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。指导这一建议的基本假设是，性激素对呼吸控制系统具有性别特异性的影响，这种影响受到年龄的影响。我们认为，随着年龄的增长，性激素水平随之下降，对呼吸的神经控制有性别特异性影响。我们认为性激素与神经递质功能密切相关，特别是5-羟色胺（5-HT）和γ-氨基丁酸（GABA），从而影响呼吸可塑性。这些性二态效应可能是呼吸障碍的基础，对年轻和老年男性和女性的影响不同。我们将研究两个群体的呼吸运动神经元在大鼠模型：舌下运动神经元支配的舌头，和膈运动神经元支配的隔膜。这两个运动神经元池在男性和女性中受到性激素的不同影响，也受到衰老的影响。提出了五个具体目标。前两个具体目标评估性激素替代疗法是否可用于逆转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，使用电生理学方法。第三个具体目的是评估是否在未麻醉的雄性和雌性大鼠的排泄控制是受影响的激素变化与衰老，特别是缺氧和高碳酸血症的排泄反应，使用气压体积描记。第四个具体的目标是在中缝核尾侧含5 HT的神经元作为性激素的作用的一个重要网站，并使用逆行跨突触的病毒标记从舌头，结合免疫反应性标记物的5 HT和性激素受体，以确定这些神经元的性别差异。第五个具体目标涉及性激素的替代或附加作用部位：与呼吸运动神经元突触的含有GABA的神经元。我们将使用免疫细胞化学，免疫印迹和RT-PCR相结合，以测量标记的GABA和GABA-A受体在舌下神经核的雄性和雌性大鼠，并评估年龄相关的变化。这些研究将有助于更好地了解老年人更频繁发生的呼吸障碍，其中最受认可的是阻塞性睡眠呼吸暂停（OSA）。阻塞性睡眠呼吸暂停综合征和其他呼吸疾病在男性中的发病率远远高于女性，拟议中的研究将有助于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.