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Copenhaver AE, LeGates TA. Sex-Specific Mechanisms Underlie Long-Term Potentiation at Hippocampus→Medium Spiny Neuron Synapses in the Medial Shell of the Nucleus Accumbens. J Neurosci 2024; 44:e0100242024. [PMID: 38806250 PMCID: PMC11223474 DOI: 10.1523/jneurosci.0100-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 05/30/2024] Open
Abstract
Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp→NAc synapses is rewarding, and mice can establish learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigated sex differences in the mechanisms underlying Hipp→NAc LTP using whole-cell electrophysiology and pharmacology. We observed similarities in basal synaptic strength between males and females and found that LTP occurs postsynaptically with similar magnitudes in both sexes. However, key sex differences emerged as LTP in males required NMDA receptors (NMDAR), whereas LTP in females utilized an NMDAR-independent mechanism involving L-type voltage-gated Ca2+ channels (VGCCs) and estrogen receptor α (ERα). We also uncovered sex-similar features as LTP in both sexes depended on CaMKII activity and occurred independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.
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Affiliation(s)
- Ashley E Copenhaver
- Department of Biological Sciences, University of Maryland, Baltimore County (UMBC), Baltimore, Maryland 21250
| | - Tara A LeGates
- Department of Biological Sciences, University of Maryland, Baltimore County (UMBC), Baltimore, Maryland 21250
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Wang Y, Lu Q, Penpat I, Wu J, Abulikemu D, Zeng FC, Huang JY, Hu ZH. Clinical effect of acupuncture at ghost points combined with fluoxetine hydrochloride on mild-to-moderate depression. World J Psychiatry 2024; 14:848-856. [PMID: 38984332 PMCID: PMC11230087 DOI: 10.5498/wjp.v14.i6.848] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/23/2024] [Accepted: 05/09/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND Depression is a common, chronic, and recurrent mood disorder that has become a worldwide health hazard. Fluoxetine hydrochloride, a common treatment method, can inhibit 5-hydroxytryptamine (5-HT) recycling in the presynaptic membrane; however, the efficacy of a single drug is inadequate. At present, mild-to-moderate depression can be treated with acupuncture of ghost caves, but the clinical curative effect of combined therapy with fluoxetine hydrochloride has not been sufficiently reported. AIM To evaluate the clinical effect of acupuncture at ghost points combined with fluoxetine hydrochloride in the treatment of mild-to-moderate depression. METHODS This retrospective study included 160 patients with mild-to-moderate depression who were admitted to Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, between January 2022 and June 2023. Patients were separated into a single-agent group (fluoxetine hydrochloride treatment, n = 80) and a coalition group (fluoxetine hydrochloride treatment combined with acupuncture at ghost points, n = 80). Pre-treatment symptoms were recorded, and the clinical curative effect and adverse reactions [Asberg Antidepressant Side Effects Scale (SERS)] were assessed. Depression before and after treatment [Hamilton Depression Scale (HAMD)-24], neurotransmitter levels [5-HT, norepinephrine (NE), dopamine (DA)], oxidative stress indicators [superoxide dismutase (SOD), malondialdehyde (MDA)], and sleep quality [Pittsburgh Sleep Quality Index (PSQI)] were compared. RESULTS The total efficacy rate was 97.50% in the coalition group and 86.25% in the single-agent group (P < 0.05). After 2, 4, 6, and 8 wk of treatment, the HAMD, self-rating depression scale, and SERS scores of the coalition and single-agent groups decreased compared with pre-treatment, and the decrease was more significant in the coalition group (P < 0.05). After 8 wk of treatment, the levels of NE, DA, 5-HT, and SOD in the coalition and single-agent groups increased, while the levels of MDA decreased; the increases and decrease in the coalition group were more significant (P < 0.05). The PSQI scores of the coalition and single-agent groups decreased, and the decrease was more significant in the coalition group (P < 0.05). CONCLUSION Acupuncture at ghost points combined with paroxetine tablets can safely improve depressive symptoms and sleep disorders, regulate neurotransmitter levels, and reduce stress responses in patients with mild-to-moderate depression.
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Affiliation(s)
- Yi Wang
- Department of Acupuncture and Moxibustion, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, The Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Qun Lu
- Department of Laboratory Medicine, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, The Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Ittipalanukul Penpat
- Department of Postgraduate Student, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Juan Wu
- Department of Radiology, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, The Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Dilinuer Abulikemu
- Department of General Practice, Shanghai University of Traditional Chinese Medicine Affiliated Shuguang Hospital, Shanghai 200120, China
| | - Fei-Cui Zeng
- General Practice of Traditional Chinese Medicine, North Bund Street Community Health Service Center, Shanghai 200080, China
| | - Jia-Ying Huang
- General Practice of Traditional Chinese Medicine, Shanghai Hongkou District Jiaxing Road Community Health Service Center, Shanghai 200082, China
| | - Zhi-Hai Hu
- Department of Acupuncture and Moxibustion, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, The Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
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Copenhaver AE, LeGates TA. Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.15.575709. [PMID: 38293132 PMCID: PMC10827060 DOI: 10.1101/2024.01.15.575709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary in order to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp-NAc synapses is rewarding, and that mice can make learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigate sex differences in the mechanisms underlying Hipp-NAc LTP using whole-cell electrophysiology and pharmacology. We found that males and females display similar magnitudes of Hipp-NAc LTP which occurs postsynaptically. However, LTP in females requires L-type voltage-gated Ca 2+ channels (VGCC) for postsynaptic Ca 2+ influx, while males rely on NMDA receptors (NMDAR). Additionally, females require estrogen receptor α (ERα) activity for LTP while males do not. These differential mechanisms converge as LTP in both sexes depends on CAMKII activity and occurs independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral excitatory pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders. SIGNIFICANCE STATEMENT Strengthening of Hipp-NAc synapses drives reward-related behaviors. Male and female mice have similar magnitudes of long-term potentiation (LTP) and both sexes have a predicted postsynaptic locus of plasticity. Despite these similarities, we illustrate here that sex-specific molecular mechanisms are used to elicit LTP. Given the bidirectional relationship between Hipp-NAc synaptic strength in mediating reward-related behaviors, the use of distinct molecular mechanisms may explain sex differences observed in stress susceptibility or response to rewarding stimuli. Discovery and characterization of convergent sex differences provides mechanistic insight into the sex-specific function of Hipp-NAc circuitry and has widespread implications for circuits mediating learning and reward-related behavior.
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Zhong Y, Du Q, Wang Z, Zheng Q, Yang M, Hu P, Yang Q, Xu H, Wu Z, Huang X, Li H, Tang M, Zeng H, Zhu L, Ren G, Cao M, Liu Y, Wang H. Antidepressant effect of Perilla frutescens essential oil through monoamine neurotransmitters and BDNF/TrkB signal pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116840. [PMID: 37355083 DOI: 10.1016/j.jep.2023.116840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 06/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine posits that affect-mind ill-being is the primary cause of depression, with Qi movement stagnation as its pathogenesis. As such, clinical treatment for depression should prioritize regulating Qi and relieving depressive symptoms. The pharmacological properties of traditional Chinese medicine indicate that Perilla frutescens may have potential therapeutic effects on depression and other neuropsychiatric diseases due to its ability to regulate Qi and alleviate depressive symptoms. Although previous studies have reported the antidepressant effects of Perilla frutescens, the mechanism underlying PFEO inhalation-mediated antidepressant effect remains unclear. AIM OF THE STUDY The aim of this investigation is to elucidate the antidepressant mechanisms of PFEO by examining its effects on monoamine neurotransmitters and the BDNF/TrkB signaling pathway. MATERIALS AND METHODS The CUMS rat model of depression was established, and the depressive state of the animals was assessed through sucrose preference and forced swim tests. ELISA assays were conducted to determine monoamine neurotransmitter levels in the hippocampus and cerebral cortex of rats. Immunohistochemistry, western blotting, and RT-PCR experiments were employed to investigate the BDNF/TrkB signaling pathway's regulation of depression via PFEO inhalation. RESULTS It has been observed that inhalation administration of PFEO can significantly enhance the preference for sugar water in CUMS rats and reduce their immobility time during forced swimming. Additionally, there was an increase in the levels of monoamine transmitters in both the hippocampus and cerebral cortex of these rats. Furthermore, there was an upregulation in the expression levels of BDNF and TrkB positive cells as well as BDNF and TrkB proteins within both regions, along with increased BDNF mRNA and TrkB mRNA expression levels. CONCLUSION The antidepressant effect of PFEO via inhalation administration is speculated to be mediated through the monoamine neurotransmitters and BDNF/TrkB signaling pathway.
