Investigating Orbitofrontal Circuit Mechanisms of Social Rank and Dominance Behavior

在整个动物王国中，群居物种建立了社会等级制度，并利用社会等级来指导对生存至关重要的统治行为的适当表达。神经生物学研究发现，内侧前额叶皮层到外侧下丘脑的投射回路在社会等级表征和社会支配行为的表达中起着关键作用。眼眶前额皮质（OFC）也被证明处理社会信息。OFC过程被认为是由来自皮层下结构的大量神经调节神经支配介导的，这些结构调节社交能力，如中缝背核（DRN）。5-羟色胺能（5-HT） DRN神经元已被确定为介导社会互动行为的关键神经基质，它们为OFC提供了大部分的5-羟色胺能神经支配。然而，目前尚不清楚DRN5-HT-OFC电路是否可以处理社会等级信息，从而影响社会等级所决定的行为。我们的研究计划旨在描述大部分未被探索的OFC在代表社会等级方面的作用，并首次揭示OFC与血清素能系统的相互作用是否在社会竞争中调节社会优势行为的表达。本研究的核心假设是，OFC编码社会竞争中的社会排名信息，DRN输入的血清素能调节优势行为的表达。为了验证这一点，本研究将使用机器学习工具来自动跟踪和分类多种动物的社会竞争行为。然后，本研究将通过测量与分类社会竞争行为相一致的种群动态来表征OFC神经元编码的行为状态。最后，本项目的实验将激活DRN5-HT-OFC投射终端，并确定在社会竞争中操纵血清素能回路活动如何改变社会优势行为的表达。项目发现将建立一种新颖的、电路特定的机制，研究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元机制，将为临床医生和转化研究人员治疗精神疾病中观察到的社会行为控制缺陷提供巨大价值。通过Tye实验室在社会行为和神经回路解剖方面的专业知识，以及扩展候选人在钙成像，光遗传学和计算分析方面的先前培训，该提案的执行将成为可能。

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.