Extinction Circuits Controlling Heroin Seeking

控制海洛因寻找的灭绝电路

基本信息

批准号：
9912742
负责人：
JAMIE PETERS
金额：
$ 34.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912742
关键词：
Address Anatomy Animals Automobile Driving Behavior Behavioral Brain Brain region Cocaine Conditioned Reflex Cues Data Desire for food Efferent Pathways Exposure to Extinction (Psychology)Female Food Fright Genetic Recombination Globus Pallidus Heroin Hypothalamic structure Lateral Lead Learning Masks Medial Mediating Memory Motivation Neuroanatomy Neurons Nucleus Accumbens Opiate Addiction Output Pathway interactions Pharmaceutical Preparations Play Population Prefrontal Cortex Process Public Health Rabies Rattus Relapse Reporting Research Retrieval Rewards Rodent Rodent Model Role Self Administration Sex Differences Site Synapses System Techniques Testing Tracer United States Viral Viral Vector Work conditioned fear craving designer receptors exclusively activated by designer drugs experimental study feeding innovation insight male memory process memory retrieval mu opioid receptors neural circuit novel recruit technological innovation theories tool vector

项目摘要

Abstract Opiate addiction is a huge public health threat in the United States currently. There is a real need for new treatments that reduce relapse rates, and a major relapse trigger is exposure to conditioned drug cues. The conditioned response to seek drug is intimately tied to the memory retrieved by these reminder cues. However, repeated exposure to these cues in the absence of reward can lead to a diminished conditioned response to seek drug, through a process known as extinction. Extinction is thought to establish an opposing inhibitory memory that suppresses the conditioned response, and has been shown to recruit portions of the prefrontal cortex. In particular, the infralimbic (IL) subregion in rodents exerts this inhibitory control over downstream effectors that would otherwise drive the conditioned response. This is true for a number of conditioned behaviors, including conditioned cocaine seeking, food seeking, and fear. Preliminary data suggest that the inhibitory function of this region is masked, but not lost, after heroin self-administration. This may be due to a primary site of action of heroin at mu opioid receptors (MORs) in IL, as activation of IL-MORs elicits feeding and a general hyper-appetitive state (Baldo 2016). Preliminary data suggest that IL-MORs also regulate the motivation to seek heroin, and is consistent with a theory separate appetitive driver and limiter functions exist within the IL cortex. These opposing functions may be encoded by distinct neuronal ensembles within IL with distinct downstream targets. Two major efferent targets of IL that are known to regulate both food and drug seeking are the lateral hypothalamus (LH) and the nucleus accumbens shell (NAshell). We propose that IL neuronal ensembles projecting to the LH drive heroin seeking, whereas those projecting to the NAshell inhibit heroin seeking. Indeed, preliminary data show that chemogenetic activation of the IL to NAshell pathway reduces cue-induced reinstatement of heroin seeking, similar to our reported effects in cocaine-seeking animals (Augur et al. 2016). We will use a novel TRAP-DREADD system to tag and reactivate different functional neuronal ensembles in IL that drive versus inhibit heroin seeking, and we will identify their downstream efferent targets by retrograde tracing. We will also use pathway-specific chemogenetics to activate these different IL efferent pathways and establish their functional role in cue-induced heroin relapse. Finally, we will use a novel trans-synaptic "trans-DREADD" strategy to examine the second-order circuits controlling heroin seeking. These experiments will determine the specific functional neural circuitry of IL and its downstream effectors, and establish their role in driving vs limiting heroin seeking. Furthermore, this work will provide new insight into the specific neuroanatomy controlling heroin seeking and the extent to which these limiter circuits can be exploited to reduce relapse.

抽象的阿片成瘾目前在美国是一个巨大的公共卫生威胁，确实需要新的药物。降低复发率的治疗方法，而主要的复发触发因素是暴露于条件药物暗示。寻求药物的条件反应与这些提醒线索检索到的记忆密切相关。在没有奖励的情况下反复接触这些线索可能会导致对这些线索的条件反应减弱寻求药物，通过称为“灭绝”的过程被认为可以建立相反的抑制作用。抑制条件反应的记忆，并已被证明可以招募部分前额叶特别是，啮齿动物的下边缘（IL）亚区域对下游发挥这种抑制控制作用。否则会驱动条件反应的效应器对于许多条件反应来说都是如此。行为，包括条件性可卡因寻求、食物寻求和恐惧。自我服用海洛因后，该区域的抑制功能被掩盖，但并未丧失。这可能是由于海洛因在 IL 中 mu 阿片受体 (MOR) 上的主要作用位点，因为 IL-MOR 的激活会引发进食和一般的食欲亢进状态（Baldo 2016）。初步数据表明 IL-MOR 也调节寻求海洛因的动机，并且与存在独立的食欲驱动器和限制器功能的理论相一致这些相反的功能可能是由 IL 内不同的神经元编码的。已知 IL 的两个主要传出靶标可调节食品和药物。我们建议寻找的是外侧下丘脑（LH）和伏隔核壳（NAshell）。投射到 LH 的神经元群驱动海洛因寻找，而投射到 NAshell 的神经元群则抑制事实上，初步数据显示 IL 至 NAshell 途径的化学遗传学激活。减少线索诱导的海洛因寻求恢复，类似于我们报告的可卡因寻求效果动物（Augur 等人，2016）。我们将使用一种新颖的 TRAP-DREADD 系统来标记和重新激活不同的动物 IL 中驱动与抑制海洛因寻找的功能性神经元群，我们将识别它们我们还将使用途径特异性化学遗传学来确定下游传出目标。激活这些不同的 IL 传出途径并确定它们在提示诱导的海洛因复吸中的功能作用。最后，我们将使用一种新颖的跨突触“trans-DREADD”策略来检查二阶电路控制海洛因寻找。这些实验将确定 IL 及其特定功能神经回路下游效应器，并确定它们在驱动与限制海洛因寻找方面的作用此外，这项工作将。为控制海洛因寻求的特定神经解剖学以及这些行为的程度提供新的见解可以利用限制器电路来减少复发。