Homeostatic Plasticity in Nucleus Accumbens

描述（由申请人提供）：与既往可卡因使用相关的线索是戒断可卡因使用者复发和可卡因经验丰富的啮齿动物寻求药物的有力触发因素。啮齿类动物研究表明，线索诱导的可卡因渴望逐步加剧的过程中，从长期获取可卡因自我管理的撤退。这种现象被称为可卡因渴望的潜伏期，可能导致难以保持对可卡因的戒断。越来越多的证据支持潜伏期与人类药物渴求的相关性。孵化过程的一个关键特征是，一旦启动，它将继续 在停药期间自动加重，无明显的外部刺激。这表明神经元可塑性的稳态形式而不是赫布形式的参与。使用小鼠模型，这个建议的目的是确定的作用，稳态可塑性的神经核（NAc），一个关键的大脑区域成瘾，在可卡因的渴望孵化。稳态可塑性是一种生理性的自我校正机制，通过这种机制，神经元补偿“不希望的”细胞变化，从而稳定其功能输出。NAc神经元中是否存在任何形式的稳态神经可塑性，可以帮助这些神经元在可卡因暴露后恢复正常功能？我们以前证明了一种形式的稳态串扰之间的兴奋性突触输入和内在的神经膜兴奋性NAc神经元。这种现象，称为稳态突触膜串扰（HSMC），使NAc神经元，以调整其内在的膜兴奋性，功能上抵消兴奋性突触强度的变化。因此，可以稳定地维持NAc神经元的最佳输出。然而，如果被“假”稳态信号误导，HSMC可能会错误地参与，触发稳态失调的级联，逐渐将神经元输出从正常设定点进一步转移。在以前的工作中，我们发现可卡因暴露增加了NAc中含有NR 2B的NMDA受体的突触水平。基于广泛的初步结果，我们的中心假设是，这构成了一个“假”稳态信号，触发HSMC和随后的稳态失调级联，最终导致膜兴奋性持续下降和突触强度增加。总之，这些变化被假设为放大了NAc神经元对可卡因相关线索的反应，并且- reby引起可卡因渴望的孵化。为了验证这一假设，该提案将表征基于HSMC的失调级联的关键分子底物（例如，谷氨酸受体和SK型钾通道），研究多巴胺在调节这些级联中的作用，并开发基于HSC的方法来减弱可卡因渴望的潜伏期。为了实现这些目标，我们将使用多学科方法，结合体内分子/药理学操作，生物化学，切片电生理学和行为测试。我们的研究结果将为旨在开发基于稳态的药物策略以恢复可卡因使用者正常NAc功能的转化研究奠定基础。

DESCRIPTION (provided by applicant): Cues associated with prior cocaine use are powerful triggers of relapse in abstinent cocaine users and of drug seeking in cocaine-experienced rodents. Rodent studies show that cue-induced cocaine craving progressively intensifies over the course of withdrawal from extended access cocaine self-administration. This phenomenon, known as incubation of cocaine craving, may contribute to the difficulty of maintaining abstinence from cocaine use. Growing evidence supports the relevance of incubation to drug craving in humans. A key feature of the incubation process is that, once initiated, it continues to exacerbate automatically during the withdrawal period, without apparent external stimulation. This suggests the involvement of homeostatic rather than Hebbian forms of neuronal plasticity. Using a mouse model, this proposal aims to determine the role of homeostatic plasticity in the nucleus accumbens (NAc), a key brain region for addiction, in the incubation of cocaine craving. Ho- meostatic plasticity is a physiological self-correcting mechanism through which neurons compensate for 'unde- sirable' cellular alterations, thus stabilizing their functional output. Are there any forms of homeostatic neural plasticity in NAc neurons that may help these neurons regain normal function following cocaine exposure? We previously demonstrated a form of homeostatic crosstalk between excitatory synaptic input and intrinsic mem- brane excitability in NAc neurons. This phenomenon, termed homeostatic synapse-membrane crosstalk (HSMC), enables NAc neurons to adjust their intrinsic membrane excitability to functionally offset alterations in excitatory synaptic strength. As a consequence, the optimal output of NAc neurons may be stably maintained. However, if misled by "false" homeostatic signals, HSMC may be erroneously engaged, triggering cascades of homeostatic dysregulation that progressively shift neuronal output further and further from the normal set-point. In previous work, we showed that cocaine exposure increases synaptic levels of NR2B-containing NMDA re- ceptors in the NAc. Our central hypothesis, based on extensive preliminary results, is that this constitutes a "false" homeostatic signal that triggers HSMC and subsequent homeostatic dysregulation cascades, ultimately resulting in a persistent decrease in membrane excitability and an increase in synaptic strength. Together, these changes are hypothesized to magnify the response of NAc neurons to cocaine-associated cues and the- reby elicit incubation of cocaine craving. To test this hypothesis, this proposal will characterize key molecular substrates for HSMC-based dysregulation cascades (e.g., glutamate receptors and SK-type potassium chan- nels), examine the role of dopamine in modulating these cascades, and develop a HSMC-based approach to attenuate incubation of cocaine craving. To achieve these goals, we will use a multidisciplinary approach com- bining in vivo molecular/pharmacological manipulations, biochemistry, slice electrophysiology, and behavioral tests. Our results will set the stage for translational studies aimed at developing a homeostasis-based pharma- cological strategy to restore normal NAc function in cocaine users.