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Affiliation(s)
- Yu Zhong
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Qing Du
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Ziqian Wang
- Jiangxi Drug Inspection Center, Nanchang, 330000, China
| | - Qin Zheng
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
| | - Ming Yang
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
| | - Pengyi Hu
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
| | - Qiyue Yang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610032, China
| | - Huanhua Xu
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Zhenfeng Wu
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Xiaoying Huang
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Huiting Li
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Mingxia Tang
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Huiming Zeng
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Liyun Zhu
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Guilin Ren
- The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Ming Cao
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Yu Liu
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Hongbo Wang
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab.of Innovation Drug and Effcient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
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Chapman B, Grunfeld EA, Derakshan N. Quality of working life can protect against cognitive and emotional vulnerability in women living with metastatic breast cancer: a cross-sectional study. J Cancer Surviv 2023; 17:1295-1308. [PMID: 35038120 PMCID: PMC8761843 DOI: 10.1007/s11764-022-01169-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 01/10/2022] [Indexed: 02/05/2023]
Abstract
PURPOSE Research focusing on the cognitive and emotional health of women with metastatic breast cancer (MBC) is limited. The focal aim of the current study was to explore how quality of working life was related to global health, perceived cognitive function, anxiety and depression. To this end, women's experience of employers after MBC diagnosis and its relationship to quality of working life was also explored. METHODS Women living with MBC (N = 88) completed online questionnaires assessing their global health status, perceived cognitive and emotional vulnerability and their experience of employers following diagnosis. Women working at the time of the study also reported on their quality of working life. RESULTS Women's experience of employers after MBC diagnosis was positively related to their quality of working life. Importantly, greater quality of working life met with better perceived cognitive function and global health, as well as lower levels of depression in working women. CONCLUSIONS Our study is the first to establish the role of quality of working life in protecting against levels of cognitive vulnerability and emotional vulnerability to depression in women with MBC. We also highlight the importance of having a positive experience with employers. Our findings suggest that educational programmes can be provided to employers to enhance their understanding and awareness of the needs of women with MBC. IMPLICATIONS FOR CANCER SURVIVORS Women with MBC may benefit from employers accessing educational (or support) programmes that can increase their awareness of the treatment-related sequelae and needs of women with MBC in the workplace.
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Affiliation(s)
- Bethany Chapman
- Department of Psychological Sciences, The BRiC Centre (Birkbeck Centre for Building Resilience in Breast Cancer), Birkbeck University of London, Malet Street, London, WC1E 7HX, UK.
| | - Elizabeth A Grunfeld
- Department of Psychological Sciences, The BRiC Centre (Birkbeck Centre for Building Resilience in Breast Cancer), Birkbeck University of London, Malet Street, London, WC1E 7HX, UK
| | - Nazanin Derakshan
- Department of Psychological Sciences, The BRiC Centre (Birkbeck Centre for Building Resilience in Breast Cancer), Birkbeck University of London, Malet Street, London, WC1E 7HX, UK
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Kupferschmidt DA, Cummings KA, Joffe ME, MacAskill A, Malik R, Sánchez-Bellot C, Tejeda HA, Yarur Castillo H. Prefrontal Interneurons: Populations, Pathways, and Plasticity Supporting Typical and Disordered Cognition in Rodent Models. J Neurosci 2022; 42:8468-8476. [PMID: 36351822 PMCID: PMC9665918 DOI: 10.1523/jneurosci.1136-22.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022] Open
Abstract
Prefrontal cortex (PFC) inhibitory microcircuits regulate the gain and timing of pyramidal neuron firing, coordinate neural ensemble interactions, and gate local and long-range neural communication to support adaptive cognition and contextually tuned behavior. Accordingly, perturbations of PFC inhibitory microcircuits are thought to underlie dysregulated cognition and behavior in numerous psychiatric diseases and relevant animal models. This review, based on a Mini-Symposium presented at the 2022 Society for Neuroscience Meeting, highlights recent studies providing novel insights into: (1) discrete medial PFC (mPFC) interneuron populations in the mouse brain; (2) mPFC interneuron connections with, and regulation of, long-range mPFC afferents; and (3) circuit-specific plasticity of mPFC interneurons. The contributions of such populations, pathways, and plasticity to rodent cognition are discussed in the context of stress, reward, motivational conflict, and genetic mutations relevant to psychiatric disease.
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Affiliation(s)
- David A Kupferschmidt
- Integrative Neuroscience Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, 20892
| | - Kirstie A Cummings
- Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, 35233
| | - Max E Joffe
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Andrew MacAskill
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom, WC1E 6BT
| | - Ruchi Malik
- Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, California, 94158
| | - Candela Sánchez-Bellot
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom, WC1E 6BT
- Laboratorio de Circuitos Neuronales, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain, 28002
| | - Hugo A Tejeda
- Unit on Neuromodulation and Synaptic Integration, National Institute of Mental Health, Bethesda, Maryland, 20892
| | - Hector Yarur Castillo
- Unit on Neuromodulation and Synaptic Integration, National Institute of Mental Health, Bethesda, Maryland, 20892
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Yuan M, Zhu H, Li Y, Ge F, Lui S, Gong Q, Qiu C, Song H, Zhang W. The DRD2 Taq1A polymorphism moderates the effect of PTSD symptom severity on the left hippocampal CA3 volume: a pilot study. Psychopharmacology (Berl) 2022; 239:3431-3438. [PMID: 34086098 PMCID: PMC9585014 DOI: 10.1007/s00213-021-05882-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 05/21/2021] [Indexed: 02/08/2023]
Abstract
RATIONALE AND OBJECTIVES The hippocampus, especially the CA1, CA3, and dentate gyrus (DG) subfields, is reported to be associated with post-traumatic stress disorder (PTSD) after trauma. However, neuroimaging studies of the associations between PTSD and hippocampal subfield volumes have failed to yield consistent findings. The aim of this study is to examine whether the dopamine D2 receptor (DRD2) Taq1A polymorphism, which is associated with both hippocampal function and PTSD, moderated the association between PTSD severity and hippocampal CA1, CA3 and DG volumes. METHODS T1-weighted images were acquired from 142 trauma survivors from the 2008 Wenchuan earthquake using a 3.0-T magnetic resonance imaging system. Hippocampal subfield segmentations were performed with FreeSurfer v6.0. We used the simple moderation model from the PROCESS v3.4 tool for SPSS 23.0 to examine the association between the rs1800497 polymorphism, PTSD severity, and hippocampal CA3 and DG volumes. RESULTS A significant genotype × PTSD symptom severity interaction was found for the left CA3 volume (ΔF = 5.01, p = 0.008, ΔR2 = 0.05). Post hoc, exploratory analyses deconstructing the interaction revealed that severe PTSD symptomatology were associated with reduced left CA3 volume among TC heterozygotes (t = - 2.86, p = 0.005). CONCLUSIONS This study suggests that DRD2 Taq1A polymorphism moderates the association between PTSD symptomatology and left CA3 volume, which promotes an etiological understanding of the hippocampal atrophy at the subfield level. This highlights the complex effect of environmental stress, and provides possible mechanism for the relationship between the dopaminergic system and hippocampal function in PTSD.
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Affiliation(s)
- Minlan Yuan
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Hongru Zhu
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yuchen Li
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Fenfen Ge
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Su Lui
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Radiology Department of the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Changjian Qiu
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Huan Song
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, 610041, Chengdu, China.
- Medical Big Data Center, Sichuan University, Chengdu, 610041, China.
| | - Wei Zhang
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China.
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China.
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, 610041, Chengdu, China.
- Medical Big Data Center, Sichuan University, Chengdu, 610041, China.
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Hu W, Zhao X, Liu Y, Ren Y, Wei Z, Tang Z, Tian Y, Sun Y, Yang J. Reward sensitivity modulates the brain reward pathway in stress resilience via the inherent neuroendocrine system. Neurobiol Stress 2022; 20:100485. [PMID: 36132434 PMCID: PMC9483565 DOI: 10.1016/j.ynstr.2022.100485] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/16/2022] [Accepted: 09/02/2022] [Indexed: 12/03/2022] Open
Abstract
In the previous 10 years, researchers have suggested a critical role for the brain reward system in stress resilience. However, no study has provided an empirical link between activity in the mesostriatal reward regions during stress and the recovery of cortisol stress response. Moreover, although reward sensitivity as a trait has been demonstrated to promote stress resilience, it remains unclear whether it modulates the brain reward system in stress resilience and how this effect is achieved by the inherent neuroendocrine system. To investigate these uncertainties, 70 young adults were recruited to participate in a ScanSTRESS task, and their brain imaging data and saliva samples (for cortisol assay) were collected during the task. In addition, we assessed reward sensitivity, cortisol awakening response, and intrinsic functional connectivity of the brain in all the participants. We found that left putamen activation during stress exposure positively predicted cortisol recovery. In addition, reward sensitivity was positively linked with activation of the left putamen, and this relationship was serially mediated by the cortisol awakening response and right hippocampus-left inferior frontal gyrus intrinsic connectivity. These findings suggest that reward sensitivity modulates reward pathways in stress resilience through the interplay of the diurnal stress response system and network of the hippocampus-prefrontal circuitry. Summarily, the current study built a model to highlight the dynamic and multifaceted interaction between pertinent allostatic factors in the reward-resilience pathway and uncovered new insight into the resilience function of the mesostriatal reward system during stress.
Cortisol recovery can be predicted by activation of the left putamen in stress. Activation of the left putamen was positively linked with reward sensitivity. This relationship was serially mediated by the cortisol awakening response and right hippocampus-left inferior frontal gyrus intrinsic coupling.
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Affiliation(s)
- Weiyu Hu
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Xiaolin Zhao
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Yadong Liu
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Yipeng Ren
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Zhenni Wei
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Zihan Tang
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Yun Tian
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
| | - Yadong Sun
- Faculty of Psychology, Southwest University, Chongqing, 400715, China
| | - Juan Yang
- Faculty of Psychology, Southwest University, Chongqing, 400715, China.,Key Laboratory of Cognition and Personality, Southwest University, Chongqing, 400715, China
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9
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Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M. Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry 2022; 27:2689-2699. [PMID: 35354926 PMCID: PMC9167750 DOI: 10.1038/s41380-022-01520-y] [Citation(s) in RCA: 177] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/22/2022] [Accepted: 03/09/2022] [Indexed: 02/07/2023]
Abstract
Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.
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Affiliation(s)
| | | | - Rene Hen
- Departments of Psychiatry, Columbia University, New York, NY, USA
- Neuroscience, Columbia University, New York, NY, USA
- Pharmacology, Columbia University, New York, NY, USA
- Integrative Neuroscience, NYS Psychiatric Institute, New York, NY, USA
| | - J John Mann
- Departments of Psychiatry, Columbia University, New York, NY, USA
- Molecular Imaging and Neuropathology, NYS Psychiatric Institute, New York, NY, USA
| | - Maura Boldrini
- Departments of Psychiatry, Columbia University, New York, NY, USA.
