Investigating corticostriatal pathways relevant to cocaine addiction with DREADDs

描述（由申请人提供）：可卡因成瘾是一种神经精神障碍，其特征是无法控制地寻求可卡因的动机。目前，对可卡因成瘾没有有效的治疗方法，部分原因是我们对这种疾病的神经回路缺乏了解。前额叶皮层（PFC）和伏隔核（NAC）都与药物滥用的奖励特性有关。然而，目前尚不清楚这些区域内部和之间的神经回路如何调节与药物成瘾相关的行为。NAC内的中棘神经元（Medium spiny neurons, MSNs）根据其投射靶点和基因表达可分为两类，通常称为“直接”通路和“间接”通路。先前的报告表明，“直接”和“间接”通路神经元在药物奖励和致敏中起着不同的作用，然而，在自我给药模型中，尚未研究NAC中的这些通路如何影响可卡因摄入和可卡因寻求。因此，我的第一个目标是研究直接和间接途径在NAC中的作用，使用在可卡因自我给药测量中选择性的直接和间接途径，模拟药物动机和复发。此外，有研究表明，从PFC到基底神经节自上而下控制的丧失与药物成瘾的慢性性质有关。PFC向NAC发送一个主要的谷氨酸输入，然而NAC也接受来自杏仁核和丘脑的输入，目前尚不清楚PFC到NAC的输入是否是调节成瘾过程的关键途径。因此，我们的第二个目标是检查从PFC到NAC的输入在调节可卡因的操作性行为中的作用。为了选择性地激活该回路，我将利用依赖于Cre-recombinase的Gi/o DREADD FLEX载体技术，仅在mPFC神经元中表达投射到NAC的DREADD。这些设计受体在操作行为中的短暂激活将揭示mPFC-NAC通路在可卡因动机中的作用。这些实验将有助于阐明直接和间接的NAC细胞群在控制药物滥用动机中的作用，以及从皮层输入到NAC的自上而下控制的丧失如何导致这些行为，这些行为是过渡到成瘾的基础。通过解开这个复杂的回路，这项工作可以帮助引导药物成瘾治疗的发展，以选择性地靶向皮质-基底神经节系统的亚组分。

DESCRIPTION (provided by applicant): Cocaine addiction is a neuropsychiatric disorder characterized by an uncontrollable motivation to seek cocaine. At present, no effective treatment exists for cocaine addiction and this is in part due to our lack of understanding of the circuitry involved in the disorder. The prefrontal cortex (PFC) and the nucleus accumbens (NAC) have both been implicated in the rewarding properties of drugs of abuse. However it is still unclear how neural circuitry within and between these regions regulates behavior relevant to drug addiction. Medium spiny neurons (MSNs) within the NAC can be divided into two populations by their projection targets and gene expression, commonly known as the 'direct' and 'indirect' pathways. Previous reports have indicated that 'direct' and 'indirect' pathway neurons play differential roles in drug reward and sensitization, however it has yet to be examined how these pathways in the NAC influence cocaine taking and cocaine seeking within a self-administration model. Thus, my first goal is to examine the role of the direct and indirect pathways within the NAC using DREADDs selective for the direct and indirect pathways in cocaine self-administration measures modeling drug motivation and relapse. Further, it has been suggested that a loss of top-down control from the PFC to the basal ganglia is related to the chronic nature of drug addiction. The PFC sends a major glutamatergic input to the NAC, however the NAC also receives input from the amygdala and thalamus and it is unknown if the input from the PFC to the NAC is the critical pathway for regulating addiction processes. Thus, our second goal is to examine the role of the input from the PFC to the NAC in regulating operant behavior for cocaine. To selectively activate this circuit, I will utilize Cre-recombinase dependent Gi/o DREADD FLEX vector technology to express DREADDs only in mPFC neurons that project to the NAC. Transient activation of these designer receptors during operant behavior will reveal the role of the mPFC-NAC pathway in motivation for cocaine. These experiments will help to elucidate the role of the direct and indirect NAC cell populations in the control of motivation for drugs of abuse, as well as how loss of top down control from cortical inputs into the NAC contributes to these behaviors that underlie a transition to addiction. By unraveling this complex circuitry, this work could help steer the development of treatments of drug addiction toward novel therapies that selectively target subcomponents of the cortico-basal ganglia system.