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

抑制饮酒的能力是戒酒的一个重大挑战，特别是在酒精存在的情况下- 关联的线索。反复酒精暴露会诱导神经适应，这种适应持续到急性戒断后，而且 增加酒精的激励突显，导致酒精摄入量的升级和抗厌恶的酒精寻求。酒精 使用还会导致与内侧前额叶皮质(MPFC)相关的认知功能障碍，这进一步加剧了 强迫饮酒和旧病复发。在啮齿类动物中，寻求酒精激活了腹侧(边缘下， MPFC的IL)和预备区(PL)，它们在控制复发行为方面扮演着截然相反的角色。而当 激活PL驱动恢复，IL中的神经元通过促进灭绝学习和抑制药物寻找 它们投射到伏隔核壳核以及基底外侧杏仁核(BLA)。然而，有一个关键的问题 关于突触机制的知识空白，这些突触机制在这些电路中驱动了不良适应可塑性 从控制性饮酒过渡到强迫性饮酒。在家长助学金申请中的实验将提供更好的 了解慢性酒精暴露和戒酒影响高管的网络特定机制 MPFC的认知功能，减少对目标导向行为的抑制性控制。这一趋势的目标是 提案，该提案是应Opportunity《促进与健康有关的多样性的研究补编》而提交的 研究(PA-21-071)“是：第一，通过培训博士Skylar Mendez女士促进与健康有关的研究的多样性 来自生物医学学科背景不足的学生，第二，加强基础科学方面的 通过测试中央假说，mPFC和BLA中的戒断激活神经元是 也是长期酒精暴露和戒酒后出现的负面情绪状态的罪魁祸首。目标1将 用来训练候选人的负面情绪的行为测量(特别是高架加迷宫，大理石 掩埋任务和新颖性抑制摄食任务)，并在长期接触乙醇和 撤退的老鼠。在目标2中，我们将使用活动群体中的定向重组(TRAP2)与Fos2AiCreer小鼠进行 在IL和PL的戒断激活神经元中分别选择性地表达卤视紫质。神经元被困在这里 在测试期间，在延长酒精接触或依赖后条件下的方式将被禁止 负性情绪(如目标1所述)，以确定这些神经元对戒断诱导的负性情绪的贡献 情感状态。在目标3中，我们将类似地在BLA中的陷阱神经元中表达卤视紫质，以测试光发生 沉默从BLA到mPFC的戒断激活的传入可以逆转酒精诱导的负性措施 影响。综上所述，这些研究将为酒精诱导的网络变化提供重要的新信息 MPFC和BLA导致负面情绪和线索诱导的恢复。这个项目将促进多样性 在与健康相关的研究方面，在多层次的研究培训和职业生涯中提供出色的培训机会 发展计划，它将通过确定是否激活特定的退出来增强父母的赠款 网络中的mPFC和BLA的负面影响，有助于复发。

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.