Cellular substrates of early life trauma

早期生命创伤的细胞基质

基本信息

批准号：
10657416
负责人：
Roger L Clem
金额：
$ 55.71万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657416
关键词：
Acute Adolescence Adolescent Adrenergic Agents Adrenergic Receptor Adult Amygdaloid structure Animals Anxiety Behavior Behavioral Biological Assay Biological Factors Brain region Calcium Cells Childhood Data Development Disease Early-life trauma Electrophysiology (science)Emotional Exhibits Exposure to Fiber Functional disorder Goals Human Image Immunohistochemistry Incidence Infusion procedures Life Life Experience Light Measures Medial Mediating Membrane Mental Depression Mental disorders Mus Neurons Norepinephrine Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Photometry Physical activity Physiological Play Predisposition Prefrontal Cortex Process Property Recording of previous events Regulation Risk Factors Rodent Role Severities Shock Signal Transduction Slice Stress Structure Synapses Synaptic Transmission Testing Time Translating Trauma age related approach avoidance behavior attenuation avoidance behavior behavioral phenotyping behavioral response early adolescence early life adversity early onset emotion regulation experience foot genetic manipulation immature animal improved in vivo innovation locus ceruleus structure neurotransmission noradrenergic optogenetics pediatric trauma pharmacologic postnatal response traumatic stress treatment response

项目摘要

Most psychiatric conditions have their highest incidence of onset in early life, and it is currently estimated that one in five adolescents will develop such a condition that persists into adulthood. A major risk factor for such disorders is the experience of childhood trauma. Among the brain regions most highly implicated in these conditions is the medial prefrontal cortex (mPFC), which forms a synaptic network that plays important roles in emotional regulation. During a developmental stage equivalent of human adolescence, rodents exhibit heightened susceptibility to stress-induced behavioral phenotypes that resemble human conditions like anxiety and depression, and that are accompanied by long-term changes in the structure and function of mPFC in adulthood. However, it remains unclear whether unique mechanisms confer susceptibility to stress in immature animals, or what processes immediately ensue upon exposure to stress in adults versus mice. The long-term goal of this project is to reveal how trauma impacts directly on mPFC neurons, delineate substrates and mechanisms in these effects, and understand the abnormal functional properties that result. In particular, our preliminary data suggest that early adolescence is a sensitive period for noradrenaline-dependent suppression of mPFC activity and excitability, and that engagement of this process during traumatic stress leads to a long- lasting increase in threat avoidance, a potential correlate of human anxiety. We will make unprecedented use of longitudinal calcium imaging in freely behaving mice to measure these physiological effects as well as changes in mPFC activity that signal abnormal avoidance behaviors. Cellular and synaptic mechanisms for hypoexcitability will be elucidated by electrophysiological recordings. Finally, we will use temporally specific optogenetic manipulations to test whether recovering mPFC activity within specific projection pathways is sufficient to reverse trauma-related phenotypes. We hope that be establishing this comprehensive paradigm of stress susceptibility, we can shed light on biological factors that potentially contribute to a high rate of childhood onset for psychiatric disorders.

大多数精神科状况在早期发病率最高，目前据估计五分之一的青少年将发展到成年后的这种情况。这样的主要风险因素疾病是童年创伤的经历。在大脑区域中，最大程度地涉及这些区域条件是内侧前额叶皮层（MPFC），它形成了突触网络，在情绪调节。在人类青春期的发展阶段，啮齿动物表现出对压力引起的行为表型的敏感性提高了类似于人类状况的焦虑等行为表型和抑郁症，并伴随着MPFC的结构和功能的长期变化成年。但是，尚不清楚独特的机制是否赋予对不成熟压力的敏感性动物，或在成年人与小鼠承受压力时立即发生的过程。长期该项目的目标是揭示创伤如何直接影响MPFC神经元，划定底物和这些作用的机制，并了解产生的异常功能特性。特别是我们的初步数据表明，青春期早期是对去甲肾上腺素依赖性抑制的敏感时期 MPFC活性和兴奋性以及创伤性压力期间该过程的参与导致长期避免威胁的持久增加，潜在的人类焦虑症相关。我们将实现前所未有的用途自由行为的小鼠纵向钙成像，以测量这些生理效应以及 MPFC活动的变化，表明异常回避行为。细胞和突触机制功能障碍将通过电生理记录来阐明。最后，我们将使用时间特定测试在特定投影途径中恢复MPFC活性是否的光遗传操作是足以逆转与创伤相关的表型。我们希望建立这种全面的范式压力敏感性，我们可以阐明生物学因素，这些因素可能有助于高率精神疾病的童年发作。