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Merrill SM, Konwar C, Fraihat Z, Parent J, Dajani R. Molecular insights into trauma: A framework of epigenetic pathways to resilience through intervention. MED 2025; 6:100560. [PMID: 39708797 DOI: 10.1016/j.medj.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 10/01/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024]
Abstract
Experiences of complex trauma and adversity, especially for children, are ongoing global crises necessitating adaptation. Bioadaptability to adversity and its health consequences emphasizes the dynamism of adaptation to trauma and the potential for research to inform intervention strategies. Epigenetic variability, particularly DNA methylation, associates with chronic adversity while allowing for resilience and adaptability. Epigenetics, including age- and site-specific changes in DNA methylation, gene-environment interactions, pharmacological responses, and biomarker characterization and evaluation, may aid in understanding trauma responses and promoting well-being by facilitating psychological and biological adaptation. Understanding these molecular processes provides a foundation for a biologically adaptive framework to shift public health strategies from restorative to long-term adaptation and resilience. Psychological, cultural, and biological trauma must be addressed in innovative interventions for vulnerable populations, particularly children and adolescents. Understanding molecular changes may provide a biopsychosocial perspective for culturally sensitive, evidence-based interventions that promote resilience and thriving in new settings.
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Affiliation(s)
- Sarah M Merrill
- Department of Psychology, University of Massachusetts Lowell, Lowell, MA, USA.
| | - Chaini Konwar
- BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada
| | - Zaid Fraihat
- School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Justin Parent
- Department of Psychology, University of Massachusetts Lowell, Lowell, MA, USA; Department of Psychology, College of Health Sciences, University of Rhode Island, Kingston, RI, USA; Emma Pendleton Bradley Hospital, East Providence, RI, USA
| | - Rana Dajani
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan.
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2
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Rabago-Barajas BV, Macías-Islas MÁ, Saldaña-Cruz AM, Arana-Yepez JE, Olivas-Flores EM, Aguayo-Arelis A. Association of the Val66Met Polymorphism of the BDNF Gene with the Depression in a Mexican Population with Multiple Sclerosis. Life (Basel) 2025; 15:213. [PMID: 40003622 PMCID: PMC11856127 DOI: 10.3390/life15020213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/15/2025] [Accepted: 01/27/2025] [Indexed: 02/27/2025] Open
Abstract
Multiple sclerosis (MS) is a chronic, autoimmune pathology that affects the nervous system. It is characterized by inflammatory lesions that cause axonal damage with neurodegeneration. The signs and symptoms present in this pathology include among others, psychiatric disorders. In MS, depression is the most frequent psychiatric disorder, with prevalence levels of 40 to 60%; to date, the cause is unknown. The brain-derived neurotrophic factor (BDNF) is a neurotrophin related to neuroplasticity. The single-nucleotide polymorphism Val66Met, encoded by the BDNF gene, has been associated with various effects, including the presence of neuropsychiatric disorders. The purpose of our study was to evaluate the association between the BDNF Val66Met polymorphism and depression in MS patients. METHODS Study design, cases, and controls: Mexican mestizo MS patients. CASES Patients diagnosed with depression. CONTROLS Patients without depression diagnosis. MEASUREMENTS For depression, the Beck Depression Inventory; for polymorphism, real-time PCR. RESULTS No statistically significant differences were found in sociodemographic and disease variables between the case and control groups. qPCR analysis showed that 68% of the participants were Val/Val wild-type homozygotes, 29% were Val/Met polymorphism heterozygotes, and 3% were Met/Met polymorphism homozygotes. The presence of the BDNF gene rs6265 polymorphism was associated with a 5.6-fold increase in the probability of depression in the cases compared to the controls. CONCLUSIONS The BDNF Val66Met Polymorphism is associated with depression in Mexican mestizo patients diagnosed with MS.
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Affiliation(s)
- Brenda Viridiana Rabago-Barajas
- Department of Applied Psychology, University Center for Health Sciences, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico;
| | - Miguel Ángel Macías-Islas
- Department of Neurosciences, University Center for Health Sciences, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico;
| | - Ana Miriam Saldaña-Cruz
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico;
| | - Jesús Emmanuel Arana-Yepez
- Pharmacology and Behavior Laboratory, Neuroscience Institute, University Center for Biological and Agricultural Sciences (CUCBA), University of Guadalajara, Guadalajara 44130, Jalisco, Mexico;
| | - Eva Maria Olivas-Flores
- Department of Anesthesiology, Specialty Hospital, National Medical Center of the West, IMSS, Guadalajara 44340, Jalisco, Mexico;
| | - Adriana Aguayo-Arelis
- Department of Applied Psychology, University Center for Health Sciences, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico;
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3
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Oyovwi MO, Ogenma UT, Onyenweny A. Exploring the impact of exercise-induced BDNF on neuroplasticity in neurodegenerative and neuropsychiatric conditions. Mol Biol Rep 2025; 52:140. [PMID: 39832087 DOI: 10.1007/s11033-025-10248-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
This review investigates the intricate relationship between exercise, brain-derived neurotrophic factor (BDNF), neuroplasticity, and cognitive function, with a focus on implications for neuropsychiatric and neurodegenerative disorders. A systematic review was conducted by searching various databases for relevant studies that explored the connections between exercise, BDNF, neuroplasticity, and cognitive health. The analysis of eligible studies revealed that exercise increases BDNF levels in the brain, promoting neuroplasticity and enhancing cognitive functions. Furthermore, we discuss the protective effects of exercise against cognitive decline and neurological disorders, suggesting that BDNF plays a critical role in mediating these effects. Regular physical activity not only elevates BDNF levels but also fosters memory and learning, offering important implications for the prevention and treatment of neuropsychiatric and neurodegenerative conditions. Our findings underscore the necessity of incorporating exercise into a healthy lifestyle to optimize brain health. Future research is essential to elucidate the underlying mechanisms of this relationship and to refine exercise interventions for improved cognitive outcomes.
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Affiliation(s)
- Mega Obukohwo Oyovwi
- Department of Physiology, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria.
| | - Ugushida Thankgod Ogenma
- Department of Public Health, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria
| | - Anthonia Onyenweny
- Department of Nursing Science, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria
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4
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Peng Z, Jia Q, Mao J, Luo X, Huang A, Zheng H, Jiang S, Ma Q, Ma C, Yi Q. Neurotransmitters crosstalk and regulation in the reward circuit of subjects with behavioral addiction. Front Psychiatry 2025; 15:1439727. [PMID: 39876994 PMCID: PMC11773674 DOI: 10.3389/fpsyt.2024.1439727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
Behavioral addictive disorders (BADs) have become a significant societal challenge over time. The central feature of BADs is the loss of control over engaging in and continuing behaviors, even when facing negative consequences. The neurobiological underpinnings of BADs primarily involve impairments in the reward circuitry, encompassing the ventral tegmental area, nucleus accumbens in the ventral striatum, and prefrontal cortex. These brain regions form networks that communicate through neurotransmitter signaling, leading to neurobiological changes in individuals with behavioral addictions. While dopamine has long been associated with the reward process, recent research highlights the role of other key neurotransmitters like serotonin, glutamate, and endorphins in BADs' development. These neurotransmitters interact within the reward circuitry, creating potential targets for therapeutic intervention. This improved understanding of neurotransmitter systems provides a foundation for developing targeted treatments and helps clinicians select personalized therapeutic approaches.
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Affiliation(s)
- Zhenlei Peng
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qiyu Jia
- Department of Trauma Orthopedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Junxiong Mao
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiao Luo
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Anqi Huang
- Child Mental Health Research Center, Nanjing Brain Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hao Zheng
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang, China
| | - Shijie Jiang
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qi Ma
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Metabolic Disease, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Chuang Ma
- Department of Trauma Orthopedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qizhong Yi
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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5
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Fan Y, Luan X, Wang X, Li H, Zhao H, Li S, Li X, Qiu Z. Exploring the association between BDNF related signaling pathways and depression: A literature review. Brain Res Bull 2025; 220:111143. [PMID: 39608613 DOI: 10.1016/j.brainresbull.2024.111143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/13/2024] [Accepted: 11/21/2024] [Indexed: 11/30/2024]
Abstract
Depression is a debilitating mental disease that inflicts significant harm upon individuals and society, yet effective treatment options remain elusive. At present, the pathogenesis of multiple depression is not fully clear, but its occurrence can be related to biological or environmental pathways, among which Brain-derived neurotrophic factor (BDNF) can unequivocally act on two downstream receptors, tyrosine kinase receptor (TrkB) and the p75 neurotrophin receptor (p75NTR), then affect the related signal pathways, affecting the occurrence and development of depression. Accumulating studies have revealed that BDNF-related pathways are critical in the pathophysiology of depression, and their interaction can further influence the efficacy of depression treatment. In this review, we mainly summarized the signaling pathways associated with BDNF and classified them according to different receptors and related molecules, providing promising insights and future directions in the treatment of depression.
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Affiliation(s)
- Yuchen Fan
- Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China; Qingdao medical college, Qingdao University, Qingdao, Shandong, China.
| | - Xinchi Luan
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
| | - Xuezhe Wang
- Qingdao medical college, Qingdao University, Qingdao, Shandong, China.
| | - Hongchi Li
- Qingdao medical college, Qingdao University, Qingdao, Shandong, China.
| | - Hongjiao Zhao
- Qingdao medical college, Qingdao University, Qingdao, Shandong, China.
| | - Sheng Li
- Qingdao medical college, Qingdao University, Qingdao, Shandong, China.
| | - Xiaoxuan Li
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
| | - Zhenkang Qiu
- Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
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Pardossi S, Fagiolini A, Cuomo A. Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Int J Mol Sci 2024; 25:13098. [PMID: 39684808 DOI: 10.3390/ijms252313098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is critical for neuroplasticity, synaptic transmission, and neuronal survival. Studies have implicated it in the pathophysiology of depression, as its expression is significantly reduced in brain areas such as the prefrontal cortex and hippocampus in patients with depression. Our narrative review focuses on the relationship between BDNF, ketamine, and esketamine, specifically by summarizing human studies investigating BDNF variations in patients treated with these two drugs. BDNF plays a pivotal role in neuroplasticity and neurotrophic mechanisms that can be enhanced by traditional antidepressants, which have been shown to increase BDNF levels both peripherally and in targeted brain regions. Ketamine and its S-enantiomer, esketamine, exert both rapid and sustained antidepressant effects through activation of glutamate-related pathways, with neurotrophic effects involving BDNF, as demonstrated in experimental studies. However, clinical findings have shown mixed results, with most indicating an increase in plasma BDNF in patients treated with intravenous ketamine, although some studies contradict these findings. In addition to this, there are few studies of BDNF and esketamine. Currently, the limited number of studies suggests the need for further research, including larger sample sizes and investigations of BDNF and intranasal esketamine, which has been approved by several regulatory agencies for the treatment of treatment-resistant depression.
