CAREER: Astrocytic Integration of Cortical Wake Signals

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The fundamental biological importance of sleep is demonstrated by the fact that sleep is observed widely across the animal kingdom, and that sleep deprivation can be harmful both physiologically and cognitively. Likewise, the importance of wake is axiomatic: reproduction, feeding, and escape from predation depend on an animal being awake. However, until recently, the neural circuits that regulate wake and sleep have remained poorly understood. One strand of inquiry has implicated a non-neuronal cell type in sleep-wake control. This cell—the astrocyte—makes up the largest class of non-neuronal cells in the brain, and it has been shown to affect the activity of surrounding neurons. However, the ways in which astrocytes are involved in sleep and wake are largely unexplored. This project tests whether astrocytes sense wake-specific signals and respond to these signals by changing the state of the brain. To perform these experiments, advanced imaging tools to watch different forms of cellular activity in the brain are used. The broader impacts of this project aim to make interdisciplinary research accessible and routine to trainees early in their careers. The motivation for this lies in the fact that trainees with experience in physical sciences are more likely to become tool builders themselves, and that watching science happening in real time can excite and empower trainees to think deeply about the biology around them.Neuromodulatory signaling is critical for animal behavior, in part by shifting the brain among various states, and the most dramatic brain state shifts are arguably those that occur between wake and sleep. However, how neuromodulatory inputs arising in subcortical nuclei are integrated at the level of the cortex to regulate population-level state shifts remains unclear. Several neuromodulatory receptors are expressed on both cortical neurons and astrocytes, raising the possibility that astrocytes are partners with neurons in sensing neuromodulatory cues to initiate and/or maintain wake in the cortex. Astrocytes are an attractive target for coordinating large-scale neuronal circuit changes, and they have also been implicated in sleep/wake via brain state-dependent changes in extracellular balance and morphology. The overarching hypothesis for this project is that neuromodulatory signaling to astrocytes, and subsequent astrocytic effects on population neuronal activity, is critical for integrating wake-state signals in the cortex, the largest area of the mammalian brain. The research addresses these questions using advanced two-photon imaging, modern neurobiological tools to modulate neural activity, and astrocyte-specific technology to probe the cell biological responses of astrocytes to neuromodulatory cues, and map astrocytic dynamics across wake and sleep, in preparation to test the effects of astrocyte activation on wake state and neural signaling in a cortical circuit.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.