Role of Lateral Hypothalamus Orexin Circuits in Cocaine Demand

下丘脑外侧食欲素回路在可卡因需求中的作用

基本信息

批准号：
9335176
负责人：
Caroline Pantazis
金额：
$ 3.92万
依托单位：
RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2020-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335176
关键词：
Affect Agonist American Animals Automobile Driving Baclofen Behavioral Bilateral Brain Diseases Brain region Cannulas Catheters Cells Cholera Toxin Protomer B Chronic Clozapine Cocaine Cocaine Dependence Contralateral Coupled Cues Disease Dopamine Drug Addiction Elements Enterobacteria phage P1 Cre recombinase Fellowship Hypothalamic structure Implant Incidence Individual Individual Differences Injectable Injection of therapeutic agent Laboratories Lateral Light Link Motivation Muscimol Neurons Neuropeptides Neurosciences Operative Surgical Procedures Output Oxides Performance Pharmaceutical Preparations Pharmacology Procedures Rattus Recruitment Activity Relapse Research Rewards Role Self Administration Signal Transduction Staining method Stains Stimulus System Techniques Testing Therapeutic Tracer Training Transgenic Organisms Tyrosine 3-Monooxygenase Ventral Tegmental Area Viral Viral Vector Withdrawal activity marker behavioral economics designer receptors exclusively activated by designer drugs dopaminergic neuron drug of abuse drug relapse drug reward drug seeking behavior hypocretin in vivo innovation knock-down neural circuit neuropathology orexin A preference public health relevance receptor relating to nervous system selective expression

项目摘要

PROJECT SUMMARY/ABSTRACT Drug addiction is a prevalent and chronically relapsing disorder that affects millions of Americans. Our laboratory has recently developed a behavioral economics (BE) paradigm that determines individual motivation for cocaine and propensity for drug relapse in a single testing session. In this paradigm, the neuropeptide orexin (also called hypocretin) is involved in driving motivation for cocaine. Lateral hypothalamus (LH) orexin neurons are highly associated with motivation for reward and project to numerous reward-associated brain regions. However, it remains unclear how LH orexin neurons are recruited to drive motivation for cocaine. Rostral lateral septum (LS) strongly innervates the LH orexin cell field and has been linked to orexin- dependent, stimulus-associated cocaine seeking. The ability of orexin to drive motivation for cocaine also may involve its extensive projections to ventral tegmental area (VTA), a region highly implicated in reward, motivation, and drug addiction. Using a within-session BE paradigm, this proposal will explore the role of LS inputs to LH orexin neurons and LH orexin projections to VTA DA neurons in demand for cocaine. I predict that both of these projections will be necessary for cocaine demand in the BE paradigm. This hypothesis will be tested using three Specific Aims. Aim 1 will determine individual differences in neuronal activity of the LS-LH orexin and LH orexin-VTA circuits using retrograde tract tracing combined with Fos staining in both LS projections to LH, and LH projections to VTA following BE. Aim 2 will utilize pharmacological and morpholino antisense approaches to specifically inhibit the LS-LH orexin circuit and determine its role in cocaine demand. Aim 3 will combine pharmacological, antisense, and chemogenetic approaches to inhibit LH orexin input to VTA DA neurons during BE performance. Together, these studies will elucidate the inputs and outputs of LH orexin neurons involved in cocaine demand to uncover neuropathology underlying drug addiction. This fellowship will train the applicant in several innovative techniques in systems and behavioral neuroscience, including chemogenetic, pharmacological, and antisense manipulations; drug self-administration and behavioral economics paradigms; cannulae and catheter surgeries; and immunohistochemical procedures.

项目概要/摘要毒瘾是一种普遍存在且长期复发的疾病，影响着数百万美国人。我们的实验室最近开发了一种决定个人动机的行为经济学（BE）范式在一次测试中检测可卡因和药物复发倾向。在这个范式中，神经肽食欲素（也称为下丘脑分泌素）参与驱动可卡因的动机。下丘脑外侧 (LH) 食欲素神经元与奖励动机高度相关，并投射到许多与奖励相关的大脑地区。然而，目前尚不清楚 LH 食欲素神经元如何被招募来驱动可卡因的动机。头侧外侧隔 (LS) 强烈支配 LH 食欲素细胞区域，并与食欲素相关。依赖的、与刺激相关的可卡因寻求。食欲素驱动可卡因动机的能力也可能涉及其对腹侧被盖区（VTA）的广泛投射，该区域与奖励高度相关，动机和毒瘾。使用会话内 BE 范式，该提案将探讨 LS 的作用 LH 食欲素神经元的输入和 LH 食欲素投射到需要可卡因的 VTA DA 神经元。我预测这两个预测对于 BE 范式中的可卡因需求都是必要的。这个假设将是使用三个特定目标进行测试。目标 1 将确定 LS-LH 神经元活动的个体差异食欲素和 LH 食欲素-VTA 回路在两个 LS 中使用逆行道追踪结合 Fos 染色 BE 后 LH 的投影，以及 LH 到 VTA 的投影。目标 2 将利用药理学和吗啉反义方法特异性抑制 LS-LH 食欲素回路并确定其在可卡因需求中的作用。目标 3 将结合药理学、反义和化学遗传学方法来抑制 LH 食欲素输入 BE 表现期间的 VTA DA 神经元。这些研究将共同阐明参与可卡因的 LH 食欲素神经元的输入和输出要求揭示药物成瘾背后的神经病理学。该奖学金将对申请人进行多项培训系统和行为神经科学的创新技术，包括化学遗传学、药理学和反义操作；药物自我管理和行为经济学范式；插管和导管手术；和免疫组织化学程序。