Investigating Orbitofrontal Circuit Mechanisms of Social Rank and Dominance Behavior

在整个动物界，社会物种建立社会等级，并使用社会等级来指导对生存至关重要的优势行为的适当表达。神经生物学研究已经证实，内侧前额叶皮质到下丘脑外侧的投射回路在代表社会等级和调节社会支配行为的表达方面起着关键作用。眼眶前额叶皮质(OFC)也被证明处理社会信息。OFC过程被认为是由皮质下结构(如中缝背核(DRN)等已知的调节社交能力的皮质下结构)的大量神经调制神经介导的。5-羟色胺(5-HT)DRN神经元被认为是调节社会交往行为的关键神经底物，它们为OFC提供大部分5-羟色胺能神经支配。然而，目前尚不清楚DRN5-HT-OFC电路是否能够处理社会排名信息来影响社会排名所决定的行为。我们的研究计划旨在表征OFC在代表社会等级中的作用，并首次揭示OFC与5-羟色胺能系统的相互作用是否调节社会竞争中社会支配行为的表达。这个项目的中心假设是，OFC在社会竞争中编码社会排名信息，来自DRN的5-羟色胺能输入调节优势行为的表达。为了验证这一点，这项研究将使用机器学习工具来自动跟踪和分类多个动物的社会竞争行为。然后，这项研究将通过测量与分类的社会竞争行为相一致的群体动态来表征由OFC神经元编码的行为状态。最后，本项目中的实验将激活DRN5-HT-OFC投射终末，并建立操纵5-羟色胺能回路活动如何改变社会竞争中社会支配行为的表达。该项目的发现将建立一种新颖的、特定于电路的机制，以确定大脑如何处理社会排名信息，从而在社会竞争中相应地调整行为。更好地了解控制社会行为适当表达的神经机制将为临床医生和翻译研究人员提供巨大的价值，他们希望治疗在精神疾病中观察到的社会行为控制缺陷。泰伊实验室在社会行为和神经回路解剖方面的专业知识将使这项建议的执行成为可能，同时还将扩大候选人先前在钙成像、光遗传学和计算分析方面的培训。

Throughout the animal kingdom, social species establish social hierarchies and use social rank to guide the appropriate expression of dominance behaviors that are critical for survival. Neurobiological investigations have identified a key role for medial prefrontal cortex to lateral hypothalamus projection circuits in representing social ranks and mediating the expression of social dominance behaviors. The orbitofrontal cortex (OFC) has also been shown to process social information. OFC processes are thought to be mediated by vast neuromodulatory innervation from subcortical structures known to regulate sociability, such as the dorsal raphe nucleus (DRN). Serotonergic (5-HT) DRN neurons have been identified as a key neural substrate for mediating social interaction behaviors and they provide the majority of serotonergic innervation to the OFC. However, it is unclear whether DRN5-HT-OFC circuits can process social ranking information to influence behaviors dictated by social ranks. Our research proposal aims to characterize the largely unexplored role of OFC in representing social ranks as well as reveal for the first time whether OFC interactions with serotonergic systems regulate the expression of social dominance behaviors during social competition. The central hypothesis of this project is that OFC encodes social ranking information during social competition and that serotonergic input from DRN modulates the expression of dominance behaviors. To test this, this research will use machine learning tools to automatically track and classify social competition behaviors in multiple animals. This research will then characterize behavioral states that are encoded by OFC neurons by measuring population dynamics aligned to classified social competition behaviors. Finally, experiments in this project will activate DRN5-HT-OFC projection terminals and establish how manipulating serotonergic circuit activity changes the expression of social dominance behaviors during social competition. Project findings will establish a novel, circuit-specific mechanism for how the brain processes social ranking information to adjust behavior accordingly during social competition. Developing a better understanding of the neuronal mechanisms governing the appropriate expression of social behaviors will provide great value to clinicians and translational researchers wanting to treat social behavior control deficits observed in psychiatric disease. Execution of this proposal will be made possible by the Tye lab’s expertise in social behaviors and neural circuit dissection as well by expanding upon candidate’s prior training in calcium imaging, optogenetics, and computational analysis.