Age,Gender, Serotonin and Respiratory Control

5-羟色胺(5-羟色胺)在呼吸和上呼吸道功能控制中起着重要作用。这项拟议的研究将检验这一假设，即随着年龄的增长，呼吸运动神经元的5-羟色胺能调制存在性别特异性的减少。由于性别差异，老年男性可能特别容易患上阻塞性睡眠呼吸暂停等呼吸障碍。我们的初步数据表明，舌下神经核内5-羟色胺免疫反应在雄性大鼠中随年龄增长而减少，而在雌性大鼠中随年龄增长而增加。此外，长期易化，即间歇性低氧后5-羟色胺依赖的呼吸运动输出增加，对老年雄性大鼠减少，但对老年雌性大鼠增加。这是第一次描述5-羟色胺能调节呼吸控制的年龄相关变化，也第一次描述了5-羟色胺能神经系统任何方面与年龄相关的变化中的性别二型性。这项拟议的研究将检验一种假设，即性腺激素在维持雌性大鼠随年龄增长的呼吸运动神经元的5-羟色胺能调制方面具有神经保护作用，并可能逆转或推迟雄性大鼠发生的与年龄相关的变化。提出了五个具体目标，每个目标对应一个可检验的假设。首先，我们将使用神经化学和解剖学分析来检测舌下和膈运动核中5-羟色胺能神经调节系统的关键元素(5-羟色胺、5-羟色胺受体和5-羟色胺再摄取转运蛋白)随年龄和性别的变化。其次，我们建议确定年龄和性别对清醒大鼠对缺氧的呼吸反应是否存在功能性后果。第三，我们将检验这一假设，即随着雄性大鼠年龄的增长，低氧呼吸反应中的5-羟色胺依赖成分选择性地减少。最后，我们建议研究绝育和激素替代疗法(雌激素、孕酮、睾酮)对雄性和雌性大鼠呼吸5-羟色胺能调节的解剖学和生理学指标的影响。据我们所知，这是第一个研究年龄和性别对呼吸控制中任何形式的可塑性影响的建议。对这些机制的了解可能会导致干预年龄相关呼吸障碍的治疗策略，这些呼吸障碍对男性和女性都有影响，如阻塞性睡眠呼吸暂停。

Serotonin (5HT) plays a major role in breathing and the control of upper airway function. The proposed research will test the hypothesis that, with increasing age, there is a gender- specific decrease in serotonergic modulation of respiratory motoneurons. Because of gender-related differences, aging males may be uniquely susceptible to breathing disorders such as obstructive sleep apnea. Our preliminary data indicate that 5HT immunoreactivity in the hypoglossal nucleus decreases with age in male rats, but increases with age in female rats. Furthermore, long term facilitation, a 5HT-dependent increase in respiratory motor output following intermittent hypoxia, decreases to older male rats, but increases to older female rats. This is the first description of age-associated change in serotonergic modulation of respiratory control, and the first description of sexual dimorphism in age-related changes in any aspect of the serotonergic nervous system. The proposed research will test the hypothesis that gonadal hormones have a neuroprotective role in the maintenance of serotonergic modulation of respiratory motoneurons in female rats with increasing age, and can potentially reverse or delay the age-associated changes that occur in male rats. Five specific aims are proposed, each corresponding to a testable hypothesis. First, we will use neurochemical and anatomical assays to detect age- and gender- related changes in key elements of the serotonergic neuromodulatory system (5HT, 5HT receptors, and the serotonin reuptake transport protein) in hypoglossal and phrenic motor nuclei. Secondly, we propose to determine if there are functional consequences of aging and gender on respiratory responses to hypoxia in awake rats. Thirdly, we will test the hypothesis that serotonin-dependent components of the hypoxic ventilatory response are decreased selectively with aging in male rats. Finally, we propose to investigate the influence of neutering and hormone replacement therapy (estrogen, progesterone, testosterone) on our anatomical and physiological indices of serotonergic modulation of respiration in male and female rats. To our knowledge, this is the first proposal to study age and gender effects on any form of plasticity in respiratory control. An understanding of these mechanisms may lead to therapeutic strategies for intervention in age-related breathing disorders that affect both men and women such as obstructive sleep apnea.