Cellular mechanisms in rodent prefrontal cortex

啮齿动物前额皮质的细胞机制

• 批准号: 10283243
• 负责人: Georgina Aldridge
• 金额: $ 11.18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283243
• 关键词: Acetylcholine; Affect; Attenuated; Behavior; Behavioral; Brain; Calcium; Cells; Clinical; Cognition; Cognitive; Data; Dopamine; Dopamine Receptor; Financial compensation; Foundations; Functional disorder; Future; Goals; Grant; Human; Image; Impaired cognition; Impairment; Intervention; Medial; Microscopy; Modeling; Motor; Mus; Neurons; Outcomes Research; Parkinson Disease; Pathologic Processes; Pathology; Patients; Performance; Phase; Population; Prefrontal Cortex; Process; Research; Rodent; Rodent Model; Source; Speech; Symptoms; Techniques; Testing; Training; Viral; Work; alpha synuclein; awake; cell cortex; cell type; cholinergic; clinically relevant; cognitive control; cognitive task; executive function; flexibility; in vivo; in vivo calcium imaging; insight; neuroregulation; non-motor symptom; novel; overexpression; synergism; time interval; two photon microscopy; two-photon

Abstract Parkinson’s disease (PD) causes deficits not only in motor function, but also in cognition and speech, leading to significant loss of independence. Few interventions are available to treat these non-motor symptoms, and current therapies can worsen them. Accumulating evidence suggests that dysfunction in the prefrontal cortex (PFC) is responsible for impaired cognition and speech in PD. Our work shows that patients with PD have impaired prefrontal 4 Hz rhythms, and these abnormal oscillations in local field potentials correlate with impaired cognitive and speech processes. However, the pathophysiology that leads to disruption of prefrontal rhythms in PD remains unclear. The overall objective of the proposed research is to determine how PFC cortical circuits are destabilized by pathophysiological processes in PD, using a combination of cell-type-specific tagging with in vivo two- photon calcium imaging in awake behaving mice. Our hypothesis is that 4 Hz rhythms are orchestrated by layer V neurons expressing D1-type dopamine receptors during interval timing. Both cognitive and speech function require temporal organization of behavior that is vital to higher-level executive functions, such as behavioral flexibility and planning. However, in patients with PD, temporal organization of behavior is abnormal. Our team has modeled temporal deficits in PD using an elementary cognitive task known as interval timing, during which a subject estimates a fixed interval of time. In PD patients, interval timing is reliably disrupted. Interestingly, 4 Hz rhythms are nearly identical in humans and rodents, and they are attenuated in both PD patients and rodent models of PD. The 4 Hz rhythms in the rodent medial PFC (functionally analogous to the human mediofrontal cortex) coordinate cognitive control during interval-timing tasks, but the cellular and laminar source of these rhythms is unknown. In Aim 1 we will use in vivo 2-photon imaging in awake behaving mice to identify the cellular source of prefrontal 4 Hz rhythms critical for interval timing tasks. In Aim 2 we will determine how PD-relevant pathophysiology, including dopaminergic, cholinergic and alpha-synuclein affects prefrontal networks. The expected outcomes of this research will be identifying the cells and circuits that give rise to endogenous 4 Hz rhythms and determining the effects of specific PD pathological processes. These insights will lead to a novel understanding of PFC function that could be relevant for understanding cognitive and speech symptoms in human PD patients.

抽象的 帕金森病（PD）不仅会导致运动功能缺陷，还会导致认知和言语缺陷， 导致严重丧失独立性的干预措施很少可用于治疗这些非运动障碍。 症状，而目前的治疗可能会使症状恶化。越来越多的证据表明，功能障碍。 前额皮质 (PFC) 负责帕金森病中的认知和言语受损。 PD 患者的前额叶 4 Hz 节律受损，并且这些局部场的异常振荡 电位与认知和言语过程受损相关，然而，病理生理学表明。 导致 PD 前额叶节律紊乱的原因尚不清楚。 拟议研究的总体目标是确定 PFC 皮质回路如何不稳定 通过PD的病理生理过程，结合使用细胞类型特异性标记和体内两种方法 我们的假设是，4 Hz 节律是精心安排的。 认知和时间间隔期间表达 D1 型多巴胺受体的 V 层神经元。 言语功能需要行为的时间组织，这对于更高级别的执行功能至关重要， 然而，在 PD 患者中，时间组织。 我们的团队使用基本认知任务对 PD 的时间缺陷进行了建模。 称为间隔计时，受试者估计固定的时间间隔。在 PD 患者中，间隔。 暗示时间确实被打乱，人类和啮齿类动物的 4 Hz 节律几乎相同，并且 它们在 PD 患者和 PD 啮齿动物模型中均减弱。啮齿动物内侧的 4 Hz 节律。 PFC（功能类似于人类中额叶皮层）协调认知控制 间隔定时任务，但这些节律的细胞和层流来源尚不清楚。 在目标 1 中，我们将在清醒行为小鼠中使用体内 2 光子成像来识别 前额叶 4 Hz 节律对于间隔计时任务至关重要，在目标 2 中，我们将确定与 PD 的相关性。 病理生理学，包括多巴胺能、胆碱能和α-突触核蛋白影响前额叶网络。 这项研究的预期结果将是确定产生的细胞和电路 内源性 4 Hz 节律并确定特定 PD 病理过程的影响。 见解将带来对 PFC 功能的新颖理解，这可能有助于理解 人类帕金森病患者的认知和言语症状。