Sleep and wake are critical for animal survival, but the mechanisms by which the brain coordinates switching between these brain states, from brainstem to cortex, remains unclear. Neuromodulatory signaling circuits are essential systems for brain state switching, both in sleep/wake and in other contexts. In the current proposal, we explore the role of one of these neuromodulators?histamine?in the regulation of sleep and wake in the cerebral cortex. Although histamine has long been known as a wake-promoting neuromodulator, it is relatively understudied compared to others, so our understanding of its cellular and circuit mechanisms of action is still in the early stages. Here, we take a holistic perspective of the cell types involved in sleep/wake circuits, and ask how the largest class of non-neuronal cells in the brain, astrocytes, are involved in sending and responding to histaminergic signals in the cortex.
We aim to address gaps in our knowledge of sleep/wake dynamics, histaminergic signaling, and astrocytic regulation of neural circuits by uncovering critical cell biological signaling systems in astrocytes. We apply advanced optical, electrophysiological, and neural manipulation techniques to reveal how astrocytes may be integrating neuromodulatory signals in cortical circuits and coordinating populations of neurons. Our main goals include: probing the cell biological mechanisms by which histamine activates astrocytes, testing the spatiotemporal dynamics of histamine and astrocytes to determine their causal relationships, and exploring the mechanisms by which astrocytes may synchronize or desynchronize neuronal activity.
While sleep and wake dynamics are critical to animals' survival and are intertwined with psychiatric diseases, how sleep- and wake-promoting signals are integrated from the brainstem to the cerebral cortex remain unclear. In this proposal, we focus on the role of astrocytes?the most abundant non-neuronal cell type in the brain?in sensing and responding to histaminergic neuromodulatory signals, and determining the sleep/wake state of the cortex. Our results will illuminate mechanisms by which astrocytes coordinate the activity of populations of neurons across brain states.