- Molecular Imaging and Neuropathology, NYS Psychiatric Institute, New York, NY, USA.
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10
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Li K, Yang WT, Perez AG. Man of Mystery: A Case Report of Dissociative Amnesia in Schizophrenia. Cureus 2021; 13:e20688. [PMID: 35106228 PMCID: PMC8786264 DOI: 10.7759/cureus.20688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/25/2021] [Indexed: 11/05/2022] Open
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11
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Bremner JD. Isotretinoin and neuropsychiatric side effects: Continued vigilance is needed. JOURNAL OF AFFECTIVE DISORDERS REPORTS 2021; 6:100230. [PMID: 37168254 PMCID: PMC10168661 DOI: 10.1016/j.jadr.2021.100230] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Isotretinoin (13-cis-retinoic acid, marketed under the names Accutane, Roaccutane, and others) is an effective treatment for acne that has been on the market for over 30 years, although reports of neuropsychiatric side effects continue to be reported. Isotretinoin is an isomer of the active form of Vitamin A, 13-trans-retinoic acid, which has known psychiatric side effects when given in excessive doses, and is part of the family of compounds called retinoids, which have multiple functions in the central nervous system. Methods The literature was reviewed in pubmed and psychinfo for research related to isotretinoin and neuropsychiatric side effects including depression, suicidal thoughts, suicide, mania, anxiety, impulsivity, emotional lability, violence, aggression, and psychosis. Results Multiple case series have shown that successful treatment of acne with isotretinoin results in improvements in measures of quality of life and self esteem However, studies show individual cases of clinically significant depression and other neuropsychiatric events that, although not common, are persistent in the literature. Since the original cases of depression were reported to the United States Food and Drug Administration, numerous cases have been reported to regulatory agencies in the United Kingdom, France, Ireland, Denmark, Australia, Canada, and other countries, making isotretinoin one of the top five medications in the world associated with depression and other neuropsychiatric side effects. Clinicians are advised to warn patients of the risks of neuropsychiatric side effects with isotretinoin which may arise from the medication itself, and not just as a side effect of acne or youth.
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Affiliation(s)
- J Douglas Bremner
- Department of Psychiatry & Behavioral Sciences, and Department of Radiology and Imaging Sciences, Emory University School of Medicine, VA Medical Center, Decatur, GA, United States
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12
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Chakraborty P, Chattarji S, Jeanneteau F. A salience hypothesis of stress in PTSD. Eur J Neurosci 2021; 54:8029-8051. [PMID: 34766390 DOI: 10.1111/ejn.15526] [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: 07/10/2021] [Revised: 09/13/2021] [Accepted: 10/30/2021] [Indexed: 11/30/2022]
Abstract
Attention to key features of contexts and things is a necessary tool for all organisms. Detecting these salient features of cues, or simply, salience, can also be affected by exposure to traumatic stress, as has been widely reported in individuals suffering from post-traumatic stress disorder (PTSD). Interestingly, similar observations have been robustly replicated across many animal models of stress as well. By using evidence from such rodent stress paradigms, in the present review, we explore PTSD through the lens of salience processing. In this context, we propose that interaction between the neurotrophin brain-derived neurotrophic factor (BDNF) and glucocorticoids determines the long lasting cellular and behavioural consequences of stress salience. We also describe the dual effect of glucocorticoid therapy in the amelioration of PTSD symptoms. Finally, by integrating in vivo observations at multiple scales of plasticity, we propose a unifying hypothesis that pivots on a crucial role of glucocorticoid signalling in dynamically orchestrating stress salience.
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Affiliation(s)
- Prabahan Chakraborty
- Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France.,Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bellary Road, Bangalore, 560065, India
| | - Sumantra Chattarji
- Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bellary Road, Bangalore, 560065, India.,Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.,Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Freddy Jeanneteau
- Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France
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13
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Ruggiero RN, Rossignoli MT, Marques DB, de Sousa BM, Romcy-Pereira RN, Lopes-Aguiar C, Leite JP. Neuromodulation of Hippocampal-Prefrontal Cortical Synaptic Plasticity and Functional Connectivity: Implications for Neuropsychiatric Disorders. Front Cell Neurosci 2021; 15:732360. [PMID: 34707481 PMCID: PMC8542677 DOI: 10.3389/fncel.2021.732360] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/01/2021] [Indexed: 01/11/2023] Open
Abstract
The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer's disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions.
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Affiliation(s)
- Rafael Naime Ruggiero
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Matheus Teixeira Rossignoli
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Danilo Benette Marques
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Bruno Monteiro de Sousa
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Cleiton Lopes-Aguiar
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - João Pereira Leite
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Papp M, Gruca P, Lason M, Litwa E, Solecki W, Willner P. Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response. J Psychopharmacol 2021; 35:1253-1264. [PMID: 34617804 PMCID: PMC8521380 DOI: 10.1177/02698811211048281] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. METHOD Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). RESULTS As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC-mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC-mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. CONCLUSIONS The synergism between VEN and vHPC-mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC-mPFC pathway.
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Affiliation(s)
- Mariusz Papp
- Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland,Mariusz Papp, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, Krakow 31-343, Poland.
| | - Piotr Gruca
- Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Magdalena Lason
- Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Ewa Litwa
- Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Wojciech Solecki
- Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, Krakow, Poland
| | - Paul Willner
- Department of Psychology, Swansea University, Swansea, UK
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Inhibitory Effect of Apomorphine on Focal and Nonfocal Plasticity in the Human Motor Cortex. Pharmaceutics 2021; 13:pharmaceutics13050718. [PMID: 34068263 PMCID: PMC8153161 DOI: 10.3390/pharmaceutics13050718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 12/02/2022] Open
Abstract
Dopamine is crucial for neuroplasticity, which is considered to be the neurophysiological foundation of learning and memory. The specific effect of dopamine on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) is determined by receptor subtype specificity, concentration level, and the kind of plasticity induction technique. In healthy human subjects, the dopamine precursor levodopa (L-DOPA) exerts a dosage-dependent non-linear effect on motor cortex plasticity. Low and high dosage L-DOPA impaired or abolished plasticity, while medium-dose preserved and reversed plasticity in previous studies. Similar dosage-dependent effects were also observed for selective D1-like and D2-like receptor activation that favor excitatory and inhibitory plasticity, respectively. However, such a dosage-dependent effect has not been explored for a nonselective dopamine agonist such as apomorphine in humans. To this aim, nonfocal and focal motor cortex plasticity induction using paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS) were performed respectively in healthy participants under 0.1, 0.2, 0.3 mg apomorphine or placebo drug. Transcranial magnetic stimulation-elicited motor-evoked potentials were used to monitor motor cortical excitability alterations. We hypothesized that, similar to L-DOPA, apomorphine will affect motor cortex plasticity. The results showed that apomorphine with the applied dosages has an inhibitory effect for focal and nonfocal LTP-like and LTD-like plasticity, which was either abolished, diminished or reversed. The detrimental effect on plasticity induction under all dosages of apomorphine suggests a predominantly presynaptic mechanism of action of these dosages.
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Desormeaux C, Demars F, Davenas E, Jay TM, Lavergne F. Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats. J Psychopharmacol 2020; 34:1443-1448. [PMID: 33256509 DOI: 10.1177/0269881120959613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Major depressive disorder is a common illness that severely decreases psychosocial functioning. Due to the major limitations of current treatments including response failure, it is crucial to develop better therapy strategies. Evidence suggests that dopamine dysregulation might play a major role in major depressive disorder physiopathology. AIMS This study investigates whether the dopamine D1 receptor agonist A77636 modulates antidepressant-like activity in rats. METHODS Rats were injected with an acute single dose of A77636 (0.75, 1.5 or 3 mg/kg), a potent and selective dopamine D1-like receptor agonist. Their locomotor activity, social interactions and behavioural response to the forced swim test were analysed 30 min after the injection. RESULTS During the forced swim test, the D1 agonist dose dependently reduced the immobility while the time of bursting was increased. Social interactions were significantly increased in the animals exposed to 3 mg/kg of A77636 whereas no significant changes were measured in general motor activity. CONCLUSIONS The present results provide evidence that pharmacological modulation of D1 receptor by the selective agonist A77636 induces antidepressant-like effects in rats, which encourages further studies regarding D1-specific modulation in major depressive disorder treatment.
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Affiliation(s)
- Cleo Desormeaux
- Pathophysiology of Psychiatric Disorders, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
| | - Fanny Demars
- Pathophysiology of Psychiatric Disorders, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
| | - Elisabeth Davenas
- Pathophysiology of Psychiatric Disorders, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
| | - Therese M Jay
- Pathophysiology of Psychiatric Disorders, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
| | - Francis Lavergne
- Pathophysiology of Psychiatric Disorders, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
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Kafetzopoulos V, Kokras N, Sousa N, Antoniou K, Sotiropoulos I, Dalla C. Nucleus Reuniens Lesion and Antidepressant Treatment Prevent Hippocampal Neurostructural Alterations Induced by Chronic Mild Stress in Male Rats. Neuroscience 2020; 454:85-93. [PMID: 32828941 DOI: 10.1016/j.neuroscience.2020.08.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 12/21/2022]
Abstract
The hippocampus-prefrontal cortex circuit plays a major role in stress and in the neurobiology of depression and its treatment. Disruption of this circuit by lesioning the thalamic nucleus reuniens (RE) has been shown to prevent the detrimental effects of chronic mild stress on prefrontal cortex neuroplasticity indices in male rats. However, it remains unknown whether hippocampal neurostructural response to stress is modified by RE lesion. In the present study, adult male rats were subjected to the chronic mild stress model of depression and were treated with either vehicle or an antidepressant (i.e. sertraline). Moreover, a group of animals was subjected to RE lesion before stress exposure with or without sertraline treatment. We demonstrated that chronic mild stress induced hippocampal CA1 dendritic atrophy and this was prevented by pre-stress RE lesion to the same extent that antidepressant treatment reversed it. The present findings highlight the importance of hippocampal-prefrontal cortex communication in chronic stress effects on hippocampal neuroplasticity and contribute to the elucidation of the role of RE in neurostructural changes underlying stress-driven depression and its treatment.
