Connectomics of relapse to aggression seeking

项目摘要 在患有精神障碍的个人中，异常社交行为的风险增加。 阿片类药物和其他药物的攻击性和成瘾之间的共同共病突出了这一点。 尤其是一种攻击形式--食欲攻击--表现出的症状与 药物成瘾，并假设食欲攻击是由于奖赏回路的失调 举止类似于吸毒成瘾。这是一个未经证实的假设，与吸毒成瘾不同，电路 啮齿动物模型中攻击行为的潜在动机成分在很大程度上是未知的。因此， 这项建议的目的是获得必要的培训，以识别、审问和操纵机械装置 潜在的故态复萌，寻求攻击性。它还将确定阿片类药物依赖对复发的影响 寻求侵略。 这项提议将首先集中于确定复发性脑损伤完整的全脑功能连接体。 攻击寻求，然后更具体地讨论伏隔核(NAC)及其 传入投射。这个大脑区域的选择是基于汇聚的初步数据，这意味着 NAC在攻击奖赏中的关键作用，以及NAC作为调节药物的关键场所的角色 上瘾。这将通过一种新的攻击性、自我管理和故态复萌的行为模式来实现。 功能和结构连接体将使用IDESCO+，一种全脑清理方法，在 结合病毒逆行示踪和Fos(神经元活动的标志)免疫组织化学。 由于学习行为过程中Fos的时间分辨率有限，觉醒行为单单位 电生理记录将被用来观察NAC神经元如何编码攻击奖赏。接下来， 将使用区域、回路和细胞类型来检查NAC及其传入投射的因果意义 特殊的化学发生操作。最后，这项建议将研究羟考酮(一种常见的 滥用处方阿片类药物)依赖复发到攻击寻求，走向识别新奇 治疗攻击性与阿片成瘾共病的治疗干预。

Project Summary There is an increased risk for abnormal social behavior in individuals suffering from psychiatric disorders. This is highlighted by the common comorbidity between aggression and addiction to opioids and other drugs. One form of aggression in particular – appetitive aggression – exhibits symptomatology that closely mimics drug addiction, and it is hypothesized that appetitive aggression is due to dysregulation of reward circuits in a manner akin to drug addiction. This is an unproven hypothesis, and in contrast to drug addiction, the circuits underlying motivational components of aggressive behavior in rodent models are largely unknown. Therefore, the aim of this proposal is to obtain the necessary training to identify, interrogate, and manipulate mechanisms underlying relapse to aggression seeking. It will also determine the effect of opioid dependence on relapse to aggression seeking. This proposal will focus first on identifying the intact whole brain functional connectome of relapse to aggression seeking, and then more specifically address the role of the nucleus accumbens (NAc) and its afferent projections. The choice of this brain region is based on converging preliminary data implicating a critical role for NAc in aggression reward, and NAc’s well established role as a critical locus regulating drug addiction. This will be achieved using a novel behavioral model of aggression self-administration and relapse. The functional and structural connectome will be identified using iDisco+, a whole brain clearing method, in conjunction with viral retrograde tracing and Fos (a marker of neuronal activity) immunohistochemistry. Because of the limited temporal resolution of Fos during learned behaviors, awake-behaving single-unit electrophysiological recording will be used to observe how NAc neurons encodes aggression reward. Next, the causal significance of the NAc and its afferent projections will be examined using region, circuit, and cell-type specific chemogenetic manipulations. Lastly, this proposal will study the effect of oxycodone (a commonly abused prescription opioid) dependence on relapse to aggression seeking, towards identification of novel therapeutic interventions for the treatment of aggression comorbid with opioid addiction.