AgRP Neurons as Modulators of Drug Reactivity

摘要 药物滥用和成瘾是严重的精神健康问题， 我们社区的负担。几十年来，人们已经知道，生理状态（饥饿和饱足）可以 影响药物寻求，服用和复吸。先前的研究表明， 这就意味着饥饿可能是加强药物反应的一个风险因素。然而，在这方面， 介导饥饿的神经元和药物反应之间的相互作用仍不清楚。在多个 与饥饿相关的神经元群体，弓状核表达Agouti相关肽（AgRP）的神经元， 下丘脑的核被认为是饥饿的中心介质。尽管它的核心作用是唤起 饥饿时，我们对AgRP神经元活性对药物反应的影响的认识存在空白。 我们的总体目标是确定AgRP神经元在调节药物行为反应性和药物依赖性中的作用。 通过募集中脑边缘奖励回路来指导行为，而中脑边缘奖励回路反过来又调节运动输出。 作为最初的探索性步骤，PI试图确定AgRP神经元活动对刺激剂驱动的 运动输出，以测量对滥用药物的行为敏感性的改变，使用斑马鱼幼虫作为 光学易处理模型。我们的中心假设是AgRP神经元的激活增强了运动- 神经元和行为的反应。我们的具体目标是确定 AgRP神经元活动对刺激物驱动的反应。我们将使用转基因斑马鱼品系， 脊髓运动神经元中的遗传编码的神经活动指标，以及 AgRP神经元中的光遗传学致动器或沉默器。为了确定AgRP神经元的激活是否是 足以或必须增加药物反应、兴奋剂驱动的运动神经元活动和行为 在光遗传学激活或抑制AgRP神经元的同时监测反应。更好的 了解AgRP神经元在药物反应中的作用可能会导致发现新的治疗药物。 控制AgRP神经元兴奋性的机会，以减轻药物成瘾。

ABSTRACT Drug abuse and addiction are serious mental health problems that impose severe economic and social burdens on our community. It has been known for decades that physiological states (hunger and satiety) can influence drug seeking, taking, and relapse. Previous studies showed that hunger-mediating hormones enhance drug use, collectively implying that hunger can be a risk factor for enhanced drug response. However, the interaction between hunger-mediating neurons and drug response remains unclear. Among multiple neuronal populations related to hunger, neurons expressing Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus are known to be a central mediator of hunger. Despite its central role in evoking hunger, there is a gap in our knowledge of the effect of AgRP neuronal activity on drug response. Our overall goal is to determine the role of AgRP neurons in modulating drug behavioral responsivity and drug- directed behavior through recruitment of mesolimbic reward circuitry which, in turn, modulates motor outputs. As an initial exploratory step, the PI seeks to determine the effect of AgRP neuronal activity on stimulant-driven motor outputs to measure alterations in behavioral sensitivity to abused drugs using zebrafish larvae as an optically tractable model. Our central hypothesis is that the activation of AgRP neurons potentiates motor- neuronal and behavioral responses to psychostimulant drugs. Our specific aim is to determine the effect of AgRP neuronal activity on stimulant-driven responses. We will use transgenic zebrafish lines that express a genetically encoded neural activity indicator in spinal motor neurons, and also a genetically encoded optogenetic actuator or silencer in AgRP neurons. To determine whether the activation of AgRP neurons is sufficient or necessary to increase drug responses, stimulant-driven motor neuronal activity and behavioral responses will be monitored while optogenetically activating or suppressing AgRP neurons. A better understanding of the role of AgRP neurons on drug response could lead to the discovery of novel therapeutic opportunities that control the AgRP neuronal excitability in order to mitigate drug addiction.