Cellular mechanisms in rodent prefrontal cortex

摘要 帕金森氏病(PD)不仅导致运动功能障碍，而且还导致认知和言语障碍， 导致严重丧失独立性。很少有干预措施可用于治疗这些非运动性疾病 症状，而目前的治疗方法可能会使它们恶化。越来越多的证据表明， 前额叶皮质(PFC)是帕金森病患者认知和语言功能受损的主要原因。我们的工作表明 帕金森病患者前额叶4赫兹节律受损，局部视野异常振荡 潜伏期与认知和言语过程受损有关。然而，这种病理生理学 导致帕金森病患者前额节律紊乱的原因尚不清楚。 拟议研究的总体目标是确定PFC皮层回路是如何不稳定的 通过帕金森病的病理生理过程，使用细胞类型特异性标记与体内两个- 清醒行为小鼠的光子钙成像。我们的假设是，4赫兹的节奏是有节奏感的 间歇期表达D1型多巴胺受体的第V层神经元。无论是认知的还是 语音功能需要对对更高级别执行功能至关重要的行为进行时间组织， 比如行为的灵活性和计划性。然而，在帕金森病患者中，时间组织 行为异常。我们的团队使用一个基本的认知任务模拟了帕金森病患者的时间缺陷 被称为间隔计时，在此期间，受试者估计固定的时间间隔。在帕金森病患者中，间隔 定时被可靠地打乱了。有趣的是，4赫兹的节律在人类和啮齿动物中几乎相同，并且 在帕金森病患者和帕金森病啮齿动物模型中，它们都被减弱。啮齿动物内侧的4赫兹节律 PFC(功能类似于人类额叶内侧皮质)协调认知控制 间歇计时任务，但这些节律的细胞和层流来源尚不清楚。 在目标1中，我们将在清醒行为的小鼠中使用活体双光子成像来确定 前额4赫兹节律对间隔计时任务至关重要。在目标2中，我们将确定PD与 包括多巴胺能、胆碱能和α-突触核蛋白在内的病理生理学影响前额叶网络。 这项研究的预期结果将是确定引起 内源性4赫兹节律，并确定特定帕金森病病理过程的影响。这些 洞察力将导致对PFC功能的新理解，这可能与理解相关 人类帕金森病患者的认知和言语症状。

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.