of the Environment and Sustainability, University of Saskatchewan, Saskatoon, SK, S7N 5C8, Canada
| | - Doug Crump
- Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, ON, K1A 0H3, Canada
| | - Niladri Basu
- Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, H9X 3V9, Canada
| | - Natacha Hogan
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada; Department of Animal and Poultry Science, College of Agriculture and Bioresources, University of Saskatchewan, Saskatoon, SK, S7N 5A8, Canada
| | - Markus Brinkmann
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada; School of the Environment and Sustainability, University of Saskatchewan, Saskatoon, SK, S7N 5C8, Canada; Global Institute for Water Security, University of Saskatchewan, Saskatoon, SK, S7N 3H5, Canada
| | - Markus Hecker
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada; School of the Environment and Sustainability, University of Saskatchewan, Saskatoon, SK, S7N 5C8, Canada; Global Institute for Water Security, University of Saskatchewan, Saskatoon, SK, S7N 3H5, Canada.
| |
Collapse
|
|
19
|
Nozari A, Gagné R, Lu C, Yauk C, Trudeau VL. Brief Developmental Exposure to Fluoxetine Causes Life-Long Alteration of the Brain Transcriptome in Zebrafish. Front Endocrinol (Lausanne) 2022; 13:847322. [PMID: 35573988 PMCID: PMC9097470 DOI: 10.3389/fendo.2022.847322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/23/2022] [Indexed: 11/25/2022] Open
Abstract
Fluoxetine (FLX) and other selective serotonin reuptake inhibitors are widely used to treat depressive disorders during pregnancy. Early-life exposure to FLX is known to disrupt the normal function of the stress axis in humans, rodents, and teleosts. We used a zebrafish line with a cortisol-inducible fluorescent transgene to study the effects of developmental daily exposure to FLX (54 µg/L) on the transcriptomic profile of brain tissues in exposed larvae and later as 6-month-old adults. High throughput RNA sequencing was conducted on brain tissues in unstressed and stressed conditions. Long-lasting effects of FLX were observed in telencephalon (Tel) and hypothalamus (Hyp) of adult zebrafish with 1927 and 5055 genes significantly (≥1.2 fold-change, false-discovery p-value < 0.05) dysregulated in unstressed condition, respectively. Similar findings were observed in Hyp with 1245 and 723 genes being significantly dysregulated in stressed adults, respectively. Differentially expressed genes converted to Homo sapiens orthologues were used for Ingenuity Pathway Analysis. The results showed alteration of pathways involved in neuroendocrine signaling, cholesterol metabolism and synaptogenesis. Enriched networks included lipid metabolism, molecular transport, and nervous system development. Analysis of putative upstream transcription regulators showed potential dysregulation of clocka and nr3c1 which control circadian rhythm, stress response, cholesterol metabolism and histone modifications. Several genes involved in epigenetic regulation were also affected by FLX, including dnmt3a, adarb1, adarb2, hdac4, hdac5, hdac8, and atf2. We report life-long disruptive effects of FLX on pathways associated with neuroendocrine signaling, stress response and the circadian rhythm, and all of which are implicated in the development of depressive disorders in humans. Our results raise concern for the persistent endocrine-disrupting potential of brief antidepressant exposure during embryonic development.
Collapse
Affiliation(s)
- Amin Nozari
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
| | - Remi Gagné
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada
| | - Chunyu Lu
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
| | - Carole Yauk
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada
| | - Vance L. Trudeau
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
- *Correspondence: Vance L. Trudeau,
| |
Collapse
|
|
20
|
Siracusano M, Riccioni A, Gialloreti LE, Carloni E, Baratta A, Ferrara M, Arturi L, Lisi G, Adulti I, Rossi R, Lucaselli A, Rossi A, Niolu C, Mazzone L. Maternal Perinatal Depression and Risk of Neurodevelopmental Disorders in Offspring: Preliminary Results from the SOS MOOD Project. CHILDREN 2021; 8:children8121150. [PMID: 34943347 PMCID: PMC8700100 DOI: 10.3390/children8121150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022]
Abstract
The latest research is attempting to define whether there may be an association between maternal Perinatal Depression (PD), the use of psychotropic medications during pregnancy, and a higher risk of neurodevelopmental disorders in children, including Autism Spectrum Disorder (ASD). A better understanding of the relation between PD and ASD is a key element to develop early interventions. This study has been developed in the context of the SOS MOOD project. Its aim is to evaluate the possible impact of maternal PD on the child’s cognitive and behavioral phenotype with a focus on ASD. Women included in the project were screened during pregnancy (1st, 2nd trimester) for PD—categorized as affected or not—and if necessary were prescribed pharmacological therapy; offspring of both groups of women underwent at a mean age of 43 months a standardized neuropsychiatric evaluation of developmental and cognitive skills, behavioral problems, autism symptoms and parental stress. Preliminary results on 59 women and 59 children do not suggest significant long-term effects of maternal PD on offspring’s development and behavior. Nonetheless further studies on wider samples are necessary in order to confirm such results and disentangle the role of possible confounding factors associated to the maternal illness.
Collapse
Affiliation(s)
- Martina Siracusano
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
- Correspondence: or ; Tel.: +39-0620900249
| | - Assia Riccioni
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy; (G.L.); (R.R.); (C.N.)
| | - Leonardo Emberti Gialloreti
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Elisa Carloni
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
| | - Antonia Baratta
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
| | - Marialaura Ferrara
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
| | - Lucrezia Arturi
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy; (G.L.); (R.R.); (C.N.)
| | - Giulia Lisi
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy; (G.L.); (R.R.); (C.N.)
- Mental Health Department, Azienda Sanitaria Locale Roma 1, 00133 Rome, Italy
| | - Ilaria Adulti
- Psychiatry and Clinical Psychology Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy;
| | - Rodolfo Rossi
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy; (G.L.); (R.R.); (C.N.)
| | - Alessia Lucaselli
- Section of Psychiatry, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.L.); (A.R.)
| | - Alessandro Rossi
- Section of Psychiatry, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.L.); (A.R.)
| | - Cinzia Niolu
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy; (G.L.); (R.R.); (C.N.)
- Psychiatry and Clinical Psychology Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy;
| | - Luigi Mazzone
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, Viale Oxford 81, 00133 Rome, Italy; (A.R.); (E.C.); (A.B.); (M.F.); (L.A.); (L.M.)
