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

测试电路可塑性在病理学和异常治疗中的作用

• 批准号: 9265946
• 负责人: Susanne Elizabeth Ahmari
• 金额: $ 47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265946
• 关键词: Address; Anxiety; Area; Autistic Disorder; Behavior; Behavioral; Biological Models; Biological Neural Networks; Brain; Brain region; Categories; Cells; Chronic; Clinical; Compulsive Behavior; Corpus striatum structure; Data; Development; Diagnostic; Disease; Disease model; Dorsal; Electrophysiology (science); Environmental Risk Factor; Event; Fluoxetine; Foundations; Fright; Functional Imaging; Gene Expression; Gene Targeting; Generations; Gilles de la Tourette syndrome; Goals; Grooming; Habits; Human; Individual; Interruption; Knowledge; Lead; Link; Location; Longitudinal Studies; Maps; Measurement; Measures; Medial; Mental disorders; Molecular; Mus; Neurocognitive; Neuronal Plasticity; Neurosciences; Obsessive-Compulsive Disorder; Onset of illness; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physiology; Population; Prevalence; Relapse; Resistance; Role; Schizophrenia; Science; Site; Specific qualifier value; Stereotyped Behavior; Stress; Structure; Symptoms; Synapses; Synaptic plasticity; System; Technology; Testing; Thalamic structure; Thinking; Time; Transcranial magnetic stimulation; Transgenic Organisms; Work; addiction; base; cost; disability; in vivo; insight; mouse model; neural circuit; novel; novel strategies; optogenetics; prevent; public health relevance; relating to nervous system; repetitive behavior; response; severe psychiatric disorder; translational study; treatment site; treatment strategy

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.

描述（由申请人提供）：刻板和强迫行为是多种严重精神疾病（包括自闭症、强迫症（OCD）和精神分裂症）中突出的、致残的和众所周知的难以治疗的症状。人们认为这些持续的行为是由这些行为引起的。多个方面的干扰 然而，导致异常重复行为的病理机制仍然未知，尽管持续行为与皮质-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机制。此外，我们对导致异常重复持续存在的因素的了解非常有限。 获得这些知识是开发新策略的关键一步，可以在持久行为形成之前中断它们，甚至完全阻止它们的发生。在这个项目中，我们将结合尖端的神经科学技术和可翻译的神经认知探针来识别分子。以及与持续行为的发作、持续和成功治疗相关的回路变化，目标是确定跨越诊断界限的新治疗策略，因为强迫症患者的聚合功能成像发现提供了这一点。为基于回路的转化研究奠定了坚实的临床基础，所获得的知识将广泛适用于具有持久思维模式和行为的其他严重精神疾病。 VMS）导致持续梳理行为的进行性且与刺激无关的增加，这是一种与人类强迫症相关的小鼠行为，同时伴随着 OFC 纹状体突触的诱发活动的增加。即使在没有刺激的情况下，行为异常仍然存在，这表明 OFC-VMS 预测的短暂但重复的过度刺激会产生回路功能的持久病理性足够的变化。在这个项目中，我们将测试关键 CSTC 的可塑性变化的中心假设。电路节点是异常重复行为诱导的基础，并且可以作为治疗途径。在目标 1 中，我们将通过使用 1) 体内可塑性变化的程度来绘制与异常重复行为发生相关的扩展神经网络。生理学和 2) 测量全脑神经可塑性标记物 fosB 的水平在目标 2 中，我们将通过阻断转基因 OCD 模型中连锁回路节点的异常活动来确定治疗强迫/刻板行为的最佳位点；将为基于大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行为的持续和复发相关的分子和环境因素，目标是找到预防症状的新目标。这些研究的最终目标是寻找新的治疗方案来消除顽固性和强迫性行为。