Neural regulation of social familiarity induced anxiolysis

 描述(申请人提供)：尽管社交熟悉诱导的焦虑症(SOFIA)现象已经被很好地记录了几十年，并且是大多数行为治疗技术的基础，但其背后的神经机制仍然知之甚少。对规范社会行为的基本原则的机制缺乏了解，严重限制了我们推进社会行为研究的能力。我们的长期目标是通过发现调节心理社会行为的机制并使改进的治疗策略得以发展来改善精神卫生保健。这项应用的总体目标是阐明社交熟悉度被编码为安全提示的基本机制，以及在社交熟悉度存在时抑制焦虑样反应的机制。我们的中心假设是，下缘皮质是调节社交熟悉度的获得和表达的神经回路中的关键部位。 诱导焦虑的减少。这项拟议的研究将定义调节索非亚获得性反应的神经回路和关键神经机制，并将确定诱导对社会熟悉的焦虑反应的关键神经通路。这一贡献意义重大，因为它将直接影响NIMH的两个优先事项：(1)增加我们对复杂社会行为的基本机制的理解；(2)阐明调节社会过程系统的RDoC域的神经回路，特别是“联系和依恋”的结构。从而提供了关键的见解，可以很容易地转化为临床研究范式，并朝着推进精神卫生保健的方向发展。目的1：确定社交熟悉性焦虑症的关键神经回路。使用CFO表达式，我们将 确定与Sofia的获得和表达有关的候选神经结构。这些结构中对获得Sofia至关重要的神经连接将使用体内光遗传学技术来确定，以瞬时失活从选定候选核到IL的投射，并确定哪一块获得Sofia。目的2：阐明社会熟悉性焦虑症的神经可塑性机制。使用高度创新的NAG(神经活动相关基因)和谷氨酸和可塑性相关基因表达阵列，我们将深入了解有助于SOFIA获得的神经元可塑性基因座。在索非亚收购阶段，IL内的定点药理学将决定特定谷氨酸受体在索非亚收购中的作用。目的3：确定调节焦虑症的关键神经联系，以回应社会熟悉度。在行为分析过程中，将使用体内光遗传技术，特别针对关键边缘结构中的IL投射，识别出表达Sofia所必需和充分的神经通路。

 DESCRIPTION (provided by applicant): Although the phenomenon of social familiarity-induced anxiolysis (SoFiA) has been well documented for decades, and is the basis of most behavioral therapy techniques, the neural mechanisms that underlie it are still poorly understood. This lack of knowledge regarding the mechanisms that regulate a basic principle governing social behavior severely limits our ability to advance social behavior research. Our long-term goal is to improve mental healthcare by discovering the mechanisms that regulate psychosocial behaviors and enabling development of improved treatment strategies. The overall objective of this application is to elucidate the fundamental mechanisms by which social familiarity becomes encoded as a safety cue and the mechanisms that suppress anxiety-like responses in its presence. Our central hypothesis is that the infralimbic cortex is the pivotal locus within the neural circuit that regulates the acquisition and expression of social familiarity induced reductions in anxiety. The proposed research will define the neural circuitry and the key neural mechanisms that mediate acquisition of SoFiA and will identify the pivotal neural pathways that induce the anxiolytic response to social familiarity. This contribution is significan because it will directly impact 2 NIMH priorities by (1) increasing our understanding of the fundamental mechanisms of complex social behavior and (2) elucidating the neural circuitry regulating the RDoC domain of Systems for Social Processes, specifically the construct "Affiliation and Attachment". Thus providing key insights that can be readily translated into clinical research paradigms and move towards advancing mental health care. Aim 1: Identify the neural circuitry critical for social familiarity-induced anxiolysis. Using cFos expression, we will identify candidate neural structures involved in the acquisition and expression of SoFiA. The neural connections within these structures that are pivotal to the acquisition of SoFiA will be determined using in vivo optogenetic techniques to transiently inactivate projections into the IL from select candidate nuclei and determine which block SoFiA acquisition. Aim 2: Elucidate neural plasticity mechanisms of social familiarity-induced anxiolysis. Using the highly innovative NARG (Neural Activity Related Gene) and glutamate- and plasticity-related genes expression array we will gain insights into the loci of neuronal plasticity that contributes to SoFiA acquisition. Site directed pharmacology within the IL during the SoFiA acquisition phase will determine the role of specific glutamate receptors in SoFiA acquisition. Aim 3: Identify the pivotal neural connections that modulate anxiolysis in response to social familiarity. Neural pathways that are necessary and sufficient for expression of SoFiA will be identified using in vivo optogenetic techniques specifically targeting IL projections in key limbic structures during behavioral assays.