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。

基本信息

  • 批准号:
    10656057
  • 负责人:
  • 金额:
    $ 22.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
摘要 该项目的重点是了解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(妥协的情境), 决策的适应性)作为睡眠剥夺(SD)的结果。认知僵化受到以下因素的影响 一种在类人灵长类和啮齿类动物中保守的纹状体脑回路,涉及一种细胞类型, 表达多巴胺2型(DrD 2)和腺苷2a型(A2 a)受体。在当前的研究中,我们将 采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, 为了询问DrD 2/A2 a纹状体苍白球脑回路在介导SD在脑内的作用, 生物化学、受体、区域(脑结构和电生理学)水平,以及探测复合物 整个生物体的行为。在目标1中,我们将确定DrD 2细胞膜定位和 纹状体中棘神经元胞内环磷酸腺苷浓度([cAMP]i)随 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 纹状体DrD 2受体可用性与[cAMP]i呈负相关, 纹状体中的睡眠压力调节剂。在目的2中,我们将检查纹状体DrD 2/A2 a的活性是否与纹状体DrD 2/A2 a的活性相关。 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 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, SD在触摸屏操作性反转任务中的行为后果。预期的结果是, 该项目将证实纹状体中棘神经元群体在神经元中的机械作用。 睡眠不足导致的性能下降。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相连脑区的信号机制 汇聚到一起来调节被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细胞类型特异性SD缓解目标,以供将来查询。它还将告知 潜在的机械和补偿方法的公众和科学界, 逆转/预防睡眠不足的有害影响。

项目成果

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Christopher John Davis其他文献

Christopher John Davis的其他文献

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{{ truncateString('Christopher John Davis', 18)}}的其他基金

"Uncoupling sleep deprivation-associated stressors from sleep loss in rodents"
“将啮齿动物睡眠不足与睡眠不足相关的压力源分开”
  • 批准号:
    8822760
  • 财政年份:
    2014
  • 资助金额:
    $ 22.95万
  • 项目类别:

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