Functional Implications of Sex Differences in Hippocampal Endocannabinoid Signaling

标题 海马内源性大麻素信号的性别差异及其功能意义 摘要 内源性大麻素（eCB）是影响行为现象的神经调质，如认知，学习， 记忆，饮食和性eCB参与情绪处理，并在调节 压力和焦虑越来越多的证据支持eCB系统中的性别差异， 与男性相比，在几个皮质结构中具有较低水平的CB 1受体。在以前的研究中， 我们证明，暴露于慢性轻度应激1）差异改变CB 1受体水平， 雄性和雌性大鼠海马的GABA能CB 1功能增加。这表明 eCB系统中的性别差异可能是对压力和压力病因学反应的性别差异的基础- 相关疾病。例如，有2：1的发病率妇女诊断为压力相关的障碍 如重度抑郁症和创伤后应激障碍。重要的是， 在精神障碍中，直到青春期才明显，此时皮质边缘回路的成熟对于 发展适当的情绪处理和适应压力的反应。不过有 目前缺乏关于eCB性别的功能（神经可塑性和行为）意义的数据 差异这些遗漏妨碍了对正常eCB功能及其在以下方面的作用的全面理解： 神经行为紊乱的病因学和病理生理学。我们公布的数据显示， CB 1在海马树突状GABA能突触的功能差异，由此雌性CB 1显示出 与男性相比，对外源性激活的敏感性更高。探索这背后的机制 不同的是，我们观察到组成型CB 1活性，紧张性eCB生产和雌激素介导的eCB的混合物 在青春期女性树突突触的生产。这与关于体周eCB的文献一致 女性的信号重要的是，这些影响在男性eCB信号传导的类似研究中没有报道。 我们假设青少年海马体树突轴上的这些性别差异 锥体细胞A）转化为eCB介导的突触可塑性的功能差异，B）是性别的基础 情绪学习和行为的差异。突触可塑性实验涉及胞外场和 全细胞膜片钳记录将分别在CA 1树突和体周层进行， 青春期的雄性和雌性动物。情绪行为将使用一个依赖于营地的 情境恐惧条件反射这些研究将进一步阐明eCB的神经和行为 在两性中发挥作用。这一结果可能有助于深入了解情绪性别差异的机制。 可能对理解性别偏见的神经行为的病理生理学有影响。 紊乱

Title Functional Implications of Sex Differences in Hippocampal Endocannabinoid Signaling Abstract Endocannabinoids (eCBs) are neuromodulators that affect behavioral phenomena such as cognition, learning, memory, eating and sex. eCBs are involved in emotional processing and are heavily implicated in regulating stress and anxiety. There is growing evidence supporting sex differences in the eCB system, whereby females possess lower levels of the CB1 receptor in several cortical structures compared to males. In previous studies, we demonstrated that exposure to chronic mild stress 1) differentially altered CB1 receptor levels in the hippocampus of male and female rats and 2) increased GABAergic CB1 function in males. This suggests that sex differences in the eCB system may underlie sex differences in response to stress and etiologies of stress- related disorders. For example, there is a 2:1 incidence rate of women diagnosed with stress-related disorders such as Major Depressive Disorder and Post-Traumatic-Stress-Disorder than men. Importantly, this disparity in mental disorders is not apparent until adolescence, when maturation of corticolimbic circuitry is critical for development of appropriate emotional processing and adaptive responses to stress. However, there is currently a dearth of data regarding the functional (neural plasticity and behavioral) significance of eCB sex differences. These omissions preclude a complete understanding of both normal eCB function and its role in the etiology and pathophysiology of neurobehavioral disorders. Our published data show a robust sex difference of CB1 function at hippocampal dendritic GABAergic synapses whereby female CB1 displays a higher sensitivity to exogenous activation compared to males. Exploring the mechanisms underlying this difference, we observe a mixture of constitutive CB1 activity, tonic eCB production and estrogen-mediated eCB production at adolescent female dendritic synapses. This is consistent with the literature on perisomatic eCB signaling in females. Importantly, these effects are not reported in similar studies of eCB signaling in males. We hypothesize that these sex differences across the somatodendritic axis in adolescent hippocampal pyramidal cells A) translate into functional differences in eCB-mediated synaptic plasticity and B) underlie sex differences in emotional learning and behavior. Synaptic plasticity experiments involving extracellular field and whole-cell patch clamp recordings will be performed in CA1 dendritic and perisomatic layers, respectively from adolescent male and female animals. Emotional behavior will be assessed using a hippocampal-dependent contextual fear conditioning. These investigations will provide further elucidation of eCB neural and behavioral function in both sexes. The results may provide insight into the mechanisms of sex differences in emotional processing and may have implications for understanding the pathophysiology of sex-biased neurobehavioral disorders.