Cell-type and projection-specific dissection of the bed nucleus of the stria terminalis in the mediation of social behavioral deficits induced by early life adversity

项目摘要 在美国，近1%的儿童在童年时受到虐待或忽视，这可能会导致终身 行为缺陷，包括社交行为障碍，如社交焦虑、依恋障碍、难相处的同伴 关系和外化行为。对调节早期生活逆境的神经机制的研究- 诱发的行为障碍主要集中在下丘脑-垂体-肾上腺的失调 (HPA)轴及其释放的应激激素促肾上腺皮质激素释放因子（CRF），其中占方面 早期生活逆境引起的焦虑和压力反应的改变。然而，社会互动 涉及促进奖励的神经回路和抑制焦虑的神经回路之间的协调， 基质介导的早期生活逆境诱导的社会缺陷可能超出HPA轴功能障碍，但 这一点尚未得到系统的调查。我们建议的研究将解决早期 逆境诱发的社交缺陷是由焦虑与奖励回路的功能障碍驱动的，这对有效地控制焦虑和奖励回路至关重要。 治疗儿童期虐待和忽视引发的疾病。我们的实验室使用小鼠母体分离， 断奶（MSEW）来模拟早期生活逆境，这强烈地减少了社会互动，增加了焦虑- 比如行为，重演童年虐待和忽视的影响。我们的初步研究表明 终纹前床核（aBNST）在MSEW诱导的社会缺陷中的调节作用， 关键的下一步是阐明控制MSEW的细胞类型和投射特异性aBNST机制， 造成社会赤字。首先，我们将调查MSEW引起的社会赤字和 焦虑和奖励机制，使用一个小电池的强大的行为分析，以确定是否社会 动机和警惕性与MSEW和控制中的社会奖励或焦虑样行为的测量相关 小鼠接下来，我们将确定aBNST中表达CRF的神经元以及aBNST投射到 下丘脑室旁核（PVN）或腹侧被盖区（VTA）有助于焦虑-和 奖励相关机制的基础MSEW引起的社会赤字使用一种多重的方法， 包括体内电生理学、结合的逆行标记和免疫荧光成像， 投射特异性化学遗传操作实验。值得注意的是，这一领域的先前工作大多忽视了 女性受试者，所以我们将包括性别作为一个生物变量，以提高我们的严谨性和可翻译性， 调查结果。拟议的研究将完全由PI实验室的本科生进行， 定期接受这里提出的每种方法的培训。这里的研究符合NIMH的使命， 精神疾病通过基础研究，将暴露本科生初级生物医学研究，并将 改善圣克拉拉大学的研究环境。

PROJECT SUMMARY Nearly one percent of children in the US experience childhood abuse or neglect, which can induce life-long behavioral deficits including social behavior disorders like social anxiety, attachment disorders, difficult peer relations, and externalizing behaviors. Investigations into the neural mechanisms mediating early life adversity- induced behavioral impairments have largely focused on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and its release of the stress hormone corticotropin-releasing factor (CRF), which account for aspects of altered anxiety and responsiveness to stress induced by early life adversity. However, social interaction involves coordination between neural circuits promoting reward and circuits inhibiting anxiety, and thus neural substrates mediating early life adversity-induced social deficits likely extend beyond HPA axis dysfunction, but this has not been systematically investigated. Our proposed studies will address the extent to which early adversity-induced social deficits are driven by dysfunction in anxiety versus reward circuits, critical for effectively treating disorders spurred by childhood abuse and neglect. Our lab uses mouse maternal separation with early weaning (MSEW) to model early life adversity, which robustly reduces social interaction and increases anxiety- like behavior, recapitulating effects of childhood abuse and neglect. Our preliminary studies evidenced a central regulatory role for the anterior bed nucleus of the stria terminalis (aBNST) in MSEW-induced social deficits, so the critical next step is to explicate cell-type and projection-specific aBNST mechanisms governing MSEW- induced social deficits. First we will investigate the relationship between MSEW-induced social deficits and anxiety and reward mechanisms using a small battery of robust behavioral assays to determine whether social motivation and vigilance correlate with measures of social reward or anxiety-like behavior in MSEW and control mice. Next we will determine how CRF-expressing neurons in the aBNST, as well as aBNST projections to the paraventricular nucleus of the hypothalamus (PVN) or ventral tegmental area (VTA) contribute to anxiety- and reward-related mechanisms underlying MSEW-induced social deficits using a multiplexed approach that includes in vivo electrophysiology, combined retrograde labeling and immunofluorescence imaging, and projection-specific chemogenetic manipulation experiments. Notably, prior work in this field has mostly neglected female subjects, so we will include sex as a biological variable to enhance the rigor and translatability of our findings. Proposed studies will be conducted exclusively by undergraduate students in the PI's lab who are regularly trained on each method proposed here. Studies here are in line with the NIMH's mission to understand mental illness through basic research, will expose undergraduates to primary biomedical research, and will enhance the research environment at Santa Clara University.