Abstract
Identifying sleep biomarkers that may reveal pathophysiological conditions or the effectiveness of therapeutics
will greatly advance our health care for psychiatric diseases including substance use disorders (SUDs). The
persistent sleep abnormalities following withdrawal from substance use may offer such opportunities. The
Huang lab has demonstrated a close relationship between rapid eye movement sleep (REMS) and cocaine
seeking after withdrawal, using a rat model of cocaine self-administration and testing for withdrawal time-
dependent intensification of cue-induced cocaine seeking – so called “incubation of cocaine craving”.
Specifically, sleep interventions that selectively increase REMS after drug withdrawal lead to reduced
incubation, and REMS fragmentation does the opposite. For example, dark-phase REMS restriction that
results in a selective increase in recovery REMS time and bout durations reduces incubation of cocaine
craving, whereas sleep fragmentation does the opposite. Moreover, environmental warming that selectively
increases REMS time and bout durations also reduces incubation after cocaine withdrawal. These results
highlight the importance of understanding REMS mechanisms in regulating drug seeking. To probe for the
mechanisms, the Huang lab identified that the melanin-concentrating hormone (MCH)-producing neurons in
the lateral hypothalamus are an important contributor to the REMS-induced effects. MCH neurons
predominantly fire during REMS. Following cocaine self-administration and withdrawal, MCH neurons exhibit
persistent reduction in membrane excitability and deficient glutamatergic transmission. Moreover,
counteracting cocaine-induced functional impairment in MCH neurons by enhancing their activities in sleep
through environmental warming, chemo-, or optogenetic stimulations decreases incubation after cocaine
withdrawal, with corresponding neurophysiological restorations in the reward circuitry. These results suggest
that MCH neuron activities may provide important functional measures for the anti-relapse effects of REMS. In
recent preliminary studies, the Huang lab discovered a sleep EEG derivative which was strongly correlated
with the real-time MCH neuron Ca2+ activities in vivo. This correlation persisted following cocaine experience
and withdrawal, as well as under different REMS manipulations. This provides a potential means for non-
invasive monitoring of MCH neuron activities in vivo through measuring surface EEG signals. Based on the
extensive published and preliminary results, this proposal will test the central hypothesis that EEG spectrogram
decoded for MCH neuron activities in REMS may produce biomarkers that predict drug-relapse propensity.
The proposed experiments and comprehensive analyses are strategically designed for characterizing and
testing such biomarkers. The anticipated novel biomarkers from this EEG feature are uniquely quantifiable and
versatile, which will have important implications for SUD research and therapeutic development. The outcomes
have high translational potential and are in line with NIH’s Sleep Research Plan (2021).