Browsing by Author "Wilson, E. Nicole"
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Item Chronic Intermittent Hypoxia Increases Oxidative Stress and Impairs Spatial Memory in Male and Female Rats(2023) Gardner, Jennifer J.; Mabry, Steve; Bradshaw, Jessica L.; Wilson, E. Nicole; Little, Joel; Goulopoulou, Styliani; Cunningham, Rebecca L.Obstructive sleep apnea (OSA) is characterized by complex phenotypes and increased long-term risk of neurodegenerative disease. The impact of OSA in women is unknown due to sex differences in clinical presentation contributing to underdiagnosis. Using chronic intermittent hypoxia (CIH) to model OSA in rodents, our previous studies have shown CIH exposure increases oxidative stress and inflammation in male rats. However, the impact of CIH in female rats remains unclear. The objective of this study was to assess sex differences in CIH-mediated oxidative stress and rodent behaviors associated with neurodegenerative disease. Young adult male and female Long Evans and Sprague Dawley rats were exposed to CIH or normoxia for 14-15 days. Spatial memory and fine and gross motor skills were assessed. Plasma oxidative stress was measured and neuronal expression in the dorsal hippocampus was quantified. Female rats exhibited better spatial memory than males with increased neuronal expression in the CA1 region of the hippocampus. In both males and females, CIH impaired spatial memory and increased circulating oxidative stress. Yet, CIH increased CA1 neuronal expression in female rats only. CIH did not impact gross or fine motor skills, regardless of sex. Our preliminary findings indicate CIH increases oxidative stress and impairs spatial memory in males and females, but the impact of CIH on hippocampal neurons and region-specific contributions to spatial memory may be sexually dimorphic.Item Hypoxia and oxidative stress reduce placental efficiency and impair the balance between autophagy and cell death mechanisms in trophoblasts(2024-03-21) Gardner, Jennifer; Bradshaw, Jessica L.; de Nazare Oliveria da, Renee; Hula, Nataliia; Mabry, Steve; Wilson, E. Nicole; Cunningham, Rebecca L.; Goulopoulou, StylianiIntroduction: Hypoxia and oxidative stress can activate autophagy, a lysosomal degradation pathway that maintains cellular homeostasis. Impairments in autophagy mechanisms have been observed in placentas from obstetric complications associated with placental hypoxia and oxidative stress, such as preeclampsia and intrauterine growth restriction. Purpose: The objective of this study was to investigate the effects of hypoxia and oxidative stress on placental autophagy. We hypothesized that exposure to oxidative stress and hypoxia would alter the balance between cytotoxic and cytoprotective mechanisms in human trophoblast cells and rat placentas and would adversely affect placental efficiency. Methods: We used an in vitro model incorporating human trophoblast cells (BeWo cells) exposed to an oxidative stressor, antimycin A (10, 100, 320 μM) or vehicle for 4 hours. Trophoblast cell death and autophagy mechanisms were assessed via flow cytometry and western blotting. Additionally, we used a rodent model of gestational sleep apnea, a pregnancy complication associated with placental hypoxia. Long Evans timed-pregnant dams were exposed to chronic intermittent hypoxia (CIH; n=6-8) or normoxia (NX; n=8-9) during their sleep cycle from gestational day (GD) 15 to 20 (late pregnancy, term=21-23 days). Results: In trophoblast cells (n=5-9 independent experiments), antimycin A increased necrosis and LC3 A/B II/I ratio (autophagy marker) at 100 μM compared to vehicle (p<0.015). Necrosis remained elevated at 320 μM, while BAX (pro-apoptotic marker) and p62 (autophagosomal flux marker) were reduced compared to vehicle (p<0.0001). LC3 A/B II/I ratio returned to vehicle levels at 320 μM (p>0.05 vs. vehicle). Placental weights from CIH exposed dams were greater (NX: 0.51±0.02 g vs. CIH: 0.60±0.03 g, p=0.015) and fetal to placental weight ratios (marker of placental efficiency) were reduced compared to control pregnancies (NX: 5.25±0.13 vs. CIH: 4.43±0.14, p=0.0006) on GD20. Gestational CIH did not affect (p>0.05) fetal weights (NX: 2.76±0.06 g vs. CIH: 2.61±0.06 g), crown to rump length (NX: 3.32±0.03 cm vs. CIH :3.18±0.12 cm), abdominal girth (NX: 3.22±0.06 cm vs. CIH: 3.32±0.12 cm), or litter size (NX: 11.9±0.90 vs. CIH: 10.5±0.82). Conclusion: Oxidative stress alters the