Functional characterization and rescue of depressive behaviors following adolescent social isolation and re-socialization

青少年社会孤立和再社会化后抑郁行为的功能表征和拯救

基本信息

批准号：
10205956
负责人：
Dan Li
金额：
$ 5.1万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-19 至 2022-06-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205956
关键词：
Actins Adolescence Adolescent Adult Affect Anhedonia Antidepressive Agents Area Axon Behavior Behavioral Brain Brain region Cells Complex Consumption Cytoskeleton Deep Brain Stimulation Dendritic Spines Depressed mood Depressive disorder Development Disease remission Electrophysiology (science)Etiology Excitatory Synapse Exhibits Failure Fluorescence Functional disorder Future Gene Expression Gene Expression Profiling Gene Silencing Gene set enrichment analysis Genetic Transcription Goals Habits Hippocampus (Brain)Human Hyperactivity Impaired cognition Long-Term Effects Longevity Maps Mediating Mental Depression Modeling Mood Disorders Motivation Mus National Institute of Mental Health Neurobiology Neurons Outcome Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Positive Valence Prefrontal Cortex Process Property Protein Isoforms Psychopathology Recording of previous events Regulation Resistance Rewards Rho-associated kinase Rodent Shapes Site Social Environment Social isolation Socialization Stimulus Stress Structure Sucrose Swimming Synapses Testing Therapeutic United States United States National Institutes of Health Vertebral column Viral adeno-associated viral vector analog base behavioral outcome cell type cohort density depressed patient depressive behavior depressive symptoms disability drug development experience fasudil feeding genome-wide hippocampal pyramidal neuron laser capture microdissection lifetime risk nerve supply neuroimaging neurotransmission novel novel therapeutics overexpression patch clamp postnatal reward circuitry small hairpin RNA social stressor symptomatology targeted treatment transcriptome sequencing transcriptomics young adult

项目摘要

PROJECT SUMMARY Depressive disorders are the leading cause of disability worldwide, and will affect ~20% of people in the U.S. within their lifetimes. Although depression symptomatology is extensive, complex, and highly heterogeneous, patients consistently exhibit deficits in NIH-defined, positive valence domains including motivation, reward sensitivity, and goal-directed action, dysregulation of which produce hallmark deficits such as amotivation, anhedonia, rumination, and behavioral inflexibility. A significant determinant of lifetime risk for depression is social adversity experienced during adolescence, a neurodevelopmental period characterized by extensive changes in the prefrontal cortex (PFC). We have developed a model of social adversity in which we socially isolate adolescent mice, and then re-house them in social cohorts as young adults, thus allowing us to isolate the long-term consequences of social adversity, even after normalization of the social milieu. As in humans, isolation during adolescence in mice produces depression-like behaviors that persist beyond the period of adversity itself. Previously isolated mice exhibit anhedonic-like behavior and develop inflexible habits at the expense of PFC-dependent, goal-directed behaviors. At the neurobiological level, they suffer failures in the pruning of dendritic spines, the primary sites of excitatory synapses in the brain, resulting in spine over-expression in adulthood. This suggests an excitatory shift in these neurons, which is particularly relevant in the ventromedial PFC (vmPFC), which is hyper-active in depressed patients and whose activity can be successfully suppressed by deep-brain stimulation (DBS) to treat depression. We also find that Rho-kinase (ROCK) inhibition, which manipulates the shape and mobility of dendritic spines, has antidepressant-like actions. However, whether this therapeutic-like effect is specifically mediated by inhibition of the neuronal isoform, ROCK2, and in the vmPFC, remains unknown. In Aim 1, I will test the hypothesis that a history of social isolation during adolescence results in long-term functional alterations in the vmPFC that can be corrected by ROCK2 inhibition. I will use neuroanatomical tract-tracing, ex vivo whole-cell patch clamp electrophysiology, and site-selective viral-mediated gene silencing to identify and correct the long- term consequences of social isolation during adolescence on vmPFC circuit connectivity, vmPFC neuronal electrophysiology, and depression-related behaviors. In Aim 2, I will leverage cell-type specific, genome-wide transcriptional profiling and utilize gene set enrichment analysis to identify the long-term effects of social isolation during adolescence on gene expression in adulthood. I will focus on layer V neurons, which suffer from dendritic spine hyper-density following isolation. My findings may provide new leads for antidepressant drug development, which is desperately needed as currently available antidepressants only confer remission in ~50% of patients, and are not disease-modifying. Understanding the mechanisms underlying the etiology of depressive behaviors is essential for the development of more effective, targeted therapies for these millions of patients.

项目摘要抑郁症是全球残疾的主要原因，将影响约20％的美国人群在他们的一生中。尽管抑郁症状学广泛，复杂且高度异质，但患者始终在NIH定义的正价领域中表现出缺陷，包括动机，奖励敏感性和目标指导的动作，失调会产生标志性赤字，例如动机， Anhedonia，反省和行为僵化。抑郁症终身风险的重要决定因素是在青春期经历的社会逆境，一个神经发育时期，其特征是前额叶皮层（PFC）的变化。我们已经开发了一种社会逆境模式，在社会上隔离青少年小鼠，然后将它们重新安置在年轻人中，从而使我们能够孤立即使在社会环境正常化之后，社会逆境的长期后果也是如此。就像在人类中一样，小鼠青春期的隔离会产生抑郁症的行为，这些行为持续超出逆境本身。以前孤立的小鼠表现出类似鼻涕的行为，并发展出不灵活的行为习惯是以依赖PFC的目标指导行为为代价。在神经生物学层面上，他们受苦树突状刺修修剪的失败，这是大脑兴奋性突触的主要部位，导致脊柱成年后的过表达。这表明这些神经元发生了兴奋性转移，这在腹侧PFC（VMPFC），在抑郁症患者中非常活跃，其活性可以是通过深脑刺激（DB）成功抑制以治疗抑郁症。我们还发现，操纵树突状的形状和迁移率的Rho-kinase（岩石）抑制刺具有抗抑郁药样作用。但是，这种类似治疗的效果是否由抑制神经元同工型Rock2和VMPFC中的抑制作用尚不清楚。在AIM 1中，我将测试假设青春期的社会隔离历史导致长期功能改变可以通过Rock2抑制校正的VMPFC。我将使用神经解剖学追踪，离体全细胞斑块夹电生理学和现场选择性病毒介导的基因沉默，以识别和纠正长期在VMPFC电路连接性的青春期期间社会隔离的期限后果，VMPFC神经元电生理学和与抑郁相关的行为。在AIM 2中，我将利用细胞类型的特异性，全基因组的特异性转录分析并利用基因集富集分析来确定社会隔离的长期影响在青春期对成年的基因表达。我将重点放在V层神经元上，该神经元患有树突状分离后脊柱高密度。我的发现可能为抗抑郁药的开发提供新的潜在客户，这是迫切需要的，因为目前可用的抗抑郁药仅在约50％的患者中赋予缓解，并且不是调整疾病。了解抑郁行为病因的基础机制对于为数百万患者开发更有效，有针对性的疗法至关重要。