Impact of alterations in mesolimbic innervation of the prefrontal cortex following adolescent alcohol exposure.

青少年酒精暴露后前额皮质中脑边缘神经支配变化的影响。

• 批准号: 10026016
• 负责人: Justine Landin
• 金额: $ 4.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-29 至 2021-04-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026016
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Affect; Alcohol abuse; Alcohols; Animal Model; Animals; Area; Aversive Stimulus; Axon; Back; Behavior; Behavior Control; Behavioral; Brain; Brain region; Chronic; Cognitive; Confocal Microscopy; Consumption; Data; Decision Making; Dendritic Spines; Development; Diffuse; Disease; Dopamine; Dopamine D1 Receptor; Environment; Ethanol; Extinction (Psychology); Fiber; Freezing; Fright; Functional disorder; Future; Goals; Growth; Immunofluorescence Immunologic; Individual; Investigation; Knowledge; Label; Lead; Life; Literature; Medial; Mediating; Mediator of activation protein; Methods; Microglia; Modeling; Morphology; Nature; Neuroglia; Neuroimmune; Neurons; Nucleus Accumbens; Pathway interactions; Phagocytosis; Play; Prefrontal Cortex; Presynaptic Terminals; Procedures; Process; Rattus; Regulation; Reporting; Research; Research Personnel; Resolution; Resources; Risk; Rodent Model; Role; Signal Transduction; Structure; Synapses; Techniques; Teenagers; Testing; Three-Dimensional Imaging; Three-dimensional analysis; Time; Training; Tyrosine 3-Monooxygenase; United States; Ventral Tegmental Area; Viral; Work; adolescent alcohol abuse; adolescent alcohol exposure; alcohol exposure; alcohol relapse; alcohol use disorder; avoidance behavior; axon guidance; behavioral impairment; binge drinking; cell type; confocal imaging; density; design; designer receptors exclusively activated by designer drugs; dopaminergic neuron; early adolescence; executive function; experimental study; flexibility; human model; innovation; insight; microscopic imaging; nerve supply; neural circuit; neuromechanism; neurotransmission; novel; postnatal development; pre-clinical; preclinical study; receptor; relating to nervous system; skills; synaptic pruning; tool; underage drinking

PROJECT SUMMARY Individuals that binge drink alcohol during adolescence are more likely to develop chronic, relapsing alcohol disorders at some point in their life. Studies in animals have also shown that repeated episodes of adolescent alcohol exposure lead to dysregulation of the medial prefrontal cortex (PFC) and deficits in inhibitory control and behavioral flexibility in adulthood. The goal of this proposal is to utilize a rodent model of adolescent intermittent ethanol (AIE) exposure to investigate mechanisms involved in alcohol-induced deficits in prefrontal function and behavioral control in adulthood. Recent research suggests that a subset of ventral tegmental area (VTA) dopaminergic projection neurons that initially innervate the nucleus accumbens (NAc) subsequently grow to the PFC, a process that is important for executive function in adulthood. While our lab has shown that AIE significantly impacts dopaminergic neurotransmission and regulation in the prelimbic (PrL) subregion of the PFC, it is unknown if the newly identified VTA-NAc-PrL pathway is altered by AIE exposure. Synaptic pruning in the medial PFC and NAc during adolescence is critical for inhibitory control and behavioral flexibility. Interestingly, accumulating data indicates that this process is facilitated through glial-mediated phagocytosis. Although it is known that alcohol can alter neuroimmune signaling, whether AIE exposure affects glial/neural interactions and glial morphology is not well understood. The overarching hypothesis of the current proposal is that AIE exposure reduces VTA innervation and neural/glial interactions in the PrL cortex, contributing to alterations in adult behavior. Specific Aim 1 will test the hypothesis that AIE exposure reduces the developmental innervation and synaptic refinement of VTA originating DA projections in the PrL cortex. This aim will use axon-initiated viral transduction, immunofluorescence, and advanced super-resolution confocal microscopy and 3D analysis to examine innervation of the PrL by VTA-DA neurons whose axons initially terminated in the NAc and then grew to the PrL during adolescence. In order to gain a broader perspective of alterations within the PrL-NAc circuit following AIE, studies will also examine glial interactions with PrL neurons that project back to the NAc. Specific Aim 2 will test the hypothesis that AIE and inhibition of the VTA-NAc-PrL projection will similarly alter active and passive avoidance in adulthood. This aim will gain insight into the impact of AIE and the VTA-NAc-PrL projection on behavioral flexibility. The novel platform-mediated avoidance task allows for the simultaneous investigation of both passive and active avoidance, an area in the developmental literature on AIE that has been relatively overlooked. Studies will also determine whether DREADD-mediated inhibition of the VTA-NAc-PrL pathway alters adult avoidance behavior in a similar manner to AIE. The novel conceptual nature of this proposal, in combination with state-of-the-art techniques and outstanding training resources will provide the PI with an increased skill set that will further the advancement towards a future as an independent academic researcher.

项目总结