Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine

• Published in: Cell reports (Cambridge) Vol. 42; no. 10; p. 113187
• Main Authors: Rocks, Devin, Jaric, Ivana, Bellia, Fabio, Cham, Heining, Greally, John M., Suzuki, Masako, Kundakovic, Marija
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.10.2023; Elsevier
• Subjects: Adverse Childhood Experiences; Chromatin; cocaine; Cocaine - pharmacology; CP: Neuroscience; early life stress; epigenetic regulation; Estrogens - pharmacology; Female; gene expression; Humans; Male; neuroplasticity; Nucleus Accumbens; ovarian hormones; reward; sex difference; reward; ovarian hormones; sex difference; cocaine; CP: Neuroscience; nucleus accumbens; chromatin; epigenetic regulation; early life stress; gene expression; neuroplasticity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113187

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here, we reveal molecular substrates in the reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine. We find shared involvement of X chromosome inactivation-related and estrogen signaling-related gene regulation in enhanced conditioning responses following early-life stress and during the low-estrogenic state in females. Low-estrogenic females respond to acute cocaine by opening neuronal chromatin enriched for the sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential chromatin closing, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, early-life stress, and absence of one X chromosome all nullify the protective effect of a high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to enable understanding of sex-specific neuronal mechanisms underlying cocaine use disorder. [Display omitted] •Early-life stress more strongly alters gene expression and cocaine reward in females•Ovarian hormone status affects cocaine-induced chromatin and behavioral changes•Acute cocaine causes sex- and estrous cycle-dependent increased accessibility of ΔFosB sites•X chromosome inactivation mechanistically links female-specific risk factors and cocaine use Rocks et al. reveal transcriptional mechanisms through which female-specific factors, early-life stress and ovarian hormones, induce sex-specific cocaine responses. Both factors alter X chromosome inactivation-related and estrogen signaling-related gene regulation in the nucleus accumbens. Cocaine acutely enhances ΔFosB-site accessibility, especially in low-estrogenic females, providing a “priming” mechanism for future exposures.