Identifying a role for the amygdala in social behavior deficits following early-life trauma

修改后的项目摘要/摘要部分 对于许多物种来说，获得关键资源，如食物、保护和接受配偶，需要高度协调和适应的社会行为系统。尽管社交行为对先前经历的敏感性可能是适应性的，但它也可能是有害的：研究表明，早期生活经历，特别是与照顾者相关的创伤，具有一种独特的能力，可以编程社交缺陷，这种缺陷会一直持续到成年。来自不同物种的数据似乎汇聚在杏仁核上，作为这些社会行为损害的中心中介。然而，杏仁核在虐待后产生社会缺陷中的具体作用，或者这种作用是否会在发育过程中发生变化，目前尚不清楚。 为了解决这一知识差距，并着眼于开发干预措施，我们建议研究早期生活虐待的啮齿动物模型中的社会行为和杏仁核功能回路。来自我们实验室的数据和为这项提议收集的试点数据支持这样的假设，即虐待照顾者会产生持续的社会缺陷，这种缺陷在断奶时出现与杏仁核回路的失调有关，并且在虐待之后的一段时间的环境丰富可以防止障碍的出现。此外，文献表明杏仁基底外侧核(BLA)和中央杏仁核(CEA)在调节社会行为方面具有特殊的作用。为了测试这一点，我们测量了在典型(对照)或虐待条件下饲养的大鼠的杏仁核激活情况，这些大鼠在断奶和成年时的社会行为测试中。接下来，我们将探索环境丰富对逆转早年虐待的效果。最后，我们将使用光遗传学工具剖析与这些效应相关的杏仁核回路。我们收集的数据表明，在受到照顾者的虐待后，同伴的社交行为缺陷将在断奶时出现(PN23)，并持续到成年(PN60)，并与BLA功能的变化有关。我们假设：1)在虐待之后，但在早期虐待导致的神经行为缺陷出现之前，丰富将恢复典型的社会行为和杏仁核功能；2)靶向光遗传抑制BLA-CEA回路将使被虐待动物的社会行为正常化，以控制水平。这里提出的工作将开始解决杏仁核回路在虐待后产生社交缺陷中的因果作用，并确定防止创伤后出现神经行为缺陷的干预措施。

Modified Project Summary/Abstract Section For many species, access to crucial resources, such as food, protection, and receptive mates, requires a highly coordinated and adaptable system of social behavior. Although the sensitivity of social behavior to previous experience can be adaptive, it also can be detrimental: research has shown that early-life experience, particularly trauma associated with a caregiver, has a unique ability to program social deficits that last well into adulthood. Data from a variety of species appears to converge on the amygdala as a central mediator of these impairments in social behavior. However, the specific role of the amygdala in producing social deficits following abuse, or whether this changes over the course of development, remain unclear. To address this gap in knowledge, and with an eye toward developing interventions, we propose to study social behavior and functional amygdala circuitry in a rodent model of early life abuse. Data from our lab and pilot data collected for this proposal supports the hypothesis that caregiver abuse produces persistent social deficits that emerge at weaning associated with dysregulation of amygdala circuitry, and that a period of environmental enrichment following abuse can prevent the emergence of impairments. Furthermore, the literature suggests a specific role for the basolateral (BLA) and central (CeA) amygdala nuclei in modulating social behavior. To test this, we have measured amygdala activation in rats that were reared in either typical (control) or abusive conditions during tests of social behavior at weaning and adulthood. Next, we will explore the efficacy of environmental enrichment on reversing the effects of early life abuse. Finally, we will dissect the amygdala circuitry causally involved in these effects using optogenetic tools. We have collected data showing that following abuse from a caregiver, peer social behavior deficits will emerge by weaning (PN23), persist into adulthood (PN60) and are linked to changes in BLA function. We hypothesize that 1) enrichment after abuse, but before emergence of neurobehavioral deficits induced by early-life abuse will restore typical social behavior and amygdala function, and 2) targeted optogenetic inhibition of the BLA-CeA circuit will normalize social behavior in abused animals to control levels. The work proposed here will begin to address the causal role of amygdala circuitry in producing social deficits following abuse and identify interventions to prevent emergence of neurobehavioral deficits following trauma.