Oxytocin signaling in the ventral hippocampus: from modulation of the local circuit to socio-sexual behavior

下丘脑神经肽催产素(OT)调节过多的社会性行为。由于社会认知和关系依赖于受试者重建和关联记忆表征的一般能力，在本项目中，我们重点关注腹侧海马区(VHippo)，它最近被报道为控制社会记忆的中枢。有趣的是，vHippo CA1区的实验抑制导致了社会行为的障碍，类似于在缺乏OT或其受体(OTR)的动物模型中观察到的情况。因此，我们认为vHippo的社会功能与OT动作有关。虽然vHippo CA1区接受直接的OT能输入，但OT介导的神经元在该结构中的调节作用及其对社会行为的功能贡献尚不清楚。在我们的初步实验中，通过实现新产生的OTR-Cre基因敲入大鼠和病毒载体，我们在vHippo中发现了两类OTR神经元：小白蛋白阳性中间神经元和主细胞(PC)，它们位于CA1主细胞层之外。在急性vHippo脑片上应用OTR激动剂可使OTR中间神经元和OTRPC共同激活，而OTRPC沉默。此外，我们基于病毒载体的追踪研究显示，OTRPC特异性地投射到副嗅球(AOB)的颗粒细胞层--性(信息素)信息处理的中枢结构。了解到OTRPC针对的是AOB，我们建议vHippo可能通过选择性地加强vHippo中的OTRPC与网络的外部组成部分-AOB之间的连接来调节对性有效嗅觉信息的感知。根据这一假设，我们将在突触、神经元和行为水平上对vHippo OTR回路的神经元成分进行详细的电生理和解剖学分析，旨在揭示下丘脑OT系统、vHippo和AOB之间的神经元合作关系及其在社会性行为协调中的作用。此外，我们的结果将有助于更好地理解患有精神疾病(如自闭症谱系障碍)的患者的性和社会变化的机制。

The hypothalamic neuropeptide oxytocin (OT) modulates a plethora of socio-sexual behaviors. Due to the fact that social cognition and relationship rely on the general ability of a subject to reconstruct and relate memory representations, in this project we focused on the ventral hippocampus (vHippo), which has been recently reported as a controlling social memory hub. Intriguingly, the experimental inhibition of CA1 region of vHippo leads to disturbance of social behavior, similar to that observed in animal models lacking OT or its receptor (OTR). Therefore, we propose that social function of the vHippo is related to OT action. Although the vHippo CA1 region receives direct OT-ergic input, neuronal types underlying OT-mediated modulation of neuronal ensembles in this structure, and their functional contribution to the social behavior remains unknown. In our preliminary experiments, implementing newly generated OTR-Cre knock-in rats and viral vectors, we identified two populations of OTR+ neurons in the vHippo: parvalbumin-positive interneurons and principal cells (PCs), which reside outside the CA1 principal cell layer. Application of OTR agonist to acute vHippo slices resulted in co-activation of both OTR+ interneurons and OTR+ PCs, while OTR- PCs were silent. Further, our viral-vector based tracing studies revealed that OTR+ PCs specifically project to granule cell layer of the accessory olfactory bulb (AOB) – the hub structure of sexual (pheromonal) information processing. Knowing that OTR+ PCs target the AOB, we propose that the vHippo may tune perception of sexually valid olfactory information via selectively strengthening the connection between OTR+ PCs in the vHippo and extrinsic component of the network – the AOB. Following this hypothesis, we will perform detailed electrophysiological and anatomical analyses of neuronal components of vHippo OTR+ circuit at synaptic, neuronal and behavioral levels aiming to uncover neuronal partnership between the hypothalamic OT system, vHippo and AOB and its role in the orchestration of socio-sexual behavior. Furthermore, our results will help to better understand mechanisms of sexual and social alterations in patients afflicted with mental pathologies, such as autism spectrum disorders.