balance between cytotoxic and cytoprotective mechanisms in trophoblast cells, promoting cell necrosis. Although assessment of autophagy machinery and cell death in placentas from hypoxic pregnancies is ongoing, our results indicate that maternal CIH during pregnancy adversely affects placental efficiency.Item Rat Strain and Housing Conditions Alter Oxidative Stress and Hormone Responses to Chronic Intermittent Hypoxia(Frontiers Media S.A., 2018-11-06) Snyder, Brina D.; Duong, Phong; Tenkorang, Mavis A. A.; Wilson, E. Nicole; Cunningham, Rebecca L.Sleep apnea has been associated with elevated risk for metabolic, cognitive, and cardiovascular disorders. Further, the role of hypothalamic-pituitary-adrenal (HPA) activation in sleep apnea has been controversial in human studies. Chronic intermittent hypoxia (CIH) is a rodent model, which mimics the hypoxemia experienced by patients with sleep apnea. Most studies of CIH in rats have been conducted in the Sprague Dawley rat strain. Previously published literature suggests different strains of rats exhibit various responses to disease models, and these effects can be further modulated by the housing conditions experienced by each strain. This variability in response is similar to what has been observed in clinical populations, especially with respect to the HPA system. To investigate if strain or housing (individual or pair-housed) can affect the results of CIH (AHI 8 or 10) treatment, we exposed individual and pair-housed Sprague Dawley and Long-Evans male rats to 7 days of CIH treatment. This was followed by biochemical analysis of circulating hormones, oxidative stress, and neurodegenerative markers. Both strain and housing conditions altered oxidative stress generation, hyperphosphorylated tau protein (tau tangles), circulating corticosterone and adrenocorticotropic hormone (ACTH), and weight metrics. Specifically, pair-housed Long-Evans rats were the most sensitive to CIH, which showed a significant association between oxidative stress generation and HPA activation under conditions of AHI of 8. These results suggest both strain and housing conditions can affect the outcomes of CIH.Item Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia(BioMed Central Ltd., 2023-11-12) Mabry, Steve; Wilson, E. Nicole; Bradshaw, Jessica L.; Gardner, Jennifer J.; Fadeyibi, Oluwadarasimi; Vera, Edward, Jr.; Osikoya, Oluwatobiloba; Cushen, Spencer C.; Karamichos, Dimitrios; Goulopoulou, Styliani; Cunningham, Rebecca L.BACKGROUND: Gestational sleep apnea is a hypoxic sleep disorder that affects 8-26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring. METHODS: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring. RESULTS: Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring. CONCLUSIONS: Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age. Sleep apnea during late pregnancy is a common pregnancy complication that can impact the brain development of children born to mothers with sleep apnea. Children with impaired brain development may present with decreased social skills, memory issues, anxiety, and compulsivity. It is unclear if there is a cause and effect relationship between sleep apnea during late pregnancy and behavioral changes in offspring. Additionally, it is unknown whether male or female sex or age of the offspring affects these relationships. In this study, we exposed pregnant rats to a model of sleep apnea called chronic intermittent hypoxia (CIH) within late gestation and examined the behavior of the offspring and brain activity during puberty and young adulthood. We found that CIH during late pregnancy had long-term effects in the offspring that were different in males and females. Notably, female offspring displayed social impairments in response to late gestation CIH, whereas male offspring displayed cognitive dysfunction.Item Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia(2023) Mabry, Steve; Wilson, E. Nicole; Bradshaw, Jessica L.; Gardner, Jennifer J.; Fadeyibi, Oluwadarasimi; Vera Jr., Edward; Karamichos, Dimitrios; Goulopoulou, Styliani; Cunningham, Rebecca L.Background: Gestational sleep apnea affects 8-26% of pregnancies and can increase the risk for autism spectrum disorder (ASD) in offspring. ASD is a neurodevelopmental disorder associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. To examine the relationship between gestational sleep apnea and ASD, we used a chronic intermittent hypoxia (CIH) protocol