Cellular mechanisms in rodent prefrontal cortex

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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.