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy; (G.L.); (R.R.); (C.N.)
| |
Collapse
|
|
21
|
Baudat M, de Kort AR, van den Hove DLA, Joosten EA. Early-life exposure to selective serotonin reuptake inhibitors: Long-term effects on pain and affective comorbidities. Eur J Neurosci 2021; 55:295-317. [PMID: 34841582 PMCID: PMC9299880 DOI: 10.1111/ejn.15544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 11/30/2022]
Abstract
A growing body of evidence indicates that early‐life exposure to selective serotonin reuptake inhibitor has long‐term consequences on the offspring's pain in addition to affective disorders like anxiety disorder and major depression. Serotonin, besides its role in regulating pain and emotions, promotes neuronal network formation. The prefrontal cortex and the amygdala are two key brain regions involved in the modulation of pain and its affective comorbidities. Thus, the aim of this review is to understand how early‐life selective serotonin reuptake inhibitor exposure alters the developing prefrontal cortex and amygdala and thereby underlies the long‐term changes in pain and its affective comorbidities in later life. While there is still limited data on the effects of early‐life selective serotonin reuptake inhibitor exposure on pain, there is a substantial body of evidence on its affective comorbidities. From this perspective paper, four conclusions emerged. First, early‐life selective serotonin reuptake inhibitor exposure results in long‐term nociceptive effects, which needs to be consistently studied to clarify. Second, it results in enhanced depressive‐like behaviour and diminished exploratory behaviour in adult rodents. Third, early‐life selective serotonin reuptake inhibitor exposure alters serotonergic levels, transcription factors expression, and brain‐derived neurotrophic factor levels, resulting in hyperconnectivity within the amygdala and the prefrontal cortex. Finally, it affects antinociceptive inputs of the prefrontal cortex and the amygdala in the spinal cord. We conclude that early‐life selective serotonin reuptake inhibitor exposure affects the maturation of prefrontal cortex and amygdala circuits and thereby enhances their antinociceptive inputs in the spinal cord.
Collapse
Affiliation(s)
- Mathilde Baudat
- Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.,Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Anne R de Kort
- Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.,Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Daniel L A van den Hove
- Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.,Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - Elbert A Joosten
- Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.,Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, The Netherlands
| |
Collapse
|
|
22
|
Pan W, Pan J, Zhao Y, Zhang H, Tang J. Serotonin Transporter Defect Disturbs Structure and Function of the Auditory Cortex in Mice. Front Neurosci 2021; 15:749923. [PMID: 34690685 PMCID: PMC8527018 DOI: 10.3389/fnins.2021.749923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/07/2021] [Indexed: 11/23/2022] Open
Abstract
Serotonin transporter (SERT) modulates the level of 5-HT and significantly affects the activity of serotonergic neurons in the central nervous system. The manipulation of SERT has lasting neurobiological and behavioral consequences, including developmental dysfunction, depression, and anxiety. Auditory disorders have been widely reported as the adverse events of these mental diseases. It is unclear how SERT impacts neuronal connections/interactions and what mechanism(s) may elicit the disruption of normal neural network functions in auditory cortex. In the present study, we report on the neuronal morphology and function of auditory cortex in SERT knockout (KO) mice. We show that the dendritic length of the fourth layer (L-IV) pyramidal neurons and the second-to-third layer (L-II/III) interneurons were reduced in the auditory cortex of the SERT KO mice. The number and density of dendritic spines of these neurons were significantly less than those of wild-type neurons. Also, the frequency-tonotopic organization of primary auditory cortex was disrupted in SERT KO mice. The auditory neurons of SERT KO mice exhibited border frequency tuning with high-intensity thresholds. These findings indicate that SERT plays a key role in development and functional maintenance of auditory cortical neurons. Auditory function should be examined when SERT is selected as a target in the treatment for psychiatric disorders.
Collapse
Affiliation(s)
- Wenlu Pan
- Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Functional Nucleic Acid Basic and Clinical Research Center, Department of Physiology, School of Basic Medical Sciences, Changsha Medical College, Changsha, China
| | - Jing Pan
- Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Hearing Research Center, Southern Medical University, Guangzhou, China
| | - Yan Zhao
- Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Hongzheng Zhang
- Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Hearing Research Center, Southern Medical University, Guangzhou, China
| | - Jie Tang
- Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Hearing Research Center, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
23
|
Perinatal SSRI Exposure Disrupts G Protein-coupled Receptor BAI3 in Developing Dentate Gyrus and Adult Emotional Behavior: Relevance to Psychiatric Disorders. Neuroscience 2021; 471:32-50. [PMID: 34293414 DOI: 10.1016/j.neuroscience.2021.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022]
Abstract
Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. A major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). Our present study shows that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms that drive adverse effects of perinatal SSRI exposure, and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia.
Collapse
|
|
24
|
Meurer YDSR, Linhares SSG, Lima ADC, de Aquino ACQ, Brandão LEM, Nôga DA, Campelo CLDC, Lima RH, Cavalcante JDS, Engelberth RCGJ, Ribeiro AM, Silva RH. Postnatal exposure to fluoxetine led to cognitive-emotional alterations and decreased parvalbumin positive neurons in the hippocampus of juvenile Wistar rats. Int J Dev Neurosci 2021; 81:616-632. [PMID: 34196404 DOI: 10.1002/jdn.10139] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/29/2021] [Accepted: 06/24/2021] [Indexed: 12/31/2022] Open
Abstract
The exposure to selective serotonin reuptake inhibitors (SSRIs) during development results in behavioural impairment in adulthood in humans and animal models. Indeed, serotonergic overexpression in early life leads to structural and functional changes in brain circuits that control cognition and emotion. However, the effects of developmental exposure to these substances on the behaviour of adolescent rats are conflicting and remain poorly characterised. We performed a behavioural screening to investigate the effects of postnatal exposure to fluoxetine on memory and behaviours related to anxiety, anhedonia, and depression, as well we evaluate the parvalbumin expression in hippocampus of juvenile (~PND45) female and male rats. Fluoxetine (daily 20 mg/kg s.c. injections from PND7-PND21)- or vehicle-treated adolescent rats went through several behavioural tasks (from PND 38 to PND52) and were subject to transcardial perfusion and brain removal for immunohistochemical analysis (PND53). We found that postnatal exposure to fluoxetine increased anxiety- and depression-like behaviours in the open field and sucrose preference and forced swimming tests, respectively. In addition, this treatment induced working memory and short-term (but not long-term) recognition memory impairments, and reduced parvalbumin-positive interneurons in the hippocampus. In addition, the results revealed developmental sex-dependent effects of fluoxetine postnatal treatment on adolescent rats' behaviour. These outcomes indicate that affective disorders and mnemonic alterations caused by SSRIs perinatal exposure can be present at adolescence.
