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
- 来源:
- 关键词:AccelerationAccidentsAdenosineAffectAnimalsAreaBehaviorBehavioralBindingBiochemicalBrainCause of DeathCell membraneCellsCognitiveComplexCorpus striatum structureCyclic AMPDataDecelerationDecision MakingDopamineDopamine D2 ReceptorDorsalElectrophysiology (science)EventFeedbackFutureGABA ReceptorGeneticGoalsHumanImageLeadLiteratureMeasuresMediatingMediatorModelingMusNeuronsOccupationsOutcomeOutputPathway interactionsPerformancePopulationPredispositionPrimatesPublishingPurinergic P1 ReceptorsRattusRecoveryResistanceRisk FactorsRodentRoleSignal TransductionSleepSleep DeprivationSleep Wake CycleSolidStructureTechniquesTestingTimeTransgenic MiceWhole OrganismWorkawakecell typecognitive functioncognitive performancecognitive processcognitive rigidityexperimental studyflexibilityin vivoneuronal excitabilitypoor sleeppressurepreventreceptorreceptor densityreceptor expressionresponsestemtouchscreen
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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