Titles and Education

1. BSc (Honors) 1971 in Zoology, University College Dublin, Ireland
2. PhD 1976 in Zoology, University College, Dublin, Ireland

Research

The Role of Age and Gender in Sleep-Related Breathing Disorders
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 GABAAreceptor ε-subunit expression on ventral respiratory column neurons protects breathing during pregnancy. PLoS ONE 7(1): e30608. doi:10.1371/journal.pone.0030608.

Cardiorespiratory Control in Hibernation

Hibernation presents a natural model of extreme physiology. The 13-lined ground squirrel (Spermophilus tridecemlineatus, a “local” species) displays seasonal neuroprotection of cardiorespiratory circuits in the brain. During torpor, these animals maintain a body temperature at or slightly above freezing and reduce their heart rates and respiratory rhythms by 99%. The major focus of this project was to understand the neuroprotective changes that accompany the hibernation phenotype. Departmental colleagues, Drs. Hannah Carey and Steve Johnson collaborated with us on this project.

Publications Related to This Topic:

• Hengen, K.B., Johnson, S.M., Carey, H.V. and M. Behan.  2007. Neural control of cardiorespiratory function in ground squirrels during hibernation. FASEB J. 21:965.15.
• Hengen, K.B., Johnson, S.M., Carey, H.V. and M. Behan. Functional and molecular partitioning of the brain provides neuroprotection to cardiorespiratory nuclei in ground squirrels during hibernation. FASEB J. 2008 22:757.2
• Hengen, K.B., Johnson, S.M., Carey, H.V., and M. Behan 2008. Seasonally expressed remodeling of GABAA receptors in the hibernating brain confers viability in the face of anesthetic overdose. Soc. Neurosci. Abstr. 531.22.
• Hengen, K.B., Johnson, S.M., Carey, H.V., Behan, M. 2009. Seasonally altered GABAA receptors in medullary cardiorespiratory nuclei make neurons unresponsive to high doses of pentobarbital in hibernating, but not summer active, ground squirrels. FASEB J.\
• Hengen, K.B., Gomez, T, Strang K, Johnson, S.M., Behan, M. 2011. Neurons in brainstem respiratory nuclei are insensitive to depression by ethanol and pentobarbital following exression of GABAA epsilon and delta subunits. A.J. Physiology-Regulatory, Integrative and Comparative Physiology. 300:272-283.

The Acute Effects of Light on Sleep-Wake Behaviors
Abrupt changes in lighting conditions have a profound effect on behavior, regardless of whether these changes in illumination occur during the day or the night. What components of the visual system are involved in mediating the effects of acute changes in lighting on sleep patterns? In collaboration with Dr. Ruth Benca, we explored this question. Our initial findings indicate that the superior colliculus and pretectum are involved. In particular, removal of the pretectum eliminates the characteristic REM sleep triggering response that is seen in albino rats following a light-to-dark transition. Using FOS immediate early gene expression, we have localized neurons in small regions of the pretectum that are active during acute light-dark transitions. Some pretectal nuclei are particularly responsive at midnight, others at midday, suggesting that the illuminance detection system is linked to the circadian system. We next asked the question: does rearing rats in continuous dark or continuous light have an impact on sleep, or on the response to acute changes in lighting conditions? Preliminary findings from dark-reared rats show a reduced retinal input to subcortical visual structures. Interestingly, these rats show no changes in overall sleep and wakefulness. However, they do show enhanced REM triggering in response to light-dark transitions, suggesting that disturbances in illumination during development have lasting effects on aspects of sleep-wake behavior. We hope these studies will lead to a better understanding of how light affects normal individuals as well as those with seasonal depression, and pre-term infants that have been exposed to continuous illumination in hospital settings.

Publications Related to This Topic:

• Miller, A.M., W.H. Obermeyer, M. Behan and R.M. Benca. 1998  Effects of superior colliculus-pretectal lesions on sleep: a novel site for mediating light induced sleep-behaviors. Proc. Natl. Acad. Sci. 95: 8957-8962. [Abstract] [Full Text] [Full Text (PDF)]
• Miller, A.M., R.B. Miller, W.H. Obermeyer, M. Behan and R.M. Benca. 1999  The pretectum mediates rapid eye movement (REM) sleep regulation by light. Behav. Neurosci. 113:755-765.[Abstract]
• Prichard, J.R., Stoffel R.T., Quimby, D.L., Obermeyer, W.H. Benca, R.M. and M. Behan, 2002. Fos immunoreactivity in rat subcortical visual shell in response to illuminance changes. Neuroscience 114:781-793.[Full text]
• Prichard, J.R., Fahy, J.L., Obermeyer, W.H., Behan, M. and Benca, R.M, 2004. Sleep responses to light and dark are shaped by early experience. Behav. Neurosci. 118:1262-1273 [Abstract]
• Fleming, M.D., Benca, R.M. and M. Behan. 2006. Retinal projections to the subcortical visual system in congenic albino and pigmented rats. Neuroscience. 143: 895-904. [Abstract] 
• Prichard, JR., Benca, R.M., and M.Behan. 2007. Light-dependent retinal innervation of the rat superior colliculus. Anat. Rec. 290:341-348. [Abstract]
• Prichard, J.R., Dabney, C., Fleming, M., Benca, R.M., Behan, M. 2009. Light-rearing alters retinal input and immediate early gene responses to light in the ventral hypothalamus in the rat. Sleep Research Society.