Oxytocin-dependent Social Salience Network Activity evoked by targeting melanocortin receptors

项目总结(项目1，Young) 来自动物研究的证据表明，催产素(OT)在促进社会行为方面发挥着重要作用。 假设催产素对社会认知的影响是通过增加社会认知的显著和显著来实现的。 社会刺激的回报价值。在动物模型工作的启发下，人体研究已经调查了 鼻腔给药对包括精神疾病在内的广泛的人类社会行为的影响 自闭症谱系障碍(ASD)患者的社会功能等结果。银杏叶提取物的临床疗效观察 然而，由于血脑屏障在脑内的穿透和扩散有限，In-OT是值得怀疑的。 刺激内源性OT释放可以绕过这些问题。调查靶向效应的研究 黑素皮质素系统已显示黑素皮质素4受体(MC4Rs)与多种神经化学物质相互作用 已知的调节社会行为的系统包括OT。我们实验室的研究表明，外围设备 注射黑色素II(MTII)，一种脑穿透性小分子选择性MC4R激动剂，促进伴侣 一夫一妻制草原田鼠的偏好形成。这种作用可被中枢输注催产素受体阻断 (OXTR)拮抗剂(OTA)。此外，MTII选择性地激活下丘脑OT神经元并增强OT 在伏隔核(NAC)释放。MTII对投影终端的OT释放没有直接影响 但被认为导致下丘脑室旁核(PVN)局部释放OT，并 从而使该区域的OT神经元对刺激有更强的反应。我们已经证明，仅MTII一项就可以 不会增加PVN外的OT释放，但当与高渗挑战相结合时，有效 对终末OT释放的刺激，导致NAC中OT释放大约增加2倍。与…一致 这一发现，来自我们实验室的初步数据表明，MTII与社会暴露相结合，也被称为 刺激催产素的释放，导致强大的大脑激活。这种影响在非社会条件下是不存在的， 通过中心注射OTA而被阻断。该项目的目的是通过以下方式进一步研究这些机制 通过研究这种化合物如何影响大脑中多个节点的激活，哪种MTII影响大脑回路 参与社交显著处理的大脑网络。我们的假设是，MTII与社会互动配对 将增加网络中节点的活跃度，并协调节点间的活动。我们进一步 假设MTII对大脑活动的影响是通过OT系统调节的，因此 通过给予OTA以及携带与低脑OXTR相关的等位基因的动物，使其变弱 密度。最后，我们将直接调查MTII的作用是否通过PVN中的OXTRs介导，通过 通过病毒载体介导的CRISPR-Cas9特异性定位对OT神经元的自动调节 删除OT神经元中的OXTRs。这些实验将给出对一种神经机制的重要见解 与翻译相关的方法来操纵OT电路，并将为进一步的非侵入性奠定基础 对加班制度的刺激。

PROJECT SUMMARY (Project 1, Young) Evidence from animal studies suggests that oxytocin (OT) plays an important role in facilitating social behavior. It is hypothesized that the influence of OT on social cognition is facilitated by increasing the salience and rewarding value of social stimuli. Human studies, inspired by the work in animal models, have investigated the effects of intranasal (IN) administration of OT on a wide range of human social behaviors, including psychiatric outcomes such as social functioning in individuals with autism spectrum disorder (ASD). The clinical efficacy of IN-OT is however questionable because of limited blood-brain-barrier penetration and diffusion within the brain. Stimulating endogenous OT release would circumvent these issues. Studies investigating the effects of targeting the melanocortin system have shown that melanocortin 4 receptors (MC4Rs) interact with several neurochemical systems known to modulate social behavior including OT. Work in our laboratory has shown that peripheral injection of melanotan II (MTII), a brain penetrant small-molecule selective MC4R agonist, facilitates partner preference formation in monogamous prairie voles. This effect is blocked by central infusion of an OT receptor (OXTR) antagonist (OTA). Further, MTII selectively activates hypothalamic OT neurons and potentiates OT release in the nucleus accumbens (NAc). MTII does not have a direct effect on OT release at projection terminals but is thought to result in local release of OT in the paraventricular nucleus of the hypothalamus (PVN) and thereby priming OT neurons in this region to be more responsive to stimuli. We have shown that MTII alone does not increase OT release outside of the PVN, but when combined with a hypertonic osmotic challenge, a potent stimulus for terminal OT release, results in approximately a 2-fold increase in OT release in the NAc. In line with this finding, preliminary data from our laboratory suggests that MTII combined with social exposure, also known to stimulate OT release, results in robust brain activation. This effect is absent under non-social conditions and blocked by central injection of an OTA. The aim of this project is to further investigate the mechanisms through which MTII affects brain circuitry by studying how this compound influences activation across multiple nodes in a brain network involved in social salience processing. Our hypothesis is that MTII paired with social interaction will result in increased activation of nodes in the network and coordinated activity across nodes. We further hypothesize that the effect of MTII on brain activity is mediated through the OT system and will therefore be attenuated by administration of an OTA, as well as in animals carrying alleles associated with low brain OXTR density. Finally, we will directly investigate if the effect of MTII is mediated through OXTRs in the PVN, through autoregulation on OT neurons, by using a viral vector mediated CRISPR-Cas9 approach to site specifically delete OXTRs in OT neurons. These experiments will give important insights into the neural mechanisms of a translationally relevant approach to manipulate the OT circuitry and will lay the ground for further non-invasive stimulation of the OT system.