Connectomics of relapse to aggression seeking

寻求攻击复发的连接组学

• 批准号: 10221661
• 负责人: Sam Golden
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221661
• 关键词: Address; Aggressive behavior; Applications Grants; Behavior; Behavioral Model; Brain; Brain imaging; Brain region; Data; Dependence; Desire for food; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug Exposure; Electrophysiology (science); Exhibits; Funding; Future; Human; Hybrids; Immunohistochemistry; Individual; Lead; Learning; Light; Mental disorders; Methods; Microscope; Morale; Morphine Dependence; Motivation; Mus; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Oxycodone; Paris, France; Pharmaceutical Preparations; Play; Procedures; Relapse; Reporting; Research; Rewards; Risk; Rodent; Rodent Model; Role; Self Administration; Site; Social Behavior; Structure; System; Techniques; Tracer; Training; Transgenic Organisms; Viral; Withdrawal; activity marker; addiction; adverse outcome; awake; base; cell type; comorbidity; connectome; designer receptors exclusively activated by designer drugs; drug addict; drug relapse; drug reward; insight; learned behavior; member; mouse model; neural circuit; neuropsychiatric disorder; novel; novel therapeutic intervention; prescription opioid; prescription opioid abuse; programs; recidivism; recruit; symptomatology; temporal measurement; violent offender

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.

项目摘要 患有精神疾病的个体出现异常社会行为的风险增加。 这一点突出表现在攻击性与阿片类药物和其他药物成瘾之间的共同共存。 特别是一种形式的攻击-食欲攻击-展示了与人类行为学密切相关的 药物成瘾，并假设食欲侵略是由于在一个 类似于吸毒成瘾。这是一个未经证实的假设，与药物成瘾相反， 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，我们认为， 该建议的目的是获得必要的培训，以识别、询问和操纵机制 潜在的复发性攻击寻求它还将确定阿片类药物依赖对复发的影响， 侵略寻求。 这项建议将首先集中在确定复发的完整的全脑功能连接体， 攻击寻求，然后更具体地解决的作用，核神经元（NAc）及其 传入投射这个大脑区域的选择是基于融合的初步数据， NAc在攻击性奖励中的关键作用，以及NAc作为关键位点调节药物的公认作用 成瘾这将通过一种新的攻击性、自我管理和复发的行为模式来实现。 将使用iDisco+（一种全脑清除方法）识别功能和结构连接体， 结合病毒逆行追踪和Fos（神经元活性的标记物）免疫组织化学。 由于有限的时间分辨率的Fos在学习行为，觉醒行为的单单位 电生理记录将用于观察NAc神经元如何编码攻击性奖赏。接下来 NAc及其传入投射的因果意义将用区域、回路和细胞类型来检验。 特定的化学遗传学操作。最后，本提案将研究羟考酮（一种常见的 滥用处方阿片类药物）依赖复发攻击寻求，对确定新的 用于治疗与阿片类药物成瘾共病的攻击行为的治疗干预。

项目成果

Taking action: empathy and social interaction in rats.

采取行动：老鼠的同理心和社交互动。

• DOI: 10.1038/s41386-019-0596-0
• 发表时间: 2020
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Venniro,Marco;Golden,SamA
• 通讯作者: Golden,SamA