Novel circuit mechanism of alcohol dependence vulnerability following early-life adversity

早年逆境后酒精依赖脆弱性的新回路机制

基本信息

批准号：
10058181
负责人：
Candice Contet
金额：
$ 26.96万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2020-08-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058181
关键词：
Adolescent Adult Affective Alcohol Phenotype Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholic Intoxication Amygdaloid structure Animals Anxiety Behavior Behavioral Brain region Caring Cell Nucleus Cells Chronic Clinical Data Corticotropin-Releasing Hormone Data Development Ethanol Ethanol dependence Exhibits Experimental Models Exposure to FOS gene Face Female Fiber Genes Genetic Genetic Polymorphism Genetic Transcription Heavy Drinking Hyperactive behavior Individual Inhalation Label Life Measures Mediating Mediator of activation protein Methodology Modeling Molecular Molecular Analysis Mood Disorders Motivation Mus Neurobiology Neurons Pathologic Pathway interactions Patients Peptides Phenotype Play Population Posterior Hypothalamus Poverty Pre-Clinical Model Prevention approach Process Public Health Recording of previous events Research Personnel Research Project Grants Risk Role Signal Transduction Substance Use Disorder Testing Transcript Variant Withdrawal Work alcohol abuse therapy alcohol exposure alcohol use disorder base childhood adversity comorbidity depressive symptoms early alcohol abuse early life adversity early life stress experience in vivo innovation male motivational processes mouse model negative affect neurobiological mechanism neurotransmission novel personalized approach personalized therapeutic postnatal development receptor recruit release factor sex sexual dimorphism transmission process vapor

项目摘要

SUMMARY Childhood adversity increases the vulnerability to develop an alcohol use disorder later in life, and variations in genes involved in corticotropin-releasing factor (CRF) signaling modulate this risk. However, the CRF-dependent mechanism(s) mediating the facilitation of alcohol abuse by early life stress is unknown. We recently discovered that CRF neurons located in the parasubthalamic nucleus (PSTN) may play a critical role in this mechanism because (1) they control voluntary ethanol drinking, and (2) they are enduringly altered by early life stress. Notably, these neurons send excitatory projections to the central nucleus of the amygdala (CeA), where CRF signaling is known to promote ethanol intake escalation in dependent animals. Accordingly, the present project will test the hypothesis that dysregulated CRF transmission from the PSTN to the CeA may facilitate the transition to alcohol dependence following early life stress. This project will leverage a novel mouse model of the interaction between early life stress and excessive ethanol intake by limiting bedding and nesting (LBN) materials during early postnatal development, a naturalistic model of simulated poverty, and exposing adult mice to voluntary ethanol drinking sessions alternated with chronic intermittent ethanol vapor inhalation (CIE). We established that LBN rearing accelerates ethanol intake escalation in male mice exposed to CIE and elicits negative affect during withdrawal. In Aim 1, we will determine the influence of sex on these phenotypes and test the hypothesis that, in vulnerable mice, LBN and CIE exert synergistic effects on the activity of PSTN→CeA CRF neurons. In Aim 2, we will attempt to reverse the enduring consequences of LBN on CIE-induced motivational and affective phenotypes by inhibiting PSTN→CeA CRF neurons using chemogenetics. Our approach capitalizes on the complementary expertise of two experienced collaborating researchers and leverages state- of-the-art methodology for the manipulation of neuronal activity in vivo. Our discoveries will pave the way for the identification of molecular mechanisms underlying the life-long pathological consequences of early life stress, which may ultimately enable the development of personalized therapeutic strategies for individuals who experienced childhood adversity and suffer from an alcohol use disorder.

概括儿童广告增加了以后生活中发展饮酒障碍的脆弱性，以及涉及皮质激素释放因子（CRF）信号传导的基因调节了这种风险。但是，依赖CRF 通过早期生活压力介导酒精滥用设施的机制尚不清楚。我们最近发现位于副脑膜核（PSTN）中的CRF神经元可能在这种机制中起关键作用因为（1）他们控制着自愿性乙醇饮酒，并且（2）他们因早期生活压力而持久改变。值得注意的是，这些神经元将兴奋性项目发送到杏仁核（CEA）的中央核，其中CRF 已知信号传导可促进依赖动物的乙醇摄入升级。根据适当的本项目将检验以下假设，即CRF从PSTN到CEA的传播失调可能促进早期生活压力过渡到酒精依赖。该项目将利用新颖的鼠标模型通过限制床上用品和嵌套（LBN）产后早期发展期间的材料，一种自然主义的模拟贫困模型，并暴露成年小鼠慢性间歇性乙醇蒸气吸入（CIE）替代自愿性乙醇饮酒课程。我们确定LBN饲养会加速乙醇的摄入量升级，暴露于CIE和引发退出期间的负面影响。在AIM 1中，我们将确定性别对这些表型和测试的影响在脆弱的小鼠中，LBN和CIE对PSTN→CEA CRF的活性产生协同作用的假设神经元。在AIM 2中，我们将尝试扭转LBN对CIE引起的励志的持久后果通过使用化学遗传学抑制PSTN→CEA CRF神经元，以及情感表型。我们的方法利用两名经验丰富的合作研究人员的完善专业知识，并利用国家在体内操纵神经元活性的艺术方法。我们的发现将为鉴定出早期生命压力的终身病理后果背后的分子机制，最终可能使个人的个性化理论策略为个人制定经验丰富的童年冒险和患有酒精疾病的障碍。