Thalamolimbic circuit mechanisms for social threat processing

创伤后应激障碍(PTSD)患者在威胁抑制方面出现衰弱缺陷，导致 高度警觉，再次经历创伤事件，以及严重的睡眠障碍。由成长中的身体支撑 科学证据表明，这些症状是由适应不良的应激反应引起的 威胁神经回路。因此，压力和威胁网络中重叠的区域--创伤可能危及 自适应威胁处理的完整性--需要进行彻底的科学检查。我最近发现了一个 丘脑中央内侧前(ACMT)细胞群，表达明确的应激信号 神经肽、促肾上腺皮质激素释放激素(CRH)和密集神经支配杏仁前基底外侧核 (ABLA)-一个在恐惧表达和消亡方面具有公认作用的大脑区域。在经历社会创伤的小鼠身上 以转化型慢性社会失败压力(CSDS)的形式，促进了对SAFE的极端防御 社交伙伴。这种适应不良的防御行为与CRH aCMT神经元活动不足有关 可以通过对该细胞群体的光遗传刺激来缓解；相反，CRH的光遗传抑制 ACMT神经元严重扰乱了CSDS-幼稚小鼠的社交能力。因此，我建议aCMT是一种 在我们对压力和恐惧交叉神经回路的理解中，重要的“缺失环节”和ABLA- 投射的aCMT(ACMTaBLA)细胞有助于社会创伤后持续的不良适应防御。使用 利用雷斯勒实验室在基因和分子技术方面的广泛专业知识和巴甫洛夫式的恐惧 条件反射，我将系统地研究CSDS对cCMTaBLA神经活动的动态影响。 EDGE转录、分子和行为神经科学方法。对于目标1，我将使用光纤光度法 在行为小鼠中，记录了来自CRH的aCMTaBLA细胞，作为社会防御系统在CSDS暴露后发展起来。我 假设防御性社会行为将与CMTaBLA神经活动负相关，我预计 在社交恐惧消退学习期间恢复神经活动。对于目标2，我将使用定向重组 激活的细胞群体(TRAP2)，以分离在之前的社会互动中激活的aCMTaBLA细胞 CSDS-此社交合奏可以通过遗传方式访问，以恢复暴露后的适应性交互 造成社会创伤。这一尖端的遗传方法将被用来研究CSDs对 ACMT和ABLA社交乐团。在CSD后恢复社交能力，社交过程中异常的神经活动 防御性将触发针对被捕获的aCMTaBLA细胞的闭环光遗传刺激。 在探索性目标3中，将分离地中海边缘社会群体，以确定转录反应 CSDs。总之，这项工作将批判性地研究社会创伤对一种新的丘脑边缘通路的影响。 -aCMTaBLA--与压力和恐惧神经回路相交。闭合环光遗传学将针对异常的社会 应激诱导aCMTaBLA社会细胞群中的神经活动以恢复适应性社交能力。

Patients with posttraumatic stress disorder (PTSD) experience debilitating deficits in threat inhibition, resulting in hypervigilance, reexperiencing traumatic events, and severe sleep disturbances. Supported by a growing body of scientific evidence, it is apparent that these symptoms result from maladaptive stress responses that derail threat neurocircuitry. Therefore, regions of overlap in stress and threat networks - where trauma could jeopardize the integrity of adaptive threat processing - warrant thorough scientific examination. I recently discovered a population of anterior central medial thalamic (aCMT) cells that expresses the well-characterized stress signaling neuropeptide, corticotropin-releasing hormone (Crh) and densely innervates the anterior basolateral amygdala (aBLA) - a brain area with a recognized role in fear expression and extinction. In mice, experiencing social trauma in the form of translational chronic social defeat stress (CSDS) promotes extreme defensiveness toward safe social partners. This maladaptive defensive behavior is associated with hypoactivity in Crh+ aCMT neurons and can be relieved through optogenetic stimulation of this cell population; conversely, optogenetic inhibition of Crh+ aCMT neurons severely disrupts sociability in CSDS-naïve mice. As such, I propose that the aCMT is an important “missing link” in our understanding of intersecting stress and fear neurocircuitries and that aBLA- projecting aCMT (aCMTaBLA) cells contribute to persistent maladaptive defensiveness after social trauma. With access to the Ressler Laboratories’ extensive expertise in genetic and molecular techniques and Pavlovian fear conditioning, I will systematically examine the dynamic effects of CSDS on aCMTaBLA neural activity using cutting- edge transcriptional, molecular and behavioral neuroscience approaches. For Aim 1, I will use fiber photometry in behaving mice to record from Crh+ aCMTaBLA cells as social defense develops after CSDS exposure. I hypothesize that defensive social behaviors will negatively correlate with aCMTaBLA neural activity and I expect neural activity to recover during social fear extinction learning. For Aim 2, I will use Targeted Recombination of Activated cell Populations (TRAP2) to isolate aCMTaBLA cells that are activated during social interactions before CSDS – this social ensemble can be accessed genetically to recover adaptive interactions following exposure to social trauma. This cutting-edge genetic methodology will be leveraged to examine the effects of CSDS on aCMT and aBLA social ensembles. To recover sociability after CSDS, aberrant neural activity during social defensiveness will trigger closed-loop optogenetic stimulations that target TRAPed aCMTaBLA cells. Thalamolimbic social ensembles will be isolated in Exploratory Aim 3 to identify transcriptional repercussions of CSDS. In summary, this work will critically examine the effects of social trauma on a novel thalamolimbic pathway - aCMTaBLA - that intersects with stress and fear neurocircuits. Closed-loop optogenetics will target aberrant social stress-induced neural activity in aCMTaBLA social cell ensembles to recover adaptive sociability.