Collapse
Affiliation(s)
- Ywlliane da Silva Rodrigues Meurer
- Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.,Memory and Cognition Studies Laboratory, Post-graduate Program of Cognitive Neuroscience and Behavior, Department of Psychology, Federal University of Paraíba, João Pessoa, Brazil.,Laboratory of Neurochemical Studies, Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Sara Sophia Guedes Linhares
- Laboratory of Neurochemical Studies, Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Alvaro da Costa Lima
- Memory and Cognition Studies Laboratory, Post-graduate Program of Cognitive Neuroscience and Behavior, Department of Psychology, Federal University of Paraíba, João Pessoa, Brazil
| | - Antonio Carlos Queiroz de Aquino
- Laboratory of Neurochemical Studies, Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | | | | | - Ramon Hypólito Lima
- Graduate Program in Neuroengineering, Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaíba, Brazil
| | - Jeferson de Souza Cavalcante
- Laboratory of Neurochemical Studies, Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | - Alessandra Mussi Ribeiro
- Laboratory of Neuroscience and Bioprospecting of Natural Products, Department of Biosciences, Federal University of São Paulo, Santos, Brazil
| | - Regina Helena Silva
- Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
25
|
Liu K, Garcia A, Park JJ, Toliver AA, Ramos L, Aizenman CD. Early Developmental Exposure to Fluoxetine and Citalopram Results in Different Neurodevelopmental Outcomes. Neuroscience 2021; 467:110-121. [PMID: 34048796 DOI: 10.1016/j.neuroscience.2021.05.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 11/25/2022]
Abstract
Although selective serotonin reuptake inhibitors are commonly prescribed for prenatal depression, there exists controversy over adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated outcomes of exposure to widely-used SSRIs Fluoxetine and Citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of Citalopram and Fluoxetine during a critical developmental period and found that different experimental groups displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the Fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, Citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for behaviors tested. Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function; however, tectal cells from Fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the Citalopram group had increased K+ currents. Both behavioral and electrophysiological findings indicate that cells and circuits in the Fluoxetine treated optic tecta are hyperexcitable, while the Citalopram group exhibits decreased excitability. Taken together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI. This may explain some discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.
Collapse
Affiliation(s)
- Karine Liu
- Department of Neuroscience, Brown University, United States
| | - Alfonso Garcia
- Department of Neuroscience, Brown University, United States
| | - Jenn J Park
- Department of Neuroscience, Brown University, United States
| | | | | | | |
Collapse
|
|
26
|
Adjimann TS, Argañaraz CV, Soiza-Reilly M. Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to psychiatric disorders. Transl Psychiatry 2021; 11:280. [PMID: 33976122 PMCID: PMC8113523 DOI: 10.1038/s41398-021-01388-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 04/16/2021] [Accepted: 04/21/2021] [Indexed: 01/22/2023] Open
Abstract
Mental disorders including depression and anxiety are continuously rising their prevalence across the globe. Early-life experience of individuals emerges as a main risk factor contributing to the developmental vulnerability to psychiatric disorders. That is, perturbing environmental conditions during neurodevelopmental stages can have detrimental effects on adult mood and emotional responses. However, the possible maladaptive neural mechanisms contributing to such psychopathological phenomenon still remain poorly understood. In this review, we explore preclinical rodent models of developmental vulnerability to psychiatric disorders, focusing on the impact of early-life environmental perturbations on behavioral aspects relevant to stress-related and psychiatric disorders. We limit our analysis to well-established models in which alterations in the serotonin (5-HT) system appear to have a crucial role in the pathophysiological mechanisms. We analyze long-term behavioral outcomes produced by early-life exposures to stress and psychotropic drugs such as the selective 5-HT reuptake inhibitor (SSRI) antidepressants or the anticonvulsant valproic acid (VPA). We perform a comparative analysis, identifying differences and commonalities in the behavioral effects produced in these models. Furthermore, this review discusses recent advances on neurodevelopmental substrates engaged in these behavioral effects, emphasizing the possible existence of maladaptive mechanisms that could be shared by the different models.
Collapse
Affiliation(s)
- Tamara S. Adjimann
- grid.7345.50000 0001 0056 1981Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carla V. Argañaraz
- grid.7345.50000 0001 0056 1981Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mariano Soiza-Reilly
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
| |
Collapse
|
|
27
|
Campbell KSJ, Williams LJ, Bjornson BH, Weik E, Brain U, Grunau RE, Miller SP, Oberlander TF. Prenatal antidepressant exposure and sex differences in neonatal corpus callosum microstructure. Dev Psychobiol 2021; 63:e22125. [PMID: 33942888 DOI: 10.1002/dev.22125] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 11/09/2022]
Abstract
Prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants may influence white matter (WM) development, as previous studies report widespread microstructural alterations and reduced interhemispheric connectivity in SSRI-exposed infants. In rodents, perinatal SSRIs had sex-specific disruptions in corpus callosum (CC) axon architecture and connectivity; yet it is unknown whether SSRI-related brain outcomes in humans are sex specific. In this study, the neonate CC was selected as a region-of-interest to investigate whether prenatal SSRI exposure has sex-specific effects on early WM microstructure. On postnatal day 7, diffusion tensor imaging was used to assess WM microstructure in SSRI-exposed (n = 24; 12 male) and nonexposed (n = 48; 28 male) term-born neonates. Fractional anisotropy was extracted from CC voxels and a multivariate discriminant analysis was used to identify latent patterns differing between neonates grouped by SSRI-exposure and sex. Analysis revealed localized variations in CC fractional anisotropy that significantly discriminated neonate groups and correctly predicted group membership with an 82% accuracy. Such effects were identified across three dimensions, representing sex differences in SSRI-exposed neonates (genu, splenium), SSRI-related effects independent of sex (genu-to-rostral body), and sex differences in nonexposed neonates (isthmus-splenium, posterior midbody). Our findings suggest that CC microstructure may have a sex-specific, localized, developmental sensitivity to prenatal SSRI exposure.
Collapse
Affiliation(s)
- Kayleigh S J Campbell
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, Canada
| | | | - Bruce H Bjornson
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Ella Weik
- BC Children's Hospital Research Institute, Vancouver, Canada
| | - Ursula Brain
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Ruth E Grunau
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Steven P Miller
- Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
| | - Tim F Oberlander
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada
| |
Collapse
|
|
28
|
Bashiri H, Houwing DJ, Homberg JR, Salari AA. The combination of fluoxetine and environmental enrichment reduces postpartum stress-related behaviors through the oxytocinergic system and HPA axis in mice. Sci Rep 2021; 11:8518. [PMID: 33875712 PMCID: PMC8055994 DOI: 10.1038/s41598-021-87800-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/06/2021] [Indexed: 02/07/2023] Open
Abstract
Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic-pituitary-adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.
Collapse
Affiliation(s)
- Hamideh Bashiri
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Sirjan School of Medical Sciences, Sirjan, Iran
| | - Danielle J Houwing
- Department of Cognitive Neuroscience, Center for Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Judith R Homberg
- Department of Cognitive Neuroscience, Center for Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ali-Akbar Salari
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran.
| |
Collapse
|
|
29
|
Postnatal Fluoxetine Treatment Alters Perineuronal Net Formation and Maintenance in the Hippocampus. eNeuro 2021; 8:ENEURO.0424-20.2021. [PMID: 33622703 PMCID: PMC8046023 DOI: 10.1523/eneuro.0424-20.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 01/20/2023] Open
Abstract
Elevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day (P)21 in Sprague Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal PV, calretinin (CalR), or Reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the formation of PNNs within the hippocampus, raising the possibility of a disruption of excitation-inhibition (E/I) balance within this key limbic brain region.
