Sexual Dimorphism in the Striatum Underlying Pathophysiological Consequences of Striatal Abnormalities

纹状体中的性别二态性是纹状体异常病理生理后果的基础

• 批准号: 10311987
• 负责人: Meghan Van Zandt
• 金额: $ 6.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311987
• 关键词: Ablation; Address; Adult; Affect; Agonist; Amphetamines; Anatomy; Basal Ganglia; Behavior; Behavioral; Biochemical; Bioinformatics; Biological Models; Brain; Brain region; Buffers; Candidate Disease Gene; Clinical Research; Corpus striatum structure; Development; Diagnosis; Disease; Doctor of Philosophy; Dorsal; Estrogens; Female; Functional disorder; Gene Expression; Genes; Genus Mentha; Gilles de la Tourette syndrome; Homeostasis; Hormonal; Human; Immunohistochemistry; Incidence; Interneurons; Investigation; Laboratories; Light; Methods; Modeling; Morphology; Motor; Mus; Neuroanatomy; Neurobiology; Neurons; Neurosciences; Parvalbumins; Pathologic; Pathology; Patients; Physiology; Population; Population Density; Prevalence; Proteins; Resistance; Series; Sex Differences; Signal Transduction; Synapses; System; Testing; Time; Tissues; Training; Work; acute stress; antagonist; anxiety-like behavior; autism spectrum disorder; brain behavior; brain circuitry; cholinergic; density; differential expression; dimorphism; experimental study; human female; insight; male; neurochemistry; neuropsychiatric disorder; neuropsychiatry; neurosteroids; preference; prevent; relating to nervous system; response; sex; sexual dimorphism; social; transcriptome; transcriptome sequencing

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.

抽象的 神经精神疾病的患病率和表现中的性别二态性很常见，但 这种二态性背后的机制仍不清楚。神经发育疾病，例如自闭症 和妥瑞氏综合症 (TS) 的男性诊断率是女性的 3 至 5 倍， 表明大脑回路和/或病理生理学中存在潜在的二态性。基底神经节 电路，特别是纹状体中间神经元的病理学，与许多 神经精神疾病，包括自闭症和 TS。我们之前描述过一个系统，其中我们 纹状体中特定中间神经元耗尽，包括胆碱能中间神经元 (CIN) 和快速尖峰 小鼠纹状体中的中间神经元（FSIs）。我们做出了令人震惊的观察，即纹状体的消融 中间神经元在基底神经节网络中产生失调的活动以及一系列行为 影响——社会偏好的丧失、焦虑样行为和重复性运动病理——但仅限于 雄性小鼠，而不是雌性小鼠。这与自闭症和 TS 患者中观察到的性别二态性相似。这 小鼠纹状体中间神经元耗竭系统提供了探索机制的独特机会 基底神经节功能和病理学中性别二态性的基础，并描绘 可能导致人类神经精神疾病二态性的机制。 为此，我们提出三个具体目标。我们的第一个目标是检查健康成年人的性别二态性 纹状体回路，表征中间神经元数量、形态、连接性和突触蛋白 通过免疫组织化学和生化方法测定密度。我们的第二个目标是检查性别—— 通过纹状体组织的 RNA-seq 生物信息分析确定特定基因表达差异 特定神经元亚型的 RNAscope 分析。我们的第三个目标旨在描绘女性特有的特征 缓冲纹状体回路失调和行为异常发展的机制 雌性小鼠纹状体 CIN 和 FSI 耗尽后。在这里，我们将测试特定候选人 机制，以我们自己和其他人的试点调查为基础。 我们假设纹状体生理学和功能中的基线性别二态性是性行为的基础 纹状体中间神经元病理性环路活动和行为变化的二态性 消耗。对小鼠这种先天二态性的理解可能最终有助于深入了解 人类神经精神疾病男性和女性的不同发病率和症状 以基底神经节功能障碍为特征。