Examining the neuronal mechanisms underlying stress-accelerated habit

大脑有两种行为控制策略。目标导向的行动依赖于预期 考虑潜在的结果和后果，以及习惯，反身性行为在没有 预先考虑到它们的后果。过度依赖习惯会导致不适应的强迫行为 以物质使用障碍和其他精神疾病为特征。压力是一个主要的易感因素 物质使用障碍，也可能导致对习惯的过度依赖。然而，我们对大脑的理解 缺乏压力影响习惯的机制，限制了我们对压力如何促进习惯的理解 物质使用障碍中的不适应强迫行为。因此，这个项目的总体目标是揭示 压力促进习惯养成的神经机制。 越来越多的证据表明，背内侧纹状体是基底神经节的一部分，负责 控制目标导向的行动。抑制背内侧纹状体，特别是DRD1直接通路 神经元，破坏目标导向的控制，导致对习惯的偏见。中央杏仁核(CEA)，多数 抑制性核团被认为是大脑压力反应的中枢。直到最近，人们还认为 CEA与背侧纹状体无直接联系。然而，现代追踪技术已经揭示了直接 我发现这两个区域之间的投射偏向背内侧纹状体。 有趣的是，在我的研究生工作中，我发现CEA投射到基底节的其他部分传达 关于厌恶刺激的信息。这让我产生了一个有趣的假说，杏仁核-纹状体投射 传达有关压力的信息，以阻止目标导向的行动，使行为偏向习惯。通过 拟议研究I将揭示中央杏仁核-纹状体投射在以下情况下的机制作用 压力强化的习惯养成。我将使用尖端的多方面方法来实现这一点 小鼠的神经科学技术。在目标1中，我将应用体内纤维光度成像和光遗传学 在复杂的行为范例中进行操作，以确定时间动态和充分性 中央杏仁核-纹状体投射在控制应激后习惯中的作用。在目标2中，我将揭示内生性 背内侧DRD1纹状体系统在习性形成过程中的活动动态及其变化 在没有CEA输入的情况下，不同之处在于使用化学遗传学。由此产生的发现将提供一个 无论是在正常情况下还是在压力暴露后，对习惯形成的机械理解。这将是 促进未来对这种现象的分子和细胞机制的研究，并为我的目标服务 改进药物使用障碍和其他应激相关疾病的治疗方法。 我将在加州大学洛杉矶分校的Wassum实验室进行这个项目，在一个出色的指导团队的指导下。 这个环境将为我提供在系统和行为方面的特殊智力和技术培训 神经科学，为我的独立研究生涯做好充分准备，研究压力在成瘾中的作用。

The brain has two strategies for behavioral control. Goal-directed actions which rely on prospective consideration of potential outcomes and consequences, and habits, reflexive behaviors executed without forethought of their consequences. Overreliance on habit causes maladaptive compulsive behavior that characterizes substance use disorder and other psychiatric conditions. Stress is a major predisposing factor to substance use disorder and can also cause an overreliance on habit. However, our understanding of the brain mechanisms by which stress influences habits is lacking, limiting our understanding of how stress promotes maladaptive compulsive behavior in substance use disorder. Therefore, the broad goal of this project is to reveal the neuronal mechanisms by which stress promotes habit formation. Accumulating evidence suggests that the dorsomedial striatum, part of the basal ganglia, is responsible for controlling goal-directed actions. Inhibition of the dorsomedial striatum, particularly Drd1+ direct pathway neurons, disrupts goal-directed control, resulting in a bias toward habits. The central amygdala (CeA), a majority inhibitory nucleus, is known to be a hub for stress-responsivity in the brain. Until recently, it was thought that the CeA and dorsal striatum are not directly connected. However, modern tracing techniques have revealed direct projections between these two regions, which I have found are biased towards the dorsomedial striatum. Interestingly, in my graduate work I discovered that CeA projections to other parts of the basal ganglia convey information about aversive stimuli. This led me to the intriguing hypothesis that amygdala-striatal projections convey information about stress to block goal-directed actions, biasing behavior toward habits. Through the proposed research I will reveal the mechanistic role of central amygdala-striatal projections in the context of stress-potentiated habit formation. I will accomplish this using a multifaceted approach of cutting-edge neuroscience techniques in mice. In Aim 1, I will apply in vivo fiber photometry imaging and optogenetic manipulation during a sophisticated behavioral paradigm to determine the temporal dynamics and sufficiency of central amygdala-striatal projections in controlling habits after stress. In Aim 2, I will reveal the endogenous activity dynamics of dorsomedial Drd1+ striatal ensembles during habit formation and how this activity is altered by stress and differs in the absence of CeA input using chemogenetics. The resulting findings will provide a mechanistic understanding of habit formation in both the normal context and after stress exposure. This will facilitate future work into the molecular and cellular mechanisms of this phenomenon and serve my goal of improving treatment approaches for substance use disorder and other stress-related conditions. I will conduct this project in the Wassum Lab at UCLA, with the guidance of a remarkable mentoring team. This environment will provide me with exceptional intellectual and technical training in systems and behavioral neuroscience, fully preparing me for an independent research career studying the role of stress in addiction.