Age,Gender, Serotonin and Respiratory Control

年龄、性别、血清素和呼吸控制

• 批准号: 6532550
• 负责人: MARY BEHAN
• 金额: $ 24.7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532550
• 关键词: aging; emotions; estrogens; gender difference; hormone therapy; hypoglossal nucleus; hypoxia; immunoregulation; laboratory rat; motor neurons; neuroregulation; ovariectomy; phrenic nerve; progesterone; protein transport; pulmonary respiration; receptor expression; serotonin; serotonin receptor; sleep apnea; testosterone; wakefulness

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.

5-羟色胺（5-HT）在呼吸和上气道功能的控制中起着重要作用。 拟议的研究将检验这一假设，即随着年龄的增长，呼吸运动神经元的多巴胺能调制存在性别特异性降低。 由于与性别有关的差异，老年男性可能是唯一易患呼吸障碍，如阻塞性睡眠呼吸暂停。 我们的初步数据表明，5-HT免疫反应性在舌下神经核随着年龄的增加，在雄性大鼠，但增加与年龄的雌性大鼠。 此外，长期易化，5 HT依赖性增加呼吸运动输出间歇性缺氧后，老年雄性大鼠减少，但老年雌性大鼠增加。 这是第一个描述的年龄相关的变化，在呼吸控制的肾上腺素能调节，和第一个描述的性别二型性的年龄相关的变化，在任何方面的肾上腺素能神经系统。 这项拟议的研究将测试以下假设：性腺激素在维持雌性大鼠呼吸运动神经元的多巴胺能调节中具有神经保护作用，并且可能逆转或延迟雄性大鼠中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测定来检测舌下神经和膈运动核中5-羟色胺能神经调节系统（5 HT、5 HT受体和5-羟色胺再吸收转运蛋白）的关键要素与年龄和性别相关的变化。 其次，我们建议，以确定是否有功能性的后果，年龄和性别对呼吸系统的反应，缺氧清醒大鼠。 第三，我们将检验雄性大鼠缺氧通气反应中的血清素依赖性成分随着年龄的增长而选择性降低的假设。 最后，我们建议调查绝育和激素替代治疗（雌激素，孕激素，睾酮）对我们的解剖和生理指标的雄鼠和雌鼠的呼吸调节。 据我们所知，这是第一个研究年龄和性别对呼吸控制任何形式可塑性影响的提议。 对这些机制的理解可能会导致对影响男性和女性的年龄相关呼吸障碍（如阻塞性睡眠呼吸暂停）进行干预的治疗策略。