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Acute intermittent hypoxia (AIH) induces neuroplasticity in the respiratory system. Specifically, AIH can lead to a progressive increase in respiratory neural activity known as long-term facilitation (LTF) or a sustained increase in minute ventilation in awake, freely-behaving rats, known as ventilatory long-term facilitation (vLTF). Previous work from our lab demonstrates that estrogen signaling is necessary for both types of AIH-induced respiratory neuroplasticity in adult female rats. Both forms of neuroplasticity only occur during stages of the estrous cycle with high levels of circulating estrogen. Further, removing the ovaries, the primary source of circulating estrogen, eliminates both forms of AIH-induced plasticity and estrogen supplementation is sufficient to bring it back. These collective results provide strong evidence that estrogen is critical for AIH-induced plasticity in females and prior reports suggest that estrogen is necessary for AIH-induced plasticity in adult male rats as well. Many biological factors influence estrogen levels such as age, gender, and diet. In fact, a Western diet is associated with increased levels of circulating estradiol in both men and postmenopausal women. The Western Diet is defined by high intakes of red and processed meats, sweets, fried food, and refined grains as well as high intakes of sugar, salt, omega-6 fatty acids, and a reduction in omega-3 fatty acids. Because the Western Diet is linked with increased estrogen, and estrogen is essential to the expression of respiratory neuroplasticity, we examined the impact of Western Diet on respiratory function and the expression of respiratory neuroplasticity (LTF and vLTF). Rats of both sexes were placed on a diet consisting of Western Diet pellets or standard chow for 12 weeks. Whole-body plethysmography was used to measure ventilatory responses over the course of the diet. After 12 weeks, plethysmography data showed no change in normoxic ventilation in either sex over the course of the diet. However, in response to hypoxia (12% and 9% O2), there appeared to be a sex-specific pattern of respiratory adaptation, with male Western Diet rats showing an increase in tidal volume, while the females showed a decrease in tidal volume but an increase in respiratory frequency with hypoxia. Preliminary findings suggest that the Western diet had a significant blunting effect on the expression of AIH-induced LTF as well. Of note, the diet did not increase body mass in either sex but did alter circulating estrogen levels in a sex-specific manner. These findings indicate that a Western Diet may influence respiratory function in a sex-specific manner and may impede the induction of respiratory neuroplasticity. UMN Rehabilitation Science Graduate Program, NHLBI R01HL146477, Craig H. Neilsen Foundation, and the UMN Medical School, Division of Physical Therapy This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Respiratory function is modulated by circulating sex steroids. Specifically, concentrations of circulating 17β-estradiol and progesterone regulate the responsiveness of the respiratory system in adult female rats. Progesterone was first noted to influence breathing following the observation that pregnancy impacted blood gasses. 17β-estradiol is the most abundant and neuroactive form of estrogen, and female respiratory neuroplasticity is dependent on its presence. Circulating sex hormone levels fluctuate across the normal estrus cycle and gradually decline as part of the natural aging process. The specific influences of sex hormones on hypoxic ventilatory response (HVR) and chemosensitivity are slowly emerging in the literature. A developing pattern is that short-term hormone fluctuations, such as estrus cycle, do not appear to significantly change basic respiratory responsiveness. However, less is known about larger hormone shifts, such as those following the loss of gonads or with natural aging. We hypothesized that the loss of sex hormones would differentially impact HVR and chemosensitivity in an ovariectomy (OVX) model versus a naturally aged female rat. Specifically, we theorized that aged rats would demonstrate reduced sensitivity to hypoxia and reduced dynamic range within ventilatory output, as compared to OVX and intact female rats. Three experimental groups of female rats were used: young rats (3 mos old; n=4), young OVX rats (n=5), and aged rats (>24 mos old; n=5). Chemosensitivity was measured during progressive hypoxic challenges at 15%, 12%, and 9% oxygen (O2) using unrestrained barometric plethysmography. Serum samples were taken for measurement of estrogen (E2) and progesterone (P) using ELISA assays. At the highest level of hypoxia (9% O2), all groups exhibited intact chemosensitivity as demonstrated by significant changes in minute ventilation (VE; < 0.05), VE controlling for metabolism (VE/ VCO2; < 0.05), and respiratory neural drive (calculated as the ratio of tidal volume (TV) to inspiratory time (Ti), controlling for metabolism; TV/Ti/VCO2; < 0.05). Further analysis showed that young and OVX groups demonstrated greater sensitivity to hypoxia as compared to the aged group. Using analyses targeting rate of change, the young and OVX groups had a faster rate of change in VE, VE/ VCO2, and TV/Ti/VCO2 (< 0.05) as the hypoxia intensity increased. ELISA analyses suggest that E2, but not P, concentration is significantly correlated with these results (< 0.05). Collectively, these data indicate that aging impacts respiratory function in complex and unique ways that differ from OVX in female rats. This may be significant since OVX is commonly used as a model of age-related physiological changes. University of Minnesota BIRCWH/Women's Health Research Program Seed Grant, National Heart Lungs Brain Institute R01HL146477, Rehabilitation Science Graduate Program, UMN Medical School This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

NEW FINDINGS What is the central question of this study? Would ovariectomy cause prolonged changes in ventilation and sustained loss of acute, intermittent hypoxia-induced neuroplasticity or would these outcomes be restored with time? What is the main finding and its importance? Our main findings demonstrate that ovariectomy elicits minimal alteration in overall breathing function but impairs acute, intermittent hypoxia-induced plasticity for ≤ 12 weeks. ABSTRACT Sex hormones are necessary to enable respiratory neuroplasticity, including phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity elicited by acute, intermittent hypoxia (AIH). Female rats exhibit a progressive increase in phrenic nerve amplitude after AIH characteristic of pLTF only during pro-oestrus, the stage of the oestrous cycle notable for elevated circulating oestradiol levels. Removal of the ovaries [ovariectomy (OVX)], the primary source of circulating oestradiol, also eliminates AIH-induced pLTF after 1 week. Ovariectomy is used routinely as a model to examine the impact of sex hormones on CNS structure and function, but the long-term impact of OVX is rarely examined. Extra-ovarian sites of oestradiol synthesis, including multiple CNS sites, have been identified and might possess the capacity to restore oestradiol levels, in part, over time, impacting respiratory function and the expression of respiratory neuroplasticity. We examined both ventilation in awake, freely behaving female rats, using barometric plethysmography, and the expression of AIH-induced pLTF in anaesthetized, ventilated female rats 2 and 12 weeks after OVX and compared them with age-matched ovarian-intact female rats. Our findings indicate that chronic OVX had little impact on baseline breathing or in the response to respiratory challenge (10% O2 , 5% CO2 , balance N2 ) during plethysmography. However, OVX rats at both 2 and 12 weeks demonstrated a persistent loss of AIH-induced pLTF relative to control animals (P