Collapse
|
|
30
|
Chen MX, Cheng S, Lei L, Zhang XF, Liu Q, Lin A, Wallis CU, Lukowicz MJ, Sham PC, Li Q, Ao LJ. The effects of maternal SSRI exposure on the serotonin system, prefrontal protein expression and behavioral development in male and female offspring rats. Neurochem Int 2021; 146:105041. [PMID: 33836218 DOI: 10.1016/j.neuint.2021.105041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 03/21/2021] [Accepted: 03/31/2021] [Indexed: 11/24/2022]
Abstract
Fluoxetine (FLX), a commonly used selective serotonin reuptake inhibitor, is often used to treat depression during pregnancy. However, prenatal exposure to FLX has been associated with a series of neuropsychiatric illnesses. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral abnormalities in offspring. Thus, the present study aimed to explore whether prenatal FLX exposure causes long-term neurobehavioral effects, and identify the underlying mechanism between FLX and abnormal behaviors. In our study, 12/mg/kg/day of FLX or equal normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX = 30, NS = 27) on gestation day 11 till birth. We assessed the physical development and behavior of offspring, and in vivo magnetic resonance spectroscopy (MRS) was conducted to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Our results showed that the offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety-like behavior, and impaired social interaction. Moreover, down-regulation of 5-HT and SERT expression were identified in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1H-MRS in the PFC of offspring. Finally, a proteomic study revealed sex-dependent differential protein expression. These findings may have translational importance suggesting that using SSRI medication alone in pregnant mothers may result in developmental delay in their offspring. Our results also help guide the choice of outcome measures in identifying of molecular and developmental mechanisms.
Collapse
Affiliation(s)
- Mo Xian Chen
- School of Rehabilitation, Kunming Medical University, Kunming, China
| | - Shu Cheng
- Department of Rehabilitation, China Resources & WISCO General Hospital, Wuhan, China
| | - Lei Lei
- Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Tai Ping Road, Luzhou, Sichuan, China
| | - Xiao Fan Zhang
- Department of Psychiatry, Tongji Hospital of Huazhong University of Science and Technology (HUST), China
| | - Qiang Liu
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Aijin Lin
- School of Rehabilitation, Kunming Medical University, Kunming, China
| | | | | | - Pak C Sham
- Department of Psychiatry, The University of Hong Kong, Hong Kong, SAR, China; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, SAR, China; Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, SAR, China
| | - Qi Li
- Department of Psychiatry, The University of Hong Kong, Hong Kong, SAR, China; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, SAR, China.
| | - Li Juan Ao
- School of Rehabilitation, Kunming Medical University, Kunming, China.
| |
Collapse
|
|
31
|
Glazova NY, Manchenko DM, Volodina MA, Merchieva SA, Andreeva LA, Kudrin VS, Myasoedov NF, Levitskaya NG. Semax, synthetic ACTH(4-10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats. Neuropeptides 2021; 86:102114. [PMID: 33418449 DOI: 10.1016/j.npep.2020.102114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 12/20/2020] [Accepted: 12/25/2020] [Indexed: 11/17/2022]
Abstract
Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression during pregnancy. SSRIs cross the placenta and may influence the maturation of the foetal brain. Clinical and preclinical findings suggest long-term consequences of SSRI perinatal exposure for the offspring. The mechanisms of SSRI effects on developing brain remain largely unknown and there are no directional approaches for prevention of the consequences of maternal SSRI treatment during pregnancy. The heptapeptide Semax (MEHFPGP) is a synthetic analogue of ACTH(4-10) which exerts marked nootropic and neuroprotective activities. The aim of the present study was to investigate the long-term effects of neonatal exposure to the SSRI fluvoxamine (FA) in white rats. Additionally, the study examined the potential for Semax to prevent the negative consequences of neonatal FA exposure. Rat pups received FA or vehicle injections on postnatal days 1-14, a time period equivalent to 27-40 weeks of human foetal age. After FA treatment, rats were administered with Semax or vehicle on postnatal days 15-28. During the 2nd month of life, the rats underwent behavioural testing, and monoamine levels in brain structures were measured. It was shown that neonatal FA exposure leads to the impaired emotional response to stress and novelty and delayed acquisition of food-motivated maze task in adolescent and young adult rats. Furthermore, FA exposure induced alterations in the monoamine levels in brains of 1- and 2- month-old rats. Semax administration reduced the anxiety-like behaviour, improved learning abilities and normalized the levels of brain biogenic amines impaired by the FA exposure. The results demonstrate that early-life FA exposure in rat pups produces long-term disturbances in their anxiety-related behaviour, learning abilities, and brain monoamines content. Semax exerts a favourable effect on behaviour and biogenic amine system of rats exposed to the antidepressant. Thus, peptide Semax can prevent behavioural deficits caused by altered 5-HT levels during development.
Collapse
Affiliation(s)
- Nataliya Yu Glazova
- Institute of Molecular Genetics, RAS, 2 Akademika Kurchatova square, Moscow 123182, Russia.
| | - Daria M Manchenko
- Lomonosov Moscow State University, Biological Faculty, 1-12 Leninskie gori, Moscow 119234, Russia
| | - Maria A Volodina
- Lomonosov Moscow State University, Biological Faculty, 1-12 Leninskie gori, Moscow 119234, Russia; Institute of Cognitive Neuroscience, Centre for Bioelectric Interfaces, NRU HSE, 13-4 Myasnitskaya, Moscow 109028, Russia
| | - Svetlana A Merchieva
- Lomonosov Moscow State University, Biological Faculty, 1-12 Leninskie gori, Moscow 119234, Russia
| | - Ludmila A Andreeva
- Institute of Molecular Genetics, RAS, 2 Akademika Kurchatova square, Moscow 123182, Russia
| | - Vladimir S Kudrin
- Zakusov Research Institute of Pharmacology RAMS, 8 Baltiyskaya, Moscow 125315, Russia
| | - Nikolai F Myasoedov
- Institute of Molecular Genetics, RAS, 2 Akademika Kurchatova square, Moscow 123182, Russia
| | - Natalia G Levitskaya
- Lomonosov Moscow State University, Biological Faculty, 1-12 Leninskie gori, Moscow 119234, Russia; Institute of Molecular Genetics, RAS, 2 Akademika Kurchatova square, Moscow 123182, Russia
| |
Collapse
|
|
32
|
5-Hydroxytryptamine Modulates Maturation and Mitochondria Function of Human Oligodendrocyte Progenitor M03-13 Cells. Int J Mol Sci 2021; 22:ijms22052621. [PMID: 33807720 PMCID: PMC7962057 DOI: 10.3390/ijms22052621] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 01/07/2023] Open
Abstract
Inside the adult CNS, oligodendrocyte progenitor cells (OPCS) are able to proliferate, migrate and differentiate into mature oligodendrocytes (OLs) which are responsible for the production of myelin sheet and energy supply for neurons. Moreover, in demyelinating diseases, OPCs are recruited to the lesion areas where they undergo differentiation and myelin synthesis. Serotonin (5-hydroxytryptamine, 5-HT) is involved in OLs’ development and myelination, but so far the molecular mechanisms involved or the effects of 5-HT on mitochondria function have not yet been well documented. Our data show that 5-HT inhibits migration and proliferation committing cells toward differentiation in an immortalized human oligodendrocyte precursor cell line, M03-13. Migration blockage is mediated by reactive oxygen species (ROS) generation since antioxidants, such as Vit C and Cu-Zn superoxide dismutase, prevent the inhibitory effects of 5-HT on cell migration. 5-HT inhibits OPC migration and proliferation and increases OL phenotypic markers myelin basic protein (MBP) and Olig-2 via protein kinase C (PKC) activation since the inhibitor of PKC, bis-indolyl-maleimide (BIM), counteracts 5-HT effects. NOX inhibitors as well, reverse the effects of 5-HT, indicating that 5-HT influences the maturation process of OPCs by NOX-dependent ROS production. Finally, 5-HT increases mitochondria function and antioxidant activity. The identification of the molecular mechanisms underlying the effects of 5-HT on maturation and energy metabolism of OPCs could pave the way for the development of new treatments for autoimmune demyelinating diseases such as Multiple Sclerosis where oligodendrocytes are the primary target of immune attack.
