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（由适用提供）：在多种严重的精神疾病中，刻板印象和强迫性行为是突出的，残疾和臭名昭著的抗药性症状，包括自闭症，强迫症（OCD）和精神分裂症。人们认为这些毅力行为是由于多个的破坏而导致的 神经认知领域，包括反应抑制和习惯形成。但是，导致异常重复行为的病理机制仍然未知。尽管持续性行为与皮质 - 纹状体 - 丘脑（CSTC）电路中的异常活性有关，但仍不清楚异常神经元活动如何触发这些不良适应性作用。此外，我们对导致异常重复性持续性的因素的洞察力非常有限 行为。获得这些知识是制定新颖策略来打断毅力行为的关键一步，甚至在他们成为顽固的行为之前，甚至完全阻止了他们的发作。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问题，以识别与发作，持久性和成功治疗持续行为相关的分子和电路变化，并识别削减跨诊断边界的新型治疗策略。尽管该项目将集中在强迫症上，因为OCD患者的收敛功能成像发现为基于电路的翻译研究提供了良好的临床基础，但获得的知识将广泛适用于具有持久性思维模式和动作的其他严重精神病患者。在先前的工作中，我们表明，反复对从轨道额皮层（OFC）到腹侧纹状体（VM）的项目反复刺激导致持续性修饰的逐渐逐渐依赖性和刺激性增加，这是与人类中OCD相关的小鼠行为。这是通过在OFC-纹状体突触上增加的诱发活性来实现的。即使没有刺激，行为异常也持续存在，这表明对OFC-VMS项目的短暂但反复的过度刺激足以在电路功能中产生持久的病理变化。在该项目中，我们将测试中心假设，即关键CSTC电路节点的可塑性是诱导异常重复行为的基础的，并且可以作为治疗途径。在AIM 1中，我们将通过确定使用体内生理学和2）测量神经元可塑性标记的大脑范围水平的范围来绘制与异常重复行为发作相关的扩展神经网络。在AIM 2中，我们将确定通过转基因强迫症模型中连接的电路节点中的封闭电路节点中的异常活性来治疗强迫性/定型行为的最佳位点；这将为基于大脑刺激治疗的策略提供依据。在AIM 3中，我们将开始确定与持久性和持久行为相关的分子和环境因素，其目的是寻找新的目标以防止症状加强。这些研究的最终目标是确定禁用持久性和强迫性行为的新治疗选择。