Cortical Alpha-Synuclein in Dementia

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Abstract Lewy-Body dementias, including Parkinson’s disease Dementia and Dementia with Lewy Bodies, are devastating, multi-system diseases and a major cause of dementia worldwide. Patients have characteristic symptoms that suggest dysfunction of the frontal-network, including difficulty with planning, fluctuating attention and impaired flexible learning. The pathology of patients with dementia includes widespread aggregates of the protein alpha-synuclein (𝛼-syn) in the frontal cortex and other extra-nigral regions. Despite this association, the role of 𝛼-syn pathology beyond the dopaminergic system remains unclear. There is a critical need to understand how -syn affects network function to develop treatments for Lewy Body dementias. Our long-term goal is to develop treatments for Lewy Body Dementia by targeting circuit-level dysfunction. Our overall hypothesis is that local -syn aggregation in the cortex disrupts prefrontal circuits, leading to executive dysfunction. Testing this overall hypothesis requires determining the regional effect of 𝛼-syn on cellular activity and neuronal plasticity in isolation from deficits secondary to other major neurotransmitter systems that project to cortex. To accomplish this goal, this proposal uses viral overexpression of -syn localized to the prefrontal cortex. By imaging the activity of individual neurons and the plasticity of dendritic spines, we can learn how cortical cells respond to this enigmatic, disease-associated protein. We propose to use 2-photon transcranial microscopy to determine how neuronal activity (Aim 1) and synaptic plasticity (Aim 2) respond to regional overexpression of -syn over the course of aging. In Aim 3, we will use a rule-learning, reversal and rule- shifting tasks adapted for head-fixed applications to determine how prefrontal-dependent learning and flexibility respond to cortical -syn. In parallel, we will correlate cognitive performance with anatomical plasticity and neuronal activity. Findings from this proposed research will provide targets for future studies to restore cortical function and treat symptoms through circuit-level manipulation. In addition, by comparing outcomes across the three aims, we will be able to connect structural plasticity, neuronal activity and frontal-cognitive behavior to provide broad insights into the prefrontal cortex.