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 improve diagnostics,
predict sex-specific clinical trajectories, and identify pathways for early precision therapeutic intervention.