Molecular and functional implications of thalamo-striatal synapse regulation in learning and memory

PROJECT ABSTRACT Cognitive changes occur as a normal process of aging and among the most important changes in cognition in normal aging are declines in cognitive flexibility (CF). CF is considered a core aspect of executive functioning and describes an individual’s ability to adapt their behavior and thinking to a changing environment.

Disruptions in CF impact functional independence, communication with others, and socialization. Despite the well-documented prevalence of CF decline in aging, and its exacerbation in neurodegeneration, the mechanisms that lead to structural and functional changes involved in the regulation of CF are not well

understood. The majority of studies related to CF impairment have focused on changes within the hippocampus and cortex, however, the dorsal striatum, particularly the dorsomedial striatum (DMS), has long been strongly associated with CF. The dorsal striatum is traditionally associated with control of motor function,

but recent human fMRI and PET analyses demonstrated that declines in striatal function predict declining cognitive abilities during aging. Striatal function is governed by the innervation of two excitatory glutamatergic circuits: cortico- (C-S) and thalamo-striatal (T-S). Importantly, T-S synapse density preferentially declines

during aging and is associated with declining CF performance. However, the regulatory mechanisms by which T-S synapses are preferentially lost in the aging striatum and how they contribute to CF decline is unknown. Depletion of the heat shock transcription factor 1 (HSF1), a transcription factor canonically known for its role in

cellular stress responses, within the striatum, accelerates T-S synapse loss and results in impairment of CF. HSF1 levels also decrease in aging and HSF1 has been shown to directly regulate the transcription of synaptic genes within the striatum and other brain regions. Taken together, the goal of this proposal is: 1) to determine

the molecular underpinning that govern the differential effects of HSF1-mediated synaptic regulation within the DMS and 2) to understand the role of HSF1 and T-S synapses in striatal dysfunction and CF impairment. I will fill these gaps in knowledge through two complementary aims. In Aim 1, I will examine the role of HSF1 in

the regulation of the synaptoproteome of excitatory striatal projections through proteomic analyses of T-S and C-S synaptic terminals and synapses from a conditional HSF1 knock-out mouse. In Aim 2, I will assess the contribution of striatal HSF1 to CF by deleting HSF1 within the adult DMS using AAVs expressing Cre-

recombinase and the necessity of T-S connectivity to CF by optostimulation of T-S terminals in DMS. Successful completion of this proposal will provide a mechanistic understanding of how synaptic dysfunction within the DMS contributes to CF which has implications in aging and neurodegeneration, as well as establish

the role of HSF1 in the regulation of striatal glutamatergic synapses and CF that may result in new therapeutic strategies to prevent CF deficits in the aging population.