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Affiliation(s)
- Simone Pardossi
- Department of Molecular Medicine, University of Siena School of Medicine, 53100 Siena, Italy
| | - Andrea Fagiolini
- Department of Molecular Medicine, University of Siena School of Medicine, 53100 Siena, Italy
| | - Alessandro Cuomo
- Department of Molecular Medicine, University of Siena School of Medicine, 53100 Siena, Italy
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Dahrendorff J, Currier G, Uddin M. Leveraging DNA methylation to predict treatment response in major depressive disorder: A critical review. Am J Med Genet B Neuropsychiatr Genet 2024; 195:e32985. [PMID: 38650309 DOI: 10.1002/ajmg.b.32985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 03/18/2024] [Accepted: 04/02/2024] [Indexed: 04/25/2024]
Abstract
Major depressive disorder (MDD) is a debilitating and prevalent mental disorder with a high disease burden. Despite a wide array of different treatment options, many patients do not respond to initial treatment attempts. Selection of the most appropriate treatment remains a significant clinical challenge in psychiatry, highlighting the need for the development of biomarkers with predictive utility. Recently, the epigenetic modification DNA methylation (DNAm) has emerged to be of great interest as a potential predictor of MDD treatment outcomes. Here, we review efforts to date that seek to identify DNAm signatures associated with treatment response in individuals with MDD. Searches were conducted in the databases PubMed, Scopus, and Web of Science with the concepts and keywords MDD, DNAm, antidepressants, psychotherapy, cognitive behavior therapy, electroconvulsive therapy, transcranial magnetic stimulation, and brain stimulation therapies. We identified 32 studies implicating DNAm patterns associated with MDD treatment outcomes. The majority of studies (N = 25) are focused on selected target genes exploring treatment outcomes in pharmacological treatments (N = 22) with a few studies assessing treatment response to electroconvulsive therapy (N = 3). Additionally, there are few genome-scale efforts (N = 7) to characterize DNAm patterns associated with treatment outcomes. There is a relative dearth of studies investigating DNAm patterns in relation to psychotherapy, electroconvulsive therapy, or transcranial magnetic stimulation; importantly, most existing studies have limited sample sizes. Given the heterogeneity in both methods and results of studies to date, there is a need for additional studies before existing findings can inform clinical decisions.
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Affiliation(s)
- Jan Dahrendorff
- Genomics Program, College of Public Health, University of South Florida, Tampa, Florida, USA
| | - Glenn Currier
- Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, Florida, USA
| | - Monica Uddin
- Genomics Program, College of Public Health, University of South Florida, Tampa, Florida, USA
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8
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Nazzari S, Grumi S, Mambretti F, Villa M, Giorda R, Bordoni M, Pansarasa O, Borgatti R, Provenzi L. Sex-dimorphic pathways in the associations between maternal trait anxiety, infant BDNF methylation, and negative emotionality. Dev Psychopathol 2024; 36:908-918. [PMID: 36855816 DOI: 10.1017/s0954579423000172] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Maternal antenatal anxiety is an emerging risk factor for child emotional development. Both sex and epigenetic mechanisms, such as DNA methylation, may contribute to the embedding of maternal distress into emotional outcomes. Here, we investigated sex-dependent patterns in the association between antenatal maternal trait anxiety, methylation of the brain-derived neurotrophic factor gene (BDNF DNAm), and infant negative emotionality (NE). Mother-infant dyads (N = 276) were recruited at delivery. Maternal trait anxiety, as a marker of antenatal chronic stress exposure, was assessed soon after delivery using the Stait-Trait Anxiety Inventory (STAI-Y). Infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells whereas infants' NE was assessed at 3 (N = 225) and 6 months (N = 189) using the Infant Behavior Questionnaire-Revised (IBQ-R). Hierarchical linear analyses showed that higher maternal antenatal anxiety was associated with greater 6-month-olds' NE. Furthermore, maternal antenatal anxiety predicted greater infants' BDNF DNAm in five CpG sites in males but not in females. Higher methylation at these sites was associated with greater 3-to-6-month NE increase, independently of infants' sex. Maternal antenatal anxiety emerged as a risk factor for infant's NE. BDNF DNAm might mediate this effect in males. These results may inform the development of strategies to promote mothers and infants' emotional well-being.
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Affiliation(s)
- Sarah Nazzari
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - Serena Grumi
- Developmental Psychobiology Lab, IRCCS Mondino Foundation, Pavia, Italy
| | - Fabiana Mambretti
- Molecular Biology Lab, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
| | - Marco Villa
- Molecular Biology Lab, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
| | - Roberto Giorda
- Molecular Biology Lab, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
| | - Matteo Bordoni
- Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Orietta Pansarasa
- Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Renato Borgatti
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
- Developmental Psychobiology Lab, IRCCS Mondino Foundation, Pavia, Italy
| | - Livio Provenzi
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
- Developmental Psychobiology Lab, IRCCS Mondino Foundation, Pavia, Italy
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9
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Eachus H, Ryu S. Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload. J Exp Biol 2024; 227:jeb246128. [PMID: 38449327 PMCID: PMC10949071 DOI: 10.1242/jeb.246128] [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] [Indexed: 03/08/2024]
Abstract
Exposure to stress during early life may alter the developmental trajectory of an animal by a mechanism known as adaptive plasticity. For example, to enhance reproductive success in an adverse environment, it is known that animals accelerate their growth during development. However, these short-term fitness benefits are often associated with reduced longevity, a phenomenon known as the growth rate-lifespan trade-off. In humans, early life stress exposure compromises health later in life and increases disease susceptibility. Glucocorticoids (GCs) are major stress hormones implicated in these processes. This Review discusses the evidence for GC-mediated adaptive plasticity in development, leading to allostatic overload in later life. We focus on GC-induced effects on brain structure and function, including neurogenesis; highlight the need for longitudinal studies; and discuss approaches to identify molecular mechanisms mediating GC-induced alteration of the brain developmental trajectory leading to adult dysfunctions. Further understanding of how stress and GC exposure can alter developmental trajectories at the molecular and cellular level is of critical importance to reduce the burden of mental and physical ill health across the life course.
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Affiliation(s)
- Helen Eachus
- Living Systems Institute & Department of Clinical and Biomedical Sciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
| | - Soojin Ryu
- Living Systems Institute & Department of Clinical and Biomedical Sciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
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Wang Y, Liang J, Xu B, Yang J, Wu Z, Cheng L. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sci 2024; 336:122282. [PMID: 38008209 DOI: 10.1016/j.lfs.2023.122282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 10/19/2023] [Accepted: 11/18/2023] [Indexed: 11/28/2023]
Abstract
As one of the most prevalent neurotrophic factors in the central nervous system (CNS), brain-derived neurotrophic factor (BDNF) plays a significant role in CNS injury by binding to its specific receptor Tropomyosin-related kinase receptor B (TrkB). The BDNF/TrkB signaling pathway is crucial for neuronal survival, structural changes, and plasticity. BDNF acts as an axonal growth and extension factor, a pro-survival factor, and a synaptic modulator in the CNS. BDNF also plays an important role in the maintenance and plasticity of neuronal circuits. Several studies have demonstrated the importance of BDNF in the treatment and recovery of neurodegenerative and neurotraumatic disorders. By undertaking in-depth study on the mechanism of BDNF/TrkB function, important novel therapeutic strategies for treating neuropsychiatric disorders have been discovered. In this review, we discuss the expression patterns and mechanisms of the TrkB/BDNF signaling pathway in CNS damage and introduce several intriguing small molecule TrkB receptor agonists produced over the previous several decades.
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Affiliation(s)
- Yujin Wang
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Medical School, Tongji University, Shanghai 200433, China
| | - Jing Liang
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; School of Stomatology, Tongji University, Shanghai 200072, China
| | - Boyu Xu
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Medical School, Tongji University, Shanghai 200433, China
| | - Jin Yang
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Medical School, Tongji University, Shanghai 200433, China
| | - Zhourui Wu
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China.
| | - Liming Cheng
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China.
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Mule S, Pawar V, Tekade M, Vasdev N, Gupta T, Singh A, Sarker SD, Tekade RK. Psychopharmacology in late life: Key challenges and opportunities. PUBLIC HEALTH AND TOXICOLOGY ISSUES DRUG RESEARCH, VOLUME 2 2024:755-785. [DOI: 10.1016/b978-0-443-15842-1.00026-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Chen N, Zhao M, Guo Y, Wu N, Cao B, Zhan B, Zhou T, Li Y, Zhu F, Chen W, Li Y, Zhang L. D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels. Transl Psychiatry 2023; 13:338. [PMID: 37914710 PMCID: PMC10620401 DOI: 10.1038/s41398-023-02636-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 11/03/2023] Open
Abstract
The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.
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Affiliation(s)
- Nuo Chen
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ming Zhao
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yaxin Guo
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Nan Wu
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Baihui Cao
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bing Zhan
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tian Zhou
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yubin Li
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Faliang Zhu
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - WanJun Chen
- Mucosal Immunology Section, NIDCR, US National Institutes of Health, Bethesda, MD, USA.
| | - Yan Li
- Department of Pathogen Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Lining Zhang
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
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13
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Lacroix A, Ramoz N, Girard M, Plansont B, Poupon D, Gorwood P, Nubukpo P. BDNF CpG methylation and serum levels covary during alcohol withdrawal in patients with alcohol use disorder: A pilot study. World J Biol Psychiatry 2023; 24:854-859. [PMID: 37526632 DOI: 10.1080/15622975.2023.2242924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/04/2023] [Accepted: 07/27/2023] [Indexed: 08/02/2023]
Abstract
OBJECTIVES Brain-derived neurotrophic factor (BDNF) levels vary in various conditions including alcohol use disorder (AUD). We aimed to identify drivers of these variations. METHODS Twelve patients with AUD were assessed at hospitalisation for alcohol withdrawal and four months later. We looked for associations between the change in serum BDNF levels and (1) length of abstinence, (2) anxiety (Hamilton Anxiety Scale) and depression (Beck-Depression Inventory), (3) one functional BDNF genotype (rs6265) and (4) methylation levels of 12 CpG sites within the BDNF gene (located in exons I, IV and IX). RESULTS While abstinence remained, serum BDNF level increased. This increase correlated with the variation of methylation levels of the BDNF gene, and more specifically of exon I. We found no significant effect of length of abstinence, rs6265, depression or anxiety on serum BDNF level. CONCLUSIONS Epigenetic regulation of the BDNF gene may be involved in variations of BDNF blood level associated with alcohol abstinence.
