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Functional Implications of Sex Differences in Hippocampal Endocannabinoid Signaling

海马内源性大麻素信号传导性别差异的功能意义

基本信息

批准号：
10436407
负责人：
CHRISTIAN G REICH
金额：
$ 30.8万
依托单位：
RAMAPO COLLEGE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436407
关键词：
Adolescence Adolescent Adrenal Glands Affect Animals Anxiety Anxiety Disorders Behavior Behavioral CNR1 gene Cells Childhood Chronic Cognition Cognitive Data Data Analyses Development Diagnosis Drug abuse Eating Emotional Endocannabinoids Estrogen Receptor alpha Estrogens Etiology Exposure to Female Female Adolescents Fright Functional disorder Hippocampus (Brain)Human Hypothalamic structure Impairment Incidence Investigation Learning Link Literature Long-Term Potentiation Major Depressive Disorder Male Adolescents Mediating Mediator of activation protein Memory Mental disorders Metaplasia Mood Disorders Neuromodulator Neuronal Plasticity Pharmacology Pituitary Gland Post-Traumatic Stress Disorders Prevalence Production Progesterone Publishing Pyramidal Cells Rattus Regulation Reporting Rodent Role Sex Bias Sex Differences Stress Structure Synapses Synaptic plasticity System Testing Translating Traumatic Brain Injury Woman base biological adaptation to stress conditioned fear data dissemination design emotional behavior endocannabinoid signaling endogenous cannabinoid system epidemiology study estrogenic experimental study extracellular hypothalamic-pituitary-adrenal axis insight learned behavior long term memory male memory recall men neural circuit neurobehavioral neurobehavioral disorder neuropsychiatric disorder neurotransmission patch clamp psychologic receptor density relating to nervous system response sex sexual dimorphism stress related disorder undergraduate student

项目摘要

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.

内源性大麻素 (eCB) 是影响认知、学习等行为现象的神经调节剂记忆、饮食和性。 eCB 参与情绪处理，并与调节密切相关压力和焦虑。越来越多的证据支持 eCB 系统中存在性别差异，即女性与男性相比，男性在多个皮质结构中的 CB1 受体水平较低。在之前的研究中，我们证明，暴露于慢性轻度压力 1) 会不同程度地改变大脑中的 CB1 受体水平雄性和雌性大鼠的海马体以及 2) 增加雄性 GABA 能 CB1 功能。这表明 ECB 系统中的性别差异可能是对压力和压力相关疾病病因的性别差异的基础。例如，被诊断患有压力相关疾病的女性发病率为 2:1 例如重度抑郁症和创伤后应激障碍的发病率高于男性。重要的是，这种差距精神障碍的症状直到青春期才明显，此时皮质边缘回路的成熟对于精神障碍至关重要发展适当的情绪处理和对压力的适应性反应。然而，有目前缺乏关于 eCB 性别功能（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 功能及其在神经行为障碍的病因学和病理生理学。我们公布的数据显示出强劲的性别海马树突 GABA 能突触的 CB1 功能差异，其中女性 CB1 显示与男性相比，对外源激活的敏感性更高。探索其背后的机制差异，我们观察到组成型 CB1 活性、强直性 eCB 产生和雌激素介导的 eCB 的混合青春期雌性树突突触的产生。这与 perisomatic eCB 的文献一致女性身上发出的信号。重要的是，在男性 eCB 信号传导的类似研究中没有报告这些影响。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。涉及细胞外场和突触可塑性实验全细胞膜片钳记录将分别在 CA1 树突层和体周层进行青春期的雄性和雌性动物。将使用海马依赖性评估情绪行为情境恐惧调节。这些研究将进一步阐明 eCB 的神经和行为在两性中都有功能。研究结果可能有助于深入了解情感上性别差异的机制。处理并可能对理解性别偏见神经行为的病理生理学产生影响失调。