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Effects of early life stress on synaptic function and DA signaling in the VTA

早期生活压力对 VTA 突触功能和 DA 信号传导的影响

基本信息

批准号：
8886380
负责人：
Fereshteh S Nugent
金额：
$ 35.83万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886380
关键词：
A kinase anchoring protein Adolescence Adolescent Adult Adverse event Affect Animal Model Animals Area Behavior Behavioral Biochemical Brain Brain Part Cells Child Child Abuse Child Abuse and Neglect Child Development Child health care Childhood Chromatin Cyclic AMP-Dependent Protein Kinases DNA Sequence Data Development Disease Dopamine Elderly Enzymes Epigenetic Process Exhibits Frequencies Gene Expression Genes Genetic Transcription Glutamates Goals Histone Acetylation Histones Impairment Intervention Knowledge Laboratories Learning Life Life Experience Life Stress Link Long-Term Effects Maternal Deprivation Mediating Memory Mental disorders Modeling Modification Molecular N-Methyl-D-Aspartate Receptors Neurobiology Neuronal Plasticity Neurons Outcome Peptides Perception Physiological Play Process Promoter Regions Protocols documentation Psychopathology Public Health Rattus Receptor Signaling Recovery Regulation Research Rewards Risk Rodent Role Scaffolding Protein Shapes Signal Transduction Signaling Molecule Staging Stress Substance abuse problem Synapses Synaptic plasticity Techniques Testing Therapeutic Time Trauma Ventral Tegmental Area addiction base cell type chromatin remodeling dopaminergic neuron epigenetic regulation experience improved inhibitor/antagonist neglect neuroadaptation neurodevelopment novel prevent psychologic public health relevance receptor relating to nervous system response reward circuitry stress related disorder synaptic function trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): Adverse early life experiences such as prolonged child neglect and abuse increase the risk of developing mental health disorders including substance abuse and psychiatric disorders in childhood, adolescence and adulthood. Understanding the consequences of child abuse and neglect on early brain development and neural processes that shape memories and guide behaviors based on past experiences are important goals of research aiming to improve prospects for successful treatment of abused children. Pathological reward-dependent learning within the ventral tegmental area (VTA) and the subsequent dysregulation of dopamine (DA) signaling from the VTA seems to be central to the onset of addiction and stress-related disorders, suggesting the potential therapeutic benefits of selective intervention in this brain area in treatment of such disorders. A single 24h episode o early maternal deprivation (MD) in rodents is widely used as an animal model of severe early life stress. Studies using this model have provided a strong link between the dysregulation of DA signaling and a later propensity to develop stress-related disorders. However it is still unknown how early MD affects the reward learning processes in the VTA. In this proposal, we will test our hypothesis that MD triggers epigenetic mechanisms that selectively reduce expression of critical memory-associated genes that support GABAergic plasticity in the VTA, and these epigenetic changes in part contribute to the development of later psychopathology. Our preliminary data also indicate that MD selectively disrupts GABAergic plasticity in the VTA through epigenetic modifications of critical signaling molecules underlying this plasticity. We will use a combination of molecular, cellular, immunohistochemical, biochemical, epigenetic, and behavioral techniques in naïve, maternally-deprived (MD), and non-maternally-deprived (non-MD) juvenile rats to drive a mechanistic understanding of experimental MD that may be highly applicable to recovery of child abuse and neglect. Understanding the effects of MD on neurons in the VTA will expand our knowledge of an important but neglected part of the cellular basis of child abuse and neglect. Consequently, we will identify novel mechanisms in the regulation of synaptic plasticity, memory formation and DA signaling within the VTA that can be selectively targeted in a cell-type and circuit-specific manner in the period immediately following an episode of MD or other severe stress during early development.