Cellular mechanisms in rodent prefrontal cortex

啮齿动物前额皮质的细胞机制

• 批准号: 10490437
• 负责人: Georgina Aldridge
• 金额: $ 8.83万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490437
• 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 帕金森氏病（PD）不仅会导致运动功能，而且在认知和言语中引起缺陷， 导致明显的独立性丧失。很少有干预措施可以治疗这些非运动器 症状和当前的疗法会想知道它们。积累的证据表明功能障碍 前额叶皮层（PFC）负责PD中的认知和语音受损。我们的工作表明 PD患者患有前额叶4 Hz节律，这些异常振荡在局部领域 潜力与认知和言语过程受损相关。但是，病理生理学 导致PD前额叶节奏的破坏尚不清楚。 拟议的研究的总体目的是确定PFC皮层电路如何不稳定 通过PD中的病理生理过程，结合了细胞类型的特异性标记与体内两种 在醒着的行为小鼠中的光子钙成像。我们的假设是4 Hz节奏是精心策划的 在间隔时间内表达D1型多巴胺受体的V层神经元。认知和 语音功能需要临时组织行为，这对于高级执行职能至关重要， 例如行为灵活性和计划。但是，在患有PD的患者中 行为是异常的。我们的团队使用基本认知任务在PD中进行了建模 被称为间隔时间，在此期间，受试者估计固定时间间隔的时间。在PD患者中，间隔 时机被可靠地破坏了。有趣的是，在人类和啮齿动物中，4 Hz节奏几乎相同，并且 它们在PD患者和PD的啮齿动物模型中都会减弱。啮齿动物介质中的4 Hz节奏 PFC（在功能上类似于人类中额皮质）在协调认知对照期间 间隔定时任务，但是这些节奏的细胞和层流来源尚不清楚。 在AIM 1中，我们将在醒着的行为小鼠中使用体内2-Photon成像来识别细胞来源 前额叶4 Hz节奏对于间隔时间任务至关重要。在AIM 2中，我们将确定PD与PD相关的方式 病理生理学，包括多巴胺能，胆碱能和α-核蛋白会影响前额叶网络。 这项研究的预期结果将确定引起的细胞和圆圈 内源性4 Hz节奏并确定特定PD病理过程的影响。这些 洞察力将导致对PFC功能的新了解，这可能与理解有关 人类PD患者的认知和语音症状。