PROJECT SUMMARY Many Parkinson’s patients develop cognitive impairment during an early, motor-asymptomatic pro- dromal period, before clinical diagnosis and motor symptoms. Cognitive impairment causes a significant disruption in quality-of-life for patients and caregivers. The onset of early cognitive impairment greatly increases risk for conversion to dementia, but such progression differs from that of other neurodegenerative diseases (like Alzheimer’s) and differs between males and females for reasons that are not clear. Cognitive abnormalities include impaired attention, slower information processing speed, and others, yet the underlying neurobiology of such early cognitive symptoms is not known, thwarting targeted therapeutic strategies which are necessary to halt or slow cognitive decline and dementia. Cognitive impairment is present in both idiopathic and hereditary forms of Parkinson’s, including that resulting from several mutations in LRRK2 that increase kinase activity. The focus of this project is on characterizing the underlying neurobiology of early cognitive deficits in a mouse model carrying a knockin G2019S gene mutation in LRRK2 that in humans increases risk of Parkinson’s-associated cognitive decline and dementia. The premise is built on our observations that young adult, male Lrrk2G2019S mice display significant deficits in attention (tested in a 5-CSRT task), slower information processing speed, and in fronto-striatal dependent instrumental learning. Such deficits could not be attributed to sensory perceptual deficits, differences in motivation or motor effects. Further, these deficits were normalized by systemic injection of the acetylcholinesterase inhibitor donepezil, implicating deficient cholinergic signaling. Anatomical analysis showed that the cholinergic innervation of mPFC was significantly sparser in male G2019S mice than in male wildtype controls. In contrast, young adult female G2019S mice showed normal instrumental learning, and an enhanced density of cholinergic innervation in mPFC compared to female wildtype controls, suggesting a compensatory response and demonstrating early sexually-dimorphic behavioral and anatomical outcomes driven by the mutation. We propose to examine cholinergic innervation of mPFC in male and female G2019S mutants across the lifespan and in the context of cognitive behavioral performance; we will interrogate projection-identified mPFC neurons by whole-cell electrophysiology to characterize cholinergic nicotinic and muscarinic receptor responses; and we will probe behaviorally-evoked ACh transients in mPFC using a genetically-encoded fluorescent ACh biosensor and will use this information to modulate cognitive function by optogenetically controling ACh signaling in mPFC during an attention task. Successful completion of these experiments will provide new insight into the earliest Parkinson’s-associated pathophysiology of mPFC cholinergic circuits and cognition, with the long-term goal to...