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Doctor of Philosophy (PhD)
Dr. Olivier Thibault
Over the past 30 years, the calcium (Ca2+) hypothesis of brain aging has provided clear evidence that hippocampal neuronal Ca2+ dysregulation is a key biomarker of aging. Indeed, age-dependent Ca2+-mediated changes in intrinsic excitability, synaptic plasticity, and activity have helped identify some of the mechanisms engaged in memory and cognitive decline. However, much of this work has been done at the single-cell level, mostly in slice preparations, and in restricted structures of the brain. Recently, our lab identified age- and Ca2+-related neuronal network dysregulation in the cortex of the anesthetized animal. Still, investigations in the awake animal are needed to test the generalizability of the Ca2+ hypothesis of brain aging and dementia. Here, we used in vigilo two-photon (2P) imaging in ambulating mice, to image GCaMP8f in the primary somatosensory cortex (S1), during ambulation and at rest. In order to investigate aging- and sex- related changes in the neuronal Ca2+ network, a continuous wavelet transform (CWT) analysis was developed (MATLAB) to extract measures of network communication while also addressing pair-wise correlations at single-cell resolution. Following imaging, gait behavior was characterized to test for changes in locomotor stability. During ambulation and compared to rest, in both young (4 months) and aged mice (22 months), an increase in connectivity and synchronicity was noted. An age-dependent increase in network synchronicity was seen in ambulating aged males only. Additionally, females displayed a greater number of active neurons, area-under-curve, and neuronal activity compared to males, particularly during ambulation. These results suggest S1 Ca2+ dynamics and network synchronicity are likely contributors of locomotor stability. We believe this work raises awareness of central elements at play in S1 where neuronal Ca2+ network dysregulation is seen with aging, perhaps highlighting potential therapeutic targets that may help offset age-dependent increases in falls.
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This work was supported by the NIH (R01AG033649-S1 and P01AG078116 to O.T.), the University of Kentucky (Chair's Pilot Research Award to S.L.C. and O.T.), and the Neurosciences Education & Research Foundation (Award to O.T.).
Case, Sami L., "AGE- AND SEX-DEPENDENT ALTERATIONS IN PRIMARY SOMATOSENSORY NEURONAL CALCIUM NETWORK DYNAMICS DURING LOCOMOTION" (2023). Theses and Dissertations--Pharmacology and Nutritional Sciences. 46.