Age,Gender, Serotonin and Respiratory Control

年龄、性别、血清素和呼吸控制

• 批准号: 6608019
• 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/6608019
• 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.

血清素 (5HT) 在呼吸和上呼吸道功能控制中发挥着重要作用。 拟议的研究将检验以下假设：随着年龄的增长，呼吸运动神经元的血清素能调节会出现性别特异性下降。 由于性别差异，老年男性可能特别容易患阻塞性睡眠呼吸暂停等呼吸系统疾病。 我们的初步数据表明，雄性大鼠舌下核中的 5HT 免疫反应性随着年龄的增长而降低，而雌性大鼠的舌下核中的 5HT 免疫反应性则随着年龄的增长而增加。 此外，长期促进作用，即间歇性缺氧后呼吸运动输出的 5HT 依赖性增加，在老年雄性大鼠中减少，但在老年雌性大鼠中增加。 这是对呼吸控制的血清素调节的年龄相关变化的首次描述，也是对血清素神经系统任何方面与年龄相关的变化的性别二态性的首次描述。 拟议的研究将检验以下假设：随着年龄的增长，性腺激素在维持雌性大鼠呼吸运动神经元的血清素能调节方面具有神经保护作用，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，每个目标都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检测来检测舌下运动核和膈运动核中血清素神经调节系统关键元件（5HT、5HT 受体和血清素再摄取转运蛋白）与年龄和性别相关的变化。 其次，我们建议确定衰老和性别是否会对清醒大鼠对缺氧的呼吸反应产生功能性影响。 第三，我们将检验以下假设：雄性大鼠的缺氧通气反应的血清素依赖性成分随着年龄的增长而选择性减少。 最后，我们建议研究绝育和激素替代疗法（雌激素、孕激素、睾酮）对雄性和雌性大鼠呼吸的血清素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可塑性的影响的第一个提议。 了解这些机制可能会导致干预治疗策略，以干预影响男性和女性的与年龄相关的呼吸障碍，例如阻塞性睡眠呼吸暂停。