Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking

强迫性饮酒发展过程中内侧前额叶皮层的突触变化

• 批准号: 10732680
• 负责人: SVEN KROENER
• 金额: $ 6.28万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10732680
• 关键词: Acute; Affect; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Anxiety; Applications Grants; Automobile Driving; Basic Science; Behavior; Chloride Channels; Chronic; Cognitive; Cognitive deficits; Collaborations; Cues; Data Analyses; Data Correlations; Development; Functional disorder; Funding Opportunities; Genetic Recombination; Glutamate Receptor; Glutamates; Goals; Halorhodopsins; Health; Impaired cognition; Impulsive Behavior; Individual; Knowledge; Light; Literature; Marble; Measures; Medial; Mental Depression; Modeling; Morphology; Motivation; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Output; Parents; Pathway interactions; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Program Development; Publications; Rattus; Receptor Up-Regulation; Relapse; Research; Research Training; Resistance; Rodent; Role; Science; Self Administration; Self Direction; Stress; Stress and Coping; Sucrose; Synapses; Synaptic plasticity; Testing; Time; Training; Training Programs; Withdrawal; Work; affective disturbance; alcohol availability; alcohol exposure; alcohol seeking behavior; anxiety-like behavior; behavior measurement; career development; cognitive function; doctoral student; drinking; drug of abuse; drug seeking behavior; executive function; experience; experimental study; feeding; flexibility; hippocampal pyramidal neuron; improved; incentive salience; interdisciplinary approach; learning extinction; negative affect; neuroadaptation; novel; optogenetics; parent grant; problem drinker; receptor upregulation; relapse prediction; research and development; response; training opportunity; vapor; Acute; Affect; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Anxiety; Applications Grants; Automobile Driving; Basic Science; Behavior; Chloride Channels; Chronic; Cognitive; Cognitive deficits; Collaborations; Cues; Data Analyses; Data Correlations; Development; Functional disorder; Funding Opportunities; Genetic Recombination; Glutamate Receptor; Glutamates; Goals; Halorhodopsins; Health; Impaired cognition; Impulsive Behavior; Individual; Knowledge; Light; Literature; Marble; Measures; Medial; Mental Depression; Modeling; Morphology; Motivation; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Output; Parents; Pathway interactions; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Program Development; Publications; Rattus; Receptor Up-Regulation; Relapse; Research; Research Training; Resistance; Rodent; Role; Science; Self Administration; Self Direction; Stress; Stress and Coping; Sucrose; Synapses; Synaptic plasticity; Testing; Time; Training; Training Programs; Withdrawal; Work; affective disturbance; alcohol availability; alcohol exposure; alcohol seeking behavior; anxiety-like behavior; behavior measurement; career development; cognitive function; doctoral student; drinking; drug of abuse; drug seeking behavior; executive function; experience; experimental study; feeding; flexibility; hippocampal pyramidal neuron; improved; incentive salience; interdisciplinary approach; learning extinction; negative affect; neuroadaptation; novel; optogenetics; parent grant; problem drinker; receptor upregulation; relapse prediction; research and development; response; training opportunity; vapor

