Modulation of task performance across arousal states by cortical astrocytes

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.

Grant Number: 1F31NS135961-01A1
NIH Institute/Center: NIH
Principal Investigator: Mitchell Bishop