Department of Biological Sciences, Fordham University, Bronx, NY, USA.
Department of Psychology, Fordham University, Bronx, NY, USA.
Cell Rep. 2023 Oct 31;42(10):113187. doi: 10.1016/j.celrep.2023.113187. Epub 2023 Sep 29.
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.
早期生活压力和卵巢激素导致女性对可卡因成瘾的易感性增加。在这里，我们通过奖励区域伏隔核揭示了分子基质，这些女性特有的因素通过这些分子基质影响可卡因的即时和条件反应。我们发现，早期生活压力和女性雌激素水平较低时，X 染色体失活相关和雌激素信号相关基因调控的共同参与增强了条件反应。雌激素水平较低的女性通过开放富含 ΔFosB 的神经元染色质对急性可卡因做出反应，ΔFosB 是一种转录因子，与慢性可卡因反应和成瘾有关。相反，高雌激素的女性通过优先关闭染色质做出反应，为限制可卡因驱动的染色质和突触可塑性提供了一种机制。我们发现，生理雌激素撤退、早期生活压力和一条 X 染色体的缺失都消除了高雌激素状态对女性可卡因条件反应的保护作用。我们的研究结果提供了一个分子框架，有助于理解可卡因使用障碍的性别特异性神经元机制。
