CNR Institute of Neuroscience, National Research Council, 09042, Monserrato, CA, Italy.
Department of Life and Environmental Sciences, Section of Neuroscience and Anthropology, University of Cagliari, 09042, Monserrato, CA, Italy.
Neuropharmacology. 2025 Jan 1;262:110212. doi: 10.1016/j.neuropharm.2024.110212. Epub 2024 Nov 7.
The long-term influence of early-life stress on brain neurophysiology has been extensively investigated using different animal models. Among these, repeated maternal separation (RMS) in rodents is one of the most commonly adopted. In this study, we elucidated the long-lasting effects of exposure to postnatal RMS in C57BL/6J adult mice on voluntary alcohol consumption and nucleus accumbens (NAc) neurophysiology. Mice were separated from their dam for 360 min daily from postnatal day 2 (PND2) to PND17, and experiments were then performed in adult (PND60) animals. In addition, as recent evidence showed that circulating estrogens may play a protective role against stress effects on brain function, including the organization and activation of neuronal structures, we also evaluated the effect of a single injection of β-estradiol 3-benzoate (EB) at PND2, which is known to disrupt male sex differentiation, in male RMS mice. The RMS exposure was associated with an increased voluntary alcohol consumption and preference in male mice, but not in female mice or male mice treated with a single injection of EB. Patch clamp experiments conducted in NAc medium spiny neurons (MSNs) revealed that excitatory but not inhibitory synaptic transmission and long-term plasticity of glutamatergic synapses were significantly impaired in male but not in female mice exposed to the RMS protocol. This effect was again prevented in RMS male mice treated with EB. Our findings strengthen the idea of a sex-dependent influence of early-life stress on long-lasting modifications in synaptic transmission and plasticity in brain areas involved in goal-directed behavior and alcohol intake.
早期生活压力对大脑神经生理学的长期影响已经通过不同的动物模型进行了广泛研究。其中，啮齿动物的反复母体分离（RMS）是最常用的方法之一。在这项研究中，我们阐明了在 C57BL/6J 成年小鼠中暴露于产后 RMS 对自愿饮酒和伏隔核（NAc）神经生理学的长期影响。从出生后第 2 天（PND2）到第 17 天，每天将幼鼠与母鼠分离 360 分钟，然后在成年（PND60）动物中进行实验。此外，最近的证据表明，循环雌激素可能对大脑功能的应激效应起到保护作用，包括神经元结构的组织和激活，我们还评估了在 PND2 时单次注射β-雌二醇 3-苯甲酸酯（EB）对雄性 RMS 小鼠的影响，已知这种方法会破坏雄性的性别分化。RMS 暴露与雄性小鼠自愿饮酒和偏好增加有关，但与雌性小鼠或接受单次 EB 注射的雄性小鼠无关。在 NAc 中进行的尖峰神经元（MSNs）膜片钳实验表明，兴奋性但不是抑制性突触传递和谷氨酸能突触的长时程可塑性在雄性而非雌性小鼠中显著受损，而在接受 RMS 方案的雄性小鼠中再次被 EB 处理所预防。我们的发现加强了早期生活压力对参与目标导向行为和酒精摄入的大脑区域中突触传递和可塑性的长期改变具有性别依赖性影响的观点。