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Affiliation(s)
- Vasilios Kafetzopoulos
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Kokras
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Portugal
| | - Katerina Antoniou
- Department of Pharmacology, Medical School, University of Ioannina, Ioannina, Greece
| | - Ioannis Sotiropoulos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga, Portugal
| | - Christina Dalla
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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18
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Stubbendorff C, Stevenson CW. Dopamine regulation of contextual fear and associated neural circuit function. Eur J Neurosci 2020; 54:6933-6947. [DOI: 10.1111/ejn.14772] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 04/29/2020] [Accepted: 05/01/2020] [Indexed: 01/07/2023]
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19
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Peng Y, Su Y, Jiang Y. Effect of the warming and tonifying kidney- yang recipe on monoamine neurotransmitters and pathological morphology of hippocampus tissue in depression model rats. Technol Health Care 2020; 28:237-244. [PMID: 32364156 PMCID: PMC7369113 DOI: 10.3233/thc-209024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE: To study the molecular mechanism of warming and tonifying kidney-yang recipe (WTKYR) in the treatment of depression. METHODS: SD rats were divided into a control group, model group, WTKYR group, and fluoxetine group. Each group consisted of 21 rats. The chronic unpredictable mild stress model was used. Body weighing and SPT were performed regularly. After treatment, histopathology of the brain tissue was performed, and concentrations of 5-HT (5-hydroxytryptamine), NE (norepinephrine), and DA (dopamine) in the hippocampus were determined. RESULTS: The WTKYR group showed higher body weight and sucrose consumption than the control groups. Moreover, the concentrations of 5-HT, NE, and DA in the hippocampus were significantly different in the WTKYR group in comparison to those in the other groups. The hippocampus histomorphology of the WTKYR group exhibited less dematous pyramidal cells and mild inflammatory cell infiltration. CONCLUSION: The treatment effect of WTKYR in depression may be based on improvement in the content of 5-HT, NE, and DA in the hippocampus, extenuating edema of the cortical surface and pyramidal cells and decreasing the infiltration of inflammatory cells into hippocampus tissue.
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Affiliation(s)
| | | | - Yong Jiang
- Corresponding author: Yong Jiang, Basic Medical College, Chengdu University of Traditional Chinese Medicine, Twelve Bridges 37, Chengdu, Sichuan, China. E-mail:
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Retinoic acid and depressive disorders: Evidence and possible neurobiological mechanisms. Neurosci Biobehav Rev 2020; 112:376-391. [DOI: 10.1016/j.neubiorev.2020.02.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 02/09/2020] [Accepted: 02/11/2020] [Indexed: 12/13/2022]
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Aleksandrova LR, Wang YT, Phillips AG. Evaluation of the Wistar-Kyoto rat model of depression and the role of synaptic plasticity in depression and antidepressant response. Neurosci Biobehav Rev 2019; 105:1-23. [DOI: 10.1016/j.neubiorev.2019.07.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/10/2019] [Accepted: 07/08/2019] [Indexed: 12/28/2022]
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Papanastasiou A, Seliniotaki T, Rizos E, Kampoli K, Ntavatzikos A, Arkadopoulos N, Tsionou C, Spandidos DA, Koumarianou A. Role of stress, age and adjuvant therapy in the cognitive function of patients with breast cancer. Oncol Lett 2019; 18:507-517. [PMID: 31289522 PMCID: PMC6540331 DOI: 10.3892/ol.2019.10361] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 05/10/2019] [Indexed: 02/05/2023] Open
Abstract
According to data largely obtained from retrospective studies, it has been postulated that chemotherapy exerts an aggravating effect on the cognitive function of patients with breast cancer. Potential individual factors related to the effects of chemotherapy on cognitive function have been indicated, such as age-related cognitive dysfunction and stress. Elderly patients differ from non-elderly patients as regards higher cognitive related comorbidities, such as dementia, as well as regarding lower stress levels, indicating that 'chemobrain' may differentially affect these two age groups. The aim of this review was to discuss the effects of stress and chemotherapy on cognitive dysfunction and identify any potential age-related differences in patients with breast cancer treated with adjuvant chemotherapy. For this purpose, a systematic review of the literature was carried out on the PubMed, Scopus and Web of Science databases. The inclusion criteria were original articles published in peer-reviewed journals, elderly and non-elderly patients with breast cancer, reporting on stress and at least one cognitive parameter pre- and/or post-treatment. Eight studies met the preset criteria and were further analyzed. In total, the data of 1,253 women were included, of whom 800 patients with breast cancer were treated with surgery only, systemic treatment only, or both. Although all the studies included a non-elderly breast cancer patient subpopulation, only two of the studies included patients over 65 years of age. All studies indicated a statistically significant association of stress with various domains of cognitive dysfunction in patients, as shown by either self-completed questionnaires, neuropsychological testing or both. An age over 60 years was linked to fewer cognitive difficulties mediated by lower levels of stress. Thus, the evidence supports the association of stress with cognitive deficits in patients with breast cancer, regardless of the type of cancer-related treatment. Therefore, stress should be appropriately addressed. However, further research is required to investigate the association of stress with cognitive function in elderly patients with breast cancer.
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Affiliation(s)
- Artemis Papanastasiou
- Second Department of Psychiatry, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Theodora Seliniotaki
- Hematology-Oncology Unit, Fourth Department of Internal Medicine, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Emmanouil Rizos
- Second Department of Psychiatry, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Katerina Kampoli
- Hematology-Oncology Unit, Fourth Department of Internal Medicine, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Anastasios Ntavatzikos
- Hematology-Oncology Unit, Fourth Department of Internal Medicine, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Nikolaos Arkadopoulos
- Fourth Department of Surgery, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Christina Tsionou
- Department of Breast Diseases, Maternity-Health, 15232 Athens, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Anna Koumarianou
- Hematology-Oncology Unit, Fourth Department of Internal Medicine, University General Hospital ‘ATTIKON’, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece
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Zou X, Zhong L, Zhu C, Zhao H, Zhao F, Cui R, Gao S, Li B. Role of Leptin in Mood Disorder and Neurodegenerative Disease. Front Neurosci 2019; 13:378. [PMID: 31130833 PMCID: PMC6510114 DOI: 10.3389/fnins.2019.00378] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 04/02/2019] [Indexed: 12/21/2022] Open
Abstract
The critical regulatory role of leptin in the neuroendocrine system has been widely reported. Significantly, leptin can improve learning and memory, affect hippocampal synaptic plasticity, exert neuroprotective efficacy and reduce the risk of several neuropsychiatric diseases. In terms of depression, leptin could modulate the levels of neurotransmitters, neurotrophic factors and reverse the dysfunction in the hypothalamic-pituitary-adrenal axis (HPA). At the same time, leptin affects neurological diseases during the regulation of metabolic homeostasis. With regards to neurodegenerative diseases, leptin can affect them via neuroprotection, mainly including Alzheimer's disease and Parkinson's disease. This review will summarize the mechanisms of leptin signaling within the neuroendocrine system with respect to these diseases and discuss the therapeutic potential of leptin.
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Affiliation(s)
- Xiaohan Zou
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Lili Zhong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Cuilin Zhu
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Haisheng Zhao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Fangyi Zhao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Shuohui Gao
- Department of Gastrointestinal Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
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Working memory moderates the association between early institutional care and separation anxiety symptoms in late childhood and adolescence. Dev Psychopathol 2019; 31:989-997. [PMID: 31038094 DOI: 10.1017/s0954579419000452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Adverse caregiving, for example, previous institutionalization (PI), is often associated with emotion dysregulation that increases anxiety risk. However, the concept of developmental multifinality predicts heterogeneity in anxiety outcomes. Despite this well-known heterogeneity, more work is needed to identify sources of this heterogeneity and how these sources interact with environmental risk to influence mental health. Here, working memory (WM) was examined during late childhood/adolescence as an intra-individual factor to mitigate the risk for separation anxiety, which is particularly susceptible to caregiving adversities. A modified "object-in-place" task was administered to 110 youths (10-17 years old), with or without a history of PI. The PI youths had elevated separation anxiety scores, which were anticorrelated with morning cortisol levels, yet there were no group differences in WM. PI youths showed significant heterogeneity in separation anxiety symptoms and morning cortisol levels, and WM moderated the link between caregiving and separation anxiety and mediated the association between separation anxiety and morning cortisol in PI youth. Findings suggest that (a) institutional care exerts divergent developmental consequences on separation anxiety versus WM, (b) WM interacts with adversity-related emotion dysregulation, and (c) WM may be a therapeutic target for separation anxiety following early caregiving adversity.
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A Resting-State Functional MR Imaging and Spectroscopy Study of the Dorsal Hippocampus in the Chronic Unpredictable Stress Rat Model. J Neurosci 2019; 39:3640-3650. [PMID: 30804096 DOI: 10.1523/jneurosci.2192-18.2019] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 01/21/2019] [Accepted: 01/29/2019] [Indexed: 01/28/2023] Open
Abstract
Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.
