Cellular substrates of early life trauma

早期生命创伤的细胞基质

• 批准号: 10100871
• 负责人: Roger L Clem
• 金额: $ 58.65万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10100871
• 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; Pharmacology; 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; base; behavioral phenotyping; behavioral response; early adolescence; early life adversity; early onset; emotion regulation; experience; foot; immature animal; improved; in vivo; innovation; locus ceruleus structure; noradrenergic; optogenetics; pediatric trauma; postnatal; response; traumatic stress; treatment response

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.

大多数精神疾病在生命早期发病率最高，目前估计 五分之一的青少年会患上这种疾病，并持续到成年。造成这种情况的一个主要风险因素是 疾病是童年创伤的经历。与这些最密切相关的大脑区域之一 条件是内侧前额叶皮层（mPFC），它形成一个突触网络，在 情绪调节。在相当于人类青春期的发育阶段，啮齿动物表现出 对压力诱发的行为表型的敏感性更高，这些行为表型类似于焦虑等人类状况 和抑郁症，并且伴随着 mPFC 结构和功能的长期变化 成年期。然而，目前尚不清楚独特的机制是否会导致未成熟的人对压力的敏感性。 动物，或者成人与小鼠在受到压力时立即发生什么过程。长期来看 该项目的目标是揭示创伤如何直接影响 mPFC 神经元、描绘基质和 这些影响的机制，并了解由此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去甲肾上腺素依赖性抑制的敏感期 mPFC 活动和兴奋性的影响，并且在创伤性应激期间参与这一过程会导致长期 威胁回避的持续增加，这是人类焦虑的潜在相关因素。我们将前所未有地利用 对自由行为的小鼠进行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 兴奋性低下将通过电生理记录来阐明。最后，我们将使用时间特定的 光遗传学操作来测试是否恢复特定投射途径内的 mPFC 活性 足以逆转创伤相关的表型。我们希望建立这种综合范式 应激敏感性，我们可以揭示可能导致高应激率的生物因素 儿童期发病的精神疾病。