Brainstem circuitry for sleep-wake control

PROJECT SUMMARY/ABSTRACT
It is now clear that poor sleep quality has dramatic health consequences, yet sleep medicine is still in great
need for safe and efficient sleep aids. Recent major advances in understanding how the brain regulates sleep-
wake cycles have opened new lines of investigations, revealing a complex regulatory network for non-rapid eye
movement (NREM) sleep control that includes multiple new sleep-promoting neuronal populations. A series of
recent work by our laboratory have demonstrated the critical importance of parafacial zone (PZ) neurons in sleep
induction and maintenance, and of the GABAergic neurons in this region in promoting the deep, restorative stage
of NREM sleep known as slow-wave sleep (SWS). There is a fundamental gap, however, in understanding the
cellular and synaptic circuit basis by which PZ neurons control sleep. The long-term goal is to understand the
cellular and circuit bases by which PZ neurons promote sleep. The central hypothesis is that the brainstem
contains a sub-population of PZ GABAergic neurons that are both sufficient and necessary for the generation of
SWS and cortical slow-wave activity (SWA). The rationale for the proposed research is that understanding how
the PZ promotes sleep is a critical first step towards manipulating this sleep-promoting circuit and will lead to
subsequent translational studies centered on the PZ aimed at reducing the burden of sleep disruption associated
with sleep-wake disorders but also other neurologic disorders. Our hypothesis will be tested by pursuing two
specific aims: 1) uncover a PZ GABAergic sub-population that is specifically sleep promoting; and 2) elucidate
the neuronal circuits by which PZ GABAergic neurons directly influence cortical activity. Guided by strong
preliminary data, in aim 1, we will uncover the role of PZ Parvalbumin expressing GABAergic neurons in sleep-
wake control using a combination of genetically-driven lesions, chemogenetic/optogenetic activation/inhibition,
fiber photometry and neuronal tracing; and in Aim 2, we will uncover a direct pathway by which the PZ directly
affects thalamo-cortical activity and drives the SWA characteristic of SWS, using in vitro electrophysiology,
optogenetic activation of PZ GABAergic projections to the thalamus, in vivo Ca2+ imaging of PZ GABAergic
neurons projecting to the thalamus, and chemogenetic activation of PZGABA in thalamic lesioned mice. The
approach is intellectually and technically innovative because it represents a new and substantive substrate of
understanding sleep regulation and because it employs a novel combination of state-of-the-art approaches. The
proposed research is significant because it is expected to provide critical knowledge of the molecular and cellular
mechanisms by which sleep is regulated. Ultimately, such knowledge is expected to guide the development of
therapeutic and interventional strategies to better regulate sleep-wake behavior and to reduce the burden
associated with sleep disruption, not only associated with sleep disorders but also with many neurological and
psychological disorders that represent a tremendous cost in the United States and worldwide.

Grant Number: 5R01NS119597-05
NIH Institute/Center: NIH
Principal Investigator: Christelle Anaclet