Thalamolimbic circuit mechanisms for social threat processing

用于社会威胁处理的丘脑环路机制

• 批准号: 10542662
• 负责人: Emily L Newman
• 金额: $ 5.16万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542662
• 关键词: Adolescent; Amygdaloid structure; Anterior; Area; Attention; Award; Behavior; Behavioral; Biosensor; Brain; Cells; Chronic; Corticotropin-Releasing Hormone; Cues; Deep Brain Stimulation; Exhibits; Exposure to; Extinction; Face; Female; Fiber; Fiber Optics; Fluorescence; Fluorescence-Activated Cell Sorting; Fright; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic; Genetic Recombination; Genetic Transcription; Glutamates; Goals; Hippocampus; Image; Impairment; Investigation; Laboratories; Learning; Link; Measures; Medial; Mediating; Methodology; Methods; Modeling; Molecular; Molecular Biology; Mus; Neurons; Neuropeptides; Neurosciences; Pathway interactions; Patients; Pattern; Photometry; Population; Post-Traumatic Stress Disorders; Reaction; Research; Role; Signal Transduction; Sleep disturbances; Social Behavior; Social Interaction; Sorting; Stress; Symptoms; Techniques; Testing; Thalamic structure; Training; Trauma; Viral; Virus; Work; biological adaptation to stress; conditioned fear; experience; fluorescence imaging; genome wide association study; genome-wide; high risk; in vivo; inducible Cre; insight; interpersonal trauma; learning extinction; male; mouse model; neural; neural circuit; novel; optical fiber; optogenetics; postsynaptic; presynaptic; selective expression; single-cell RNA sequencing; social; social contact; social defeat; social stress; stressor; traumatic event

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.

患有创伤后应激障碍（PTSD）的患者在威胁抑制方面经历了令人衰弱的缺陷， 过度警觉，重新经历创伤事件，以及严重的睡眠障碍。由不断增长的身体支撑 根据科学证据，很明显，这些症状是由适应不良的压力反应造成的， 威胁神经回路因此，压力和威胁网络的重叠区域-创伤可能危及 自适应威胁处理的完整性-需要彻底的科学检查。我最近发现了一个 前中央内侧丘脑（aCMT）细胞群，表达特征明确的应激信号 神经肽，促肾上腺皮质激素释放激素（Crh）和密集支配前基底外侧杏仁核 （aBLA）-一个在恐惧表达和消退中具有公认作用的大脑区域。在老鼠身上，经历社会创伤 以转化的慢性社会失败压力（CSDS）的形式促进对安全的极端防御 社会伙伴。这种适应不良的防御行为与Crh+ aCMT神经元的活动减退有关， 可以通过该细胞群的光遗传学刺激来缓解;相反，Crh+的光遗传学抑制 aCMT神经元严重破坏CSDS-幼稚小鼠的社交能力。因此，我建议该委员会是一个 重要的“缺失环节”，在我们的理解交叉压力和恐惧神经回路和aBLA- 突出的aCMT（aCMTaBLA）细胞有助于社会创伤后的持续适应不良防御。与 获得雷斯勒实验室在遗传和分子技术以及巴甫洛夫恐惧方面的广泛专业知识 条件反射，我将系统地研究CSDS对aCMTaBLA神经活动的动态影响，使用切割- 边缘转录，分子和行为神经科学方法。对于目标1，我将使用光纤测光 在行为小鼠中，从Crh+ aCMTaBLA细胞记录CSDS暴露后社会防御的发展。我 假设防御性社会行为与aCMTaBLA神经活动呈负相关，我预计 在社交恐惧消退学习过程中恢复神经活动。对于目标2，我将使用 活化细胞群（TRAP 2），以分离在社交互动期间活化的aCMTaBLA细胞， CSDS -这种社会群体可以通过遗传方式获得，以恢复暴露后的适应性互动 社会创伤。这种尖端的遗传学方法将被用来研究CSDS对 aCMT和aBLA社会合奏。为了恢复CSDS后的社交能力，社交过程中异常的神经活动 防御性将触发靶向TRAPed aCMTaBLA细胞的闭环光遗传学刺激。 在探索性目标3中，将分离丘脑边缘的社会性集合，以确定 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交叉。闭环光遗传学将针对异常的社会 aCMTaBLA社会细胞集合中应激诱导的神经活动以恢复适应性社会性。

项目成果

Automatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress.

• DOI: 10.1038/s41467-023-40040-3
• 发表时间: 2023-07-18
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bordes, Joeri;Miranda, Lucas;Reinhardt, Maya;Narayan, Sowmya;Hartmann, Jakob;Newman, Emily L.;Brix, Lea Maria;van Doeselaar, Lotte;Engelhardt, Clara;Dillmann, Larissa;Mitra, Shiladitya;Ressler, Kerry J.;Puetz, Benno;Agakov, Felix;Mueller-Myhsok, Bertram;Schmidt, Mathias V.
• 通讯作者: Schmidt, Mathias V.