Impact of Prenatal Alcohol Exposure on CRF1R Mediated Neural Mechanisms and Social Behavior

产前酒精暴露对 CRF1R 介导的神经机制和社会行为的影响

• 批准号: 10751645
• 负责人: Kelcie Schatz
• 金额: $ 6.91万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751645
• 关键词: Address; Adult; Adult Children; Affect; Air; Alcohol consumption; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain region; Cells; Central Medial Thalamic Nucleus; Communication; Corticotropin-Releasing Hormone; Development; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Experimental Designs; FOS gene; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal alcohol effects; Future; Genetic; Glutamates; Goals; Impairment; Individual; Investigation; Knowledge; Learning; Longevity; Measures; Medial; Mediating; Mentors; Mus; Neurobiology; Neurons; Pattern; Persons; Physiology; Pre-Clinical Model; Prefrontal Cortex; Pregnancy; Rattus; Regulation; Reporting; Research Design; Research Personnel; Role; Science; Scientist; Social Behavior; Social Functioning; Social Interaction; Stains; Synapses; System; Techniques; Testing; Time; Training; United States; alcohol exposure; antagonist; anxiety-like behavior; anxiety-related behavior; career; cell type; design; emotion regulation; experimental study; gamma-Aminobutyric Acid; in utero; in vivo; male; midbrain central gray substance; neural circuit; neuroadaptation; neurobiological mechanism; neurogenesis; neuromechanism; neuronal excitability; neurotransmission; novel; offspring; patch clamp; prenatal experience; receptor; response; skills; social; social anxiety; social defeat; social influence; synaptic function; therapy development; transmission process

PROJECT SUMMARY/ABSTRACT Fetal Alcohol Spectrum Disorder is a set of diverse conditions caused by prenatal alcohol exposure (PAE) that can produce a wide variety of physical, behavioral, and intellectual deficits persisting throughout the lifespan. Importantly, PAE is also associated with deficits in emotional regulation, including increased non-social and social anxiety. However, the PAE-induced neurobiological changes that underlie this heightened vulnerability to develop increased social anxiety are not well understood. This gap in knowledge is problematic because a precise understanding of neuroadaptations resulting from PAE is necessary to develop targeted treatments for individuals experiencing PAE-related social impairments. Activity of corticotropin-releasing factor (CRF) and its receptor (CRF1R) in the medial subnucleus of the central amygdala (CeM), has long been known to regulate anxiety-like behavior, and disruption of the function of the CeM CRF system could contribute to increased social anxiety-like behavior in individuals exposed to PAE. Our lab has recently demonstrated that moderate PAE on gestational day (G)12, around the time of neurogenesis in the rat amygdala, increased social anxiety- like behavior in adult male rats. Additionally, G12 PAE disrupted CRF1R modulated inhibitory neurotransmission and non-social anxiety-like behavior in male rats, suggesting that moderate G12 PAE impairs CeM CRF1R regulated synaptic and behavioral function in adult male rats. These deficits could subsequently alter the function of CeM downstream projection targets, such as the periaqueductal gray, which is a brain region known to regulate defensive behaviors in response to threats, including social threats. This led us to the development of our central hypothesis, that moderate G12 PAE increases social anxiety-like behavior due to decreased function of the CRF1R positive (+) CeM-PAG projection in male rats. To test this, we will use whole-cell patch clamp electrophysiology to assess differences in neuronal excitability and neurotransmission in PAG-projecting CRF1R+ cells. Additionally, we will chemogenetically stimulate the CRF1R+ CeM-PAG projection prior to testing in a modified social interaction test to generate a measure of social anxiety-like behavior. Finally, we will further explore the possibility that the PAG underlies PAE-induced social impairments by assessing differences in cellular activation in the PAG following social interaction testing in male and female rats. The proposed experiments will expand our understanding of PAE-induced alterations in neural mechanisms, how these alterations relate to social anxiety-like behavior, and provide evidence to inform future studies designed to investigate the neuroadaptations resulting from moderate PAE. Additionally, successful completion of the goals outlined in this proposal will provide me with training in cutting-edge techniques, science communication, and mentoring that will prepare me for a career as an independent scientist.

项目总结/文摘