Testing the Role of Circuit Plasticity in the Pathology and Treatment of Abnormal

描述(由申请人提供)：刻板印象和强迫行为是多种严重精神疾病的突出、残疾和臭名昭著的治疗抵抗症状，包括自闭症、强迫症(OCD)和精神分裂症。据认为，这些持之以恒的行为是由于多次中断造成的 神经认知领域，包括反应抑制和习惯形成。然而，导致异常重复行为的病理机制仍不清楚。虽然持之以恒的行为与皮质-纹状体-丘脑(CSTC)回路的异常活动有关，但仍不清楚异常的神经活动是如何触发这些适应不良行为的。此外，我们对导致不正常重复的持续存在的因素的洞察非常有限 行为。获得这些知识是开发新的策略的关键一步，这些策略可以在坚持不懈的行为变得根深蒂固之前中断它们，甚至完全阻止它们的发生。在这个项目中，我们将结合尖端神经科学技术和可翻译的神经认知探针来识别与持续性行为的开始、持续和成功治疗相关的分子和电路变化，目标是确定跨越诊断界限的新治疗策略。虽然这个项目将专注于强迫症，因为来自强迫症患者的聚合功能成像结果为基于电路的翻译研究提供了坚实的临床基础，但所获得的知识将广泛适用于具有坚持不懈思维模式和行动的其他严重精神障碍。在以前的工作中，我们发现重复超刺激从眼眶额叶皮质(OFC)到腹内侧纹状体(VMS)的投射导致持续性梳理的渐进性和非刺激性增加，这是一种与人类强迫症相关的小鼠行为。伴随而来的是OFC-纹状体突触的诱发活动增加。即使在没有刺激的情况下，行为异常仍然存在，这表明短暂但重复的OFC-VMS投射的过度刺激足以导致电路功能的长期病理变化。在这个项目中，我们将检验这一中心假设，即CSTC关键电路节点的可塑性变化是诱导异常重复行为的基础，并可能作为治疗的途径。在目标1中，我们将通过1)体内生理学和2)测量神经可塑性标记物�FosB的全脑水平来确定可塑性变化的程度，从而绘制与异常重复行为的开始相关的扩展神经网络。在目标2中，我们将通过阻断转基因强迫症模型中连接回路节点的异常活动来确定治疗强迫/刻板行为的最佳部位；这将为基于脑刺激的治疗提供靶向策略。在目标3中，我们将开始识别与持续性行为的持续和复发相关的分子和环境因素，以期找到新的靶点来防止症状的根深蒂固。这些研究的最终目标是确定新的治疗方案，以消除坚持不懈和强迫行为。

DESCRIPTION (provided by applicant): Stereotyped and compulsive behaviors are prominent, disabling, and notoriously treatment-resistant symptoms in multiple severe psychiatric disorders, including autism, Obsessive Compulsive Disorder (OCD), and schizophrenia. It is thought that these perseverative behaviors result from disruptions in multiple neurocognitive domains, including response inhibition and habit formation. However, the pathologic mechanisms leading to abnormal repetitive behaviors are still unknown. Though perseverative behaviors are associated with abnormal activity in cortico-striatal-thalamic (CSTC) circuits, it is still unclear how aberrant neural activity triggers these maladaptive actions. In addition, we have very limited insight into factors that lead to persistence of abnormal repetitive behaviors. Obtaining this knowledge is a critical step towards developing novel strategies for interrupting perseverative behaviors before they become hard-wired, or even completely preventing their onset. In this project, we will combine cutting-edge neuroscience technologies and translatable neurocognitive probes to identify molecular and circuit changes linked to onset, persistence, and successful treatment of perseverative behaviors, with a goal of identifying novel treatment strategies that cut across diagnostic boundaries. Though this project will focus on OCD since convergent functional imaging findings from OCD patients provide a strong clinical foundation for circuit-based translational studies, knowledge gained will be broadly applicable to other severe psychiatric disorders with perseverative thought patterns and actions. In previous work, we showed that repeated hyperstimulation of projections from orbitofrontal cortex (OFC) to ventromedial striatum (VMS) led to a progressive and stimulation-independent increase in perseverative grooming, a mouse behavior relevant to OCD in humans. This was accompanied by increased evoked activity at OFC-striatal synapses. Behavioral abnormalities persisted even in the absence of stimulation, suggesting that brief but repeated hyperstimulation of OFC-VMS projections is sufficient to yield long-lasting pathologic changes in circuit function. In this project, we will test the central hypothesis that plasticity changes at key CSTC circuit nodes underlie the induction of abnormal repetitive behaviors, and may serve as an avenue for treatment. In Aim 1, we will map the extended neural network associated with onset of abnormal repetitive behaviors, by determining the extent of plasticity changes using 1) in vivo physiology and 2) measurement of brain-wide levels of a neural plasticity marker, �fosB. In Aim 2, we will determine optimal sites for treatment of compulsive/ stereotyped behaviors via blockade of abnormal activity in linked circuit nodes in transgenic OCD models; this will inform targeting strategies for brain-stimulation based treatments. In Aim 3, we will begin to identify molecular and environmental factors associated with persistence and relapse of perseverative behaviors, with a goal of finding new targets to prevent symptom entrenchment. The ultimate goal of these studies is to identify new treatment options for disabling perseverative and compulsive behaviors.