Corticostriatal-hypothalamic circuits and opioid seeking

项目摘要 阿片类药物使用障碍（OUD）的特征是过度的寻求药物的动机驱动和/或丧失 抑制性自上而下控制药物寻求，导致复发和复发性药物寻求。初步数据 来自我们实验室的研究显示，两个相反的回路起源于边缘下（IL）皮层，其中一个是“驱动”海洛因的 寻求行为和一个“限制”海洛因寻求行为。这些“驱动”和“限制”途径从 IL到皮层下奖励和动机中心，如核壳（NAsh）和外侧 下丘脑（LH）。我们的实验室已经表明，IL-1 LH回路驱动海洛因寻求和复吸，而 IL-16-NAsh通路限制海洛因寻求。IL-16-NAsh限制通路的功能性下游输出 目前还不清楚。LH被很好地描述为动机行为的驱动器， 来自NAsh β LH投射的GABA能抑制性投射与药物抑制有关。 灭绝后的寻找行为，表明LH的抑制是减少药物作用的机制。 寻找在目标1中，我将研究NAsh β LH通路作为海洛因寻求的潜在限制因素，使用 化学遗传学操作，以改变该回路的活性，并测量药物寻求的行为结果， OUD的临床前模型。我认为这一途径是以前鉴定的IL-16-NAsh的延伸， 限制器途径，涉及NAsh中的神经元集合，其既接收来自IL的输入，又投射来自IL的信号。 到LH。我假设这种独特的神经元群体将最终负责限制海洛因寻求 行为双突触的IL-β-NAsh-β-LH限制器通路在IL和LH之间插入GABA能中继， 提供了一种潜在的机制，通过该机制实现了限制通路的功能。因此，可能的是， 双突触的IL-β NAsh-β LH限制器电路和IL-β LH驱动器电路会聚在LH上，其中抑制 NAsh的投射可能与IL的兴奋性投射竞争控制海洛因觅药。 彼得斯实验室的初步数据显示，LH食欲素神经元数量与海洛因的指标相关 动机，并用双重食欲素受体拮抗剂（DORA）全身阻断食欲素受体， 海洛因复吸，强烈暗示LH食欲素神经元群体在控制海洛因寻求 行为。此外，这些LH食欲素神经元投射到IL皮质，并阻断IL皮质内的食欲素受体。 IL皮层抑制动机行为。在目标2中，我将使用化学遗传学来确定LH是否能抑制 pathway途径drives驱动drug药物seeking寻找.然后，我将确定IL内食欲素受体激活是否是 海洛因寻求，使用大脑特定部位药理学。如果限制器和驱动器路径确实在竞争 在LH内，这种对IL皮质的食欲素能反馈可能会加强驾驶员， 海洛因需求的不平衡拟议的实验将确定新的电路和受体 影响海洛因寻求行为的机制。重要的是我们要进一步了解神经 这些发现将阐明新治疗策略的潜在靶点。

PROJECT SUMMARY Opioid use disorder (OUD) is characterized by excessive motivational drive to seek drugs and/or a loss of inhibitory top-down control of drug seeking, resulting in relapse and recurrent drug seeking. Preliminary data from our lab show two opposing circuits originating from the infralimbic (IL) cortex, one that ‘drives’ heroin seeking behavior and one that ‘limits’ heroin seeking behavior. These ‘driver’ and ‘limiter’ pathways project from the IL to subcortical reward and motivational hubs, such as the nucleus accumbens shell (NAsh) and the lateral hypothalamus (LH). Our lab has shown that the ILLH circuit drives heroin seeking and relapse, while the ILNAsh pathway limits heroin seeking. The functional downstream outputs of the ILNAsh limiter pathway are, however, currently unknown. The LH is well characterized as a driver of motivated behavior, and the GABAergic inhibitory projection from the NAshLH projection has been implicated in the suppression of drug seeking behavior after extinction, suggesting inhibition of the LH is a mechanism for decreasing drug seeking. In Aim 1, I will investigate the NAshLH pathway as a potential limiter of heroin seeking, using chemogenetic manipulations to alter activity in this circuit and measure behavioral outcomes on drug seeking in a preclinical model of OUD. I propose that this pathway is an extension of the previously identified ILNAsh limiter pathway, involving an ensemble of neurons in the NAsh that both receive input from the IL and project to the LH. I hypothesize this unique neuronal population will ultimately be responsible for limiting heroin-seeking behavior. The disynaptic ILNAshLH limiter pathway interposes a GABAergic relay between the IL and LH, providing a potential mechanism by which the limiter pathway function is actualized. Thus, it is possible that the disynaptic ILNAshLH limiter circuit and the ILLH driver circuit converge on the LH, where the inhibitory projection from the NAsh may compete with the excitatory projection from the IL to control heroin seeking. Preliminary data from the Peters lab has shown that LH orexin neuron number correlates with metrics of heroin motivation, and systemic blockade of orexin receptors with a dual orexin receptor antagonist (DORA) decreases heroin relapse, strongly implicating the LH orexin neuron population in controlling heroin-seeking behaviors. Further, these LH orexin neurons project to the IL cortex, and blockade of orexin receptors within the IL cortex dampens motivated behaviors. In Aim 2, I will use chemogenetics to determine whether the LHIL pathway drives drug seeking. I will then determine whether intra-IL orexin receptor activation is required for heroin seeking, using brain-site specific pharmacology. If indeed the limiter and driver pathways are competing within the LH, this orexinergic feedback to the IL cortex might be expected to strengthen the driver, leading to an imbalance in heroin seeking. The proposed experiments will identify novel circuits and receptor mechanisms that influence heroin-seeking behavior. It is essential that we further our understanding of the neural circuitry underlying OUD, as these findings will illuminate potential targets for new therapeutic strategies.