Mechanisms of Nucleus Accumbens Cell-Type Specific Deep Brain Stimulation in Cocaine Reinstatement

项目摘要/摘要 可卡因成瘾是美国的一个重大公共卫生问题，目前还没有有效的 以防止复发为目标的治疗。深部脑刺激(DBS)已在临床上取得成功 减轻几种神经和精神疾病的症状，并已被提议作为一种潜在的 抑制药物渴求和复发的治疗。之前的临床前研究已经确定 传统的伏隔核(NAC)壳内DBS可有效地防止 寻找可卡因，复发的动物模型。这笔赠款将利用最近的方法进步，以便 以更高的特异性检查NAC DBS疗效的细胞和生理机制。 我们将研究光激活通道视紫红质(ChR2)所引起的DBS样刺激的效应。 在NAC壳的特定神经元亚型中表达。神经元特异性将通过病毒实现 D1DR选择性表达Cre重组酶转基因大鼠的研究 或表达D2DR的中棘神经元(MSN)。目标1将检查电生理效应 雄性和雌性大鼠D1DR或D2DR-MSN的光遗传DBS样活化。整个细胞 膜片钳实验将评估OPTO-DBS参与的突触机制，并确定 如果有特定细胞亚型的影响。目标2将由平行的行为实验组成，以检查 OPTO-DBS对可卡因诱发复吸的影响光纤将被植入NAC外壳，以及 D1DR-或D2DR-MSN将以光遗传方式激活，频率类似于DBS 评估这种操纵对寻求可卡因行为的影响。以前的调查结果和 初步数据支持最重要的假设，即NAC壳的DBS阻止可卡因激发 通过诱导D2DR-MSN中的突触去增强来恢复。未来的方向将审查 在精确的下游区域选择性光遗传抑制D1DR-或D2DR-MSN信号的影响。 光纤将被植入腹侧苍白球(VP)或腹侧被盖区(VTA)。 可卡因刺激时，表达卤视紫红质的D1DR或D2DR轴突终末将被激活 复职。这将决定是否可以将NAC外壳MSN的DBS等同于对 神经活动。总体而言，确定DBS影响可卡因寻求意愿的具体机制 为未来针对可卡因成瘾的细胞和途径特异性疗法提供关键的见解。

Project Summary/Abstract Cocaine addiction is a major public health issue in the United States, and there are currently no effective treatments targeted towards preventing relapse. Deep brain stimulation (DBS) has been successful clinically at reducing symptoms of several neurological and psychiatric disorders and has been proposed as a potential therapy for the suppression of drug craving and relapse. Previous preclinical research has identified that conventional DBS in the nucleus accumbens (NAc) shell can be effective at preventing reinstatement of cocaine seeking, an animal model of relapse. This grant will exploit recent methodological advances in order to examine the cellular and physiological mechanisms underlying the efficacy of NAc DBS with greater specificity. We will examine the effects of DBS-like stimulation induced by light activation of channelrhodopsin (ChR2) expressed in specific neuronal subtypes of the NAc shell. Neuronal specificity will be achieved through viral expression in transgenic rat lines that express Cre recombinase selectively in D1 dopamine receptor (D1DR)- or D2DR-expressing medium spiny neurons (MSNs). Aim 1 will examine the electrophysiological effects of optogenetic DBS-like (opto-DBS) activation of D1DR- or D2DR-MSNs in male and female rats. Whole cell patch clamp experiments will assess the synaptic mechanisms that are engaged by opto-DBS, and determine if there are cell subtype-specific effects. Aim 2 will consist of parallel behavioral experiments to examine the effects of opto-DBS on cocaine-primed reinstatement. Optic fibers will be implanted in the NAc shell, and D1DR- or D2DR-MSNs will be activated optogenetically, at DBS-like frequencies following a priming dose of cocaine to assess the effects of this manipulation on cocaine-seeking behavior. Previous findings and preliminary data support the overarching hypothesis that DBS of the NAc shell blocks cocaine-primed reinstatement by inducing synaptic depotentiation specifically in D2DR-MSNs. Future directions will examine the effects of selective optogenetic inhibition of D1DR- or D2DR-MSN signaling in precise downstream regions. Optic fibers will be implanted in either the ventral pallidum (VP) or ventral tegmental area (VTA) and halorhodopsin-expressing D1DR- or D2DR- axon terminals will be activated during cocaine-primed reinstatement. This will determine whether DBS of NAc shell MSNs can be equated to overall suppression of neural activity. Overall, identification of the specific mechanisms by which DBS influences cocaine seeking will provide critical insights for future cell- and pathway-specific therapeutics for cocaine addiction.