An Electroencephalogram Signature of Melanin-Concentrating Hormone Neuron Activities Predicts Cocaine Seeking

Abstract

Background: Identifying biomarkers that predict substance use disorder propensity may better strategize antiaddiction treatment. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus critically mediate interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers.

Methods: Surface EEG signals and real-time calcium (Ca²⁺) activities of lateral hypothalamus MCH neurons (Ca²⁺_MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca²⁺_MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca²⁺_MCH either before or after cocaine experience were used to predict future drug-seeking behaviors.

Results: An EEG waveform derivative-a modified theta-delta-theta peak ratio (EEG_TDT ratio)-accurately tracked real-time Ca²⁺_MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through vigilance states, sleep manipulations, and circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG_TDT ratio, suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG_TDT ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG_TDT ratio also exhibited advantages over conventional REMS measures for the predictions.

Conclusions: The identified EEG_TDT ratio may serve as a noninvasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker for predicting drug use propensity.

Keywords: Biomarker; Cocaine; EEG; MCH; REM sleep.