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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG018760-01A1
Application #
6371112
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Monjan, Andrew A
Project Start
2001-08-15
Project End
2004-07-31
Budget Start
2001-08-15
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$246,986
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hengen, Keith B; Nelson, Nathan R; Stang, Kyle M et al. (2015) Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ?-subunit containing GABA ARs. PLoS One 10:e0119351
Hengen, Keith B; Nelson, Nathan R; Stang, Kyle M et al. (2012) Increased GABA(A) receptor ?-subunit expression on ventral respiratory column neurons protects breathing during pregnancy. PLoS One 7:e30608
Behan, Mary; Moeser, Adam E; Thomas, Cathy F et al. (2012) The effect of tongue exercise on serotonergic input to the hypoglossal nucleus in young and old rats. J Speech Lang Hear Res 55:919-29
Holley, Heidi S; Behan, Mary; Wenninger, Julie M (2012) Age and sex differences in the ventilatory response to hypoxia and hypercapnia in awake neonatal, pre-pubertal and young adult rats. Respir Physiol Neurobiol 180:79-87
Hengen, K B; Gomez, T M; Stang, K M et al. (2011) Changes in ventral respiratory column GABAaR ýý- and ýý-subunits during hibernation mediate resistance to depression by EtOH and pentobarbital. Am J Physiol Regul Integr Comp Physiol 300:R272-83
Behan, Mary; Kinkead, Richard (2011) Neuronal control of breathing: sex and stress hormones. Compr Physiol 1:2101-39
Nelson, N R; Bird, I M; Behan, M (2011) Testosterone restores respiratory long term facilitation in old male rats by an aromatase-dependent mechanism. J Physiol 589:409-21
Hengen, Keith B; Behan, Mary; Carey, Hannah V et al. (2009) Hibernation induces pentobarbital insensitivity in medulla but not cortex. Am J Physiol Regul Integr Comp Physiol 297:R1028-36
Wenninger, J M; Olson Jr, E B; Cotter, C J et al. (2009) Hypoxic and hypercapnic ventilatory responses in aging male vs. aging female rats. J Appl Physiol (1985) 106:1522-8
Barker, Jessica R; Thomas, Cathy F; Behan, Mary (2009) Serotonergic projections from the caudal raphe nuclei to the hypoglossal nucleus in male and female rats. Respir Physiol Neurobiol 165:175-84

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