Age,Gender, Serotonin and Respiratory Control

5 -羟色胺（5HT）在呼吸和上呼吸道功能的控制中起着重要作用。拟议的研究将测试假设，随着年龄的增长，呼吸运动神经元的血清素能调节存在性别特异性下降。由于与性别相关的差异，老年男性可能特别容易患呼吸障碍，如阻塞性睡眠呼吸暂停。我们的初步数据表明，雄性大鼠舌下核的5HT免疫反应性随着年龄的增长而降低，而雌性大鼠则随着年龄的增长而增加。此外，长期促进作用（间歇性缺氧后5ht依赖性的呼吸运动输出增加）在老年雄性大鼠中减少，但在老年雌性大鼠中增加。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，也是第一次描述5 -羟色胺能神经系统任何方面的年龄相关变化中的性别二态性。拟议的研究将验证性激素在维持雌性大鼠呼吸运动神经元的血清素能调节中具有神经保护作用的假设，并可能逆转或延缓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分析来检测舌下和膈肌运动核中5 -羟色胺能神经调节系统（5HT、5HT受体和5 -羟色胺再摄取转运蛋白）关键元素的年龄和性别相关变化。其次，我们建议确定是否有衰老和性别对清醒大鼠缺氧呼吸反应的功能影响。第三，我们将验证雄性大鼠缺氧通气反应中血清素依赖成分随着年龄的增长而选择性降低的假设。最后，我们建议研究绝育和激素替代疗法（雌激素、孕酮、睾酮）对雄性和雌性大鼠血清素能调节呼吸的解剖和生理指标的影响。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。对这些机制的理解可能会导致干预与年龄相关的呼吸障碍的治疗策略，这些呼吸障碍影响男性和女性，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.