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26
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Liu F, Gong X, Yao X, Cui L, Yin Z, Li C, Tang Y, Wang F. Variation in the CACNB2 gene is associated with functional connectivity of the Hippocampus in bipolar disorder. BMC Psychiatry 2019; 19:62. [PMID: 30744588 PMCID: PMC6371424 DOI: 10.1186/s12888-019-2040-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 01/28/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Calcium voltage-gated channel auxiliary subunit β2 is a protein that, in humans, is encoded by the CACNB2 gene. The β2 subunit is an auxiliary protein of voltage-gated calcium channels, which is predominantly expressed in hippocampal pyramidal neurons. A single-nucleotide polymorphism at the CACNB2 gene (rs11013860) has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural effects of rs11013860 expression are unknown. Thus, the current study investigated the mechanisms of how the CACNB2 gene influences hippocampal-cortical limbic circuits in patients with bipolar disorder (BD). METHODS A total of 202 subjects were studied [69 BD patients and 133 healthy controls (HC)]. Participants agreed to undergo resting-state functional magnetic resonance imaging (rs-fMRI) and have blood drawn for genetic testing. Participants were found to belong to either a CC group homozygous for the C-allele (17 BD, 41 HC), or an A-carrier group carrying the high risk A-allele (AA/CA genotypes; 52 BD, 92 HC). Brain activity was assessed using resting-state functional connectivity (rs-FC) analyses. RESULTS A main effect of genotype showed that the rs-FC of the AA/CA group was elevated more than that of the CC-group between the hippocampus and the regions of right-inferior temporal, fusiform, and left-inferior occipital gyri. Additionally, a significant diagnosis × genotype interaction was noted between the hippocampus and right pars triangularis. Furthermore, in BD patients, the AA/CA group showed lower rs-FC when compared to that of the CC group. Additionally, individuals from HC within the AA/CA group showed higher rs-FC than that of the CC group. Finally, within C-allele-carrying groups, individuals with BD showed significantly increased rs-FC compared to that of HC. CONCLUSIONS Our study demonstrates that BD patients with the CACNB2 rs11013860 AA/CA genotype may exhibit altered hippocampal-cortical connectivity.
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Affiliation(s)
- Fang Liu
- grid.412636.4Department of Psychiatry, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang, 110001 Liaoning China ,0000 0004 0369 4060grid.54549.39The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaohong Gong
- A605, Building School of Life SCiences, Songhu Road 2005, Dinstric Yangpu, Shanghai, China
| | - Xudong Yao
- grid.412636.4Department of Psychiatry, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang, 110001 Liaoning China ,0000 0004 0369 4060grid.54549.39The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Lingling Cui
- grid.412636.4Department of Radiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning People’s Republic of China
| | - Zhiyang Yin
- grid.412636.4Department of Psychiatry, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang, 110001 Liaoning China
| | - Chao Li
- grid.412636.4Department of Radiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning People’s Republic of China
| | - Yanqing Tang
- Department of Psychiatry, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, China. .,Department of Geriatric Medicine, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China.
| | - Fei Wang
- Department of Psychiatry, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, China. .,Department of Radiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China. .,Brain Function Research Section, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China.
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27
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Madadi Asl M, Vahabie AH, Valizadeh A. Dopaminergic Modulation of Synaptic Plasticity, Its Role in Neuropsychiatric Disorders, and Its Computational Modeling. Basic Clin Neurosci 2019; 10:1-12. [PMID: 31031889 PMCID: PMC6484184 DOI: 10.32598/bcn.9.10.125] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/25/2017] [Accepted: 02/05/2018] [Indexed: 01/14/2023] Open
Abstract
Neuromodulators modify intrinsic characteristics of the nervous system in order to reconfigure the functional properties of neural circuits. This reconfiguration is crucial for the flexibility of the nervous system to respond on an input-modulated basis. Such a functional rearrangement is realized by modification of intrinsic properties of the neural circuits including synaptic interactions. Dopamine is an important neuromodulator involved in motivation and stimulus-reward learning process, and adjusts synaptic dynamics in multiple time scales through different pathways. The modification of synaptic plasticity by dopamine underlies the change in synaptic transmission and integration mechanisms, which affects intrinsic properties of the neural system including membrane excitability, probability of neurotransmitters release, receptors’ response to neurotransmitters, protein trafficking, and gene transcription. Dopamine also plays a central role in behavioral control, whereas its malfunction can cause cognitive disorders. Impaired dopamine signaling is implicated in several neuropsychiatric disorders such as Parkinson’s disease, drug addiction, schizophrenia, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and Tourette’s syndrome. Therefore, dopamine plays a crucial role in the nervous system, where its proper modulation of neural circuits may enhance plasticity-related procedures, but disturbances in dopamine signaling might be involved in numerous neuropsychiatric disorders. In recent years, several computational models are proposed to formulate the involvement of dopamine in synaptic plasticity or neuropsychiatric disorders and address their connection based on the experimental findings.
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Affiliation(s)
- Mojtaba Madadi Asl
- Department of Physics, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran
| | - Abdol-Hossein Vahabie
- School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Alireza Valizadeh
- Department of Physics, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran.,School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
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28
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Stubbendorff C, Hale E, Cassaday HJ, Bast T, Stevenson CW. Dopamine D1-like receptors in the dorsomedial prefrontal cortex regulate contextual fear conditioning. Psychopharmacology (Berl) 2019; 236:1771-1782. [PMID: 30656366 PMCID: PMC6602997 DOI: 10.1007/s00213-018-5162-7] [Citation(s) in RCA: 21] [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: 10/17/2018] [Accepted: 12/21/2018] [Indexed: 11/29/2022]
Abstract
RATIONALE Dopamine D1 receptor (D1R) signalling is involved in contextual fear conditioning. The D1R antagonist SCH23390 impairs the acquisition of contextual fear when administered systemically or infused locally into the dorsal hippocampus or basolateral amygdala. OBJECTIVES We determined if state dependency may account for the impairment in contextual fear conditioning caused by systemic SCH23390 administration. We also examined if the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens (NAc), and ventral hippocampus (VH) are involved in mediating the effect of systemic SCH23390 treatment on contextual fear conditioning. METHODS In experiment 1, SCH23390 (0.1 mg/kg) or vehicle was given before contextual fear conditioning and/or retrieval. In experiment 2, SCH23390 (2.5 μg/0.5 uL) or vehicle was infused locally into dmPFC, NAc, or VH before contextual fear conditioning, and retrieval was tested drug-free. Freezing was quantified as a measure of contextual fear. RESULTS In experiment 1, SCH23390 given before conditioning or before both conditioning and retrieval decreased freezing at retrieval, whereas SCH23390 given only before retrieval had no effect. In experiment 2, SCH23390 infused into dmPFC before conditioning decreased freezing at retrieval, while infusion of SCH23390 into NAc or VH had no effect. CONCLUSIONS The results of experiment 1 confirm those of previous studies indicating that D1Rs are required for the acquisition but not retrieval of contextual fear and rule out state dependency as an explanation for these findings. Moreover, the results of experiment 2 provide evidence that dmPFC is also part of the neural circuitry through which D1R signalling regulates contextual fear conditioning.
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Affiliation(s)
- Christine Stubbendorff
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK.
| | - Ed Hale
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD UK
| | - Helen J. Cassaday
- School of Psychology@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK ,School of Neuroscience@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK
| | - Tobias Bast
- School of Psychology@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK ,School of Neuroscience@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK
| | - Carl W. Stevenson
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD UK
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29
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Borsook D, Youssef AM, Simons L, Elman I, Eccleston C. When pain gets stuck: the evolution of pain chronification and treatment resistance. Pain 2018; 159:2421-2436. [PMID: 30234696 PMCID: PMC6240430 DOI: 10.1097/j.pain.0000000000001401] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
It is well-recognized that, despite similar pain characteristics, some people with chronic pain recover, whereas others do not. In this review, we discuss possible contributions and interactions of biological, social, and psychological perturbations that underlie the evolution of treatment-resistant chronic pain. Behavior and brain are intimately implicated in the production and maintenance of perception. Our understandings of potential mechanisms that produce or exacerbate persistent pain remain relatively unclear. We provide an overview of these interactions and how differences in relative contribution of dimensions such as stress, age, genetics, environment, and immune responsivity may produce different risk profiles for disease development, pain severity, and chronicity. We propose the concept of "stickiness" as a soubriquet for capturing the multiple influences on the persistence of pain and pain behavior, and their stubborn resistance to therapeutic intervention. We then focus on the neurobiology of reward and aversion to address how alterations in synaptic complexity, neural networks, and systems (eg, opioidergic and dopaminergic) may contribute to pain stickiness. Finally, we propose an integration of the neurobiological with what is known about environmental and social demands on pain behavior and explore treatment approaches based on the nature of the individual's vulnerability to or protection from allostatic load.
