Investigating corticostriatal pathways relevant to cocaine addiction with DREADDs

描述(申请人提供)：可卡因成瘾是一种神经精神障碍，其特征是寻求可卡因的动机无法控制。目前，对可卡因成瘾还没有有效的治疗方法，这在一定程度上是因为我们缺乏对参与这种疾病的回路的了解。前额叶皮质(PFC)和伏隔核(NAC)都与滥用药物的奖赏特性有关。然而，目前还不清楚这些区域内和这些区域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(MSN)根据其投射靶点和基因表达可分为两类，即通常所说的“直接”和“间接”途径。以前的报道表明，直接和间接通路神经元在药物奖赏和敏化中发挥着不同的作用，然而，在自我给药模式中，NAC中的这些通路如何影响可卡因的摄取和寻找还有待研究。因此，我的第一个目标是使用DREADDS在模拟药物动机和复发的可卡因自我给药措施中选择性地使用直接和间接途径来检查NAC内直接和间接途径的作用。此外，有人认为，从前额叶到基底节的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能输入，而NAC也接受来自杏仁核和丘脑的输入，目前尚不清楚从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研究从PFC到NAC的输入在调节可卡因的可卡因操作行为中的作用。为了选择性地激活这一通路，我将利用依赖于Cre重组酶的Gi/o DREADD flex载体技术，仅在投射到NAC的mPFC神经元中表达DREADD。这些设计者受体在操作行为中的瞬时激活将揭示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，以及从皮质输入到NAC的自上而下控制的丧失如何有助于这些行为的形成，从而奠定向成瘾的过渡。通过解开这一复杂的回路，这项工作可以帮助引导药物成瘾治疗的发展，转向选择性地针对皮质-基底神经节系统的亚成分的新疗法。

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.