Aberrant dopamine system function in a rodent model of perimenopause: relevance to psychosis

项目摘要/摘要： 过渡到更年期(或围绝经期)对女性来说是一个独特的脆弱时期，在这段时间里 是发展成精神障碍的风险增加或先前存在的疾病的恶化，例如 首发精神分裂症/精神病或双相情感障碍。用于治疗精神病症状的抗精神病药物有 并不总是有效的，经常由于不良副作用而停用。此外，当给予 围绝经期妇女服用抗精神病药物会加重这一时期的常见症状(即体重增加和 高催乳素血症)。这一点很重要，因为精神病症状会使人虚弱，并可能严重 影响女性的生活质量。在本提案中，我们将机械地理解如何 腹侧海马区对中脑边缘多巴胺系统的异常调节与症状有关。 围绝经期精神错乱。我们将使用体内电生理学、化学遗传学和 有三个特定目的的行为：1)检测vHipp对VTA、多巴胺神经元和多巴胺的调节 围绝经期VCD啮齿动物模型中与精神病相关的依赖行为。2)评估 年龄对VCD精神病样效应的影响。3)确定α5-GABAAR PAM作为治疗性药物的效用 恢复多巴胺系统功能和相关多巴胺依赖行为的干预 VCD模型的围绝经期。我们的主要假设是vHipp对 围绝经期的中脑边缘多巴胺系统是精神病相关行为改变的基础。 此外，我们推测α5-GABAAR调节剂在绝经期间可能具有治疗作用 过渡。

Project Summary/Abstract: The transition to menopause (or perimenopause) is a period of unique vulnerability for a woman, in which there is an increased risk of developing a psychotic disorder or the exacerbation of a pre-existing condition, such as first onset schizophrenia/psychosis or bipolar disorder. Antipsychotics used to treat symptoms of psychosis, are not always effective and are often discontinued due to adverse side effects. Further, when given to perimenopausal women, antipsychotics can worsen common symptoms of this period (i.e., weight gain and hyperprolactinemia). This is important to note because psychotic symptoms are debilitating and can severely affect a woman’s quality of life. In the present proposal we will provide a mechanistic understanding into how aberrant regulation of the mesolimbic dopamine system, by the ventral hippocampus, contributes to symptoms of psychosis during perimenopause. We will address this using in vivo electrophysiology, chemogenetics, and behavior with three specific aims: 1) Examine vHipp regulation of VTA dopamine neurons and dopamine- dependent behaviors associated with psychosis in the VCD rodent model of perimenopause. 2) Evaluate the impact of age on the psychosis-like effects of VCD. 3) Determine the utility of α5-GABAAR PAMs as a therapeutic intervention for restoring dopamine system function and dopamine-dependent behaviors associated with perimenopause in the VCD model. Our overarching hypothesis is that aberrant vHipp regulation of the mesolimbic dopamine system during perimenopause underlies behavioral changes associated with psychosis. Furthermore, we posit that α5-GABAAR modulators may have therapeutic utility during the menopausal transition.