Homeostatic Plasticity in Nucleus Accumbens

描述(由申请人提供)：与以前使用可卡因有关的线索是戒除可卡因使用者复发和有可卡因经验的啮齿类动物寻求毒品的有力触发因素。啮齿动物研究表明，线索诱导的可卡因渴求在戒断长时间接触可卡因自我管理的过程中逐渐加剧。这种现象被称为对可卡因的渴望的孵化，可能会导致难以保持戒除可卡因的使用。越来越多的证据支持孵化与人类毒瘾的相关性。孵化过程的一个关键特征是，一旦启动，它将继续 在戒断期间自动加重，没有明显的外部刺激。这表明，神经元的可塑性与稳态有关，而不是Hebbian形式。这项建议利用小鼠模型，旨在确定伏隔核(NAC)的稳态可塑性在可卡因渴求孵化中的作用。伏隔核是成瘾的关键大脑区域。HO平衡可塑性是一种生理自我纠正机制，神经元通过这种机制来补偿“难以理解的”细胞变化，从而稳定其功能输出。NAC神经元中是否存在某种形式的动态平衡神经可塑性，可以帮助这些神经元在可卡因暴露后恢复正常功能？我们以前在NAC神经元中证明了兴奋性突触输入和固有膜兴奋性之间存在某种形式的稳态串扰。这种现象被称为稳态突触-膜串扰(HSMC)，使NAC神经元能够调节其固有的膜兴奋性，从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“错误的”稳态信号误导，HSMC可能会被错误地参与，触发一连串的稳态失调，逐渐使神经元的输出越来越远离正常的设定点。在以前的工作中，我们证明了可卡因暴露增加了NAC中含有NR2B的NMDA受体的突触水平。我们的中心假设是，基于广泛的初步结果，这构成了一个“虚假的”稳态信号，触发HSMC和随后的稳态失调级联反应，最终导致膜兴奋性的持续性下降和突触强度的增加。综上所述，这些变化被认为是为了放大NAC神经元对可卡因相关线索的反应，并诱导对可卡因的渴望的孵化。为了验证这一假说，这项建议将表征基于HSMC的失调级联反应的关键分子底物(例如谷氨酸受体和SK类型的钾通道)，研究多巴胺在调节这些级联反应中的作用，并开发基于HSMC的方法来抑制对可卡因的渴望。为了实现这些目标，我们将使用一种多学科的方法，结合体内分子/药物操作、生物化学、切片电生理学和行为测试。我们的结果将为旨在开发一种基于动态平衡的药理学策略以恢复可卡因使用者正常NAC功能的转译研究奠定基础。

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.