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

 描述（由申请人提供）：创伤后应激障碍（PTSD）是一种慢性、使人衰弱的综合征，在美国估计终生患病率约为7%。虽然有情感行为和药物治疗创伤后应激障碍，在治疗方面仍然存在很大的差距。因此，产生新的治疗方案至关重要。在PTSD患者中一直观察到腹内侧前额叶皮层（vmPFC）的激活减少，这可能是治疗的生物学靶点。然而，vmPFC功能的改变如何有助于PTSD神经病学，或者该区域如何成为靶点，目前尚不清楚。虽然以前的研究结果表明，这一大脑区域可能是重要的减少恐惧反应的刺激时，他们不再预测的威胁（恐惧灭绝），最近的证据表明，vmPFC也可能发挥作用，减少恐惧状态的泛化的情况下，威胁还没有经历过（恐惧泛化）。本提案中的研究旨在促进我们对vmPFC功能减退如何导致PTSD风险和创伤学的理解，并提供新的见解，以了解PTSD中恐惧消退和恐惧泛化的缺陷如何由vmPFC的不同下游输出结构产生。使用PTSD的啮齿动物模型，拟议的实验将首先确定vmPFC活动减退可能导致症状的时间点。这将通过比较在创伤时、恐惧泛化时或恐惧消退时失活vmPFC的影响来完成。这将有助于确定针对vmPFC的干预措施何时可能有益。此外，这项工作将为旨在了解VMPFC在调节恐惧反应中与其他大脑区域协同工作的研究奠定基础。第二，使用新技术，允许vmPFC和选定的大脑区域之间的特定连接被灭活，这将确定不同的vmPFC连接是否在恐惧消退和恐惧泛化中发挥不同的作用。特别是，要测试的假设是，预测从VMPFC的杏仁核的闰细胞介导的恐惧灭绝，而预测从VMPFC的终纹床核介导的恐惧泛化。通过阐明VMPFC与PTSD相关行为中其他脑区相互作用的直接机制，可以发现潜在的新治疗靶点。

 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.