Astrocyte-Neuron Network Activity During In Vivo Brain Stimulation

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PROJECT SUMMARY Intracortical microstimulation (ICMS) is a primary component of fundamental neuroscience research and holds great potential for sensory restoration or sensory feedback in neuroprosthetics. Despite the wide use of electrical stimulation in neuroprosthetics and interventions such as spinal cord stimulation and deep brain stimulation (DBS), the fundamental physiological and mechanistic properties defining therapeutic efficacy remain poorly understood. For example, it is still unclear which cell types are activated, what role they play in therapeutic outcomes, and how to tune stimulation parameters to selectively elicit relevant activity in those cell types for sensory restoration. Of particular interest is the contribution of non-neuronal cells such as astrocytes. Astrocytes are emerging as important cells in the modulation of neuronal activity during sensory processing in which they respond to neurotransmitters with calcium elevations leading to the release of neuroactive substances to regulate synaptic function (i.e., gliotransmission). Importantly, the time scale in which astrocytes modulate neuronal and synaptic activity is consistent with ICMS-induced neural activity. It is because of these recently appreciated roles regarding astrocyte-neuron communication that astrocytes have been suggested as a vital component to brain stimulation. However, it is unclear how astrocytes respond to clinically relevant stimulation parameters on a network level and how that activation subsequently modulates neuronal activity in an awake animal. To address this gap in knowledge, this proposal will first quantify the calcium activity in cortical astrocytes and across a larger network induced by ICMS with different frequencies and temporal patterns known to have differential therapeutic efficacy using both two-photon microscopy and mesoscale imaging. Next, this proposal will quantify how ICMS- induced neuronal activity is modulated when astrocyte calcium activity is selectively increased (optogenetics) or decreased (viral transduction of a plasma membrane calcium pump) to determine how astrocytes regulate neuronal network activity during ICMS. Because astrocyte calcium activity regulates how these important cells modulate neuronal activity, the cumulative results of this proposal will provide valuable insight for fundamental neuroscience research and the design of stimulation paradigms to elicit astrocyte activity relevant to sensory restoration.