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Affiliation(s)
- Aurélie Lacroix
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
| | - Nicolas Ramoz
- Université Paris Cité, INSERM, U1266 (Institute of Psychiatry and Neuroscience of Paris), Paris, France
| | - Murielle Girard
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
| | - Brigitte Plansont
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
| | - Daphnée Poupon
- Clinique des Maladies Mentales et de l'Encéphale (CMME), Sainte-Anne Hospital, GHU Paris Psychiatrie et Neurosciences, Paris, France
| | - Philip Gorwood
- Université Paris Cité, INSERM, U1266 (Institute of Psychiatry and Neuroscience of Paris), Paris, France
- Clinique des Maladies Mentales et de l'Encéphale (CMME), Sainte-Anne Hospital, GHU Paris Psychiatrie et Neurosciences, Paris, France
| | - Philippe Nubukpo
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
- Pôle Universitaire d'Addictologie, Centre Hospitalier Esquirol, Limoges, France
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14
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Jeong S, Chokkalla AK, Davis CK, Vemuganti R. Post-stroke depression: epigenetic and epitranscriptomic modifications and their interplay with gut microbiota. Mol Psychiatry 2023; 28:4044-4055. [PMID: 37188778 PMCID: PMC10646155 DOI: 10.1038/s41380-023-02099-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 04/21/2023] [Accepted: 05/02/2023] [Indexed: 05/17/2023]
Abstract
Epigenetic and epitranscriptomic modifications that regulate physiological processes of an organism at the DNA and RNA levels, respectively, are novel therapeutic candidates for various neurological diseases. Gut microbiota and its metabolites are known to modulate DNA methylation and histone modifications (epigenetics), as well as RNA methylation especially N6-methyladenosine (epitranscriptomics). As gut microbiota as well as these modifications are highly dynamic across the lifespan of an organism, they are implicated in the pathogenesis of stroke and depression. The lack of specific therapeutic interventions for managing post-stroke depression emphasizes the need to identify novel molecular targets. This review highlights the interaction between the gut microbiota and epigenetic/epitranscriptomic pathways and their interplay in modulating candidate genes that are involved in post-stroke depression. This review further focuses on the three candidates, including brain-derived neurotrophic factor, ten-eleven translocation family proteins, and fat mass and obesity-associated protein based on their prevalence and pathoetiologic role in post-stroke depression.
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Affiliation(s)
- Soomin Jeong
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
- Neuroscience Training Program, University of Wisconsin, Madison, WI, USA
| | - Anil K Chokkalla
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Charles K Davis
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.
- Neuroscience Training Program, University of Wisconsin, Madison, WI, USA.
- William S. Middleton Veterans Hospital, Madison, WI, USA.
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15
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Flores-Gómez GD, Apam-Castillejos DJ, Juárez-Díaz I, Fuentes-Medel E, Díaz A, Tendilla-Beltrán H, Flores G. Aripiprazole attenuates the medial prefrontal cortex morphological and biochemical alterations in rats with neonatal ventral hippocampus lesion. J Chem Neuroanat 2023; 132:102316. [PMID: 37481172 DOI: 10.1016/j.jchemneu.2023.102316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/24/2023]
Abstract
Schizophrenia is a neurodevelopmental disorder characterized by a loss of dendritic spines in the medial prefrontal cortex (mPFC). Multiple subclinical and clinical studies have evidenced the ability of antipsychotics to improve neuroplasticity. In this study, it was evaluated the effect of the atypical antipsychotic aripiprazole (ARI) on the behavioral and mPFC neuronal disturbances of rats with neonatal ventral hippocampus lesion (nVHL), which is a heuristic developmental model relevant to the study of schizophrenia. ARI attenuated open field hyperlocomotion in the rats with nVHL. Also, ARI ameliorated structural neuroplasticity disturbances of the mPFC layer 3 pyramidal cells, but not in the layer 5 neurons. These effects can be associated with the ARI capability of increasing brain-derived neurotrophic factor (BDNF) levels. Moreover, in the animals with nVHL, ARI attenuated the immunoreactivity for some oxidative stress-related molecules such as the nitric oxide synthase 2 (NOS-2), 3-nitrotyrosine (3-NT), and cyclooxygenase 2 (COX-2), as well as the reactive astrogliosis in the mPFC. These results contribute to current knowledge about the neurotrophic, anti-inflammatory, and antioxidant properties of antipsychotics which may be contributing to their clinical effects and envision promising therapeutic targets for the treatment of schizophrenia.
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Affiliation(s)
| | | | - Ismael Juárez-Díaz
- Facultad de Estomatología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Estefania Fuentes-Medel
- Facultad de Ciencias Químicas (FCQ), Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Alfonso Díaz
- Facultad de Ciencias Químicas (FCQ), Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Hiram Tendilla-Beltrán
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Gonzalo Flores
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico.
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16
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Miao B, Xing X, Bazylianska V, Madden P, Moszczynska A, Zhang B. Methamphetamine-induced region-specific transcriptomic and epigenetic changes in the brain of male rats. Commun Biol 2023; 6:991. [PMID: 37758941 PMCID: PMC10533900 DOI: 10.1038/s42003-023-05355-3] [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: 07/13/2022] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Psychostimulant methamphetamine (METH) is neurotoxic to the brain and, therefore, its misuse leads to neurological and psychiatric disorders. The gene regulatory network (GRN) response to neurotoxic METH binge remains unclear in most brain regions. Here we examined the effects of binge METH on the GRN in the nucleus accumbens, dentate gyrus, Ammon's horn, and subventricular zone in male rats. At 24 h after METH, ~16% of genes displayed altered expression and over a quarter of previously open chromatin regions - parts of the genome where genes are typically active - showed shifts in their accessibility. Intriguingly, most changes were unique to each area studied, and independent regulation between transcriptome and chromatin accessibility was observed. Unexpectedly, METH differentially impacted gene activity and chromatin accessibility within the dentate gyrus and Ammon's horn. Around 70% of the affected chromatin-accessible regions in the rat brain have conserved DNA sequences in the human genome. These regions frequently act as enhancers, ramping up the activity of nearby genes, and contain mutations linked to various neurological conditions. By sketching out the gene regulatory networks associated with binge METH in specific brain regions, our study offers fresh insights into how METH can trigger profound, region-specific molecular shifts.
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Affiliation(s)
- Benpeng Miao
- Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Department of Genetics, Center for Genomic Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Xiaoyun Xing
- Department of Genetics, Center for Genomic Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Viktoriia Bazylianska
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Pamela Madden
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Anna Moszczynska
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48201, USA.
| | - Bo Zhang
- Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
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17
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Shkundin A, Halaris A. Associations of BDNF/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder. J Pers Med 2023; 13:1395. [PMID: 37763162 PMCID: PMC10533016 DOI: 10.3390/jpm13091395] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Brain-Derived Neurotrophic Factor (BDNF) is crucial for various aspects of neuronal development and function, including synaptic plasticity, neurotransmitter release, and supporting neuronal differentiation, growth, and survival. It is involved in the formation and preservation of dopaminergic, serotonergic, GABAergic, and cholinergic neurons, facilitating efficient stimulus transmission within the synaptic system and contributing to learning, memory, and overall cognition. Furthermore, BDNF demonstrates involvement in neuroinflammation and showcases neuroprotective effects. In contrast, BDNF antisense RNA (BDNF-AS) is linked to the regulation and control of BDNF, facilitating its suppression and contributing to neurotoxicity, apoptosis, and decreased cell viability. This review article aims to comprehensively overview the significance of single nucleotide polymorphisms (SNPs) in BDNF/BDNF-AS genes within psychiatric conditions, with a specific focus on their associations with depression, schizophrenia, and bipolar disorder. The independent influence of each BDNF/BDNF-AS gene variation, as well as the interplay between SNPs and their linkage disequilibrium, environmental factors, including early-life experiences, and interactions with other genes, lead to alterations in brain architecture and function, shaping vulnerability to mental health disorders. The potential translational applications of BDNF/BDNF-AS polymorphism knowledge can revolutionize personalized medicine, predict disease susceptibility, treatment outcomes, and guide the selection of interventions tailored to individual patients.
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Affiliation(s)
| | - Angelos Halaris
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
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18
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Costa GA, de Gusmão Taveiros Silva NK, Marianno P, Chivers P, Bailey A, Camarini R. Environmental Enrichment Increased Bdnf Transcripts in the Prefrontal Cortex: Implications for an Epigenetically Controlled Mechanism. Neuroscience 2023; 526:277-289. [PMID: 37419403 DOI: 10.1016/j.neuroscience.2023.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 06/26/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023]
Abstract
Environmental enrichment (EE) is a condition characterized by its complexity regarding social contact, exposure to novelty, tactile stimuli and voluntary exercise, also is considered as a eustress model. The impact of EE on brain physiology and behavioral outcomes may be at least partly underpinned by mechanisms involving the modulation of the brain-derived neurotrophic factor (BDNF), but the connection between specific Bdnf exon expression and their epigenetic regulation remain poorly understood. This study aimed to dissect the transcriptional and epigenetic regulatory effect of 54-day exposure to EE on BDNF by analysing individual BDNF exons mRNA expression and the DNA methylation profile of a key transcriptional regulator of the Bdnf gene, exon IV, in the prefrontal cortex (PFC) of C57BL/6 male mice (sample size = 33). Bdnf exons II, IV, VI and IX mRNA expression were upregulated and methylation levels at two CpG sites of exon IV were reduced in the PFC of EE mice. As deficit in exon IV expression has also been causally implicated in stress-related psychopathologies, we also assessed anxiety-like behavior and plasma corticosterone levels in these mice to determine any potential correlation. However, no changes were observed in EE mice. The findings may suggest an EE-induced epigenetic control of BDNF exon expression via a mechanism involving exon IV methylation. The findings of this study contribute to the current literature by dissecting the Bdnf gene topology in the PFC where transcriptional and epigenetic regulatory effect of EE takes place.
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Affiliation(s)
- Gabriel Araújo Costa
- Pharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Priscila Marianno
- Pharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Priti Chivers
- School of Biosciences & Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK
| | - Alexis Bailey
- Pharmacology Section, Institute of Medical and Biomedical Education, St George's University of London, London, UK.
| | - Rosana Camarini
- Pharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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19
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Grezenko H, Ekhator C, Nwabugwu NU, Ganga H, Affaf M, Abdelaziz AM, Rehman A, Shehryar A, Abbasi FA, Bellegarde SB, Khaliq AS. Epigenetics in Neurological and Psychiatric Disorders: A Comprehensive Review of Current Understanding and Future Perspectives. Cureus 2023; 15:e43960. [PMID: 37622055 PMCID: PMC10446850 DOI: 10.7759/cureus.43960] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 08/26/2023] Open
Abstract
The burgeoning field of epigenetics offers transformative insights into the complex landscape of neurological and psychiatric disorders. By unraveling the intricate interplay between genetic, epigenetic, environmental, and lifestyle factors, this comprehensive review highlights the multifaceted nature of mental health. The exploration reveals the potential of epigenetic modifications to revolutionize our understanding, diagnosis, treatment, and prevention of these disorders. Emphasizing the importance of multidisciplinary collaborations, large-scale studies, technological advancements, and ethical considerations, the review asserts the promise of epigenetics as a vital tool for personalized medicine, early intervention, and public health strategies. While acknowledging the challenges in a still-emerging field, the review paints an optimistic picture of epigenetics as a groundbreaking approach that can reshape mental healthcare, offering hope for those affected by neurological and psychiatric conditions. The future trajectory of the field relies on interdisciplinary efforts, ethical diligence, innovative technologies, and translating scientific insights into real-world applications, thereby unlocking the vast potential of epigenetics in mental health.
