Sensitivity of the S1 neuronal calcium network to insulin and Bay-K 8644 in vivo: Relationship to gait, motivation, and aging processes

Goals of the lab

The Thibault lab has been investigating hippocampal neuronal calcium dysregulation with aging for nearly 30 years. Techniques used to probe neuronal calcium range from single cell electrophysiology (afterhyperpolarization-AHP; L-type voltage-gated calcium channels) to imaging (epifluorescence and confocal microscopy of calcium transients). Unfortunately, while these techniques helped identify mechanisms and targets responsible for altered neuronal communication at the single cell level, they did not address network activity in groups of neurons in vivo.

We are now addressing this shortcoming using multiphoton imaging of somatosensory cortex neuronal communication during peripheral tactile stimulation in young and aged rats and in young and aged mice, during ambulation. We are focusing on central mechanisms underlying increases in falls with aging, and investigating neuronal calcium networks (activation, synchronization and size derived from GCaMP8f signals). We also test the hypothesis that age-dependent alterations in network properties across large groups of cells can be redressed with intranasal insulin delivery. In essence, we are redirecting single hippocampal neuron research to a new area encompassing a new modality and function, this time, associated with motor control. With a 30-40% annual rate of fall, individuals 65 years and older represent a population target with elevated injury-related morbidity and mortality, yet it is surprising that few central mechanisms have been investigated and few, if any, strategies are available for the prevention of falls in the elderly.

Overview of the study

In our recent Aging Cell manuscript we used 2P imaging of calcium in neurons to characterize potential central mechanisms underlying age-dependent changes in locomotor stability. We tested for the presence of neuronal Ca²⁺ network dysregulation in vivo in the primary somatosensory cortex of young and aged Fisher 344 rats using single-cell resolution techniques, and associated these findings with ambulatory performance. Compared to young, aged animals displayed decreased ambulatory speed and increased overall activity and connectivity of the network. In aged animals, intranasal insulin increased ambulatory speed as well as network synchronicity. In young animals, delivery of the L-VGCC modifier Bay-K 8644 altered network properties and enabled the development of the aged phenotype, reinforcing the role of L-VGCC-mediated Ca²⁺ dynamics in altering neuronal network properties.

These results suggest that Ca²⁺ dysregulation, often rooted in the hippocampus, may be generalizable to other areas, such as the somatosensory cortex, and engage modalities that are associated with locomotor stability. Further, given the safety profile of intranasal insulin in the clinic and the evidence presented here showing that this central dysregulation is sensitive to insulin, we suggest that these processes can be targeted to potentially increase motivation and coordination while also reducing fall frequency with age.

This video shows layer 2/3 somatosensory neurons flickering (GCaMP8f) in response to movement while the animal is ambulating.

Read more on this study here

Dr Olivier Thibault, University of Kentucky

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