Chemical-genetic dissection of the role of lateral habenula in cocaine relapse

描述（由申请人提供）：可卡因成瘾治疗中的一个重要问题是，即使在戒断数年后，可卡因使用的复发。暴露于压力在促使复发方面发挥着重要作用。因此，研究压力诱发复发的神经回路对于开发有效的成瘾治疗方法是必要的。虽然许多大脑区域有助于表达应激诱导的复发，但对外侧缰的确切作用知之甚少。使用自我管理，恢复程序，我们建议直接检查这个大脑区域的作用，在压力诱导的复发可卡因寻求使用国家的最先进的遗传和化学靶向方法。在这项提案中，我们将利用DREADD（设计师受体独家激活的设计师药物）技术，通过该技术，我们将操纵外侧缰核神经元的方式是选择性的，快速的和可逆的，并研究这些操作对应激诱导的复发的影响。利用神经科学领域现有的方法，研究参与特定行为的特定突触连接的贡献一直是一个挑战。我们建议利用一种独特的双病毒策略，其中我们将使用一种组合的floxed，倒置DREADD的引入外侧缰核神经元和一种逆行运输的犬腺病毒2工程表达Cre重组酶，研究神经元回路参与可卡因复发。在具体目标1中，我们将研究外侧缰核神经元活动的瞬时调制是否影响应激诱导的可卡因寻求恢复。在具体目标2中，我们将验证双病毒方法来解剖突触连接，并研究从外侧缰到单胺能核的投射神经元是否参与了可卡因寻求的应激诱导恢复。除了提供关于外侧缰核在可卡因复吸中的作用的新信息外，我们还将验证双病毒策略的使用，该策略有可能被广泛用作研究可卡因复吸的有价值的工具。 清醒的行为动物的神经回路。我们的研究结果将为神经元回路提供新的见解，这些神经元回路是压力诱导的复发的基础，并可能为治疗可卡因成瘾的治疗选择开辟新的途径。

DESCRIPTION (provided by applicant): An important problem in the treatment of cocaine addiction is relapse to cocaine use even years after abstinence. Exposure to stress plays an important role in precipitating relapse. Thus, studying the neuronal circuitry that underlies stress-induced relapse is necessary for the development of effective treatments for addiction. While many brain regions contribute to the expression of stress-induced relapse, very little is known about the precise role of the lateral habenula. Using the self-administration-reinstatement procedure, we propose to directly examine the role of this brain region in stress-induced relapse to cocaine seeking using state-of-the-art genetic and chemical targeting approaches. In this proposal, we will utilize the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology, by which we will manipulate lateral habenula neurons in a manner that is selective, rapid and reversible and study the effect of these manipulations on stress-induced relapse. With the methods currently available in the field of neuroscience, it has been a challenge to study the contribution of specific synaptic connections involved in a specific behavior. We propose to utilize a unique dual-virus strategy in which we will use a combination of floxed, inverted DREADD's introduced into lateral habenula neurons and a retrogradely transported canine adenovirus 2 engineered to express Cre recombinase, to study neuronal circuits involved in cocaine relapse. In specific aim 1, we will investigate whether transient modulation of lateral habenula neuronal activity influences stress-induced reinstatement of cocaine-seeking. In specific aim 2, we will validate the dual-virus approach to dissect synaptic connections and study whether projection neurons from the lateral habenula to monoaminergic nuclei are involved in stress-induced reinstatement of cocaine seeking. In addition to providing novel information on the role of the lateral habenula in cocaine relapse, we will validate the use of the dual-virus strategy which has the potential to be widely used as a valuable tool in studying neuronal circuits in awake, behaving animals. Results from our studies will offer new insights into the neuronal circuitry that underlies stress-induced relapse and possibly open up new avenues for therapeutic options for the treatment of cocaine addiction.