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: 10428598
• 负责人: Marvin Rafael Diaz
• 金额: $ 34.71万
• 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/10428598
• 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; Investigation; Lead; Life; Long-Term Effects; Longevity; Male Adolescents; Marble; Measures; Medial; Mediating; Messenger RNA; Microinjections; Modeling; Neurobiology; Pathway interactions; Pattern; Phenotype; Population; Pregnancy; Prevalence; Proxy; Rattus; Risk-Taking; Role; Sex Differences; Signal Transduction; Site; Stress; Structure; Suggestion; 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; base; epidemiologic data; gamma-Aminobutyric Acid; in vivo; innovation; male; neurobiological mechanism; neurogenesis; neuromechanism; novel; novel strategies; offspring; preference; prenatal; receptor; sex; showing emotion; time-to-pregnancy; 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.

摘要