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Affiliation(s)
- David Borsook
- Center for Pain and the Brain, Boston Children’s (BCH), McLean and Massachusetts Hospitals (MGH), Boston MA
- Departments of Anesthesia (BCH), Psychiatry (MGH, McLean) and Radiology (MGH)
| | - Andrew M Youssef
- Center for Pain and the Brain, Boston Children’s (BCH), McLean and Massachusetts Hospitals (MGH), Boston MA
| | - Laura Simons
- Department of Anesthesia, Stanford University, Palo Alto, CA
| | | | - Christopher Eccleston
- Centre for Pain Research, University of Bath, UK
- Department of Clinical and Health Psychology, Ghent University, Belgium
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30
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Hashizume K, Yamanaka M, Ueda S. POU3F2 participates in cognitive function and adult hippocampal neurogenesis via mammalian-characteristic amino acid repeats. GENES BRAIN AND BEHAVIOR 2017; 17:118-125. [PMID: 28782255 DOI: 10.1111/gbb.12408] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 07/02/2017] [Accepted: 08/03/2017] [Indexed: 12/15/2022]
Abstract
POU3F2/BRN-2 is a transcription factor that is mainly expressed in the central nervous system and plays an important role in brain development. The transactivation domain of POU3F2 includes multiple mammalian-characteristic tandem amino acid repeats (homopolymeric amino acid repeats). We previously generated knock-in mice (Pou3f2Δ/Δ mice) in which all three homopolymeric amino acid repeats were deleted from the Pou3f2 transactivation domain and identified phenotypic impairments in maternal behavior and pup recognition. Yet, the exact biological implications of homopolymeric repeats are not completely understood. In this study, we investigated cognitive function and hippocampal neurogenesis in Pou3f2Δ/Δ mice. Pou3f2Δ/Δ mice exhibited cognitive impairment in object recognition and object location tests. Immunohistochemistry for doublecortin, a marker of immature neurons, showed a lower number of newborn neurons in the dentate gyrus of adult Pou3f2Δ/Δ mice compared with wild-type mice. Consistent with this observation, adult Pou3f2Δ/Δ mice had lower numbers of 5-bromo-2'-deoxyuridine (BrdU) and NeuN double-positive cells at 4 weeks after BrdU injection compared with control mice, indicating the decreased generation of mature granule cells in Pou3f2Δ/Δ mice. Taken together, these results suggest that POU3F2 is involved in cognitive function as well as adult hippocampal neurogenesis, and that homopolymeric amino acid repeats in this gene play a functional role.
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Affiliation(s)
- K Hashizume
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - M Yamanaka
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - S Ueda
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
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31
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Andino-Pavlovsky V, Souza AC, Scheffer-Teixeira R, Tort ABL, Etchenique R, Ribeiro S. Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats. Front Neural Circuits 2017; 11:29. [PMID: 28536507 PMCID: PMC5422429 DOI: 10.3389/fncir.2017.00029] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 04/10/2017] [Indexed: 11/13/2022] Open
Abstract
Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC.
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Affiliation(s)
- Victoria Andino-Pavlovsky
- Departamento de Química Inorganica, Analítica y Química Física, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos AiresBuenos Aires, Argentina
| | - Annie C Souza
- Instituto do Cérebro, Federal University of Rio Grande do NorteNatal, Brazil
| | | | - Adriano B L Tort
- Instituto do Cérebro, Federal University of Rio Grande do NorteNatal, Brazil
| | - Roberto Etchenique
- Departamento de Química Inorganica, Analítica y Química Física, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos AiresBuenos Aires, Argentina
| | - Sidarta Ribeiro
- Instituto do Cérebro, Federal University of Rio Grande do NorteNatal, Brazil
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Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways. Transl Psychiatry 2017; 7:e1130. [PMID: 28509906 PMCID: PMC5534962 DOI: 10.1038/tp.2017.94] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 03/21/2017] [Accepted: 03/29/2017] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine-phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.
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Ye Y, Li H, Yang JW, Wang XR, Shi GX, Yan CQ, Ma SM, Zhu W, Li QQ, Li TR, Xiao LY, Liu CZ. Acupuncture Attenuated Vascular Dementia–Induced Hippocampal Long-Term Potentiation Impairments via Activation of D1/D5 Receptors. Stroke 2017; 48:1044-1051. [DOI: 10.1161/strokeaha.116.014696] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 01/21/2017] [Accepted: 01/31/2017] [Indexed: 12/28/2022]
Abstract
Background and Purpose—
Emerging evidence suggests that acupuncture could improve cognitive impairment in vascular dementia by enhancing synaptic plasticity in the hippocampus. The purpose of this study is to investigate whether dopamine, a key mediator of synaptic plasticity, is involved in this cognitive improvement.
Methods—
Vascular dementia model was established by bilateral common carotid arteries occlusion in male Wistar rats. Three days after the operation, animals received acupuncture treatment for 2 weeks, once daily. The D1/D5 receptors antagonist SCH23390 was administered intraperitoneally 15 minutes before each acupuncture treatment. Morris water maze was examined after acupuncture. Long-term potentiation was studied by an electrophysiological technique. Dopamine and metabolites levels were detected by microdialysis and high-performance liquid chromatography from brain tissue. The expression of D1R and D5R was analyzed by immunofluorescence.
Results—
Acupuncture remarkably reversed cognitive deficits in 2-vessel occlusion model (2VO) rats, and the acupuncture points Zusanli (ST36) and Baihui (GV20) were confirmed to be the most effective combination. Electrophysiological recording data showed that 2VO-induced impairments of long-term potentiation were prevented by acupuncture. In addition, acupuncture promoted the release of dopamine and its major metabolites in the hippocampus of 2VO rats. The immunofluorescence experiment showed that the decrease of D1R and D5R in hippocampal dentate gyrus region of 2VO rats was reversed by acupuncture. Furthermore, we found that the effects of acupuncture against 2VO-induced impairments in cognition and synaptic plasticity were abolished by SCH23390.
Conclusions—
Improvement in cognition and hippocampal synaptic plasticity induced by acupuncture was achieved via activation of D1/D5 receptors in 2VO rats.
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Affiliation(s)
- Yang Ye
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Hui Li
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Jing-Wen Yang
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Xue-Rui Wang
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Guang-Xia Shi
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Chao-Qun Yan
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Si-Ming Ma
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Wen Zhu
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Qian-Qian Li
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Tian-Ran Li
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Ling-Yong Xiao
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
| | - Cun-Zhi Liu
- From the Acupuncture and Moxibustion Department (Y.Y., H.L., J.-W.Y., X.-R.W., G.-X.S., C.-Q.Y., S.-M.M., W.Z., Q.-Q.L., T.-R.L., C.-Z.L.) and Beijing Key Laboratory of Acupuncture Neuromodulation (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, China; and Beijing University of Chinese Medicine, China (Y.Y., L.-Y.X.)
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Hayes JP, Logue MW, Reagan A, Salat D, Wolf EJ, Sadeh N, Spielberg JM, Sperbeck E, Hayes SM, McGlinchey RE, Milberg WP, Verfaellie M, Stone A, Schichman SA, Miller MW. COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume. J Psychiatry Neurosci 2017; 42:95-102. [PMID: 28234210 PMCID: PMC5373706 DOI: 10.1503/jpn.150339] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. METHODS Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. RESULTS We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. LIMITATIONS The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. CONCLUSION Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.
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Affiliation(s)
- Jasmeet P. Hayes
- Correspondence to: J.P. Hayes, National Center for PTSD (116B-2), VA Boston Healthcare System, 150 S. Huntington Ave., Boston MA 02130;
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Urban KR, Valentino RJ. Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex. Cereb Cortex 2017; 27:244-253. [PMID: 28013234 PMCID: PMC5939192 DOI: 10.1093/cercor/bhw388] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 11/12/2016] [Indexed: 11/14/2022] Open
Abstract
Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident-intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence.
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Affiliation(s)
- Kimberly R. Urban
- Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Rita J. Valentino
- Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Magalhães R, Bourgin J, Boumezbeur F, Marques P, Bottlaender M, Poupon C, Djemaï B, Duchesnay E, Mériaux S, Sousa N, Jay TM, Cachia A. White matter changes in microstructure associated with a maladaptive response to stress in rats. Transl Psychiatry 2017; 7:e1009. [PMID: 28117841 PMCID: PMC5545740 DOI: 10.1038/tp.2016.283] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 12/29/2022] Open
Abstract
In today's society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one's quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague-Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to stress, SD rats were found to have lower values of corticosterone when compared with F344 rats. Overall, stress was found to lead to an overall increase in fractional anisotropy (FA), on top of a reduction in mean and radial diffusivity (MD and RD) in several white matter bundles of the brain. No effect of strain on the white matter diffusion properties was observed. The strain-by-stress interaction revealed an effect on SD rats in MD, RD and axial diffusivity (AD), with lower diffusion metric levels on stressed animals. These effects were localized on the left side of the brain on the external capsule, corpus callosum, deep cerebral white matter, anterior commissure, endopiriform nucleus, dorsal hippocampus and amygdala fibers. The results possibly reveal an adaptation of the SD strain to the stressful stimuli through synaptic and structural plasticity processes, possibly reflecting learning processes.
