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Abstract：
Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp→NAc synapses is rewarding, and mice can establish learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigated sex differences in the mechanisms underlying Hipp→NAc LTP using whole-cell electrophysiology and pharmacology. We observed similarities in basal synaptic strength between males and females and found that LTP occurs postsynaptically with similar magnitudes in both sexes. However, key sex differences emerged as LTP in males required NMDA receptors (NMDAR), whereas LTP in females utilized an NMDAR-independent mechanism involving L-type voltage-gated Ca2+ channels (VGCCs) and estrogen receptor α (ERα). We also uncovered sex-similar features as LTP in both sexes depended on CaMKII activity and occurred independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.
摘要：
性别差异使我们对许多生存关键行为的神经生物学基础的理解变得复杂。因此，继续阐明性别之间的异同对于深入了解大脑功能和脆弱性是必要的。海马（Hipp）和伏隔核（NAc）之间的连接是神经元活动调节介导奖励相关行为的关键位点。我们以前的工作表明，Hipp-NAc突触的长期增强（LTP）是有益的，小鼠可以在这些突触的LTP和发生LTP的上下文环境之间建立学习的关联。这里,我们使用全细胞电生理学和药理学研究了Hipp-NAcLTP潜在机制的性别差异.我们观察到男性和女性之间基础突触强度的相似性，并发现LTP在两种性别的突触后发生，幅度相似。然而,关键的性别差异出现在男性的LTP需要NMDA受体（NMDAR），而女性的LTP则利用了不依赖NMDAR的机制，涉及L型电压门控Ca2通道（VGCC）和雌激素受体α（ERα）。我们还发现了两性LTP的性别相似特征，这取决于CaMKII活性，并且独立于多巴胺-1受体（D1R）激活而发生。我们的结果阐明了LTP在介导奖励相关行为的完整途径中的性别特异性分子机制，强调在机械研究中将性别视为变量的重要性。对可塑性潜在的性别特异性机制的持续表征将为行为的神经生理学基础提供新的见解，对于理解不同的过程如何介导行为并导致对发展中的精神疾病的脆弱性具有重要意义。意义陈述海马-伏隔核（Hipp-NAc）突触的增强驱动奖励相关行为。长时程增强（LTP）在男性和女性中的发生幅度相似，男女都有预测的突触后可塑性位点。尽管有这些相似之处,在这里，我们说明性别特异性分子机制是Hipp-NAc突触LTP的基础。鉴于Hipp-NAc突触强度在介导奖励相关行为中的双向关系，使用不同的分子机制可以解释在应激易感性或对奖励刺激的反应中观察到的性别差异。发现这些潜在的性别差异可以更深入地了解这种与行为相关的突触的性别特定功能，并对学习和奖励相关行为背后的电路产生广泛影响。
