Prenatal Alcohol and Anxiety: An Ontogenetic Role for CRF

产前酒精和焦虑：CRF 的个体发生作用

• 批准号: 10827692
• 负责人: Marvin Rafael Diaz
• 金额: $ 6.41万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10827692
• 关键词: Acute; Adolescent; Adult; Affect; Age; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Blood; Brain; Brain region; Cells; Central Medial Thalamic Nucleus; Child; Childhood; Corticotropin-Releasing Hormone; Coupling; Data; Development; Electrophysiology (science); Emotional; Ethanol; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; GTP-Binding Proteins; Growth; Human; Impairment; In Vitro; Individual; Infusion procedures; Investigation; Life; Long-Term Effects; Longevity; Male Adolescents; Marble; Measures; Medial; Mediating; Messenger RNA; Microinjections; Modeling; Neurobiology; Pathway interactions; Pattern; Phase; Phenotype; Population; Pregnancy; Prevalence; Proxy; Rattus; Risk Taking; Role; Sex Differences; Signal Transduction; Site; Stress; Structure; Synapses; Syndrome; System; Testing; Time; adolescent alcohol exposure; adolescent offspring; age related; alcohol abuse during pregnancy; alcohol exposure; alcohol use disorder; anxiety-like behavior; anxiety-related behavior; epidemiologic data; gamma-Aminobutyric Acid; in vivo; innovation; male; neurobiological mechanism; neurogenesis; neuromechanism; novel; novel therapeutic intervention; offspring; preference; prenatal; receptor; sex; showing emotion; transmission process; vapor

Abstract Alcohol drinking and alcohol abuse during pregnancy is surprisingly high which can lead to a spectrum of deficits in offspring termed Fetal Alcohol Spectrum Disorders. One of the most common consequences of prenatal alcohol exposure (PAE) is the emergence of anxiety disorders that are apparent in childhood and persist through adulthood. Coincident and highly associated with anxiety is the prevalence of alcohol abuse in individuals with PAE. Importantly, these observations are evident even following exposure to moderate levels of ethanol – a common pattern of alcohol consumption in pregnancy. Despite compelling epidemiological data, the neurobiological mechanisms underlying moderate PAE-induced anxiety are not well understood. The actions of corticotropin-releasing factor (CRF) through its cognate receptor, CRF1R, are involved in alcohol exposure-induced anxiety and alcohol preference in adult males, and their expression is altered by PAE in anxiety-related brain structures. However, the developmental time-course of CRF1R function and how its function is altered by PAE across ontogeny is unknown. We have recently characterized a model of moderate PAE using a single exposure to vaporized ethanol on gestational day (G) 12, a developmental epoch during which the amygdala begins to appear, that produces increased anxiety-like behaviors in adolescent male offspring and affects emotional processing in adult males, with no apparent effects in females. Based on this, we hypothesize that G12 PAE reduces CRF1R function through ontogeny, which contributes to the biphasic anxiety phenotype and results in alterations in acute alcohol and CRF1R interactions. To test our hypothesis, Aim 1 will determine the developmental time-course of CRF1R function within the central amygdala and its relation to anxiety-like behaviors. Aim 2 will examine the impact of moderate G12 PAE on alterations to CRF1R function within the central amygdala across development and into adulthood, as it contributes to PAE-induced alterations in anxiety-like behavior. Finally, Aim 3 will test the effect of moderate G12 PAE on acute ethanol- CRF1R interactions within the central amygdala and how CRF1R contribute to ethanol intake across ontogeny. These innovative studies will test novel and unique hypotheses surrounding the long-term effects of moderate PAE and describe neural mechanisms specific to deficits in anxiety-like behaviors and its association with elevated ethanol intake in an age- and sex-specific manner.

抽象的 怀孕期间饮酒和酗酒的高度很高，可能导致一系列 后代的缺陷称为胎儿酒精谱系。最常见的后果之一 产前酒精暴露（PAE）是童年时代显而易见的焦虑症的出现 坚持成年。一致的焦虑是焦虑的高度关联的是滥用酒精的率 患有PAE的人。重要的是，这些观察甚至是在接触现代水平之后的证据 乙醇 - 妊娠中饮酒的常见模式。尽管令人信服的流行病学数据，但 现代PAE引起的动画的神经生物学机制尚不清楚。 通过其同源受体CRF1R的皮质激素释放因子（CRF）的作用参与酒精 暴露于成年男性的暴露引起的动画和酒精偏爱，并且在 与焦虑有关的大脑结构。但是，CRF1R功能的发展时间及其如何 PAE在个体发育中改变了功能是未知的。我们最近描述了一种现代模型 PAE在妊娠日（g）12使用一次性乙醇暴露，一个发育时期 杏仁核开始出现的，这会产生青春期男性的焦虑样行为 后代并影响成年男性的情绪加工，对女性没有明显的影响。基于此， 我们假设G12 PAE通过个体发育降低CRF1R功能，这有助于双相 焦虑表型并导致急性酒精和CRF1R相互作用的改变。为了检验我们的假设， AIM 1将确定中央杏仁核内CRF1R功能的发展时间顺序及其 与焦虑般的行为有关。 AIM 2将检查中等G12 PAE对CRF1R改变的影响 在整个开发和成年期的中央杏仁核中的功能，因为它有助于PAE引起的 焦虑般的行为改变。最后，AIM 3将测试现代化G12 PAE对急性乙醇的影响 中央杏仁核内的CRF1R相互作用以及CRF1R如何促进整个个体发育的乙醇摄入量。 这些创新的研究将检验围绕现代长期影响的新颖和独特的假设 PAE并描述针对动画般的行为定义的神经机制及其与之关联 以年龄和性别的方式升高乙醇的摄入量。