How does sleep work?

This fundamental question has been under investigation for several centuries. It is not until recent technological developments (e.g., chemogenetics, optogenetics...) combined with classical EEG measures that we could causally define discrete sleep/wake circuits with any precision. Indeed, in the past few years, investigation of neural control of sleep and wakefulness has ramped up significantly. 

I aim to take advantage of these newly developed tools to (1) uncover novel sleep/wake circuitry, (2) understand the functional heterogeneity of these circuits, and (3) use this knowledge to develop new targets for the treatment of sleep and psychiatric disorders. 

I've started by completing population-level calcium imaging (using fiber photometry) in a cell type specific manner in the hypothalamus (see below). 

Population activity of GABA neurons within the lateral hypothalamus (LH) varies by arousal state. These are heat maps showing the relative activity of VGAT-Cre neurons in the LH during transitions between different states (NREM sleep, REM sleep, and wakefulness) (Image Credit: JCB) (Note: These data are preliminary and subject to change, any use without the author's consent is forbidden).

Population activity of GABA neurons within the lateral hypothalamus (LH) varies by arousal state. These are heat maps showing the relative activity of VGAT-Cre neurons in the LH during transitions between different states (NREM sleep, REM sleep, and wakefulness) (Image Credit: JCB) (Note: These data are preliminary and subject to change, any use without the author's consent is forbidden).

The hypothalamus regulates fundamental aspects of behavior, including sleep/wake cycles, thirst and hunger, reproduction, and body temperature, among others. It is a highly heterogenous structure composed of several nuclei with distinct functions. A large population of cells within the lateral hypothalamus are neurons that produce the fast inhibitory neurotransmitter GABA. Using mice that express Cre under the vesicular GABA transporter (VGAT) promoter allows us to specifically manipulate them and understand their function.

Genetically encoded calcium indicator (GCaMP6s) expression in lateral/perifornical hypothalamic GABA neurons. The fiber optic tract is highlighted by a dashed line. The activity of these neurons is measured across normal sleep/wake cycles (VGAT-Cre mouse). (Image Credit: JCB).

Genetically encoded calcium indicator (GCaMP6s) expression in lateral/perifornical hypothalamic GABA neurons. The fiber optic tract is highlighted by a dashed line. The activity of these neurons is measured across normal sleep/wake cycles (VGAT-Cre mouse). (Image Credit: JCB).

After investigating how these neurons operate in relation to sleep/wake cycles, their causal role in promoting arousal can be tested with optogenetics (see image below). In the future I aim to uncover the functional heterogeneity of these neurons (as they are made up of many different subpopulations), and use these data to inform computational models of sleep/wake regulation.

Optogenetic stimulation of lateral hypothalamic GABA neurons induces rapid arousal from NREM, but not REM sleep. These findings are consistent with those of  Herrera et al., 2016  (image credit: JCB) (Note: These data are preliminary and are subject to change, any use without the author's consent is forbidden).

Optogenetic stimulation of lateral hypothalamic GABA neurons induces rapid arousal from NREM, but not REM sleep. These findings are consistent with those of Herrera et al., 2016 (image credit: JCB) (Note: These data are preliminary and are subject to change, any use without the author's consent is forbidden).

Banner Image: hM4Di-mCherry, RFP-Alexa488, DAPI in lateral hypothalamus.

All rights reserved: Jeremy Borniger, PhD