Collapse
|
|
33
|
Van der Knaap N, Wiedermann D, Schubert D, Hoehn M, Homberg JR. Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats. Sci Rep 2021; 11:1680. [PMID: 33462357 PMCID: PMC7814075 DOI: 10.1038/s41598-021-81327-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 01/05/2021] [Indexed: 01/29/2023] Open
Abstract
Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring's brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.
Collapse
Affiliation(s)
- Noortje Van der Knaap
- Donders Institute for Brain, Cognition and Behaviour, Radboud University and Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Dirk Wiedermann
- In-Vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Dirk Schubert
- Donders Institute for Brain, Cognition and Behaviour, Radboud University and Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Mathias Hoehn
- In-Vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Judith R Homberg
- Donders Institute for Brain, Cognition and Behaviour, Radboud University and Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Kapittelweg 29, 6525 EN, Nijmegen, The Netherlands.
| |
Collapse
|
|
34
|
Carvajal-Oliveros A, Campusano JM. Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly? Front Behav Neurosci 2021; 14:601449. [PMID: 33510625 PMCID: PMC7835640 DOI: 10.3389/fnbeh.2020.601449] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/14/2020] [Indexed: 12/31/2022] Open
Abstract
Serotonin is a biogenic amine that acts as neurotransmitter in different brain regions and is involved in complex behaviors, such as aggression or mood regulation. Thus, this amine is found in defined circuits and activates specific receptors in different target regions. Serotonin actions depend on extracellular levels of this amine, which are regulated by its synthetic enzymes and the plasma membrane transporter, SERT. Serotonin acts also as a neurotrophic signal in ontogeny and in the mature brain, controlling cell proliferation, differentiation, neurogenesis, and neural plasticity. Interestingly, early alterations in serotonergic signaling have been linked to a diversity of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), or mental illnesses like schizophrenia or depression. It has been proposed that given the complex and numerous actions of serotonin, animal models could better serve to study the complexity of serotonin actions, while providing insights on how hindering serotonergic signaling could contribute to brain disorders. In this mini-review, it will be examined what the general properties of serotonin acting as a neurotransmitter in animals are, and furthermore, whether it is possible that Drosophila could be used to study the contribution of this amine to neurodevelopmental and mental disorders.
Collapse
Affiliation(s)
- Angel Carvajal-Oliveros
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Jorge M Campusano
- Laboratorio Neurogenética de la Conducta, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro Interdisciplinario de Neurociencia UC, Pontificia Universidad Católica de Chile, Santiago, Chile
| |
Collapse
|
|
35
|
Hutchison SM, Mâsse LC, Pawluski JL, Oberlander TF. Perinatal selective serotonin reuptake inhibitor (SSRI) and other antidepressant exposure effects on anxiety and depressive behaviors in offspring: A review of findings in humans and rodent models. Reprod Toxicol 2021; 99:80-95. [DOI: 10.1016/j.reprotox.2020.11.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 11/04/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022]
|
|
36
|
Sylte OC, Johansen JS, Heinla I, Houwing DJ, Olivier JDA, Heijkoop R, Snoeren EMS. Effects of perinatal fluoxetine exposure on novelty-induced social and non-social investigation behaviors in a seminatural environment. Psychopharmacology (Berl) 2021; 238:3653-3667. [PMID: 34557946 PMCID: PMC8629781 DOI: 10.1007/s00213-021-05984-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 09/15/2021] [Indexed: 11/17/2022]
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed as medication for various affective disorders during pregnancy. SSRIs cross the placenta and affect serotonergic neurotransmission in the fetus, but the neurobehavioral consequences for the offspring remain largely unclear. Recent rodent research has linked perinatal SSRI exposure to alterations in both social and non-social aspects of behavior. However, this research has mainly focused on behavior within simplified environments. The current study investigates the effects of perinatal SSRI exposure on social and non-social investigation behaviors of adult rat offspring upon introduction to a novel seminatural environment with unknown conspecifics. During the perinatal period (gestational day 1 until postnatal day 21), rat dams received daily treatment with either an SSRI (fluoxetine, 10 mg/kg) or vehicle. Adult male and female offspring were observed within the first hour after introduction to a seminatural environment. The results showed that perinatal fluoxetine exposure altered aspects of non-social investigation behaviors, while not altering social investigation behaviors. More specifically, both fluoxetine-exposed males and females spent more total time on locomotor activity than controls. Furthermore, fluoxetine-exposed females spent less time exploring objects and specific elements in the environment. The data suggest that perinatal exposure to SSRIs leads to a quicker, less detailed investigation strategy in novel environments and that the alteration is mostly pronounced in females.
Collapse
Affiliation(s)
- Ole Christian Sylte
- grid.10919.300000000122595234Department of Psychology, UiT the Arctic University of Norway, 9037 Tromsø, Norway
| | - Jesper Solheim Johansen
- grid.10919.300000000122595234Department of Psychology, UiT the Arctic University of Norway, 9037 Tromsø, Norway
| | - Indrek Heinla
- grid.10919.300000000122595234Department of Psychology, UiT the Arctic University of Norway, 9037 Tromsø, Norway
| | - Danielle J. Houwing
- grid.10919.300000000122595234Department of Psychology, UiT the Arctic University of Norway, 9037 Tromsø, Norway ,grid.4830.f0000 0004 0407 1981Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands
| | - Jocelien D. A. Olivier
- grid.4830.f0000 0004 0407 1981Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands
| | - Roy Heijkoop
- grid.10919.300000000122595234Department of Psychology, UiT the Arctic University of Norway, 9037 Tromsø, Norway
| | - Eelke M. S. Snoeren
- grid.10919.300000000122595234Department of Psychology, UiT the Arctic University of Norway, 9037 Tromsø, Norway ,Regional Health Authority of North Norway, Bodø, Norway
| |
Collapse
|
|
37
|
Hanswijk SI, Spoelder M, Shan L, Verheij MMM, Muilwijk OG, Li W, Liu C, Kolk SM, Homberg JR. Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link. Int J Mol Sci 2020; 21:E5850. [PMID: 32824000 PMCID: PMC7461571 DOI: 10.3390/ijms21165850] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/24/2020] [Accepted: 08/11/2020] [Indexed: 12/21/2022] Open
Abstract
Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other's impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.
