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 该项目的重点是理解性能不足背后发生的机制 睡眠不足。特别是，人类的研究已经确定了认知僵化（情况下的情境差异 由于睡眠剥夺（SD）的结果，决策中的适应性）。认知僵化受到 在亚人类灵长类动物和啮齿动物中保守的纹状体金脑回路，并涉及一种细胞类型 表达多巴胺型2（DRD2）和腺苷型2A（A2A）受体。在当前的研究中，我们将 除了大鼠认知，采用小鼠电生理记录和实时纹状体事件成像 容易受到SD的灵活性任务。我们将将这些技术应用于转基因小鼠和大鼠模型 为了询问DRD2/A2A纹状体脑电路在介导SD的影响中的作用 除探测复合物外，生化，受体，区域（脑结构和电生理学）水平 整个生物行为。在AIM 1中，我们将确定DRD2细胞膜定位的程度和 纹状体培养基神经元中的细胞内循环腺苷浓度（[CAMP] I）随着变化而变化 自发和SD诱导的睡眠/唤醒周期的功能。该实验将解决我们的动态 纹状体DRD2受体的可用性和与反相关的[CAMP I的功能充当细胞的相互作用假设 纹状体中睡眠压力的介体。在AIM 2中，我们将检查纹状体DRD2/A2A的活性是否 细胞是必要的，足以赋予SD对认知灵活性的负面影响。我们预测 细胞类型的特异性化学激活或这些神经元的灭活将分别模仿或营救 SD在触摸屏操作逆转任务中的行为后果。预期结果 项目将确认纹状体培养基中刺神经元种群的机械作用 性能降低，导致睡眠损失。在这里，我们的重点是多巴胺能信号，但是我们 长期目标是阐明纹状体和连接大脑区域中的信号传导机制 收敛以调节SD损害的认知过程。总的来说，这项工作将奠定舞台 通过确认纹状体电路中的细胞类型特异性SD缓解靶标的查询。它也将告知 潜在的机械和补偿方法的公共和科学选区 逆转/防止睡眠损失的有害影响。