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。早期生活逆境的神经机制研究 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)轴及其释放应激激素促肾上腺皮质激素释放因子(CRF)，这解释了 早期生活中的逆境引起的焦虑和对压力反应的改变。然而，社交 相互作用涉及促进奖励的神经回路和抑制焦虑的回路之间的协调，以及 因此，调节早期生活逆境导致的社会缺陷的神经底物可能超出了HPA轴 功能障碍，但这还没有得到系统的调查。我们的父母助学金旨在解决 早期逆境导致的社会缺陷在多大程度上是由焦虑与奖励的功能障碍驱动的 循环，对于有效治疗因童年虐待和忽视而引起的障碍至关重要。我们的实验室用的是老鼠 母体分离与早期断奶(MSEW)模拟早期生活逆境，这有力地减少了社会 相互作用和增加焦虑类行为，重述童年虐待和忽视的影响。之前 我和其他人的实验室的研究结果一直表明，啮齿动物的母体分离程序对 对女性的影响大于对男性的影响。这反映了人类的临床人口，正如女性所展示的那样 与焦虑相关的障碍和抑郁的发生率比男性更高。在为父母的资助进行研究时 考虑到性是一个实验因素，我们设计了一项研究，以进一步研究早期生活的暴露 逆境干扰了性二态神经系统的发展，使其永久改变 行为。Janet Ronquillo女士将在毕业后的空档年期间进行这项实验 她还将遵循一个严格的计划，为她未来的职业道路上的成功奠定基础。

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 accounts 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 parent grant is designed to 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. Prior findings in my and others’ labs have consistently shown that rodent maternal separation procedures adversely affect females to a greater extent than males. This mirrors the human clinical population, as females exhibit greater rates of anxiety-related disorders and depression than males. While research for the parent grant considers sex as an experimental factor, we have devised a study to further examine how exposure to early life adversity interferes with the development of sexually dimorphic neuronal systems to permanently alter behavior. Ms. Janet Ronquillo will carry out this experimentation during a post-baccalaureate gap year, during which she will also follow a rigorous plan to set her up for success in her future career path.