Neuronal Mechanisms underlying sex differences in dystonia

肌张力障碍的特征是不随意的肌肉收缩，导致扭曲的运动和姿势。许多 肌张力障碍在女性中比在男性中更常见，然而这些性别差异的机制是 大部分未开发。基底神经节功能障碍始终涉及许多形式的肌张力障碍。的 基底神经节的主要输入结构是纹状体，其中雌激素发挥神经调节作用。事实上， 已知纹状体多刺投射神经元（SPN）的生理特性根据生物学特性而变化 性和发情周期阶段。直接通路SPN（dSPN）投射到内部苍白球，以促进 运动间接途径SPN（iSPN）投射到外部苍白球以抑制运动。虽然 dSPN和iSPN被分离成单独的通路，它们协同作用以调节和细化运动。 在肌张力障碍患者中，这种协调活动被破坏，因为功能成像研究和微电极 记录表明dSPN和iSPN都是功能失调的。然而，两者背后的机制 肌张力障碍的SPN病理生理学和性别差异仍然未知。 一些挑战阻碍了我们理解病理生理学和生物学的关系的能力。 性张力障碍首先，通过研究患者获得的信息必然非常有限。二是尽管 流行病学研究表明，性别差异的表达肌张力障碍，性别作为一种生物学 变量很少被纳入检查患者或动物肌张力障碍潜在机制的研究中 模型第三，我们缺乏对健康对照的基础研究，以解开生物性别对 纹状体细胞类型。事实上，在正常的纹状体生理学特征的性别差异的研究没有 区分SPN亚型，而研究检查dSPN和iSPN的分子特性 没有把性别作为一个生物学变量来研究。本建议涉及这些知识差距。 我们对肌张力障碍的病理生理学的理解也由于缺乏动物模型而受到阻碍 由纹状体功能障碍引起的两性异形肌张力障碍为了解决这一差距，我们创建了一个敲入 多巴反应性肌张力障碍（DRD）小鼠模型。在患者中，DRD以女性为主，与许多形式的 肌张力障碍DRD也是理解肌张力障碍中基底神经节功能障碍的原型障碍。 在DRD小鼠中，纹状体在介导肌张力障碍中起中心作用，并且dSPN和iSPN信号传导被破坏。 此外，DRD小鼠中肌张力障碍的表现在雄性和雌性之间是显著不同的，并且DRD小鼠中肌张力障碍的表现在雄性和雌性之间是显著不同的。 肌张力障碍随发情周期波动。因此，这是第一次，有可能阐明的神经代码， 在驱动性别差异的机制背景下的肌张力障碍。具体目标是：1。以确定 卵巢激素在肌张力障碍表达中的作用。2.以确定肌张力障碍的分子特征， 雄性和雌性DRD小鼠中的dSPN和iSPN。3.定义基础的dSPN和iSPN活动模式 雄性和雌性DRD小鼠的肌张力障碍。

Dystonia is characterized by involuntary muscle contractions that cause twisting movements and postures. Many dystonias are more common in females than in males yet the mechanisms underlying these sex differences are largely unexplored. Basal ganglia dysfunction is consistently implicated across many forms of dystonia. The major input structure of the basal ganglia is the striatum where estrogen exerts neuromodulatory effects. In fact, the physiological properties of striatal spiny projection neurons (SPNs) are known to vary depending on biological sex and estrous cycle phase. Direct pathway SPNs (dSPNs) project to the internal globus pallidus to promote movement. Indirect pathway SPNs (iSPNs) project to the external globus pallidus to inhibit movement. Although dSPNs and iSPNs are segregated into separate pathways, they act in concert to mediate and refine movements. In dystonia patients, this coordinated activity is disrupted as functional imaging studies and microelectrode recordings suggest that both dSPNs and iSPNs are dysfunctional. However, the mechanisms underlying both SPN pathophysiology and sex differences in dystonia remain unknown. Several challenges have stymied our ability to understand the pathophysiology and the relationship to biological sex in dystonia. First, information obtained by studying patients is, by necessity, quite limited. Second, despite the epidemiological studies demonstrating sex differences in the expression of dystonia, sex as a biological variable is rarely incorporated into studies examining mechanisms underlying dystonia in patients or animal models. Third, we lack foundational studies in healthy controls that disentangle the effects of biological sex on striatal cell types. Indeed, studies characterizing sex differences in normal striatal physiology have not distinguished between SPN subtypes, while studies examining the molecular properties of dSPNs and iSPNs have not examined sex as a biological variable. This proposal addresses these gaps in knowledge. Our understanding of the pathophysiology of dystonia has also been hampered by the lack of animal models with sexually dimorphic dystonia caused by striatal dysfunction. To address this gap, we created a knockin mouse model of DOPA-responsive dystonia (DRD). In patients, DRD is female predominant, like many forms of dystonia in humans. DRD is also a prototype disorder for understanding basal ganglia dysfunction in dystonia In DRD mice, the striatum plays a central role in mediating dystonia and dSPN and iSPN signaling is disrupted. Further, the presentation of dystonia in DRD mice is significantly different between males and females and the dystonia fluctuates with the estrus cycle. Thus, for the first time, it is possible to elucidate the neural code of dystonia in the context of the mechanisms that drive the sex differences. The Specific Aims are: 1. to determine the role of ovarian hormones in the expression of dystonia. 2. to identify the molecular signature of dystonia in dSPNs and iSPNs in male and female DRD mice. 3. to define the pattern of dSPN and iSPN activity underlying dystonia in male and female DRD mice.