THE ROLE OF MEDIUM SPINY NEURONS IN SLEEP DEPRIVATION-INDUCED COGNITIVE RIGIDITY.

摘要 本项目的重点是了解以下情况下发生的性能缺陷背后的机制 睡眠不足。特别是，对人类的研究已经确定了认知僵化(折衷的情景 决策适应性)是睡眠剥夺(SD)的结果。认知僵化受以下因素影响 一种纹状体双侧脑回路，在亚人类灵长类动物和啮齿类动物中保存，并涉及一种细胞类型， 表达多巴胺-2型(DRD2)和腺苷-2a(A2a)受体。在目前的研究中，我们将 使用小鼠电生理记录和实时纹状体事件成像，除了大鼠认知 易受SD影响的灵活性任务。我们将把这些技术应用于转基因小鼠和大鼠模型中 目的：探讨DRD2/A2a纹状体苍白质脑回路在SD大鼠大脑中的作用。 生化、受体、区域(脑结构和电生理)水平以及探测复合体 整个有机体行为。在目标1中，我们将确定DRD2细胞膜定位和 纹状体中棘神经元细胞内环磷酸腺苷浓度([cAMP]i)变化如下 自发性和SD诱导的睡眠/觉醒周期的一种功能。这项实验将解决我们的动态 纹状体DRD2受体的可用性和反向相关的[cAMP]i作为细胞功能的相互作用假说 纹状体中睡眠压力的中介物。在目标2中，我们将检查纹状体DRD2/A2a的活性 细胞是SD对认知灵活性产生负面影响的必要条件和充分条件。我们预测 这些神经元的细胞类型特异性化学发生激活或失活将分别模拟或拯救， 触摸屏操作反转任务中SD的行为后果。这样做的预期结果是什么 该项目将证实纹状体苍白质中棘神经元群在 由于睡眠不足而导致的性能下降。在这里，我们的重点是多巴胺能信号，但我们的 长期目标是阐明纹状体和连接的大脑区域中的信号机制 收敛以调节被SD损害的认知过程。总体而言，这项工作将为 通过确认纹状体回路中特定细胞类型的SD缓解目标，供未来查询。它还将通知 潜在的机械性和补偿性方法的公众和科学支持者 逆转/预防睡眠不足的有害影响。

ABSTRACT This project is focused on understanding the mechanisms behind performance deficits that occur with insufficient sleep. In particular, studies in humans have identified cognitive rigidity (compromised situational adaptability in decision making) as a consequence of sleep deprivation (SD). Cognitive rigidity is influenced by a striatopallidal brain circuit that is conserved in subhuman primates and rodents and involves a cell type that expresses dopamine-type 2 (DrD2) and adenosine-type 2a (A2a) receptors. In the current studies, we will employ mouse electrophysiology recordings and real-time striatal event imaging, in addition to a rat cognitive flexibility task that is susceptible to SD. We will apply these techniques to transgenic mouse and rat models in order to interrogate the role of the DrD2/A2a striatopallidal brain circuit in mediating the effects of SD at the biochemical, receptor, regional (brain structure and electrophysiology) levels in addition to probing complex whole organism behavior. In Aim 1, we will determine the extent to which DrD2 cell membrane localization and intracellular cyclic adenosine monophosphate concentration ([cAMP]i) in striatal medium spiny neurons vary as a function of spontaneous and SD-induced sleep/wake cycles. This experiment will address our dynamic interplay hypothesis that striatal DrD2 receptor availability and the inversely-related [cAMP]i function as cellular mediators of sleep pressure in the striatum. In Aim 2, we will examine whether the activity of striatal DrD2/A2a cells is necessary and sufficient to confer the negative impacts of SD on cognitive flexibility. We predict that cell-type specific chemogenetic activation or inactivation of these neurons will mimic or rescue, respectively, the behavioral consequences of SD in a touchscreen operant reversal task. The anticipated results of this project will confirm the mechanistic role of the striatopallidal medium spiny neuron population in the performance decrements that stem from sleep loss. Here, our focus is on dopaminergic signaling, but our long-term objective is to elucidate how signaling mechanisms in the striatum and connected brain areas converge to regulate the cognitive processes that are compromised by SD. Overall, this work will set the stage for future inquiries by confirming cell type-specific SD mitigation targets in striatal circuitry. It will also inform the public and scientific constituencies of potential mechanistic and compensatory approaches to reversing/preventing the deleterious effects of sleep loss.