Collapse
Affiliation(s)
- Sabrina I. Hanswijk
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, 6525 EN Nijmegen, The Netherlands; (S.I.H.); (M.S.); (M.M.M.V.); (O.G.M.)
| | - Marcia Spoelder
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, 6525 EN Nijmegen, The Netherlands; (S.I.H.); (M.S.); (M.M.M.V.); (O.G.M.)
| | - Ling Shan
- Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands;
| | - Michel M. M. Verheij
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, 6525 EN Nijmegen, The Netherlands; (S.I.H.); (M.S.); (M.M.M.V.); (O.G.M.)
| | - Otto G. Muilwijk
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, 6525 EN Nijmegen, The Netherlands; (S.I.H.); (M.S.); (M.M.M.V.); (O.G.M.)
| | - Weizhuo Li
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China; (W.L.); (C.L.)
| | - Chunqing Liu
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China; (W.L.); (C.L.)
| | - Sharon M. Kolk
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, 6525 AJ Nijmegen, The Netherlands;
| | - Judith R. Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, 6525 EN Nijmegen, The Netherlands; (S.I.H.); (M.S.); (M.M.M.V.); (O.G.M.)
| |
Collapse
|
|
38
|
Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neurosci Biobehav Rev 2020; 114:53-69. [DOI: 10.1016/j.neubiorev.2020.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 03/29/2020] [Accepted: 04/09/2020] [Indexed: 12/15/2022]
|
|
39
|
Heinla I, Heijkoop R, Houwing DJ, Olivier JDA, Snoeren EMS. Third-party prosocial behavior in adult female rats is impaired after perinatal fluoxetine exposure. Physiol Behav 2020; 222:112899. [PMID: 32348809 DOI: 10.1016/j.physbeh.2020.112899] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 03/27/2020] [Accepted: 03/27/2020] [Indexed: 10/24/2022]
Abstract
SSRIs are commonly used to treat pregnant women with depression. However, SSRIs can cross the placenta and affect the development of the fetus. The effects of perinatal SSRI exposure, and especially the effects on social behavior, are still incompletely documented. This study first aims to investigate whether rats show prosocial behavior in the form of consolation behavior. Secondly, it aims to investigate whether perinatal SSRI exposure affects this prosocial behavior. At last, we investigate whether the behavior changed after the rats had been exposed to an additional white-noise stressor. Rat dams received 10 mg/kg/d fluoxetine (FLX) or vehicle (CTR) via oral gavage from gestational day 1 until postnatal day 21. At adulthood, the rat offspring were housed in four cohorts of 4 females and 4 males in a seminatural environment. As prosocial behaviors are more prominent after stressful situations, we investigated the behavioral response of rats immediately after natural aggressive encounters (fights). Additionally, we studied whether a stressful white-noise exposure would alter this response to the aggressive encounters. Our study indicates that CTR-female rats are able to show third party prosocial behavior in response to witnessing aggressive encounters between conspecifics in a seminatural environment. In addition, we showed that perinatal FLX exposure impairs the display of prosocial behavior in female rats. Moreover, we found no signs of prosocial behavior in CTR- and FLX-males after natural aggressive encounters. After white-noise exposure the effects in third party prosocial behavior of CTR-females ceased to exist. We conclude that female rats are able to show prosocial behavior, possibly in the form of consolation behavior. In addition, the negative effects of perinatal fluoxetine exposure on prosocial behavior could provide additional evidence that SSRI treatment during pregnancy could contribute to the risk for social impairments in the offspring.
Collapse
Affiliation(s)
- Indrek Heinla
- Department of Psychology, UiT The Arctic University of Norway, Norway
| | - Roy Heijkoop
- Department of Psychology, UiT The Arctic University of Norway, Norway
| | - Danielle J Houwing
- Department of Psychology, UiT The Arctic University of Norway, Norway; Groningen Institute for Evolutionary Life Sciences, University of Groningen, the Netherlands
| | - Jocelien D A Olivier
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, the Netherlands
| | - Eelke M S Snoeren
- Department of Psychology, UiT The Arctic University of Norway, Norway; Regional Health Authority of North Norway.
| |
Collapse
|
|
40
|
Rotem-Kohavi N, Williams LJ, Oberlander TF. Advanced neuroimaging: A window into the neural correlates of fetal programming related to prenatal exposure to maternal depression and SSRIs. Semin Perinatol 2020; 44:151223. [PMID: 32122645 DOI: 10.1016/j.semperi.2020.151223] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Fetal programming is a conceptual framework whereby the in utero environment shapes the offspring's neurodevelopment. Maternal depression and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy are common prenatal exposures that affect critical early life developmental programming processes. Prenatal depression and SSRIs both have been reported to increase the risks for preterm birth, low birth weight, and are associated with behavioral disturbances across the early life span. However, not all exposures lead to adverse developmental outcomes and distinguishing how each exposure contributes to variations in development remains challenging. Advances in neuroimaging, using MR and EEG, offer novel insights into central processes that might reveal the neural correlates of fetal programming. This review focuses on emerging findings from neuroimaging studies reflecting early brain functional and structural development associated with prenatal exposure to maternal depression and SSRI antidepressants. Suggestions for future research directions that use neuroimaging as a tool to advancing our understanding of the early origins of developmental plasticity are offered.
Collapse
Affiliation(s)
- Naama Rotem-Kohavi
- Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | | | - Tim F Oberlander
- BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
| |
Collapse
|
|
41
|
Fukushima S, Kurganov E, Hiratsuka D, Miyata S. Effect of fluoxetine on proliferation and/or survival of microglia and oligodendrocyte progenitor cells in the fornix and corpus callosum of the mouse brain. Pharmacol Rep 2020; 72:340-349. [PMID: 32109308 DOI: 10.1007/s43440-020-00079-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 11/23/2019] [Accepted: 12/30/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Fluoxetine is one of the most widely prescribed antidepressants and a selective inhibitor of presynaptic 5-HT transporters. The fornix is the commissural and projection fiber that transmits signals from the hippocampus to other parts of the brain and opposite site of hippocampus. The corpus callosum (CC) is the largest of the commissural fibers that link the cerebral cortex of the left and right cerebral hemispheres. These brain regions play pivotal roles in cognitive functions, and functional abnormalities in these regions have been implicated in the development of various brain diseases. The purpose of the present study was to investigate the effects of fluoxetine on the proliferation and/or survival of microglia and oligodendrocyte progenitor cells (OPCs) in the fornix and CC, the white matter connecting cortical-limbic system, of the adult mouse brain. METHODS The effects of fluoxetine on the proliferation and/or survival of microglia and OPCs were examined in lipopolysaccharide (LPS)-treated and normal mice. Proliferating cells were detected in mice that drank water containing the thymidine analog, bromodeoxyuridine (BrdU), using immunohistochemistry. RESULT Fluoxetine significantly attenuated LPS-induced increases in the number of BrdU-labeled microglia and morphological activation from the ramified to ameboid shape, and decreased the number of BrdU-labeled OPCs under basal conditions. CONCLUSIONS The present results indicate that fluoxetine exerts inhibitory effects on LPS-induced increases in the proliferation and/or survival and morphological activation of microglia and basal proliferation and/or survival of OPCs in the fornix and CC of adult mice.
