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.

描述（由适用提供）：诸如长期忽视和虐待之类的不良早期生活经历增加了患精神健康疾病的风险，包括童年，青少年和成年后的药物滥用和精神疾病。了解虐待儿童和忽视儿童对早期大脑发育和神经过程的后果，这些过程塑造了基于过去经验的记忆和指导行为，这是研究的重要目标，旨在改善成功治疗受虐待儿童的前景。腹侧对接区域（VTA）内的病理奖励依赖性学习以及随后从VTA的多巴胺信号（DA）信号失调似乎是成瘾和与压力相关疾病发作的核心，这表明在这种脑区域治疗这种异常方面，选择性干预的潜在治疗益处的潜在治疗益处。啮齿动物中的单个24h发作o早期孕产妇剥夺（MD）被广泛用作严重的早期生活压力的动物模型。使用此模型的研究提供了DA信号传导失调与后来的可靠性之间的牢固联系，以发展与压力相关的疾病。但是，仍然未知MD如何影响VTA中的奖励学习过程。在该提案中，我们将检验我们的假设，即MD触发表观遗传机制，这些机制有选择地减少支持VTA中GABA能可塑性的关键记忆相关基因的表达，并且这些表观遗传变化部分有助于后来的精神病理学的发展。我们的初步数据还表明，MD通过对这种可塑性的临界信号分子的表观遗传修饰进行选择性破坏VTA中的GABA能可塑性。我们将使用一个组合在幼稚的，主要剥夺（MD）和非剥夺（非MD）少年大鼠的分子，细胞，免疫组织化学，生化，表观遗传和行为技术中，以驱动对实验MD的机械理解，可高度适用于对虐待儿童的恢复，以驱动对实验MD的机械理解。了解MD对VTA中神经元的影响将扩大我们对虐待和忽视儿童的细胞基础的重要但被忽视的部分的了解。因此，我们将在VTA内的突触可塑性，记忆形成和DA信号的调节中确定新的机制，在早期发育期间MD或其他严重压力之后，可以选择性地以细胞类型和电路特异性方式靶向。