Connectomics of relapse to aggression seeking

寻求攻击复发的连接组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要患有精神疾病的个体出现异常社会行为的风险增加。阿片类药物和其他药物的攻击性和成瘾性之间的常见合并症凸显了这一点。特别是一种攻击形式——食欲性攻击——表现出与毒瘾，并且有人质疑攻击性的食欲是由于大脑中奖赏回路的失调造成的。类似于吸毒成瘾，这是一个未经证实的假设，与吸毒成瘾相反，电路。因此，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。该提案的目的是获得必要的培训来识别、询问和操纵机制它也将决定阿片类药物依赖对复发的影响。寻求侵略。该提案将首先侧重于识别复发的完整全脑功能连接组攻击寻求，然后更具体地讨论伏隔核（NAc）及其作用该大脑区域的选择是基于收敛的初步数据。 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明确作用这将通过一种新颖的攻击性自我管理和复发行为模型来实现。将使用 iDisco+（一种全脑清理方法）来识别功能和结构连接组。结合病毒逆行追踪和 Fos（神经元活动标记）免疫组织化学。由于学习行为期间 Fos 的时间分辨率有限，清醒行为的单个单元电生理记录将用于观察 NAc 神经元如何编码攻击性奖励。 NAc 的因果意义及其传入投射将使用区域、电路和细胞类型进行检查最后，该提案将研究羟考酮（一种常见的药物）的作用。滥用处方阿片类药物）对复发的依赖，寻求攻击，识别新奇用于治疗与阿片类药物成瘾共存的攻击行为的治疗干预措施。