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Affiliation(s)
- Han Grezenko
- Translational Neuroscience, Barrow Neurological Institute, Phoenix, USA
| | - Chukwuyem Ekhator
- Neuro-Oncology, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, USA
| | - Nkechi U Nwabugwu
- Public Health, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | | | - Maryam Affaf
- Internal Medicine, Women Medical College, Abbottabad, PAK
| | - Ali M Abdelaziz
- Internal Medicine, Alexandria University Faculty of Medicine, Alexandria, EGY
| | | | | | - Fatima A Abbasi
- Cardiology, Shifa International Hospital Islamabad, Islamabad, PAK
| | - Sophia B Bellegarde
- Pathology and Laboratory Medicine, American University of Antigua, St. John's, ATG
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20
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Lau S, Stern S. Editorial: Advances in neural reprogramming, disease modeling and therapeutic insights. Front Aging Neurosci 2023; 15:1259765. [PMID: 37577353 PMCID: PMC10420048 DOI: 10.3389/fnagi.2023.1259765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 07/20/2023] [Indexed: 08/15/2023] Open
Affiliation(s)
- Shong Lau
- Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, United States
| | - Shani Stern
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
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21
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Athaide Rocha KM, Machado FR, Poetini M, Giacomeli R, Boeira SP, Jesse CR, Gomes de Gomes M. Assessment of suberoylanilide hydroxamic acid on a Alzheimer's disease model induced by β-amyloid (1-42) in aged female mice: Neuromodulatory and epigenetic effect. Chem Biol Interact 2023; 375:110429. [PMID: 36870467 DOI: 10.1016/j.cbi.2023.110429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that affects several elderly people per years. AD is a pathology of multifactorial etiology, resulting from multiple environmental and genetic determinants. However, there is no effective pharmacological alternative for the treatment of this illness. In this sense, the purpose of current study was to characterize the mechanisms by which Aβ1-42 injection via intracerebroventricular induces neurobehavioral changes in a time-course curve. In addition, suberoylanilide hydroxamic acid (SAHA) inhibitor of histone deacetylase (HDAC) was used to investigate the involvement of epigenetic modifications Aβ1-42-caused in aged female mice. In general manner, Aβ1-42 injection induced a major neurochemical disturbance in hippocampus and prefrontal cortex of animals and a serious impairment of memory. Overall, SAHA treatment attenuated neurobehavioral changes caused by Aβ1-42 injection in aged female mice. The subchronic effects presented of SAHA were through modulation of HDAC activity, regulation of brain-derived neurotrophic factor (BDNF) levels and expression of BDNF mRNA, accompanied by unlocking cAMP/PKA/pCREB pathway in hippocampus and prefrontal cortex of animals.
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Affiliation(s)
- Kellen Mariane Athaide Rocha
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil
| | - Franciele Romero Machado
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil
| | - Márcia Poetini
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil
| | - Renata Giacomeli
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil
| | - Silvana Peterini Boeira
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil
| | - Cristiano Ricardo Jesse
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil
| | - Marcelo Gomes de Gomes
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, CEP 97650-000, RS, Brazil.
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22
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Rovný R, Marko M, Michalko D, Mitka M, Cimrová B, Vančová Z, Jarčušková D, Dragašek J, Minárik G, Riečanský I. BDNF Val66Met polymorphism is associated with consolidation of episodic memory during sleep. Biol Psychol 2023; 179:108568. [PMID: 37075935 DOI: 10.1016/j.biopsycho.2023.108568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 04/12/2023] [Accepted: 04/16/2023] [Indexed: 04/21/2023]
Abstract
The brain-derived neurotrophic factor (BDNF) is an essential regulator of synaptic plasticity, a candidate neurobiological mechanism underlying learning and memory. A functional polymorphism in the BDNF gene, Val66Met (rs6265), has been linked to memory and cognition in healthy individuals and clinical populations. Sleep contributes to memory consolidation, yet information about the possible role of BDNF in this process is scarce. To address this question, we investigated the relationship between the BDNF Val66Met genotype and consolidation of episodic declarative and procedural (motor) non-declarative memories in healthy adults. The carriers of Met66 allele, as compared with Val66 homozygotes, showed stronger forgetting overnight (24hours after encoding), but not over shorter time (immediately or 20minutes after word list presentation). There was no effect of Val66Met genotype on motor learning. These data suggest that BDNF plays a role in neuroplasticity underlying episodic memory consolidation during sleep.
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Affiliation(s)
- Rastislav Rovný
- Department of Behavioural Neuroscience, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Martin Marko
- Department of Behavioural Neuroscience, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Drahomír Michalko
- Department of Behavioural Neuroscience, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Milan Mitka
- Department of Behavioural Neuroscience, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Barbora Cimrová
- Department of Behavioural Neuroscience, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Zuzana Vančová
- 1st Department of Psychiatry, Faculty of Medicine, Pavol Jozef Šafárik University and University Hospital, Košice, Slovakia
| | - Dominika Jarčušková
- 1st Department of Psychiatry, Faculty of Medicine, Pavol Jozef Šafárik University and University Hospital, Košice, Slovakia
| | - Jozef Dragašek
- 1st Department of Psychiatry, Faculty of Medicine, Pavol Jozef Šafárik University and University Hospital, Košice, Slovakia
| | | | - Igor Riečanský
- Department of Behavioural Neuroscience, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia; Department of Psychiatry, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia.
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23
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Pisani A, Paciello F, Del Vecchio V, Malesci R, De Corso E, Cantone E, Fetoni AR. The Role of BDNF as a Biomarker in Cognitive and Sensory Neurodegeneration. J Pers Med 2023; 13:jpm13040652. [PMID: 37109038 PMCID: PMC10140880 DOI: 10.3390/jpm13040652] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) has a crucial function in the central nervous system and in sensory structures including olfactory and auditory systems. Many studies have highlighted the protective effects of BDNF in the brain, showing how it can promote neuronal growth and survival and modulate synaptic plasticity. On the other hand, conflicting data about BDNF expression and functions in the cochlear and in olfactory structures have been reported. Several clinical and experimental research studies showed alterations in BDNF levels in neurodegenerative diseases affecting the central and peripheral nervous system, suggesting that BDNF can be a promising biomarker in most neurodegenerative conditions, including Alzheimer's disease, shearing loss, or olfactory impairment. Here, we summarize current research concerning BDNF functions in brain and in sensory domains (olfaction and hearing), focusing on the effects of the BDNF/TrkB signalling pathway activation in both physiological and pathological conditions. Finally, we review significant studies highlighting the possibility to target BDNF as a biomarker in early diagnosis of sensory and cognitive neurodegeneration, opening new opportunities to develop effective therapeutic strategies aimed to counteract neurodegeneration.
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Affiliation(s)
- Anna Pisani
- Department of Otolaryngology Head and Neck Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Fabiola Paciello
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Valeria Del Vecchio
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
| | - Rita Malesci
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
| | - Eugenio De Corso
- Department of Otolaryngology Head and Neck Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Elena Cantone
- Department of Neuroscience, Reproductive Sciences and Dentistry-ENT Section, University of Naples Federico II, 80131 Naples, Italy
| | - Anna Rita Fetoni
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
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Quaioto BR, Borçoi AR, Mendes SO, Doblas PC, Dos Santos Vieira T, Arantes Moreno IA, Dos Santos JG, Hollais AW, Olinda AS, de Souza MLM, Freitas FV, Pinheiro JA, Cunha ER, Sorroche BP, Arantes LMRB, Álvares-da-Silva AM. Tobacco use modify exon IV BDNF gene methylation levels in depression. J Psychiatr Res 2023; 159:240-248. [PMID: 36753898 DOI: 10.1016/j.jpsychires.2023.01.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023]
Abstract
This study aimed to investigate BDNF gene methylation in individuals with depression based on tobacco use. Therefore, 384 adults from southeastern Brazil were recruited to assess depression, socioeconomic status, lifestyle, and methylation by pyrosequencing exon IV promoter region of the BDNF gene. The Generalized Linear Model (GzLM) was used to check the effect of depression, tobacco, and the interaction between depression and tobacco use in methylation levels. In addition, the Kruskal-Wallis test, followed by Dunn's post hoc test, was used to compare methylation levels. Interaction between depression and tobacco use was significant at levels of BDNF methylation in the CpG 5 (p = 0.045), 8 (p = 0.016), 9 (p = 0.042), 10 (p = 0.026) and mean 5-11 (p < 0.001). Dunn's post hoc test showed that individuals with depression and tobacco use compared to those with or without depression who did not use tobacco had lower levels of BDNF methylation in CpG 5, 6, 7, 8, 9, 11, and mean 5-11. Therefore, we suggest that tobacco use appears to interfere with BDNF gene methylation in depressed individuals.
