Saturday, May 10, 2025
5/10/2025
Developing a sleep EEG-based biomarker for drug relapse propensity - 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).
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).