Science

Current lab interests have recently shifted, and we now use state-of-the-art calcium imaging techniques to identify cellular changes in calcium signaling with aging and Alzheimer's disease (AD) in the somatosensory cortex (S1). We have moved away from measuring electrophysiology and imaging of single neurons in the hippocampal slice to infer on elements that contribute to memory decline, and now instead, focus on ambulatory decline, S1 neuronal and astrocytic calcium responses (Scientifica 2P Hyperscope) during head-restrained ambulation (Neurotar environment) as well as gait dysregulation. We are investigating network properties in neurons and astrocytes using GCaMP8 or GCaMP6 (respectively) using non-traditional (i.e., no threshold) calcium analyses and a pipeline developed in house using a continuous wavelet transform data extraction routine. This approach helps us report on network synchronicity, activity, density and pacing during ambulation across different substrates (2-5 mm grids).

We also continue to develop new protocols for measuring bioenergetics with sufficient spatial and temporal resolution for analysis in single live cells in cultures and in tissue slices. This uses PercevalHR, a ratiometric ATP:ADP nanosensor, which we have succesfully expressed in vivo. We now routinely image changes in S1 astrocyte calcium levels during ambulation.

We continue to use intranasal insulin delivery to try to offset cognitive decline in animal models of amyloidosis and are now overexpressing and knocking out the insulin receptor in astrocytes. A current focus is on understanding the mechanism(s) by which insulin alters brain function, perhaps via altering motivation to ambulate or by manipulating network properties in S1 that help control gait parameters.

Our combined efforts, including behavioral and molecular approaches are aimed at identifying novel therapeutic targets that may contribute to prevention of fall and associated negative consequences in aging and/or AD.