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Affiliation(s)
- Bárbara Risse Quaioto
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil.
| | - Aline Ribeiro Borçoi
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Suzanny Oliveira Mendes
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Paola Cerbino Doblas
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Tamires Dos Santos Vieira
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Ivana Alece Arantes Moreno
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Joaquim Gasparini Dos Santos
- ICESP, Center for Translational Research in Oncology, Instituto Do Câncer Do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Multiprofessional Residency Program in Adult Oncology Care, Comissão de Residência Multiprofissional/Hospital Das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - André Willian Hollais
- Department of Physiological Sciences, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Amanda Sgrancio Olinda
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | | | - Flávia Vitorino Freitas
- Department of Pharmacy and Nutrition, Universidade Federal Do Espírito Santo, Alegre, Espírito Santo, Brazil
| | - Júlia Assis Pinheiro
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Ester Ribeiro Cunha
- Department of Morphology, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Bruna Pereira Sorroche
- Molecular Oncology Research Center, Hospital Do Câncer de Barretos, Barretos, São Paulo, Brazil
| | | | - Adriana Madeira Álvares-da-Silva
- Biotechnology Postgraduate Program/RENORBIO, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil; Department of Morphology, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil
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25
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Zhao T, Piao LH, Li DP, Xu SH, Wang SY, Yuan HB, Zhang CX. BDNF gene hydroxymethylation in hippocampus related to neuroinflammation-induced depression-like behaviors in mice. J Affect Disord 2023; 323:723-730. [PMID: 36529411 DOI: 10.1016/j.jad.2022.12.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 10/31/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Neuroinflammation is a multifactorial condition related to glial cells and neurons activation, and it is implicated in CNS disorders including depression. BDNF is a crucial molecule that related to the pathology of depression, and it is the target of DNA methylation. DNA hydroxymethylation, an active demethylation process can convert 5-mC to 5-hmC by Tets catalyzation to regulate gene transcription. The regulatory function for BDNF gene in response to neuroinflammation remains poorly understood. METHODS Neuroinflammation and depressive-like behaviors were induced by lipopolysaccharide (LPS) administration in mice. The microglial activation and cellular 5-hmC localization in the hippocampus were confirmed by immunostaining. The transcripts of Tets and BDNF were examined by qPCR method. The global 5-hmC levels and enrichment of 5-hmC in BDNF gene in the hippocampus were analyzed using dot bolt and hMeDIP-sequencing analysis. RESULTS LPS administration induced a spectrum of depression-like behaviors (including behavioral despair and anhedonia) and increased expression of Iba-1, a marker for microglia activation, in hippocampus, demonstrating that LPS treatment cloud provide stable model of neuroinflammation with depressive-like behaviors as expected. Our results showed that Tet1, Tet2 and Tet3 mRNA expressions and consequent global 5-hmC levels were significantly decreased in the hippocampus of LPS group compared to saline group. We also demonstrated that 5-hmC fluorescence in the hippocampus located in excitatory neurons identified by CaMK II immunostaining. Furthermore, we demonstrated that the enrichment of 5-hmC in BDNF gene was decreased and corresponding BDNF mRNA was down-regulated in the hippocampus in LPS group compared to saline group. CONCLUSION Neuroinflammation-triggered aberrant BDNF gene hydroxymethylation in the hippocampus is an important epigenetic element that relates with depression-like behaviors.
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Affiliation(s)
- Te Zhao
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Lian-Hua Piao
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Dan-Ping Li
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Shi-Han Xu
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Shu-Yi Wang
- The Second Bethune Clinical Medical College of Jilin University, Changchun, Jilin 130021, China
| | - Hai-Bo Yuan
- Department of Respiratory Medicine & Sleep Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Chun-Xiao Zhang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
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Cammisuli DM, Castelnuovo G. Neuroscience-based psychotherapy: A position paper. Front Psychol 2023; 14:1101044. [PMID: 36860785 PMCID: PMC9968886 DOI: 10.3389/fpsyg.2023.1101044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/11/2023] [Indexed: 02/15/2023] Open
Abstract
In the recent years, discoveries in neuroscience have greatly impacted upon the need to modify therapeutic practice starting from the evidence showing some cerebral mechanisms capable of coping with mental health crisis and traumatic events of the individual's life history by redesigning the narrative plot and the person's sense of the Self. The emerging dialogue between neuroscience and psychotherapy is increasingly intense and modern psychotherapy cannot ignore the heritage deriving from studies about neuropsychological modification of memory traces, neurobiology of attachment theory, cognitive mechanisms involved in psychopathology, neurophysiology of human empathy, neuroimaging evidence about psychotherapeutic treatment, and somatoform disorders connecting the brain and the body. In the present article, we critically examined sectorial literature and claimed that psychotherapy has to referred to a neuroscience-based approach in order to adopt the most tailored interventions for specific groups of patients or therapy settings. We also provided recommendations for care implementation in clinical practice and illustrated challenges of future research.
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Affiliation(s)
| | - Gianluca Castelnuovo
- Department of Psychology, Catholic University, Milan, Italy,Psychology Research Laboratory, Istituto Auxologico Italiano IRCCS, Milan, Italy,*Correspondence: Gianluca Castelnuovo ✉
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Scotti-Muzzi E, Chile T, Vallada H, Otaduy MCG, Soeiro-de-Souza MG. BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects. Brain Imaging Behav 2023; 17:282-293. [PMID: 36630045 DOI: 10.1007/s11682-023-00757-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/12/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.
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Affiliation(s)
- Estêvão Scotti-Muzzi
- Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil.
| | - Thais Chile
- Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil
| | - Homero Vallada
- Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil
| | - Maria Concepción Garcia Otaduy
- Laboratory of Magnetic Resonance in Neuroradiology LIM44, Department and Institute of Radiology, School of Medicine, University of São Paulo (FMUSP), São Paulo, Brazil
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Pathak H, Borchert A, Garaali S, Burkert A, Frieling H. BDNF exon IV promoter methylation and antidepressant action: a complex interplay. Clin Epigenetics 2022; 14:187. [PMID: 36572893 PMCID: PMC9793565 DOI: 10.1186/s13148-022-01415-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 12/19/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND BDNF exon IV promoter methylation is a potential biomarker for treatment response to antidepressants in MDD. We have previously shown CpG-87 methylation as a successful biomarker for the prediction of non-response to monoaminergic antidepressants like the SSRI Fluoxetine or the SNRI Venlafaxine. This study aimed to dissect the biological evidence and mechanisms for the functionality of CpG-87 methylation in a cell culture model. RESULTS We observed a significant interaction between methylation and antidepressant-mediated transcriptional activity in BDNF exon IV promoter. In addition, antidepressant treatment increased the promoter methylation in a concentration-dependent manner. Further single CpG methylation of -87 did not change the promoter activity, but methylation of CREB domain CpG-39 increased the transcriptional activity in an antidepressant-dependent manner. Interestingly, DNMT3a overexpression also increases the BDNF exon IV transcription and more so in Venlafaxine-treated cells. CONCLUSIONS The study strengthens the previously reported association between antidepressant treatment and BDNF exon IV promoter methylation as well as hints toward the mechanism of action. We argue that potential CpG methylation biomarkers display a complex synergy with the molecular changes at the neighboring CpG positions, thus highlighting the importance of epiallele analyses.
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Affiliation(s)
- Hansi Pathak
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neuroscience, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Anton Borchert
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neuroscience, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Sara Garaali
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neuroscience, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Alexandra Burkert
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neuroscience, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Helge Frieling
- grid.10423.340000 0000 9529 9877Laboratory for Molecular Neuroscience, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School (MHH), 30625 Hannover, Germany
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29
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Wang Y, Meng W, Liu Z, An Q, Hu X. Cognitive impairment in psychiatric diseases: Biomarkers of diagnosis, treatment, and prevention. Front Cell Neurosci 2022; 16:1046692. [DOI: 10.3389/fncel.2022.1046692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
Psychiatric diseases, such as schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder, place a huge health burden on society. Cognitive impairment is one of the core characteristics of psychiatric disorders and a vital determinant of social function and disease recurrence in patients. This review thus aims to explore the underlying molecular mechanisms of cognitive impairment in major psychiatric disorders and identify valuable biomarkers for diagnosis, treatment and prevention of patients.
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30
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Schurgers G, Walter S, Pishva E, Guloksuz S, Peerbooms O, Incio LR, Arts BMG, Kenis G, Rutten BPF. Longitudinal alterations in mRNA expression of the BDNF neurotrophin signaling cascade in blood correlate with changes in depression scores in patients undergoing electroconvulsive therapy. Eur Neuropsychopharmacol 2022; 63:60-70. [PMID: 36067540 DOI: 10.1016/j.euroneuro.2022.07.183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 12/26/2022]
Abstract
Electroconvulsive therapy (ECT) appears to be the most effective treatment for severe depression. However, its mechanisms of action are incompletely understood. Evidence suggests ECT enhances neuroplasticity and neurogenesis. While studies on ECT-induced neuroplasticity focused on brain-derived neurotrophic factor (BDNF), other factors of the BDNF/TrkB signaling cascade remain underinvestigated. We assessed longitudinal changes in depression scores, serum BDNF protein levels, and mRNA expression of BDNF/TrkB related genes (BDNF, AKT1, ERK1, CREB), NR3C1 and IGF1 in peripheral blood in 19 treatment-resistant depressed patients undergoing ECT. We also analysed DNA methylation patterns at various timepoints to explore possible epigenetic regulation of mRNA expression. Using multilevel regression, we found a negative association between depression scores and blood-based mRNA expression of BDNF/TrkB related genes and NR3C1. Expression of BDNF, ERK1 and NR3C1 increased significantly over time (BDNF: β = 0.0295, p = 0.003; ERK1: β = 0.0170, p = 0.034; NR3C1: β = 0.0035, p = 0.050). For these three genes changes in mRNA expression were highly correlated (R = 0.59 - 0.88) with changes in DNA methylation for multiple CpG sites in the respective genes. Also, serum BDNF protein levels increased across the study period (β = 0.11, p = 0.001). Our findings show that the antidepressant effects of ECT are associated with changes in expression of BDNF and its signaling molecules and that these molecular markers can be detected in peripheral blood. Alterations in DNA methylation could be a key mechanism whereby ECT influences gene expression.
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Affiliation(s)
- Geert Schurgers
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands.
| | - Sharon Walter
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Ehsan Pishva
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands; University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Sinan Guloksuz
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands; Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Odette Peerbooms
- Mutsaersstichting, Pediatric Mental Health Care, Venlo, the Netherlands
| | - Laura Rodriguez Incio
- Psychiatry Outpatient Clinic, Tarragona, Spain; University Hospital Institut Pere Mata, Reus, Spain; University of Rovira i Virgili, Tarragona, Spain
| | - Baer M G Arts
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Gunter Kenis
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands.
| | - Bart P F Rutten
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, the Netherlands
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31
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Guo Y, Li S, Zhang L, Xuan Q, He L, Ye Q, Ma J, Peng L, Xiong Y, Yang J, Yu H, Xie J, Shao H, Yuan Y. Depression and anxiety of medical students at Kunming Medical University during COVID-19: A cross-sectional survey. Front Public Health 2022; 10:957597. [PMID: 36159294 PMCID: PMC9490216 DOI: 10.3389/fpubh.2022.957597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/15/2022] [Indexed: 01/24/2023] Open
Abstract
An isolation strategy was used to control the transmission and rapid spread of COVID-19 in Yunnan. As a result, students were supposed to stay at home and disrupted their outside activities. It led to a detrimental influence on students' mental health. The purpose of this study was to investigate the prevalence and risk factors of depression and anxiety among medical students and to provide ideas for the prevention of depression and anxiety in medical students. A cross-sectional survey was conducted among 2,116 medical students at Kunming Medical University from July 8 to July 16, 2020. Participants' demographic and living conditions were collected. Depression and anxiety were measured using the Patient Health Questionnaire 9 and General Anxiety Disorder-7, respectively. Uni- and multivariate logistic regression analyses were performed to detect risk factors associated with depression and anxiety. The prevalence rates of depression and anxiety among medical students were 52.5 and 29.6%, respectively. Depression was more likely to be caused by low grades, lack of physical exercise, drug use, irregular diet, extensive screen time on mobile phones, being greatly affected by the COVID-19 pandemic, and inadaptability to offline courses. Anxiety was more likely to be caused by lack of physical exercise, drug use, irregular diet, and inadaptability to offline courses. Depression and anxiety are highly comorbid. Our study showed predictive factors for depression and anxiety and identified a major mental health burden on medical students during the COVID-19 outbreak. More targeted measures should be taken to improve the mental state of students to reduce the incidence of depression and anxiety.
