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

项目总结 在美国，近1%的儿童经历过童年虐待或忽视，这可能会导致终生 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-肾上腺的调节失调。 (HPA)轴及其应激激素促肾上腺皮质激素释放因子(CRF)的释放 早期生活中的逆境改变了焦虑和对压力的反应。然而，社会互动 涉及促进奖励的神经回路和抑制焦虑的回路之间的协调，因此神经 调节早期生活逆境导致的社会缺陷的底物可能超出了HPA轴功能障碍，但 这还没有得到系统的调查。我们建议的研究将在多大程度上解决 逆境导致的社交缺陷是由焦虑与回报回路的功能障碍驱动的，这对有效地 治疗由儿童期虐待和忽视引起的精神障碍。我们的实验室使用的是小鼠母体早期分离 断奶(MSEW)模拟早期生活逆境，它有力地减少了社交互动，增加了焦虑- 类似的行为，重述了童年虐待和忽视的影响。我们的初步研究证明了一个中心 终纹前床核(ABNST)在MSEW所致社会功能障碍中的调节作用 关键的下一步是阐明管理MSEW的细胞类型和投影特定的aBNST机制- 导致社会赤字。首先，我们将调查MSEW导致的社会缺陷与 焦虑和奖励机制使用一小组稳健的行为分析来确定社交 动机和警觉性与MSEW和控制组的社会奖励或焦虑样行为的测量相关 老鼠。接下来，我们将确定aBNST中CRF表达的神经元以及aBNST向 下丘脑室旁核(PVN)或腹侧被盖区(VTA)与焦虑有关--以及 MSEW诱发社会缺陷的奖励相关机制使用多路方法 包括体内电生理学、联合逆行标记和免疫荧光成像，以及 特定于投影的化学发生操作实验。值得注意的是，这一领域以前的工作大多被忽视了 女性受试者，因此我们将性作为一个生物变量来增强我们的 调查结果。建议的研究将只由PI实验室的本科生进行，他们是 定期接受关于这里提出的每种方法的培训。这里的研究与NIMH的使命是一致的 精神疾病通过基础研究，将使本科生接触到初级生物医学研究，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.