Cellular mechanisms in rodent prefrontal cortex

摘要 帕金森病（PD）不仅导致运动功能缺陷，而且还导致认知和言语缺陷， 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 症状，而目前的治疗方法可能会使其恶化。越来越多的证据表明， 前额叶皮层（PFC）负责PD中的认知和言语受损。我们的工作表明， PD患者的前额叶4 Hz节律受损，这些异常振荡在局部场 电位与受损的认知和言语过程相关。然而， 导致PD患者前额叶节律紊乱的机制尚不清楚。 这项研究的总体目标是确定PFC皮层电路是如何不稳定的 通过PD中的病理生理过程，使用细胞类型特异性标记与体内两种- 清醒行为小鼠的光子钙成像。我们的假设是4赫兹的节奏是经过精心安排的 通过在间隔计时期间表达D1型多巴胺受体的V层神经元。认知和 言语功能需要对行为进行时间组织， 比如行为灵活性和计划性。然而，在PD患者中， 行为不正常。我们的团队已经使用基本认知任务模拟了PD的时间缺陷 称为间隔计时，在此期间，受试者估计固定的时间间隔。在PD患者中，间隔 定时被可靠地中断。有趣的是，人类和啮齿动物的4 Hz节律几乎相同， 它们在PD患者和PD的啮齿动物模型中均被减弱。啮齿类动物中的4 Hz节律 PFC（功能上类似于人类中额叶皮层）协调认知控制， 间隔定时任务，但这些节奏的细胞和层流源是未知的。 在目标1中，我们将在清醒行为小鼠中使用体内双光子成像来识别细胞来源。 前额叶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相关性如何 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网络。 这项研究的预期结果将是确定引起神经元功能障碍的细胞和电路。 内源性4 Hz节律和确定特定PD病理过程的影响。这些 这些见解将导致对PFC功能的新理解， 人类PD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.