Collapse
Affiliation(s)
- Shohei Fukushima
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Erkin Kurganov
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Daishi Hiratsuka
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Seiji Miyata
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan.
| |
Collapse
|
|
42
|
Nakamichi N, Matsumoto Y, Kawanishi T, Ishimoto T, Masuo Y, Horikawa M, Kato Y. Maturational Characterization of Mouse Cortical Neurons Three-Dimensionally Cultured in Functional Polymer FP001-Containing Medium. Biol Pharm Bull 2020; 42:1545-1553. [PMID: 31474714 DOI: 10.1248/bpb.b19-00307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of the present study is to construct and characterize a novel three-dimensional culture system for mouse neurons using the functional polymer, FP001. Stereoscopically extended neurites were found in primary mouse cortical neurons cultured in the FP001-containing medium. Neurons cultured with FP001 were distributed throughout the medium of the observation range whereas neurons cultured without FP001 were distributed only on the bottom of the dish. These results demonstrated that neurons can be three-dimensionally cultured using the FP001-containing medium. The mRNA expression of the glutamatergic neuronal marker vesicular glutamate transporter 1 in neurons cultured in the FP001-containing medium were higher than that in neurons cultured in the FP001-free medium. Expression of the matured neuronal marker, microtubule-associated protein 2 (MAP2) a,b, and the synapse formation marker, Synapsin I, in neurons cultured with FP001 was also higher than that in neurons cultured without FP001. The expression pattern of MAP2a,b in neurons cultured with FP001, but not that in neurons cultured without FP001, was similar to that in the embryonic cerebral cortex. Exposure to glutamate significantly increased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction activity in neurons cultured with FP001 compared to that in neurons cultured without FP001. These results suggested that glutamatergic neurotransmission in neurons three-dimensionally cultured in the FP001-containing medium may be upregulated compared to neurons two-dimensionally cultured in the FP001-free medium. Thus, neurons with the properties close to those in the embryonic brain could be obtained by three-dimensionally culturing neurons using FP001, compared to two-dimensional culture with a conventional adhesion method.
Collapse
Affiliation(s)
- Noritaka Nakamichi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| | - Yuta Matsumoto
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| | - Takumi Kawanishi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| | - Takahiro Ishimoto
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| | - Yusuke Masuo
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| | - Masato Horikawa
- Advanced Materials and Planning Division, Nissan Chemical Industries, Ltd
| | - Yukio Kato
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| |
Collapse
|
|
43
|
Bond C, Johnson J, Chaudhary V, McCarthy E, McWhorter M, Woehrle N. Perinatal fluoxetine exposure results in social deficits and reduced monoamine oxidase gene expression in mice. Brain Res 2020; 1727:146282. [DOI: 10.1016/j.brainres.2019.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 05/28/2019] [Accepted: 06/01/2019] [Indexed: 12/27/2022]
|
|
44
|
Grieb ZA, Ragan CM. The effects of perinatal SSRI exposure on anxious behavior and neurobiology in rodent and human offspring. Eur Neuropsychopharmacol 2019; 29:1169-1184. [PMID: 31427116 DOI: 10.1016/j.euroneuro.2019.07.239] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 07/10/2019] [Accepted: 07/27/2019] [Indexed: 12/22/2022]
Abstract
While the postpartum period is typically associated with increased positive affect, many women will develop a depressive- or anxiety-related disorder during this time, which can degrade the mother-infant bond and lead to detrimental consequences for the infant. Given the potential for negative consequences, effective treatments have been critical, with selective serotonin reuptake inhibitors (SSRIs) being the most commonly-prescribed pharmaceutical agents to treat postpartum depression and anxiety. However, SSRIs can readily cross the placenta and are present in breast milk, so they might, therefore, unintentionally interact with the developing fetus/infant. There is already experimental evidence that perinatal SSRI exposure has a number of long-term effects on offspring, but this review focuses on the current literature examining the timing and consequences of perinatal SSRI exposure specifically on anxiety-like behaviors in rodents and humans, with an emphasis on the anxiety-related brain regions of the amygdala and hippocampus. This review also discusses discrepancies between the rodent and human literatures and how they might inform future studies. Finally, some key factors to consider when examining the role of perinatal SSRIs on offspring anxiety will be discussed, such as the duration of SSRI exposure and the potential neuroprotective effects of SSRIs. Given the extensive prescribing of SSRIs, the potential health consequences of perinatal SSRI exposure, and the discrepancies in the literature, it will be necessary to critically examine the factors underlying offspring anxiety outcomes.
Collapse
Affiliation(s)
- Z A Grieb
- Neuroscience Institute, 880 Petit Science Center, Georgia State University, Atlanta, GA 30303, United States.
| | - C M Ragan
- Department of Psychology, Library Student Faculty Building, Room 63, Purdue University Northwest, Westville, IN 46391, United States
| |
Collapse
|
|
45
|
Rotem-Kohavi N, Williams LJ, Muller AM, Abdi H, Virji-Babul N, Bjornson BH, Brain U, Werker JF, Grunau RE, Miller SP, Oberlander TF. Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants. Depress Anxiety 2019; 36:753-765. [PMID: 31066992 DOI: 10.1002/da.22906] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/07/2019] [Accepted: 04/10/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Prenatal maternal depression (PMD) and selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood. METHODS We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state functional magnetic resonance imaging at postnatal Day 6. At 6 months, temperament was assessed using Infant Behavioral Questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time series to assess group differences in modularity, and connector and provincial hubs. RESULTS Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl's gyrus relative to the depressed-only group. PLSR showed that newborns' hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups. CONCLUSIONS Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age.
