Modulation of task performance across arousal states by cortical astrocytes

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Project Summary/Abstract The nervous system constantly integrates external stimuli and internal states to produce optimal behavior. More specifically, the internal state of arousal modulates task performance such that arousal states at the extremes are detrimental to success, and peak performance in complex tasks occurs at some middle level of arousal. This phenomenon has primarily been attributed to neuromodulatory influences from the brainstem nucleus Locus Coeruleus and its primary signaling molecule, norepinephrine (NE). However, our current understanding of how NE changes neuronal population activity, thus affecting task performance, is incomplete. Astrocytes, the glial cells of the nervous system known for their roles in promoting synaptic formation, maintaining homeostasis of the cellular environment, and regulating the blood-brain barrier, may be uniquely situated to fill this knowledge gap. Astrocytes express adrenergic receptors, can influence neuronal populations with their interconnected syncytia, and, most importantly, have been shown to exhibit NE-mediated changes in intracellular calcium and lactate dynamics during arousal increases in mice. Nonetheless, these results have yet to be applied in the context of task performance or connection with population activity. My central hypothesis is that cortical astrocytic activity is necessary - and may be sufficient - to affect task performance and population coding across arousal states. My proposal will test this hypothesis in common marmosets trained to perform an auditory discrimination task. In Aim 1, I will determine the necessity of cortical astrocytic activity to modulate task performance and neuronal population coding across arousal states by inhibiting α1 Adrenergic receptor signaling for behavioral and neural encoding effects of arousal states. In Aim 2, I will test the sufficiency of DREADD Gq activation in auditory cortex astrocytes for modulating task performance across arousal states. The training involved in this proposal will include in vivo two-photon calcium imaging, stereotaxic viral vector injections, behavioral tasks, and computational approaches to understanding population activity. These skills will be crucial in the applicant’s goals of becoming an independent investigator pursuing a systems-level understanding of state-dependent behavior and circuit activity.