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Affiliation(s)
- Ying Guo
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China,*Correspondence: Ying Guo
| | - Shunda Li
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Lanchun Zhang
- School of Pharmaceutical Science, Department of Zoology and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China
| | - Qun Xuan
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Liu He
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Qingyan Ye
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Jiaqing Ma
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Li Peng
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Yunxia Xiong
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Jianyu Yang
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China
| | - Haofei Yu
- School of Pharmaceutical Science, Department of Zoology and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China
| | - Jianping Xie
- Library, Yunnan Minzu University, Kunming, China,Jianping Xie
| | - Heng Shao
- Department of Geriatrics, First People's Hospital of Yunnan Province and Affiliated Hospital of Kunming University of Science and Technology, Kunming, China,Heng Shao
| | - Yun Yuan
- Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China,Yun Yuan
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Vasilopoulou F, Bellver-Sanchis A, Companys-Alemany J, Jarne-Ferrer J, Irisarri A, Palomera-Ávalos V, Gonzalez-Castillo C, Ortuño-Sahagún D, Sanfeliu C, Pallàs M, Griñán-Ferré C. Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice. Cells 2022; 11:cells11162603. [PMID: 36010679 PMCID: PMC9406492 DOI: 10.3390/cells11162603] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/14/2022] [Accepted: 08/19/2022] [Indexed: 11/21/2022] Open
Abstract
Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer’s Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model.
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Affiliation(s)
- Foteini Vasilopoulou
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Aina Bellver-Sanchis
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Júlia Companys-Alemany
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Júlia Jarne-Ferrer
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Alba Irisarri
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Verónica Palomera-Ávalos
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | | | - Daniel Ortuño-Sahagún
- Laboratorio de Neuroinmunología Molecular, Instituto de Investigación de Ciencias Biomédicas (IICB) CUCS, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Coral Sanfeliu
- Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
- Correspondence:
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33
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Lee B, Shin E, Song I, Chang B. Depression in Adolescence and Brain-Derived Neurotrophic Factor. Front Mol Neurosci 2022; 15:947192. [PMID: 35875661 PMCID: PMC9302599 DOI: 10.3389/fnmol.2022.947192] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/20/2022] [Indexed: 12/27/2022] Open
Abstract
The incidence of depression among adolescents has been rapidly increasing in recent years. Environmental and genetic factors have been identified as important risk factors for adolescent depression. However, the mechanisms underlying the development of adolescent depression that are triggered by these risk factors are not well understood. Clinical and preclinical studies have focused more on adult depression, and differences in depressive symptoms between adolescents and adults make it difficult to adequately diagnose and treat adolescent depression. Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the pathophysiology of many psychiatric disorders, including depression. However, there are still few studies on adolescent depression. Therefore, in this review paper, the causes and treatment of adolescent depression and the function of BDNF are investigated.
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Suzuki T, Tanaka KF. Downregulation of Bdnf Expression in Adult Mice Causes Body Weight Gain. Neurochem Res 2022; 47:2645-2655. [PMID: 34982395 DOI: 10.1007/s11064-021-03523-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 10/19/2022]
Abstract
Gain or loss of appetite and resulting body weight changes are commonly observed in major depressive disorders (MDDs). Brain-derived neurotrophic factor (BDNF) is broadly expressed in the brain and is thought to play a role in the pathophysiology of MDDs and obesity. Congenital loss of function of BDNF causes weight gain in both humans and rodents; however, it is not clear whether acquired loss of function of BDNF also affects body weight. Thus, we exploited mutant mice in which the Bdnf expression level is regulated by the tetracycline-dependent transcriptional silencer (tTS)-tetracycline operator sequence (tetO) system. Time-controlled Bdnf expression using this system allowed us to establish congenital and acquired loss of function of Bdnf in mice. We demonstrated that changes in Bdnf expression influenced body weight during not only the developmental stage but also the adult stage of mice. Although it is still unclear whether acquired Bdnf loss of function in rodents mimics the pathology of MDD, our findings may bridge the mechanistic gap between MDDs and body weight gain in line with BDNF dysfunction.
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Affiliation(s)
- Toru Suzuki
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Kenji F Tanaka
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
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Provenzi L, Villa M, Mambretti F, Citterio A, Grumi S, Bertazzoli E, Biasucci G, Decembrino L, Gardella B, Giacchero R, Magnani ML, Nacinovich R, Pisoni C, Prefumo F, Orcesi S, Scelsa B, Giorda R, Borgatti R. Is Brain-Derived Neurotropic Factor Methylation Involved in the Association Between Prenatal Stress and Maternal Postnatal Anxiety During the COVID-19 Pandemic? Front Psychiatry 2022; 13:950455. [PMID: 35911240 PMCID: PMC9329563 DOI: 10.3389/fpsyt.2022.950455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/14/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The COVID-19 pandemic is a collective trauma that may expose susceptible individuals to high levels of stress. Pregnant women represent a high-risk population, considering that pregnancy is a period of heightened neuroplasticity and susceptibility to stress through epigenetic mechanisms. Previous studies showed that the methylation status of the BDNF gene is linked with prenatal stress exposure. The goals of this study were (a) to assess the association between pandemic-related stress and postnatal anxiety and (b) to investigate the potential role of maternal BDNF methylation as a significant mediator of this association. METHODS In the present study, we report data on the association among pandemic-related stress during pregnancy, maternal BDNF methylation, and postnatal anxiety symptoms. Pandemic-related stress and postnatal anxiety were assessed through self-report instruments. BDNF methylation was estimated in 11 CpG sites in DNA from mothers' buccal cells. Complete data were available from 108 mothers. RESULTS Results showed that pandemic-related stress was associated with an increased risk of postnatal anxiety, r = 0.20, p < 0.05. CpG-specific BDNF methylation was significantly associated with both prenatal pandemic-related stress, r = 0.21, p < 0.05, and postnatal maternal anxious symptoms, r = 0.25, p = 0.01. Moreover, a complete mediation by the BDNF CpG6 methylation emerged between pandemic-related stress during pregnancy and postnatal maternal anxiety, ACME = 0.66, p < 0.05. CONCLUSION These findings suggest that BDNF epigenetic regulation by pandemic-related stress might contribute to increase the risk of anxiety in mothers. Policymakers should prioritize the promotion of health and wellbeing in pregnant women and mothers during the present healthcare emergency.
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Affiliation(s)
- Livio Provenzi
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.,Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Marco Villa
- Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
| | | | | | - Serena Grumi
- Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
| | | | | | | | - Barbara Gardella
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.,Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | | | - Renata Nacinovich
- ASST Monza, Monza, Italy.,Department of Medicine and Surgery, Università Bicocca, Milan, Italy
| | | | - Federico Prefumo
- ASST Spedali Civili, Brescia, Italy.,Division of Obstetrics and Gynecology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Simona Orcesi
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.,Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
| | | | - Roberto Giorda
- Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
| | - Renato Borgatti
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.,Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
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Li Y, Cao J, Hao Z, Liu A, Li X, Li H, Xia N, Wang Z, Zhang Z, Bai J, Zhang H. Aspirin ameliorates the cognition impairment in mice following benzo[a]pyrene treatment via down-regulating BDNF IV methylation. Neurotoxicology 2021; 89:20-30. [PMID: 34979192 DOI: 10.1016/j.neuro.2021.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/14/2021] [Accepted: 12/29/2021] [Indexed: 12/19/2022]
Abstract
Benzo[a]pyrene (B[a]P) is neurotoxic, however, the mechanisms remain unclear and there is no effective prevention. Available evidence suggests a role of DNA methylation in B[a]P-induced neurotoxicity. This study investigated the brain-derived neurotrophic factor (BDNF) IV methylation in the development of and aspirin intervention against B[a]P's neurotoxicity in mice and HT22 cells. Mice were intraperitoneally treated with solvent or B[a]P (0.5, 2, and 10 mg/kg b.w.) for 60 days. An intervention group was treated simultaneously with B[a]P (10 mg/kg, i.p.) and aspirin (10 mg/kg, daily water-drinking). The treated mice showed a dose-dependent cognitive and behavioral impairment, and cerebral cell apoptosis, which were alleviated by aspirin co-treatment. Following B[a]P treatment, DNA methyltransferase (DNMTs) and BDNF IV hypermethylation were increased in the cerebral cortex of mice compared to controls, while significant decreases were found in BDNF IV and BDNF mRNA, and BDNF protein levels. Aspirin co-treatment rescued DNMTs activation and BDNF IV hypermethylation, and mitigated the recession in BDNF mRNA and protein induced by B[a]P treatment. Similar results were shown in HT22 cells. These findings reveal a critical role of BDNF IV methylation in the neurotoxicity of B[a]P, and demonstrate a promising prevention of aspirin against B[a]P-induced cognitive impairment via inhibiting BDNF IV hypermethylation.
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Affiliation(s)
- Yangyang Li
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Jingjing Cao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Zhongsuo Hao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Aixiang Liu
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Xin Li
- Center of Disease Control and Prevention, Taiyuan Iron and Steel Company, Taiyuan, 030003, Shanxi, China
| | - Huan Li
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Na Xia
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Zemin Wang
- Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University School of Public Health, 1025 E 7th St, Bloomington, IN, 47405, USA
| | - Zhihong Zhang
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Jianying Bai
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Hongmei Zhang
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China; Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, 030001, Shanxi, China; Key Laboratory of Cellular Physiology, Shanxi Province, Taiyuan, 030001, Shanxi, China; Department of Physiology, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
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Ropret S, Kouter K, Zupanc T, Videtic Paska A. BDNF methylation and mRNA expression in brain and blood of completed suicides in Slovenia. World J Psychiatry 2021; 11:1301-1313. [PMID: 35070779 PMCID: PMC8717036 DOI: 10.5498/wjp.v11.i12.1301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Suicide is a major public health problem. Worldwide, around 800000 people die by suicide every year. Suicide is a multifactorial disorder, with numerous environmental and genetic risk factors involved. Among the candidate genes, changes in the BDNF locus at the gene, epigenetic, mRNA, and protein expression levels have been implicated in psychiatric disorders, including suicidal behavior and completed suicides. AIM To investigate changes in BDNF methylation and expression of four alternative BDNF transcripts for association with completed suicide. METHODS This case-control study included 42 unrelated male Caucasian subjects, where 20 were control subjects who died following acute cardiac arrest, and 22 were suicide victims who died by hanging. DNA and RNA were extracted from brain tissue (Brodmann area 9 and hippocampus) and from blood. DNA methylation and mRNA expression levels were determined by targeted bisulfite next-generation sequencing and reverse-transcription quantitative PCR. Statistical analysis was done by use of two-tailed Student's t tests for two independent samples, and the Benjamini-Hochberg procedure was implemented for correction for multiple comparisons. RESULTS In DNA from brain tissue, there were no significant differences in BDNF methylation between the study groups. However, data showed significantly reduced DNA methylation of the BDNF region upstream of exon I in blood samples of suicide victims compared to the controls (5.67 ± 0.57 vs 6.83 ± 0.64, P corr = 0.01). In Brodmann area 9 of the brain of the suicide victims but not in their hippocampus, there was higher expression of BDNF transcript I-IX (NM_170731.4) compared to the controls (0.077 ± 0.024 vs 0.05 ± 0.013, P = 0.042). In blood, expression analysis for the BDNF transcripts was not feasible due to extensive RNA degradation. CONCLUSION Despite the limitations of the study, the obtained data further support a role for BDNF in suicidality. However, it should be noted that suicidal behavior is a multifactorial disorder with numerous environmental and genetic risk factors involved.