Collapse
Affiliation(s)
- Naama Rotem-Kohavi
- Graduate Program in Neuroscience, School of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lynne J Williams
- BC Children Hospital MRI Research Facility, Vancouver, BC, Canada
| | - Angela M Muller
- Department of Physical Therapy, University of British Columbia, Vancouver, Canada
| | - Hervé Abdi
- School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas
| | - Naznin Virji-Babul
- Department of Physical Therapy, University of British Columbia, Vancouver, Canada
| | - Bruce H Bjornson
- Brain Mapping, Neuroinformatics and Neurotechnology Laboratory, Division of Neurology, British Columbia Children's Hospital, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada.,BC Children Hospital MRI Research Facility, Vancouver, BC, Canada
| | - Ursula Brain
- Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Janet F Werker
- Department of Psychology, University of British Columbia, Vancouver, Canada
| | - Ruth E Grunau
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Steven P Miller
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
| | - Tim F Oberlander
- BC Children's Hospital Research Institute, Vancouver, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
46
|
Jiang J, Zheng Y, Chen Y, Zahra A, Long C, Yang L. Exposure to prenatal antidepressant alters medial prefrontal-striatal synchronization in mice. Brain Res 2019; 1717:27-34. [DOI: 10.1016/j.brainres.2019.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/21/2019] [Accepted: 04/11/2019] [Indexed: 11/28/2022]
|
|
47
|
Houwing DJ, Heijkoop R, Olivier JDA, Snoeren EMS. Perinatal fluoxetine exposure changes social and stress-coping behavior in adult rats housed in a seminatural environment. Neuropharmacology 2019; 151:84-97. [PMID: 30959021 DOI: 10.1016/j.neuropharm.2019.03.037] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 03/29/2019] [Accepted: 03/30/2019] [Indexed: 02/07/2023]
Abstract
The use of selective serotonin reuptake inhibitors (SSRI) during pregnancy has increased tremendously, but the consequences for the offspring remain largely unclear. Several studies have described potential effects of perinatal SSRI-exposure on neurobehavioral outcomes using simplified rodent test set-ups, however these set-ups only assess a small fraction of the behavior. For translational purposes it is important to take the environmental influences into account which children are exposed to in real life. By using a seminatural environmental set-up, this study is the first to assess behavioral outcomes in offspring exposed to perinatal SSRI exposure under seminatural circumstances. Mothers received daily the SSRI fluoxetine (FLX, 10 mg/kg p.o.) or vehicle (CTR) from gestational day 1 until postnatal day 21. To assess the effect of FLX exposure during early development, female and male offspring were behaviorally tested in the seminatural environment at adulthood. Baseline behavior was measured in addition to responses during and after stressful white-noise events. Behavior was observed on two days, day 4 on which females were sexually non-receptive, and day 7, on which females were sexual receptive. Perinatal FLX exposure reduced general activity in females and increased behavior related to a social context in both males and females. After a stressful white-noise event some behaviors switched. Whereas FLX-females switch from resting socially to resting more solitarily, FLX-males show an increase in self-grooming behavior after the stressor and showed more freezing behavior in the open area. We conclude that perinatal FLX exposure leads to alterations in social and stress-coping behaviors in adulthood, when observed in a seminatural environment. Whether these adaptations in behavior are advantageous or disadvantageous remains to be established.
Collapse
Affiliation(s)
- Danielle J Houwing
- Department of Psychology, UiT the Arctic University of Norway, Tromsø, Norway; Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands
| | - Roy Heijkoop
- Department of Psychology, UiT the Arctic University of Norway, Tromsø, Norway
| | - Jocelien D A Olivier
- Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands
| | - Eelke M S Snoeren
- Department of Psychology, UiT the Arctic University of Norway, Tromsø, Norway.
| |
Collapse
|
|
48
|
Sujan AC, Öberg AS, Quinn PD, D’Onofrio BM. Annual Research Review: Maternal antidepressant use during pregnancy and offspring neurodevelopmental problems - a critical review and recommendations for future research. J Child Psychol Psychiatry 2019; 60:356-376. [PMID: 30515808 PMCID: PMC6438736 DOI: 10.1111/jcpp.13004] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2018] [Indexed: 12/11/2022]
Abstract
Children of women treated with antidepressants during pregnancy are more likely to develop neurodevelopmental problems than are unexposed children. Associations between prenatal antidepressant exposure and neurodevelopmental problems could reflect a causal effect or could be partially or fully explained by other factors that differ between exposed and unexposed offspring, including having mothers with conditions requiring antidepressant treatment (e.g. depression), environmental risk factors, and/or genetic risk factors shared across disorders. This translational review aims to provide a brief overview of findings from rodent experiments and critically evaluate observational studies in humans to assess the extent to which associations between prenatal antidepressant exposure and neurodevelopmental problems are due to causal mechanisms versus other influences. We focus our review on two important neurodevelopmental outcomes - autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). In general, rodent studies have reported adverse effects of perinatal antidepressant exposure on neurodevelopment. Between-species differences raise questions about the generalizability of these findings to humans. Indeed, converging evidence from studies using multiple designs and approaches suggest that observed associations between prenatal antidepressant exposure and neurodevelopmental problems in humans are largely due to confounding factors. We also provide specific recommendations for future research. Animal research should explicitly evaluate the impact of timing of exposure and dosage of medications, as well as better map outcome measures in rodents to human neurodevelopmental problems. Observational studies should investigate specific confounding factors, specific antidepressant drugs and classes, the potential impact of timing of exposure, and a wider range of other potential offspring outcomes. The findings summarized in this review may help women and their doctors make informed decisions about antidepressant use during pregnancy by providing reassurance that use of these medications during pregnancy is unlikely to substantially increase the risk of ASD and ADHD.
Collapse
Affiliation(s)
- Ayesha C. Sujan
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - A. Sara Öberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Patrick D. Quinn
- Department of Applied Health Science, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Brian M. D’Onofrio
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
49
|
Yu W, Yen YC, Lee YH, Tan S, Xiao Y, Lokman H, Ting AKT, Ganegala H, Kwon T, Ho WK, Je HS. Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice. Mol Brain 2019; 12:29. [PMID: 30935412 PMCID: PMC6444596 DOI: 10.1186/s13041-019-0452-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 03/18/2019] [Indexed: 12/21/2022] Open
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.
Collapse
Affiliation(s)
- Weonjin Yu
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore.,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yi-Chun Yen
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Young-Hwan Lee
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Shawn Tan
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Yixin Xiao
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Hidayat Lokman
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Audrey Khoo Tze Ting
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Hasini Ganegala
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Taejoon Kwon
- Department of Biomedical Engineering, School of Life Science, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Republic of Korea
| | - Won-Kyung Ho
- Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
| | - H Shawn Je
- Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore. .,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
| |
Collapse
|
|
50
|
The development of synaptic transmission is time-locked to early social behaviors in rats. Nat Commun 2019; 10:1195. [PMID: 30867422 PMCID: PMC6416358 DOI: 10.1038/s41467-019-09156-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 02/24/2019] [Indexed: 11/19/2022] Open
Abstract
The development of functional synapses is a sequential process preserved across many brain areas. Here, we show that glutamatergic postsynaptic currents anticipated GABAergic currents in Layer II/III of the rat neocortex, in contrast to the pattern described for other brain areas. The frequencies of both glutamatergic and GABAergic currents increased abruptly at the beginning of the second postnatal week, supported by a serotonin upsurge. Integrative behaviors arose on postnatal day (P)9, while most motor and sensory behaviors, which are fundamental for pup survival, were already in place at approximately P7. A reduction in serotonin reuptake accelerated the development of functional synapses and integrative huddling behavior, while sparing motor and sensory function development. A decrease in synaptic transmission in Layer II/III induced by a chemogenetic approach only inhibited huddling. Thus, precise developmental sequences mediate early, socially directed behaviors for which neurotransmission and its modulation in supragranular cortical layers play key roles. The development of functional synapses is a key milestone in neurodevelopment. Here, the authors show how serotonin signalling coordinates development of glutamatergic and GABAergic currents and triggers the emergence of integrative behavior (huddling) in rat pups.
Collapse
|