Projection-specific contributions of the ventromedial prefrontal cortex to fear extinction and fear generalization

腹内侧前额叶皮层对恐惧消退和恐惧泛化的投射特异性贡献

基本信息

批准号：
8982002
负责人：
Zachary Thomas Pennington
金额：
$ 3.44万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8982002
关键词：
Accounting Affect Affective Amygdaloid structure Anxiety Behavior Behavior Therapy Biological Biological Markers Brain region Cell Nucleus Chronic Development Disease Environment Excitotoxic lesion Experimental Designs Exposure to Extinction (Psychology)Foundations Freezing Fright Functional disorder Generations Individual Intercalated Cell Intervention Laboratories Lead Light Mediating Memory Modeling Neurons Output Pathway interactions Patients Pharmacological Treatment Play Post-Traumatic Stress Disorders Prefrontal Cortex Prevalence Prevention program Process Public Health Rattus Recruitment Activity Relative (related person)Resistance Risk Factors Rodent Rodent Model Role Stimulus Structure Structure of terminal stria nuclei of preoptic region Symptoms Synapses Syndrome Testing Thinking Time Trauma Treatment Efficacy United States Work base conditioned fear disorder prevention disorder risk experience fear memory insight learning extinction memory process new technology new therapeutic target novel novel strategies novel therapeutics public health relevance research study response stressor therapeutic target traumatic event vigilance

项目摘要

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is a chronic, debilitating, syndrome, with an estimated lifetime prevalence of approximately 7% in the United States. Although there are affective behavioral and pharmacological treatments for PTSD, substantial gaps in treatment remain. The generation of novel treatment options is therefore paramount. Reduced activation of the ventromedial prefrontal cortex (vmPFC) has consistently been observed in PTSD patients, and may represent a biological target for treatment. However, just how alterations in vmPFC function contribute to PTSD symptomology, or how this region might be pharmacologically targeted, is presently unknown. Although previous findings suggest that this brain region is likely to be important for the reduction of fear responses to stimuli whe they are no longer predictive of threat (fear extinction), recent evidence suggests that the vmPFC may also play a role in reducing the generalization of fear states to situations in which a threat has not been experienced (fear generalization). The studies in this proposal seek to advance our understanding of how hypofunction of the vmPFC contributes to PTSD risk and symptomology, and provide novel insight into how deficits in fear extinction and fear generalization in PTSD might be generated by distinct downstream output structures of the vmPFC. Using a rodent model of PTSD, the proposed experiments will first determine the time points at which vmPFC hypoactivity are likely to contribute to symptoms. This will be done by comparing the effects of inactivating the vmPFC at the time of trauma, at the time of fear generalization, or at the time of fear extinction. This will help to identify when interventions directed at the vmPFC are likely to be beneficial. Furthermore, this work will be the foundation for studies aimed at understanding what other brain regions the vmPFC works in concert with in the modulation of fear responses. Second, using novel technology that allows specific connections between the vmPFC and selected brain regions to be inactivated, it will be determined whether different vmPFC connections play distinct roles in fear extinction and fear generalization. In particular, the hypothesis to be tested is that projections from the vmPFC to the intercalated cells of the amygdala mediate fear extinction, whereas projections from the vmPFC to the bed nucleus of the stria terminalis mediate fear generalization. By elucidating the direct mechanism by which the vmPFC interacts with other brain regions in PTSD-related behaviors, potentially novel therapeutic targets can be discovered.

描述（由适用提供）：创伤后应激障碍（PTSD）是一种慢性，衰弱的，综合征，估计终生患病率约为7％。尽管有针对性PTSD的情感行为和药物治疗，但仍有大幅度的治疗差异。因此，新颖的治疗选择的产生至关重要。腹侧前额叶皮层（VMPFC）的激活减少，尽管以前的发现表明，当该大脑区域不再预测威胁（恐惧延伸）时，对于减少对刺激的恐惧反应可能很重要，但最近的证据表明，VMPFC在恐惧状态的普遍性中也可能在恐惧状态下起作用，而不是恐惧的普遍性，而不是恐惧的普遍性（这是一项局势的普遍性）。该提案中的研究旨在促进我们对VMPFC的功能障碍有助于PTSD风险和症状的理解，并提供新的见解，以了解如何通过VMPFC的不同下游输出结构来产生PTSD中恐惧扩展和恐惧概括的定义。使用PTSD的啮齿动物模型，拟议的实验将首先确定VMPFC低连贯性可能导致症状的时间点。这将通过比较在创伤时，恐惧概括或恐惧扩展时灭活VMPFC的效果来完成。这将有助于确定何时针对VMPFC的干预措施可能是有益的。此外，这项工作将是旨在理解VMPFC在恐惧反应调节中协同工作的其他大脑区域的基础。其次，使用允许VMPFC和选定的大脑区域之间特定连接的新型技术被灭活，将确定不同的VMPFC连接是否在恐惧扩展和恐惧概括中起着独特的作用。特别是，要检验的假设是，从VMPFC到杏仁核的插入细胞的项目介导了恐惧的扩展，而从VMPFC到Stria terminalis末端的床核的项目介导了恐惧的概括。通过阐明VMPFC与PTSD相关行为中其他大脑区域相互作用的直接机制，可以发现潜在的新型治疗靶点。