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Affiliation(s)
- Sandra Ropret
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Katarina Kouter
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Tomaž Zupanc
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Alja Videtic Paska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
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Velásquez MM, Gómez-Maquet Y, Ferro E, Cárdenas W, González-Nieves S, Lattig MC. Multidimensional Analysis of Major Depression: Association Between BDNF Methylation, Psychosocial and Cognitive Domains. Front Psychiatry 2021; 12:768680. [PMID: 34970165 PMCID: PMC8712447 DOI: 10.3389/fpsyt.2021.768680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/22/2021] [Indexed: 11/29/2022] Open
Abstract
Major Depression is a complex disorder with a growing incidence worldwide and multiple variables have been associated with its etiology. Nonetheless, its diagnosis is continually changing and the need to understand it from a multidimensional perspective is clear. The purpose of this study was to identify risk factors for depression in a case-control study with 100 depressive inpatients and 87 healthy controls. A multivariate logistic regression analysis was performed including psychosocial factors, cognitive maladaptive schema domains, and specific epigenetic marks (BDNF methylation levels at five CpG sites in promoter IV). A family history of depression, the cognitive schemas of impaired autonomy/performance, impaired limits, other-directedness, and the methylation level of a specific CpG site were identified as predictors. Interestingly, we found a mediating effect of those cognitive schemas in the relationship between childhood maltreatment and depression. Also, we found that depressive patients exhibited hypomethylation in a CpG site of BDNF promoter IV, which adds to the current discussion about the role of methylation in depression. We highlight that determining the methylation of a specific region of a single gene offers the possibility of accessing a highly informative an easily measurable variable, which represents benefits for diagnosis. Following complete replication and validation on larger samples, models like ours could be applicable as additional diagnostic tools in the clinical context.
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Affiliation(s)
- María Marcela Velásquez
- Centro de Investigaciones Genéticas en Enfermedades Humanas, Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá, Colombia
| | | | - Eugenio Ferro
- Instituto Colombiano del Sistema Nervioso, Clínica Montserrat, Bogotá, Colombia
| | - Wilmer Cárdenas
- Centro de Investigaciones Genéticas en Enfermedades Humanas, Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá, Colombia
| | - Silvia González-Nieves
- Centro de Investigaciones Genéticas en Enfermedades Humanas, Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá, Colombia
| | - María Claudia Lattig
- Centro de Investigaciones Genéticas en Enfermedades Humanas, Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá, Colombia
- SIGEN alianza Universidad de los Andes – Fundación Santa Fe de Bogotá, Bogotá, Colombia
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Ionescu-Tucker A, Butler CW, Berchtold NC, Matheos DP, Wood MA, Cotman CW. Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner. Front Aging Neurosci 2021; 13:798297. [PMID: 34970138 PMCID: PMC8712855 DOI: 10.3389/fnagi.2021.798297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/16/2021] [Indexed: 11/29/2022] Open
Abstract
Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3's catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.
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Affiliation(s)
- Andra Ionescu-Tucker
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
| | - Christopher W. Butler
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
| | - Nicole C. Berchtold
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
| | - Dina P. Matheos
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, United States
| | - Marcelo A. Wood
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, United States
| | - Carl W. Cotman
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
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de Mendonça Filho EJ, Barth B, Bandeira DR, de Lima RMS, Arcego DM, Dalmaz C, Pokhvisneva I, Sassi RB, Hall GBC, Meaney MJ, Silveira PP. Cognitive Development and Brain Gray Matter Susceptibility to Prenatal Adversities: Moderation by the Prefrontal Cortex Brain-Derived Neurotrophic Factor Gene Co-expression Network. Front Neurosci 2021; 15:744743. [PMID: 34899157 PMCID: PMC8652300 DOI: 10.3389/fnins.2021.744743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/22/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and prenatal adversity conditions on cognitive development trajectories and gray matter density. Methods: We analyzed the moderation effects of an expression polygenic score (ePRS) for the Brain-derived Neurotrophic Factor gene network (BDNF ePRS) on the association between prenatal adversity and child cognitive development. A score based on genes co-expressed with the prefrontal cortex (PFC) BDNF was created, using the effect size of the association between the individual single nucleotide polymorphisms (SNP) and the BDNF expression in the PFC. Cognitive development trajectories of 157 young children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort were assessed longitudinally in 4-time points (6, 12, 18, and 36 months) using the Bayley-II mental scales. Results: Linear mixed-effects modeling indicated that BDNF ePRS moderates the effects of prenatal adversity on cognitive growth. In children with high BDNF ePRS, higher prenatal adversity was associated with slower cognitive development in comparison with those exposed to lower prenatal adversity. Parallel-Independent Component Analysis (pICA) suggested that associations of expression-based SNPs and gray matter density significantly differed between low and high prenatal adversity groups. The brain IC included areas involved in visual association processes (Brodmann area 19 and 18), reallocation of attention, and integration of information across the supramodal cortex (Brodmann area 10). Conclusion: Cognitive development trajectories and brain gray matter seem to be influenced by the interplay of prenatal environmental conditions and the expression of an important BDNF gene network that guides the growth and plasticity of neurons and synapses.
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Affiliation(s)
- Euclides José de Mendonça Filho
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
| | - Barbara Barth
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
- Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Denise Ruschel Bandeira
- Programa de Pós-Graduação em Psicologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Randriely Merscher Sobreira de Lima
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
- Programa de Pós-Graduação em Bioquímica e Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Danusa Mar Arcego
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
| | - Carla Dalmaz
- Programa de Pós-Graduação em Bioquímica e Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Irina Pokhvisneva
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
| | | | - Geoffrey B. C. Hall
- Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada
| | - Michael J. Meaney
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Patricia Pelufo Silveira
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Center, Montreal, QC, Canada
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Lozupone M, Mollica A, Berardino G, Sardone R, Panza F. Could epigenetics play a role in suicidal behavior in older age? Epigenomics 2021; 14:73-79. [PMID: 34784757 DOI: 10.2217/epi-2021-0390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Tweetable abstract There is growing evidence of a role of environmental exposures in the pathogenesis and epigenetics of suicidal behavior in older age.
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Affiliation(s)
- Madia Lozupone
- Neurodegenerative Disease Unit, Department of Basic Medical Sciences, Neuroscience & Sense Organs, University of Bari Aldo Moro, Bari, 70100, Italy
| | - Anita Mollica
- Psychiatric Unit, Department of Clinical & Experimental Medicine, University of Foggia, Foggia, 71122, Italy
| | - Giuseppe Berardino
- Psychiatric Unit, Department of Clinical & Experimental Medicine, University of Foggia, Foggia, 71122, Italy
| | - Rodolfo Sardone
- Salus In Apulia Study: Frailty Phenotypes Research Unit, National Institute of Gastroenterology 'Saverio de Bellis', Research Hospital, Castellana Grotte Bari, 70013, Italy
| | - Francesco Panza
- Salus In Apulia Study: Frailty Phenotypes Research Unit, National Institute of Gastroenterology 'Saverio de Bellis', Research Hospital, Castellana Grotte Bari, 70013, Italy
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Andreatta M, Pauli P. Contextual modulation of conditioned responses in humans: A review on virtual reality studies. Clin Psychol Rev 2021; 90:102095. [PMID: 34763127 DOI: 10.1016/j.cpr.2021.102095] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 10/20/2022]
Abstract
Conditioned response (CRs) triggered by stimuli predicting aversive consequences have been confirmed across various species including humans, and were found to be exaggerated in anxious individuals and anxiety disorder patients. Importantly, contextual information may strongly modulate such conditioned responses (CR), however, there are several methodological boundaries in the translation of animal findings to humans, and from healthy individuals to patients. Virtual Reality (VR) is a useful technological tool for overcoming such boundaries. In this review, we summarize and evaluate human VR conditioning studies exploring the role of the context as conditioned stimulus or occasion setter for CRs. We observe that VR allows successful acquisition of conditioned anxiety and conditioned fear in response to virtual contexts and virtual cues, respectively. VR studies also revealed that spatial or temporal contextual information determine whether conditioned anxiety and conditioned fear become extinguished and/or return. Novel contexts resembling the threatening context foster conditioned fear but not conditioned anxiety, suggesting distinct context-related generalization processes. We conclude VR contexts are able to strongly modulate CRs and therefore allow a comprehensive investigation of the modulatory role of the context over CR in humans leading to conclusions relevant for non-VR and clinical studies.
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Affiliation(s)
- Marta Andreatta
- Department of Psychology (Biological Psychology, Clinical Psychology and Psychotherapy), University of Würzburg, Würzburg, Germany; Department of Psychology, Educational Sciences, and Child Studies, Erasmus University Rotterdam, the Netherlands.
| | - Paul Pauli
- Department of Psychology (Biological Psychology, Clinical Psychology and Psychotherapy), University of Würzburg, Würzburg, Germany; Center of Mental Health, University of Würzburg, Würzburg, Germany.
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Lo Iacono L, Mancini C, Babicola L, Pietrosanto M, Di Segni M, D'Addario SL, Municchi D, Ielpo D, Pascucci T, Cabib S, Ferlazzo F, D'Amato FR, Andolina D, Helmer-Citterich M, Cifani C, Ventura R. Early life adversity affecting the attachment bond alters ventral tegmental area transcriptomic patterning and behavior almost exclusively in female mice. Neurobiol Stress 2021; 15:100406. [PMID: 34660854 PMCID: PMC8503667 DOI: 10.1016/j.ynstr.2021.100406] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/22/2021] [Accepted: 10/02/2021] [Indexed: 02/07/2023] Open
Abstract
Early life experiences that affect the attachment bond formation can alter developmental trajectories and result in pathological outcomes in a sex-related manner. However, the molecular basis of sex differences is quite unknown. The dopaminergic system originating from the ventral tegmental area has been proposed to be a key mediator of this process. Here we exploited a murine model of early adversity (Repeated Cross Fostering, RCF) to test how interfering with the attachment bond formation affects the VTA-related functions in a sex-specific manner. Through a comprehensive behavioral screening, within the NiH RDoC framework, and by next-generation RNA-Seq experiments, we analyzed the long-lasting effect of RCF on behavioral and transcriptional profiles related to the VTA, across two different inbred strains of mouse in both sexes. We found that RCF impacted to an extremely greater extent VTA-related behaviors in females than in males and this result mirrored the transcriptional alterations in the VTA that were almost exclusively observed in females. The sexual dimorphism was conserved across two different inbred strains in spite of their divergent long lasting consequences of RCF exposure. Our data suggest that to be female primes a sub-set of genes to respond to early environmental perturbations. This is, to the best of our knowledge, the first evidence of an almost exclusive effect of early life experiences on females, thus mirroring the extremely stronger impact of precocious aversive events reported in clinical studies in women.
