Photomicrograph of serotonin containing axons (green) in close
proximity to hypoglossal nerve cells (red).
Very
little is known about the effects of age on regions of the brain
and spinal cord that are involved in the control of respiration.
We believe that aging results in structural and functional changes
in these respiratory control areas that may predispose people to
breathing disorders. Moreover, we hypothesize that age-associated
changes in respiratory areas of the brain and spinal cord are quite
different in men and women.
I
am particularly interested in the role of the neurotransmitter serotonin
in the control of breathing. We have found that in male rats with
increasing age, serotonin levels decrease in areas of the brain
that help to keep the upper airway functioning normally. In contrast,
these changes are not seen in aging female rats. In other studies
on rats, we have recorded an age-associated decline in the normal
response to episodes of hypoxia in male rats. Once again, similar
changes were not seen in female rats. These data led us to conclude
that aging has a gender-specific effect on how serotonin can modulate
the respiratory control system. For
over a century it has been known that fluctuations in female hormone
levels associated with the estrus cycle and with pregnancy have
profound effects on breathing, and recent evidence supports a role
for the female gonadal hormones, estrogen and progesterone in the
neural control of breathing. The male gonadal hormone testosterone
may also be involved in the control of breathing, as it can be converted
to estrogen in the brain. Gonadal hormone levels decline with age.
We believe that there is a link between increasing age, levels of
gonadal hormones, serotonin, and the neural control of breathing.
Recent results from our laboratory show that levels of serotonin
in brain regions involved in the control of breathing fluctuate
during the rat estrus cycle, and decrease following gonadectomy.
The responses of the respiratory system to episodes of hypoxia also
change with hormone levels in both male and female rats. Taken together,
our data support the hypothesis that gonadal hormones play a critical
role in the maintenance of respiratory function with increasing
age through their action on the serotonergic system in the brain.
Preliminary studies suggest that manipulations of gonadal hormone
levels can reverse or delay the age-associated changes in the neural
control of breathing. These studies provide a better understanding
of the age and gender-related contributions of the serotonergic
system to sleep-associated breathing disorders such as obstructive
sleep apnea (OSA). OSA is an age-associated disease that is far
more prevalent in men than women, and also more prevalent in women
after menopause who are not taking hormone replacement therapy.
Publications
Related to This Topic:
Behan,
M. and M. S. Brownfield. 1999 Age-related changes in serotonin in
the hypoglossal nucleus of rat: Implications for sleep-disordered
breathing. Neurosci. Lett. 267:133-136. [Abstract]
Fuller,
D.D., Baker, T.L., Behan, M. and G.S. Mitchell, 2001.
Expression of hypoglossal long term facilitation differs between
sub-strains of Sprague-Dawley rat. Physiol. Genomics 4;175-181 [Full
text]
Zabka,
A.G., Behan, M. and G.S. Mitchell, 2001.
Long term facilitation (LTF) of phrenic and hypoglossal motor output
decreases with age in male rats. J. Physiol. 531:509-514 [Full
text ]
Zabka,
A.G., Behan, M. and G.S. Mitchell, 2001. Time dependent hypoxic
respiratory responses in female rats are influenced by age and by
the estrus cycle. J. Appl. Physiol. 91:2831-2838 [Full
text]
Behan,
M., Zabka, A.G., and G.S. Mitchell. 2002. Age and gender effects
on serotonin-dependent plasticity in respiratory motor control.
Respir. Physiol. and Neurobio. 131:65-77. [Abstract]
Behan,
M., Zabka, A.G., Thomas, C.F., and G.S. Mitchell, 2003. Sex steroid
hormones and the neural control of breathing. Respir. Physiology.
and Neurobio. 136:249-263. [Abstract]
Behan,
M., and C.F. Thomas. 2005. Sex hormone receptors are expressed in
identified respiratory motoneurons in male and female rats. Neuroscience
130:725-734. [Abstract]
Zabka,
A.G., Mitchell, G.S. and M. Behan. 2005. Aging and gonadectomy have
similar effects on hypoglossal long-term facilitation in male Fisher
rats. J. Physiol. Mar 1;563(Pt 2):557-68. [Abstract]
Zabka,
A.G., Mitchell, G.S., and M. Behan. 2006. Conversion from testosterone
to estradiol is required to modulates respiratory long-term facilitation
in male rats. J. Physiol. 576: 903-912. [Abstract]
Seebart
B.R., Stoffel, R. T. and M. Behan. 2007. Age-related Changes in
the Serotonin 2A Receptor in the Hypoglossal Nucleus of Male and
Female Rats. Resp. Phys. Neurobiol. 158: 14-21. [Abstract]
Behan,
M., and J. Wenninger. 2008. Sex hormones and modulation of respiratory
motoneurons. Resp. Phys. Neurobiol. 164: 213-221 [Abstract]
Schwarz,
E.C., Thompson, J. M., Connor, N.P. and M. Behan. 2009. The effects
of aging on hypoglossal motoneurons in rats. Dysphagia, 24:40-48.
[Abstract]
Barker
J, Thomas CF, and Behan M. 2009. Serotonergic input to the hypoglossal
nucleus in male and female rats. Resp. Phys. Neurobiol. 165:175-184.
PMC Journal - In Process.
Wenninger,
J.M., Cotter, C.J., Olson, E.B., Thomas, C.F., and M. Behan. Ventilatory
Responses to Hypoxia and Hypercapnea in Young, Middle Aged and Old
Male and Female Rats. J. Appl. Physiol. 106:1522-1528
Nelson,
N.R., Bird, I. and M. Behan. 2011. Testosterone restores respiratory
long term facilitation in old male rats. J. Physiol. 589:409-421.
Hengen,
K.B., Gomez, T, Stang, K, Johnson, S.M., Behan, M. 2011. Neurons
in brainstem respiratory nuclei are insensitive to depression by
ethanol and pentobarbital following expression of GABAA epsilon
and delta subunits. A.J. Physiology-Regulatory, Integrative and
Comparative Physiology. 300:272-283.
Behan,
M. and R. Kinkead. 2011. Neuronal control of breathing: sex and
stress hormones. Handbook of Physiology. American Physiological
Society. Comprehensive Physiology.. 1:2101-2139.
Holley,
HS, Behan, M. and Wenninger, JM. 2012. Age and sex differences in
the ventilatory response to hypoxia and hypercapnia in awake neonatal,
juvenile and young adult rats. Resp. Physiol. Neurobiol. 180:79-87
Hengen
KB, Nelson NR, Stang KM, Johnson SM, Crader SM, Watters JJ, Mitchell
GS, Behan M. 2012. Increased GABAA
receptor ε-subunit expression on ventral respiratory column
neurons protects breathing during pregnancy. PLoS ONE 7(1): e30608.
doi:10.1371/journal.pone.0030608.