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Affiliation(s)
- R Magalhães
- Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal,ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - J Bourgin
- Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France,Université Paris Descartes, Sorbonne Paris Cité, Paris, France,Faculté de Médecine Paris Descartes, Service Hospitalo Universitaire, Centre Hospitalier Sainte-Anne, Paris, France
| | | | - P Marques
- Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal,ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | | | - C Poupon
- Neurospin, I2BM, CEA, Gif/Yvette, France
| | - B Djemaï
- Neurospin, I2BM, CEA, Gif/Yvette, France
| | | | - S Mériaux
- Neurospin, I2BM, CEA, Gif/Yvette, France
| | - N Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal,ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - T M Jay
- Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France,Université Paris Descartes, Sorbonne Paris Cité, Paris, France,Faculté de Médecine Paris Descartes, Service Hospitalo Universitaire, Centre Hospitalier Sainte-Anne, Paris, France
| | - A Cachia
- Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France,Université Paris Descartes, Sorbonne Paris Cité, Paris, France,Laboratoire de Psychologie du développement et de l’Education de l’Enfant, CNRS UMR 8240, Paris, France,Institut Universitaire de France, Paris, France,Centre de Psychiatrie et Neurosciences, INSERM UMR_S 894, 2 ter rue d’Alésia, Paris 75014, France. E-mail:
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Papp M, Gruca P, Lason-Tyburkiewicz M, Litwa E, Niemczyk M, Tota-Glowczyk K, Willner P. Dopaminergic mechanisms in memory consolidation and antidepressant reversal of a chronic mild stress-induced cognitive impairment`. Psychopharmacology (Berl) 2017; 234:2571-2585. [PMID: 28567697 PMCID: PMC5548836 DOI: 10.1007/s00213-017-4651-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/12/2017] [Indexed: 01/27/2023]
Abstract
Cognitive deficits in depression can be modelled using the novel object recognition (NOR) test, performance in which is impaired by chronic mild stress (CMS). We aimed to examine the involvement of mesocorticolimbic DA terminal regions, and to establish the substrate for CMS-induced impairment of NOR and its reversal by chronic antidepressant treatment. In experiments 1 and 2, we examined the effect of infusions into medial PFC, dorsal hippocampus (HPC), and nucleus accumbens (NAc) shell of D1 and D2 antagonists and D3 agonist, which were predicted to impair NOR with a short (1 h) delay, and of D1 and D2 agonists and D3 antagonist, which were predicted to facilitate NOR with a long (24 h) delay. Using optimal doses identified in experiment 2, in experiments 3 and 4, we examined effects on drug-stimulated NOR of CMS and chronic treatment with venlafaxine (VFX) or risperidone (RSP). We found a wide involvement of DA systems in memory for NOR: D1 receptors in PFC, HPC, and NAc; D3 receptors in PFC and HPC; and D2 receptors in PFC. CMS impaired D2- and D3-mediated effects in PFC and HPC; antidepressants rescued those effects in PFC but not HPC. The involvement of DA in NOR is multifaceted, but the effects of CMS and antidepressants are more discrete, involving D2 and D3 receptors in PFC specifically. While raising many difficult questions, these results suggest that the D2 and D3 receptors in the medial PFC may be an important substrate for cognitive deficits in depression and their remediation.
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Affiliation(s)
- Mariusz Papp
- Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland.
| | - Piotr Gruca
- Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland
| | | | - Ewa Litwa
- Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland
| | - Monika Niemczyk
- Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland
| | - Katarzyna Tota-Glowczyk
- Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland
| | - Paul Willner
- Department of Psychology, Swansea University, Swansea, UK
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Rajkumar R, Kumar JR, Dawe GS. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiol Learn Mem 2016; 138:215-225. [PMID: 27400867 DOI: 10.1016/j.nlm.2016.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/30/2016] [Accepted: 07/06/2016] [Indexed: 01/09/2023]
Abstract
Priming phenomenon, in which an earlier exposure to a stimulus or condition alters synaptic plasticity in response to a subsequent stimulus or condition, known as a challenge, is an example of metaplasticity. In this review, we make the case that the locus coeruleus noradrenergic system-medial perforant path-dentate gyrus pathway is a neural ensemble amenable to studying priming-challenge effects on synaptic plasticity. Accumulating evidence points to a tyrosine hydroxylase-dependent priming effect achieved by pharmacological (nicotine and antipsychotics) or physiological (septal theta driving) manipulations of the locus coeruleus noradrenergic system that can facilitate noradrenaline-induced synaptic plasticity in the dentate gyrus of the hippocampus. The evidence suggests the hypothesis that behavioural experiences inducing tyrosine hydroxylase expression in the locus coeruleus may be sufficient to prime this form of metaplasticity. We propose exploring this phenomenon of priming and challenge physiologically, to determine whether behavioural experiences are sufficient to prime the locus coeruleus, enabling subsequent pharmacological or behavioural challenge conditions that increase locus coeruleus firing to release sufficient noradrenaline to induce long-lasting potentiation in the dentate gyrus. Such an approach may contribute to unravelling mechanisms underlying this form of metaplasticity and its importance in stress-related mnemonic processes.
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Affiliation(s)
- Ramamoorthy Rajkumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore
| | - Jigna Rajesh Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore
| | - Gavin S Dawe
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore.
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Hamson DK, Roes MM, Galea LAM. Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning. Compr Physiol 2016; 6:1295-337. [DOI: 10.1002/cphy.c150031] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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40
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Silkis IG. The contribution of dopamine to the functioning of the hippocampus during spatial learning (a hypothetical mechanism). NEUROCHEM J+ 2016. [DOI: 10.1134/s181971241601013x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Effects of Dopamine and Serotonin Systems on Modulating Neural Oscillations in Hippocampus-Prefrontal Cortex Pathway in Rats. Brain Topogr 2016; 29:539-51. [PMID: 26969669 DOI: 10.1007/s10548-016-0485-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 03/07/2016] [Indexed: 10/22/2022]
Abstract
Theta and gamma oscillations are believed to play an important role in cognition and memory, and their phase coupling facilitates the information transmission in hippocampal-cortex network. In a rat model of chronic stress, the phase coupling of both theta and gamma oscillations between ventral hippocampal CA1 (vCA1) and medial prefrontal cortex (mPFC) was found to be disrupted, which was associated with the impaired synaptic plasticity in the pathway. However, little was known about the mechanisms underlying the process. In order to address this issue, both dopamine and serotonin as monoaminergic neurotransmitters were involved in this study, since they were crucial factors in pathological basis of depressive disorder. Local field potentials (LFPs) were recorded simultaneously at both vCA1 and mPFC regions under anesthesia, before and after the injection of dopamine D1 receptor antagonist and 5-HT1A receptor agonist, respectively. The results showed that the blockage of D1 receptor could lead to depression-like decrement on theta phase coupling. In addition, the activation of 5-HT1A receptor enhanced vCA1-mPFC coupling on gamma oscillations, and attenuated CA1 theta-fast gamma cross frequency coupling. These data suggest that the theta phase coupling between vCA1 and mPFC may be modulated by dopamine system that is an underlying mechanism of the cognitive dysfunction in depression. Besides, the serotonergic system is probably involved in the regulation of gamma oscillations coupling in vCA1-mPFC network.
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Janakiraman U, Manivasagam T, Thenmozhi AJ, Essa MM, Barathidasan R, SaravanaBabu C, Guillemin GJ, Khan MAS. Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice. PLoS One 2016; 11:e0146671. [PMID: 26765842 PMCID: PMC4713092 DOI: 10.1371/journal.pone.0146671] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 12/21/2015] [Indexed: 12/31/2022] Open
Abstract
Parkinson's disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5-HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters-2 (VMAT 2) and α-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.
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Affiliation(s)
- Udaiyappan Janakiraman
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, 608002, Tamilnadu, India
| | - Thamilarasan Manivasagam
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, 608002, Tamilnadu, India
- * E-mail:
| | - Arokiasamy Justin Thenmozhi
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, 608002, Tamilnadu, India
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman
- Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
| | - Rajamani Barathidasan
- Centre for Toxicology and Developmental Research, Sri Ramachandra University, Porur, Chennai-600 116, Tamilnadu, India
| | - Chidambaram SaravanaBabu
- Centre for Toxicology and Developmental Research, Sri Ramachandra University, Porur, Chennai-600 116, Tamilnadu, India
| | - Gilles J. Guillemin
- Neuropharmacology group, Faculty of Medicine and Health Sciences, Deb Bailey MND Research Laboratory, Macquarie University, NSW, 2109, Australia
| | - Mohammed A. S. Khan
- Harvard Medical School, Massachusetts General Hospital, Shriners Hospital for Children, Boston, Massachusetts, 02114, United States of America
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Zhou J, Liu Z, Yu J, Han X, Fan S, Shao W, Chen J, Qiao R, Xie P. Quantitative Proteomic Analysis Reveals Molecular Adaptations in the Hippocampal Synaptic Active Zone of Chronic Mild Stress-Unsusceptible Rats. Int J Neuropsychopharmacol 2015; 19:pyv100. [PMID: 26364272 PMCID: PMC4772275 DOI: 10.1093/ijnp/pyv100] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 08/31/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND While stressful events are recognized as an important cause of major depressive disorder, some individuals exposed to life stressors maintain normal psychological functioning. The molecular mechanism(s) underlying this phenomenon remain unclear. Abnormal transmission and plasticity of hippocampal synapses have been implied to play a key role in the pathoetiology of major depressive disorder. METHODS A chronic mild stress protocol was applied to separate susceptible and unsusceptible rat subpopulations. Proteomic analysis using an isobaric tag for relative and absolute quantitation coupled with tandem mass spectrometry was performed to identify differential proteins in enriched hippocampal synaptic junction preparations. RESULTS A total of 4318 proteins were quantified, and 89 membrane proteins were present in differential amounts. Of these, SynaptomeDB identified 81 (91%) having a synapse-specific localization. The unbiased profiles identified several candidate proteins within the synaptic junction that may be associated with stress vulnerability or insusceptibility. Subsequent functional categorization revealed that protein systems particularly involved in membrane trafficking at the synaptic active zone exhibited a positive strain as potential molecular adaptations in the unsusceptible rats. Moreover, through STRING and immunoblotting analysis, membrane-associated GTP-bound Rab3a and Munc18-1 appear to coregulate syntaxin-1/SNAP25/VAMP2 assembly at the hippocampal presynaptic active zone of unsusceptible rats, facilitating SNARE-mediated membrane fusion and neurotransmitter release, and may be part of a stress-protection mechanism in actively maintaining an emotional homeostasis. CONCLUSIONS The present results support the concept that there is a range of potential protein adaptations in the hippocampal synaptic active zone of unsusceptible rats, revealing new investigative targets that may contribute to a better understanding of stress insusceptibility.
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Affiliation(s)
- Jian Zhou
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Zhao Liu
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Jia Yu
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Xin Han
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Songhua Fan
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Weihua Shao
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Jianjun Chen
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Rui Qiao
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie)
| | - Peng Xie
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Chongqing Key Laboratory of Neurobiology, Chongqing, China (Drs Zhou, Liu, Yu, Han, Fan, Shao, Chen, Qiao, and Xie); Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Drs Liu, Han, Fan, Shao, and Xie).
