TY - JOUR
T1 - Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress
AU - Ma, S.
AU - Mifflin, S. W.
AU - Cunningham, J. T.
AU - Morilak, D. A.
N1 - Funding Information:
Expert technical assistance was provided by Tiffany M. Fleming and Myrna Herrera-Rosales. This work was supported by a Presidential Research Enhancement Fund (PREF) award from the University of Texas Health Science Center at San Antonio, and by research grants from the National Institutes of Health (MH053851 and MH072672 to D.A.M.; HL062579 to J.T.C.; HL086804 to S.W.M.). The authors have no conflicts of interest to report, financial or otherwise, that may have influenced the conduct, interpretation or presentation of these studies.
PY - 2008/7/17
Y1 - 2008/7/17
N2 - Obstructive sleep apnea (OSA) is associated with several pathophysiological conditions, including hypertension, obesity, insulin resistance, hypothalamic-pituitary-adrenal (HPA) dysregulation, and other endocrine and metabolic disturbances comprising the "metabolic syndrome." Repeated episodes of hypoxia in OSA may represent a chronic intermittent stress, leading to HPA dysregulation. Alterations in HPA reactivity could then contribute to or exacerbate other pathophysiological processes. We showed previously that another metabolic stressor, chronic intermittent cold stress, enhanced noradrenergic facilitation of acute HPA stress reactivity. In this study, we investigated whether chronic intermittent hypoxia (CIH), a rat model for the arterial hypoxemia that accompanies OSA, similarly sensitizes the HPA response to novel acute stress. Rats were exposed to CIH (alternating cycles of normoxia [3 min at 21% O2] and hypoxia [3 min at 10% O2], repeated continuously for 8 h/day during the light portion of the cycle for 7 days). On the day after the final CIH exposure, there were no differences in baseline plasma adrenocorticotropic hormone (ACTH), but the peak ACTH response to 30 min acute immobilization stress was greater in CIH-stressed rats than in controls. Induction of Fos expression by acute immobilization stress was comparable following CIH in several HPA-modulatory brain regions, including the paraventricular nucleus, bed nucleus of the stria terminalis, and amygdala. Fos induction was attenuated in lateral hypothalamus, an HPA-inhibitory region. By contrast, acute Fos induction was enhanced in noradrenergic neurons in the locus coeruleus following CIH exposure. Thus, similar to chronic cold stress, CIH sensitized acute HPA and noradrenergic stress reactivity. Plasticity in the acute stress response is important for long-term adaptation, but may also contribute to pathophysiological conditions associated with states of chronic or repeated stress, such as OSA. Determining the neural mechanisms underlying these adaptations may help us better understand the etiology of such disorders, and inform the development of more effective treatments.
AB - Obstructive sleep apnea (OSA) is associated with several pathophysiological conditions, including hypertension, obesity, insulin resistance, hypothalamic-pituitary-adrenal (HPA) dysregulation, and other endocrine and metabolic disturbances comprising the "metabolic syndrome." Repeated episodes of hypoxia in OSA may represent a chronic intermittent stress, leading to HPA dysregulation. Alterations in HPA reactivity could then contribute to or exacerbate other pathophysiological processes. We showed previously that another metabolic stressor, chronic intermittent cold stress, enhanced noradrenergic facilitation of acute HPA stress reactivity. In this study, we investigated whether chronic intermittent hypoxia (CIH), a rat model for the arterial hypoxemia that accompanies OSA, similarly sensitizes the HPA response to novel acute stress. Rats were exposed to CIH (alternating cycles of normoxia [3 min at 21% O2] and hypoxia [3 min at 10% O2], repeated continuously for 8 h/day during the light portion of the cycle for 7 days). On the day after the final CIH exposure, there were no differences in baseline plasma adrenocorticotropic hormone (ACTH), but the peak ACTH response to 30 min acute immobilization stress was greater in CIH-stressed rats than in controls. Induction of Fos expression by acute immobilization stress was comparable following CIH in several HPA-modulatory brain regions, including the paraventricular nucleus, bed nucleus of the stria terminalis, and amygdala. Fos induction was attenuated in lateral hypothalamus, an HPA-inhibitory region. By contrast, acute Fos induction was enhanced in noradrenergic neurons in the locus coeruleus following CIH exposure. Thus, similar to chronic cold stress, CIH sensitized acute HPA and noradrenergic stress reactivity. Plasticity in the acute stress response is important for long-term adaptation, but may also contribute to pathophysiological conditions associated with states of chronic or repeated stress, such as OSA. Determining the neural mechanisms underlying these adaptations may help us better understand the etiology of such disorders, and inform the development of more effective treatments.
KW - adrenocorticotropic hormone
KW - metabolic syndrome
KW - norepinephrine
KW - obstructive sleep apnea
KW - paraventricular nucleus
KW - stress
UR - http://www.scopus.com/inward/record.url?scp=45849105537&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2008.04.068
DO - 10.1016/j.neuroscience.2008.04.068
M3 - Article
C2 - 18554809
AN - SCOPUS:45849105537
SN - 0306-4522
VL - 154
SP - 1639
EP - 1647
JO - Neuroscience
JF - Neuroscience
IS - 4
ER -