The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol‐ associated cues. Repeated alcohol exposure induces neuroadaptations that persist beyond acute withdrawal, and which increase alcohol's incentive salience, leading to escalation of alcohol intake and aversion‐resistant alcohol seeking. Alcohol use also causes deficits in cognitive functions associated with the medial prefrontal cortex (mPFC), which further fuel compulsive drinking and relapse. In rodents, alcohol seeking activates specialized networks within the ventral (infralimbic, IL) and prelimbic (PL) regions of the mPFC, which play largely opposite roles in the control of relapse behavior. While activation of the PL drives reinstatement, neurons in the IL facilitate extinction learning and inhibit drug‐seeking through their projections to the Nucleus Accumbens shell, as well as the basolateral amygdala (BLA). However, there is a critical gap in the knowledge about the synaptic mechanisms that drive maladaptive plasticity in these circuits during the transition from controlled to compulsive alcohol‐seeking. Experiments in the parent grant application will provide a better understanding of network‐specific mechanisms through which chronic alcohol exposure and withdrawal affect executive cognitive functions of the mPFC and diminish inhibitory control over goal‐directed behavior. The objectives of this current proposal, which is submitted in response to opportunity “Research Supplement to Promote Diversity in Health‐Related Research (PA‐21‐071)”, are: First, to promote diversity in health‐related research by training Ms. Skylar Mendez, a PhD student from a background underrepresented in bio‐medical sciences, and second, to enhance a basic science aspect of the parent application by testing the central hypothesis that withdrawal‐activated neurons in the mPFC and the BLA are also responsible for negative affective states that emerge after prolonged alcohol exposure and withdrawal. Aim 1 will serve to train the candidate in behavioral measures of negative affect (specifically the Elevated Plus Maze, the Marble Burying Task, and the Novelty Suppressed Feeding Task) and to validate these measures in chronically EtOH‐exposed and withdrawn mice. In Aim 2 we will use Targeted Recombination in Active Populations (TRAP2) with Fos2AiCreER mice to express halorhodopsin selectively in withdrawal‐activated neurons in the IL and PL, respectively. Neurons TRAPed in this manner following either extended access to alcohol or under post‐dependent conditions will then be inhibited during tests of negative affect (as described in Aim 1) to determine the contribution of these neurons to withdrawal‐induced negative affective states. In Aim 3 we will similarly express halorhodopsin in TRAPed neurons in the BLA to test whether optogenetic silencing of withdrawal‐activated afferents from the BLA to the mPFC can reverse alcohol‐induced measures of negative affect. Taken together, these studies will provide important novel information about alcohol‐induced changes in networks of the mPFC and BLA that contribute to negative affect and cue‐induced reinstatement. This project will promote diversity in health‐related research, provide outstanding training opportunities in a multi‐level research training and career development program, and it will enhance the parent grant by determining whether specific withdrawal‐activated networks in the mPFC and BLA negative affect that contributes to relapse.

抑制饮酒的能力是恢复酗酒者的重大挑战，尤其是在酗酒的情况下 相关提示。反复的酒精暴露会引起神经适应的持续超出急性感谢和 增加酒精的激励性显着性，从而导致酒精摄入量和抗厌食症寻求饮酒。 使用还会导致与介质前额叶皮层（MPFC）相关的认知功能的防御能力，这进一步燃料 强迫性饮酒和救济。在啮齿类 MPFC的IL）和前比（PL）区域，它们在控制继电器行为中起着很大相反的作用。尽管 PL的激活驱动器恢复原状，IL中的神经元制备的扩展学习并通过 他们的项目投向了伏隔核的壳，以及基体杏仁核（BLA）。但是，有关键 关于在这些电路中驱动不良适应可塑性的突触机制的知识差距 从受控的寻求饮酒。父母赠款申请中的实验将提供更好的 了解慢性酒精暴露和戒断影响高管的网络特异性机制 MPFC的认知功能，并减少对目标指导行为的抑制作用。此电流的对象 提案，该提案是为了响应机会的“研究补充，以促进与健康相关的多样性的研究补充 研究（PA-21-071）”，是：首先，通过培训Skylar Mendez女士，促进与健康相关的研究的多样性，博士学位 来自生物医学科学的背景不足的学生，其次是为了增强基础科学方面 通过测试MPFC中戒断激活的神经元的中心假设是通过测试父母的应用。 还负责延长酒精暴露和戒断后出现的负面情感状态。目标1意志 服务以训练候选人的负面影响行为度量（特别是高架迷宫，大理石 埋葬任务以及新颖性抑制了喂养任务），并在长期暴露于EtOH的情况下验证这些措施 撤回的老鼠。在AIM 2中，我们将使用FOS2AICREER小鼠在活动种群（TRAP2）中使用有针对性的重组 分别在IL和PL中的戒断激活的神经元中选择性表达甲状腺素。神经元在此中被发现 在测试期间，将抑制延长酒精或在依赖后情况下的饮酒或在依赖后情况下的方式 负面影响（如目标1所述），以确定这些神经元对戒断阴性的贡献 在AIM 3中，我们将类似地表达BLA中曲面神经元中的卤代汀，以测试是否光遗传学 从BLA到MPFC的戒断激活传入的沉默可以反向酒精诱导的负数。 影响。综上所述，这些研究将提供有关酒精引起的网络变化的重要新颖信息 MPFC和BLA有助于负面影响和提示诱导的恢复原状。该项目将促进多样性 在与健康相关的研究中，在多级研究培训和职业中提供出色的培训机会 开发计划，它将通过确定特定的撤离激活来增强父母的赠款 MPFC和BLA负面影响的网络有助于退休。