Sexual Dimorphism in the Striatum Underlying Pathophysiological Consequences of Striatal Abnormalities

摘要 在神经精神疾病的患病率和表现中，性二型是常见的，但 这种二相性背后的机制尚不清楚。神经发育疾病，如自闭症 多发性抽动症(TS)在男性中的发病率是女性的3到5倍， 表明大脑回路和/或病理生理学上存在潜在的二态现象。基底节 环路，特别是纹状体中间神经元的病理，与许多 神经精神障碍，包括自闭症和TS。我们之前描述了一种系统，在该系统中，我们 纹状体特定中间神经元耗竭，包括胆碱能中间神经元(CINs)和快速放电 小鼠纹状体内的中间神经元(FSIS)。我们做了令人震惊的观察，纹状体的消融 中间神经元在基底节网络中产生异常活动和一系列行为 影响--社交偏好的丧失、焦虑样行为和重复的运动病理--但仅限于 雄性老鼠，而不是雌性老鼠。这与自闭症和TS患者的性二型性相似。这 小鼠纹状体神经元间质耗竭系统为探讨其发病机制提供了独特的机会 性二型在基底节功能和病理中的基础，并描绘 可能导致人类神经精神疾病二形性的机制。 为此，我们提出了三个具体目标。我们的第一个目标是检查健康成年人的性二型性 纹状体回路，表征中间神经元的数量、形态、连通性和突触蛋白 通过免疫组织化学和生化方法检测细胞密度。我们的第二个目标是检验性- 纹状体组织特异性基因表达差异的RNA-SEQ生物信息学分析 特定神经元亚型的RNAScope分析。我们的第三个目标是刻画女性特有的 延缓纹状体回路失调和行为异常发展的机制(S) 在雌性小鼠纹状体CINs和FSIS耗尽后。在这里，我们将测试特定的候选人 机制，以我们自己和其他国家的试点调查为基础。 我们假设纹状体生理和功能中的基线性二型性是性行为的基础 纹状体中间神经元病理迂回活动和行为改变的二形性 耗尽。对小鼠这种先天的二形性的理解最终可能会为我们提供对 人类神经精神疾病在男性和女性中的发病率和症状学差异 以基底节功能障碍为特征。

ABSTRACT Sexual dimorphism in the prevalence and presentation in neuropsychiatric disease is common, but the mechanisms underlying this dimorphism remain unclear. Neurodevelopmental diseases such as autism and Tourette’s syndrome (TS) are diagnosed at a 3 to 5 times more often in males than females, suggesting an underlying dimorphism in brain circuitry and/or in pathophysiology. The basal ganglia circuitry, and in particular pathology of interneurons in the striatum, is implicated in many neuropsychiatric disorders, including autism and TS. We have previously described a system in which we depleted specific interneurons in the striatum, including cholinergic interneurons (CINs) and fast spiking interneurons (FSIs), in the mouse striatum. We made the startling observation that ablation of striatal interneurons produces dysregulated activity in the basal ganglia network and a range of behavioral effects – loss of social preference, anxiety-like behavior, and repetitive motor pathology – but only in male mice, not in females. This parallels the sexual dimorphism seen in patients with autism and TS. This mouse striatal interneuron depletion system provides a unique opportunity to probe the mechanistic underpinnings of sexual dimorphism in basal ganglia function and pathology, and to delineate mechanisms that may contribute to dimorphism in human neuropsychiatric disease. To this end, we propose three Specific Aims. Our first Aim examines sexual dimorphism in healthy adult striatal circuitry, characterizing interneuron number, morphology, connectivity, and synaptic protein density through immunohistochemistry and biochemical methods. Our second Aim will examine sex- specific gene expression differences through RNA-seq bioinformatic analysis of striatal tissue and RNAscope analysis of specific neuronal subtypes. Our third Aim seeks to characterize the female-specific mechanism(s) that buffer the development of striatal circuit dysregulation and behavioral abnormalities following depletion of striatal CINs and FSIs in female mice. Here, we will test specific candidate mechanisms, grounded in our own and others’ pilot investigations. We hypothesize that baseline sexual dimorphism in striatal physiology and function underlies the sexual dimorphism in pathological circuity activity and behavioral changes following striatal interneuron depletion. An understanding of this innate dimorphism in mice may ultimately provide insight into the differential incidence and symptomology in males and females of human neuropsychiatric conditions characterized by basal ganglia dysfunction.