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

中型棘神经元在睡眠剥夺引起的认知僵化中的作用。

• 批准号: 10656057
• 负责人: Christopher John Davis
• 金额: $ 22.95万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656057
• 关键词: Acceleration; Accidents; Adenosine; Affect; Animals; Area; Behavior; Behavioral; Binding; Biochemical; Brain; Cause of Death; Cell membrane; Cells; Cognitive; Complex; Corpus striatum structure; Cyclic AMP; Data; Deceleration; Decision Making; Dopamine; Dopamine D2 Receptor; Dorsal; Electrophysiology (science); Event; Feedback; Future; GABA Receptor; Genetic; Goals; Human; Image; Lead; Literature; Measures; Mediating; Mediator; Modeling; Mus; Neurons; Occupations; Outcome; Output; Pathway interactions; Performance; Population; Predisposition; Primates; Publishing; Purinergic P1 Receptors; Rattus; Recovery; Resistance; Risk Factors; Rodent; Role; Signal Transduction; Sleep; Sleep Deprivation; Sleep Wake Cycle; Solid; Structure; Techniques; Testing; Time; Transgenic Mice; Whole Organism; Work; awake; cell type; cognitive function; cognitive performance; cognitive process; cognitive rigidity; experimental study; flexibility; in vivo; neuronal excitability; poor sleep; pressure; prevent; receptor; receptor density; receptor expression; response; stem; touchscreen

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.

抽象的 该项目的重点是了解绩效缺陷背后的机制 睡眠不足。特别是，对人类的研究已经发现认知僵化（情境受损） 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 纹状体苍白球脑回路，在非人类灵长类动物和啮齿类动物中保守，涉及一种细胞类型 表达 2 型多巴胺 (DrD2) 和 2a 型腺苷 (A2a) 受体。在当前的研究中，我们将 除了大鼠认知之外，还采用小鼠电生理学记录和实时纹状体事件成像 易受 SD 影响的灵活性任务。我们将把这些技术应用到转基因小鼠和大鼠模型中 为了探究 DrD2/A2a 纹状体苍白球脑回路在介导 SD 效应中的作用 除了探测复合体之外，生化、受体、区域（脑结构和电生理学）水平 整个有机体的行为。在目标 1 中，我们将确定 DrD2 细胞膜定位和 纹状体中型多棘神经元细胞内环磷酸腺苷浓度 ([cAMP]i) 变化如下 自发和 SD 诱导的睡眠/觉醒周期的函数。这个实验将解决我们的动态 相互作用假设：纹状体 DrD2 受体的可用性和负相关的 [cAMP]i 功能作为细胞 纹状体睡眠压力的调节因子。在目标 2 中，我们将检查纹状体 DrD2/A2a 的活性是否 SD 对认知灵活性产生负面影响是必要且充分的。我们预测 这些神经元的细胞类型特异性化学遗传学激活或失活将分别模拟或拯救， SD 在触摸屏操作逆转任务中的行为后果。本次活动的预期结果 该项目将确认纹状体中型多棘神经元群在 由于睡眠不足而导致的表现下降。在这里，我们的重点是多巴胺能信号传导，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传导机制如何 集中调节受到 SD 损害的认知过程。总的来说，这项工作将为 通过确认纹状体电路中特定细胞类型的 SD 缓解目标，以供未来查询。它还将告知 潜在的机械和补偿方法的公众和科学界人士 扭转/预防睡眠不足的有害影响。