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Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 2015; 5:e623. [PMID: 26285133 PMCID: PMC4564568 DOI: 10.1038/tp.2015.115] [Citation(s) in RCA: 235] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 05/06/2015] [Accepted: 07/08/2015] [Indexed: 12/31/2022] Open
Abstract
Schizophrenia is a disease of abnormal brain development. Considerable evidence now indicates that environmental factors have a causative role in schizophrenia. Elevated incidence of the disease has been linked to a wide range of disturbances in the prenatal environment and to social factors and drug intake during adolescence. Here we examine neurodevelopment of the prefrontal cortex in the first trimester of gestation and during adolescence to gain further insight into the neurodevelopmental processes that may be vulnerable in schizophrenia. Early embryonic development of the prefrontal cortex is characterized by cell proliferation, including renewal of progenitor cells, generation of early transient cell populations and neurogenesis of subcortical populations. Animal models show that curtailing early gestational cell proliferation produces schizophrenia-like pathology in the prefrontal cortex and mimics key behavioral and cognitive symptoms of the disease. At the other end of the spectrum, elimination of excitatory synapses is the fundamental process occurring during adolescent maturation in the prefrontal cortex. Adverse social situations that elevate stress increase dopamine stimulation of the mesocortical pathway and may lead to exaggerated synaptic pruning during adolescence. In a non-human primate model, dopamine hyperstimulation has been shown to decrease prefrontal pyramidal cell spine density and to be associated with profound cognitive dysfunction. Development of the prefrontal cortex in its earliest stage in gestation and in its final stage in adolescence represents two critical periods of vulnerability for schizophrenia in which cell proliferation and synaptic elimination, respectively, may be influenced by environmental factors.
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Han X, Shao W, Liu Z, Fan S, Yu J, Chen J, Qiao R, Zhou J, Xie P. iTRAQ-based quantitative analysis of hippocampal postsynaptic density-associated proteins in a rat chronic mild stress model of depression. Neuroscience 2015; 298:220-92. [DOI: 10.1016/j.neuroscience.2015.04.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 03/20/2015] [Accepted: 04/02/2015] [Indexed: 01/26/2023]
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46
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Zhang G, Zhang Y, Yang J, Hu M, Zhang Y, Liang X. Altered serous levels of monoamine neurotransmitter metabolites in patients with refractory and non-refractory depression. Neural Regen Res 2015; 7:1113-8. [PMID: 25722703 PMCID: PMC4340026 DOI: 10.3969/j.issn.1673-5374.2012.14.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Accepted: 04/23/2012] [Indexed: 11/18/2022] Open
Abstract
The study examined plasma metabolite changes of monoamine neurotransmitters in patients with treatment-resistant depression (TRD) and non-TRD before and after therapy. All 30 TRD and 30 non-TRD patients met the diagnostic criteria for a depressive episode in accordance with the International Classification of Diseases, Tenth Revision. Before treatment, and at 4, 6, and 8 weeks after treatment, the plasma metabolite products of monoamine neurotransmitters in TRD group, including 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenyl ethylene glycol and homovanillic acid, were significantly lower than those in the non-TRD group. After two types of anti-depressive therapy with 5-serotonin and norepinephrine reuptake inhibitor, combined with psychotherapy, the Hamilton Depression Rating Scale scores were significantly reduced in both groups of patients, and the serous levels of 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenyl ethylene glycol were significantly increased. In contrast, the homovanillic acid level exhibited no significant change. The levels of plasma metabolite products of peripheral monoamine neurotransmitters in depressive patients may predict the degree of depression and the therapeutic effects of treatment.
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Affiliation(s)
- Guiqing Zhang
- Department of Rehabilitation and Psychology, the First Affiliated Hospital of Shihezi University Medical College, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Yanxia Zhang
- Department of Rehabilitation and Psychology, the First Affiliated Hospital of Shihezi University Medical College, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Jianxia Yang
- Department of Rehabilitation and Psychology, the First Affiliated Hospital of Shihezi University Medical College, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Min Hu
- Department of Rehabilitation and Psychology, the First Affiliated Hospital of Shihezi University Medical College, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Yueqi Zhang
- Department of Rehabilitation and Psychology, the First Affiliated Hospital of Shihezi University Medical College, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Xia Liang
- Department of Rehabilitation and Psychology, the First Affiliated Hospital of Shihezi University Medical College, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
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47
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Sudakov SK, Bashkatova VG. Effect of peripheral D₂ dopamine receptor antagonist domperidone on metabolism, feeding behavior, and locomotor activity of rats. Bull Exp Biol Med 2014; 155:705-7. [PMID: 24288745 DOI: 10.1007/s10517-013-2231-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We studied the possibility of activation of the central dopaminergic system compartment by modulating activity of D2 dopamine receptors in the gastrointestinal tract with domperidone, an antagonist not crossing the blood-brain barrier. Intragastric administration of 0.1 mg/kg domperidone to rats was followed by a significant decrease in feeding behavior and stimulation of basal metabolism, but had no effect on locomotor activity of animals in a Phenomaster system. These effects are typical of psychostimulant agents that stimulate dopamine release from nerve endings in the nucleus accumbens and some regions of the brain cortex. Our results indicate that physiological functions associated with activity of the central dopaminergic system can be modulated through peripheral dopamine receptors.
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Affiliation(s)
- S K Sudakov
- P. K. Anokhin Research Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia.
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48
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Dominguez G, Faucher P, Henkous N, Krazem A, Piérard C, Béracochéa D. Stress induced a shift from dorsal hippocampus to prefrontal cortex dependent memory retrieval: role of regional corticosterone. Front Behav Neurosci 2014; 8:166. [PMID: 24860451 PMCID: PMC4030165 DOI: 10.3389/fnbeh.2014.00166] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 04/18/2014] [Indexed: 12/25/2022] Open
Abstract
Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hippocampo-prefrontal cortex interplay. The role of the stress-induced regional corticosterone increase in such dysfunction remains however unclear, since there is no published study as yet dedicated to measuring corticosterone concentrations simultaneously in both the prefrontal cortex (mPFC) and the hippocampus (dHPC) in relation with memory impairments. To that aim, we first showed in Experiment 1 that an acute stress (3 electric footschocks; 0.9 mA each) delivered before memory testing reversed the memory retrieval pattern (MRP) in a serial discrimination task in which mice learned two successive discriminations. More precisely, whereas non-stressed animals remembered accurately the first learned discrimination and not the second one, stressed mice remembered more accurately the second discrimination but not the first one. We demonstrated that local inactivation of dHPC or mPFC with the anesthetic lidocaine recruited the dHPC activity in non-stress conditions whereas the stress-induced MRP inversion recruited the mPFC activity. In a second experiment, we showed that acute stress induced a very similar time-course evolution of corticosterone rises within both the mPFC and dHPC. In a 3rd experiment, we found however that in situ injections of corticosterone either within the mPFC or the dHPC before memory testing favored the emergence of the mPFC-dependent MRP but blocked the emergence of the dHPC-dependent one. Overall, our study evidences that the simultaneous increase of corticosterone after stress in both areas induces a shift from dHPC (non-stress condition) to mPFC-dependent MRP and that corticosterone is critically involved in mediating the deleterious effects of stress on cognitive functions involving the mPFC-HPC interplay.
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Affiliation(s)
- Gaelle Dominguez
- INSERM U-930, Université François Rabelais, Parc Grandmont Tours, France
| | - Pierre Faucher
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Nouvelle Université de Bordeaux Talence, France
| | - Nadia Henkous
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Nouvelle Université de Bordeaux Talence, France
| | - Ali Krazem
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Nouvelle Université de Bordeaux Talence, France
| | | | - Daniel Béracochéa
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Nouvelle Université de Bordeaux Talence, France
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49
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Kapczinski F, Frey BN, Kauer-Sant’Anna M, Grassi-Oliveira R. Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Expert Rev Neurother 2014; 8:1101-13. [DOI: 10.1586/14737175.8.7.1101] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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50
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Diwadkar VA, Bustamante A, Rai H, Uddin M. Epigenetics, stress, and their potential impact on brain network function: a focus on the schizophrenia diatheses. Front Psychiatry 2014; 5:71. [PMID: 25002852 PMCID: PMC4066368 DOI: 10.3389/fpsyt.2014.00071] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 06/04/2014] [Indexed: 01/21/2023] Open
Abstract
The recent sociodevelopmental cognitive model of schizophrenia/psychosis is a highly influential and compelling compendium of research findings. Here, we present logical extensions to this model incorporating ideas drawn from epigenetic mediation of psychiatric disease, and the plausible effects of epigenetics on the emergence of brain network function and dysfunction in adolescence. We discuss how gene-environment interactions, effected by epigenetic mechanisms, might in particular mediate the stress response (itself heavily implicated in the emergence of schizophrenia). Next, we discuss the plausible relevance of this framework for adolescent genetic risk populations, a risk group characterized by vexing and difficult-to-explain heterogeneity. We then discuss how exploring relationships between epigenetics and brain network dysfunction (a strongly validated finding in risk populations) can enhance understanding of the relationship between stress, epigenetics, and functional neurobiology, and the relevance of this relationship for the eventual emergence of schizophrenia/psychosis. We suggest that these considerations can expand the impact of models such as the sociodevelopmental cognitive model, increasing their explanatory reach. Ultimately, integration of these lines of research may enhance efforts of early identification, intervention, and treatment in adolescents at-risk for schizophrenia.
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Affiliation(s)
- Vaibhav A Diwadkar
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine , Detroit, MI , USA
| | - Angela Bustamante
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine , Detroit, MI , USA
| | - Harinder Rai
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine , Detroit, MI , USA
| | - Monica Uddin
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine , Detroit, MI , USA ; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine , Detroit, MI , USA
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