Age, Gender, Serotonin and Respiratory Control

描述（由申请人提供）：本研究的长期目标是了解男性和女性呼吸控制系统随年龄增长而发生的变化。指导这一提议的基本假设是性激素对受年龄影响的呼吸控制系统具有性别特异性作用。我们认为，随着年龄的增长和性激素水平的下降，对呼吸的神经控制有性别特异性的影响。我们认为性激素与神经递质功能密切相关，特别是血清素（5HT）和γ氨基丁酸（GABA），从而影响呼吸可塑性。这些两性二态效应可能是影响男女老少的呼吸障碍的根本原因。我们将在大鼠模型中研究两类呼吸运动神经元：支配舌头的舌下运动神经元和支配膈肌的膈运动神经元。这两个运动神经元池受到雄性和雌性性激素的不同影响，也受到年龄的影响。提出了五个具体目标。前两个具体目的是评估性激素替代疗法是否可以使用电生理方法来逆转在雄性和雌性大鼠中观察到的与年龄相关的呼吸可塑性下降。第三个具体目的是评估未麻醉的雄性和雌性大鼠的通气控制是否受到与衰老相关的激素变化的影响，特别是低氧和高碳酸血症的通气反应，使用气压容积描记仪。第四个特异性目的是将中叶尾核中含有5HT的神经元作为性激素的重要作用位点，并利用舌头逆行的跨突触病毒标记，结合5HT和性激素受体的免疫反应标记，来识别这些神经元的性别差异。第五个具体目标是解决性激素的另一个或额外的作用部位：含有GABA的神经元在呼吸运动神经元上突触。我们将采用免疫细胞化学、免疫印迹和RT-PCR相结合的方法测量雄性和雌性大鼠舌下核中GABA和GABA受体的标记物，并评估与年龄相关的变化。这些研究将使人们更好地了解老年人中更常见的呼吸障碍，其中最广为人知的是阻塞性睡眠呼吸暂停（OSA）。阻塞性睡眠呼吸暂停综合症和其他呼吸障碍在男性中比在女性中更为普遍，拟议的研究将使人们更好地理解为什么会出现这种性别差异。最终，这些研究可能使我们能够确定适合年龄和性别的呼吸障碍药物干预措施。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the changes that take place in the respiratory control system with aging in both males and females. The fundamental hypothesis guiding this proposal is that sex hormones have gender-specific effects on the respiratory control system that are affected by age. We propose that with increasing age, and an accompanying decline in sex hormone levels, there are gender- specific effects on the neural control of breathing. We propose that sex hormones are tightly linked to neurotransmitter function, specifically serotonin (5HT) and gamma aminobutyric acid (GABA), and thereby influence respiratory plasticity. These sexually dimorphic effects may underlie breathing disorders that differentially affect both young and old men and women. We will study two populations of respiratory motoneurons in a rat model: hypoglossal motoneurons innervating the tongue, and phrenic motoneurons innervating the diaphragm. These two motor neuron pools are differentially affected by sex hormones in males and females, and also by aging. Five specific aims are proposed. The first two specific aims assess whether sex hormone replacement therapy can be used to reverse the age-associated decline in respiratory plasticity that is seen in male and female rats, using an electrophysiological approach. The third specific aim is designed to assess whether ventilatory control in unanesthetized male and female rats is affected by the hormonal changes associated with aging, particularly the hypoxic and hypercapnic ventilatory responses, using barometric plethysmography. The fourth specific aim targets 5HT-containing neurons in the caudal raphe nuclei as an important site of action of sex hormones, and uses retrograde trans-synaptic viral labeling from the tongue, combined with immunoreactive markers for both 5HT and sex hormone receptors, to identify sex differences in these neurons. The fifth specific aim addresses an alternative or additional site of action of sex hormones: neurons containing GABA that synapse on respiratory motor neurons. We will use a combination of immunocytochemistry, immunoblot and RT-PCR to measure markers of GABA and the GABA-A receptor in the hypoglossal nuclei of male and female rats, and assess age-associated changes. These studies will lead to a greater understanding of breathing disorders that occur more frequently in older people, the best-recognized of which is obstructive sleep apnea (OSA). OSA and other breathing disorders are far more prevalent in men than in women, and the proposed studies will lead to a greater understanding of why such sex differences occur. Ultimately, these studies may enable us to identify age- and gender-appropriate pharmacological interventions for breathing disorders.