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Affiliation(s)
- Luisa Lo Iacono
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy
| | | | - Lucy Babicola
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Marco Pietrosanto
- Centre for Molecular Bioinformatics, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Sebastian Luca D'Addario
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy.,Behavioral Neuroscience PhD Programme, Sapienza University, Rome, Italy
| | - Diana Municchi
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy.,Behavioral Neuroscience PhD Programme, Sapienza University, Rome, Italy
| | - Donald Ielpo
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy.,Behavioral Neuroscience PhD Programme, Sapienza University, Rome, Italy
| | - Tiziana Pascucci
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy
| | - Simona Cabib
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Fabio Ferlazzo
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy
| | - Francesca R D'Amato
- Biochemistry and Cell Biology Institute, National Research Council, Via E Ramarini 32, 00015, Monterotondo Scalo, Roma, Italy
| | - Diego Andolina
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Manuela Helmer-Citterich
- Centre for Molecular Bioinformatics, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Cifani
- University of Camerino School of Pharmacy, Camerino, Italy
| | - Rossella Ventura
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.,IRCCS Fondazione Santa Lucia, Roma, Italy
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44
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Early-life trauma endophenotypes and brain circuit-gene expression relationships in functional neurological (conversion) disorder. Mol Psychiatry 2021; 26:3817-3828. [PMID: 32051548 PMCID: PMC7423688 DOI: 10.1038/s41380-020-0665-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 01/02/2020] [Accepted: 01/28/2020] [Indexed: 12/14/2022]
Abstract
Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network-trauma relationships in this population. In this neuroimaging-gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar-hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.
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45
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Altered neurodevelopmental DNA methylation status after fetal growth restriction with brain-sparing. J Dev Orig Health Dis 2021; 13:378-389. [PMID: 34325767 DOI: 10.1017/s2040174421000374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR <1, n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis.
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Involvement of 5-HT1A receptor-mediated histone acetylation in the regulation of depression. Neuroreport 2021; 32:1049-1057. [PMID: 34232131 DOI: 10.1097/wnr.0000000000001693] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Depression is one of the most common and disabling mental disorders. There is growing evidence that 5-HT1A receptor is involved in the regulation of depressive-related behaviors. However, the exact mechanism underlying the role of 5-HT1A receptor in depression remains unknown. Histone acetylation is associated with the pathophysiology and treatment of depression. In the current study, we investigated whether the epigenetic histone deacetylase (HDAC)-induced histone acetylation mediates the regulation of 5-HT1A receptor in depressive behaviors. We showed that 5-HT1A receptor selective agonist (±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide led to significant increase in acetylation of H3 at lysine 9 (Ac-H3K9) and H4 at lysine 5 (Ac-H4K5) and lysine 12 (Ac-H4K12) with obviously decreasing histone deacetylase 1 (HDAC1), histone deacetylase 2 (HDAC2), histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5) expression in hippocampus of mice. Conversely, 5-HT1A receptor selective antagonist NAN-190 decreased the level of acetylation of H3 and H4 with increasing the expression of HDAC1, HDAC2, HDAC4 and HDAC5 in the hippocampus. Furthermore, we found that HDAC inhibitors, trichostatin A or suberoylanilide hydroxamic acid infusion to hippocampus prevented the depressive behaviors induced by NAN-190, as well as histone H3 and H4 acetylation in mice. Our results suggested that epigenetic histone acetylation coupled with 5-HT1A receptor may play vital role in the pathophysiology and treatment of depressive disorders.
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Meng F, Liu J, Dai J, Lian H, Jiang S, Li Q, Wu M, Wang W, Wang D, Zhao D, Liu C, Qiu C, Li C. PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway. Mol Neurobiol 2021; 58:3529-3544. [PMID: 33745117 DOI: 10.1007/s12035-021-02340-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/22/2021] [Indexed: 12/15/2022]
Abstract
Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light-dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus-mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon-specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. These results may suggest that PPM1F regulates anxiety-related behaviors by modulating BDNF expression and H3S10 phosphorylation-mediated epigenetic modification, which may be served as potentially pathological genes associated with anxiety or other mental diseases.
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Affiliation(s)
- Fantao Meng
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Jing Liu
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Juanjuan Dai
- Cancer Research Institute, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Haifeng Lian
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Shujun Jiang
- Department of Physiology, Binzhou Medical University, Yantai, China
| | - Qiongyu Li
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Min Wu
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Wentao Wang
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Dan Wang
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Di Zhao
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Cuilan Liu
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Changyun Qiu
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China
| | - Chen Li
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, Shandong, China.
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48
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Li Z, Wang H, Xiao G, Du H, He S, Feng Y, Zhang B, Zhu Y. Recovery of post-stroke cognitive and motor deficiencies by Shuxuening injection via regulating hippocampal BDNF-mediated Neurotrophin/Trk Signaling. Biomed Pharmacother 2021; 141:111828. [PMID: 34146848 DOI: 10.1016/j.biopha.2021.111828] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
A mild ischemic stroke may cause both debilitating locomotor and cognitive decline, for which the mechanism is not fully understood, and no therapies are currently available. In this study, a nonfatal stroke model was constructed in mice by a modified middle cerebral artery occlusion (MCAO) procedure, allowing an extended recovery period up to 28 days. The extended MCAO model successfully mimicked phenotypes of a recovery phase post-stroke, including locomotor motor and cognitive deficiencies, which were effectively improved after Shuxuening injection (SXNI) treatment. Tissue slices staining showed that SXNI repaired brain injury and reduced neuronal apoptosis, especially in the hippocampus CA3 region. Transcriptomics sequencing study revealed 565 differentially expressed genes (DEGs) in the ischemic brain after SXNI treatment. Integrated network pharmacological analysis identified Neurotrophin/Trk Signaling was the most relevant pathway, which involves 15 key genes. Related DEGs were further validated by RT-PCR. Western-blot analysis showed that SXNI reversed the abnormal expression of BDNF, TrkB, Mek3 and Jnk1after stroke. ELISA found that SXNI increased brain level of p-Erk and Creb. At sub-brain level, the expression of BDNF and TrkB was decreased and GFAP was increased on the hippocampal CA3 region in the post-stroke recovery phase and this abnormality was improved by SXNI. In vitro experiments also found that oxygen glucose deprivation reduced the expression of BDNF and TrkB, which was reversed by SXNI. In summary, we conclude that SXNI facilitates the recovery of cognitive and locomotor dysfunction by modulating Neurotrophin/Trk Signaling in a mouse model for the recovery phase of post-ischemic stroke.
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Affiliation(s)
- Zhixiong Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
| | - Huanyi Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
| | - Guangxu Xiao
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
| | - Hongxia Du
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
| | - Shuang He
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
| | - Yuxin Feng
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
| | - Boli Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yan Zhu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China.
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49
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Iamjan SA, Thanoi S, Watiktinkorn P, Fachim H, Dalton CF, Nudmamud-Thanoi S, Reynolds GP. Changes of BDNF exon IV DNA methylation are associated with methamphetamine dependence. Epigenomics 2021; 13:953-965. [PMID: 34008409 DOI: 10.2217/epi-2020-0463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Aim: We investigated DNA methylation of BDNF in methamphetamine (METH) dependence in humans and an animal model. Materials & methods: BDNF methylation at exon IV was determined by pyrosequencing of blood DNA from METH-dependent and control subjects, and from rat brain following an escalating dose of METH or vehicle. Bdnf expression was determined in rat brain. Results: BDNF methylation was increased in human METH dependence, greatest in subjects with psychosis and in prefrontal cortex of METH-administered rats; rat hippocampus showed reduced Bdnf methylation and increased gene expression. Conclusion: BDNF methylation is abnormal in human METH dependence, especially METH-dependent psychosis, and in METH-administered rats. This may influence BDNF expression and contribute to the neurotoxic effects of METH exposure.
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Affiliation(s)
- Sri-Arun Iamjan
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand.,Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
| | - Samur Thanoi
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand
| | | | - Helene Fachim
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK.,Department of Endocrinology and Metabolism, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
| | - Caroline F Dalton
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK
| | - Sutisa Nudmamud-Thanoi
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand
| | - Gavin P Reynolds
- Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand.,Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK
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50
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Businaro R, Vauzour D, Sarris J, Münch G, Gyengesi E, Brogelli L, Zuzarte P. Therapeutic Opportunities for Food Supplements in Neurodegenerative Disease and Depression. Front Nutr 2021; 8:669846. [PMID: 34055858 PMCID: PMC8160227 DOI: 10.3389/fnut.2021.669846] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022] Open
Abstract
Emerging evidence is showing nutrition as a crucial factor in the high prevalence and incidence of neurodegenerative mental disorders. Preventive interventions on neuroinflammation seem to be able to interfere with neurodegeneration. Supplementation of essential nutrients, such as long-chain-polyunsaturated fatty acids, vitamin E and mineral elements, may minimize inflammation, enhancing antioxidative defense, and lowering the risk and incidence of age-related diseases, such as cardiovascular diseases and neurodegenerative diseases. This manuscript reviews the current evidence on the role of neuroinflammation in the pathophysiology of neurodegenerative and mental disorders, and preventive strategies for food supplementation in these neuropsychiatric diseases. Dietary supplementation-based strategies have been demonstrated to be effective in subjects with mild cognitive impairment, while weaker results have been obtained in patients with advance neurodegenerative disease. Adjunctive supplementation has also been demonstrated to improve depression, this being of marked benefit considering the comorbidity between cognitive impairment/dementia and depression. Further research is needed to improve the prescriptive precision of supplementation in patients, and to better understand potential interactions with clinical and pharmacokinetic factors.
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Affiliation(s)
- Rita Businaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - David Vauzour
- Faculty of Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Jerome Sarris
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia.,Professorial Unit, The Melbourne Clinic, Department of Psychiatry, Melbourne University, Melbourne, VIC, Australia
| | - Gerald Münch
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Erika Gyengesi
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | | | - Pedro Zuzarte
- Psychiatric Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.,Neuropsychiatry Research Department, GNR Clinical Center, Lisbon, Portugal
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