between gestational days (GD) 15-19 in pregnant rats to model gestational sleep apnea during the third trimester of pregnancy. We hypothesized that late gestational CIH would produce sex- and age-specific social, mood, and cognitive impairments in offspring. Methods: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine ASD phenotype, we quantified ASD-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, neuronal activation, and neurogenesis), and circulating hormones in offspring. Results: Late gestational CIH induced sex- and age-specific differences in social, repetitive and memory functions in offspring. These effects were mostly transient and present during puberty. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, suppressed circulating estradiol but did not impact memory. In contrast, CIH impaired spatial memory and suppressed circulating estradiol in pubertal male offspring but did not impact social or repetitive functions. Long term effects of gestational CIH were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating estradiol during puberty was maintained in young adulthood. No effects of gestational CIH were observed on anxiety-like behaviors, hippocampal activity, circulating testosterone, or circulating corticosterone, regardless of sex or age of offspring. Conclusions: Our results indicate that hypoxia-associated pregnancy complications during the third trimester can increase the risk for ASD, such as pubertal social dysfunction, neuroendocrine suppression, and memory impairments. Current clinical recommendations support ASD screening for all children up to their 24-month checkup. Based on our findings, children from hypoxia-associated pregnancies should be screened for ASD throughout puberty.Item Sex-dependent effects of chronic intermittent hypoxia: implication for obstructive sleep apnea(BioMed Central Ltd., 2024-04-26) Mabry, Steve; Bradshaw, Jessica L.; Gardner, Jennifer J.; Wilson, E. Nicole; Cunningham, Rebecca L.BACKGROUND: Obstructive sleep apnea (OSA) affects 10-26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). METHODS: Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1beta, IL-6, IL-10, TNF-alpha), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. RESULTS: Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. CONCLUSIONS: Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments. Sleep apnea is a common sleeping condition in adults with a wide range of symptoms that include inflammation, oxidative stress, memory problems, anxiety, and compulsivity. Men are diagnosed with sleep apnea more often than women. Although there is limited information on how sleep apnea affects men and women differently, previous studies suggest that women may exhibit different sleep apnea symptoms than men. To examine the impact of male and female sex on common sleep apnea symptoms, we exposed adult male and female rats to a model of sleep apnea called chronic intermittent hypoxia (CIH). We found that many effects of CIH were different in males and females. CIH females had increased inflammation and motor problems, whereas CIH males had increased oxidative stress and compulsivity. To investigate the reason for these CIH sex differences, we blocked mitochondrial oxidative stress. Blocking mitochondrial oxidative stress decreased CIH associated sex differences. However, blocking mitochondrial oxidative stress had no impact on CIH-induced memory impairment that was observed in male and female rats. Our findings support previous reports that suggest that women exhibit different sleep apnea symptoms than men. Further, we extend these findings by showing that mitochondrial oxidative stress is involved in these sex differences. Clinically, patients diagnosed with sleep apnea are typically treated with continuous positive airway pressure (CPAP) machines, which have high rates of non-compliance (15-40%). Therefore, understanding why sleep apnea is causing these symptoms will be important in developing therapeutics.Item The impact of healthy pregnancy on maternal cognitive impairment in Sprague Dawley rats(2022) Wilson, E. Nicole; Bradshaw, Jessica L.; Tucker, Selina; Gardner, Jennifer; Goulopoulou, Styliani; Cunningham, RebeccaIntroduction/Background: There is clinical evidence of impaired attention, learning, and memory in pregnant women during pregnancy and in the postpartum period, suggesting an association between pregnancy and maternal cognitive dysfunction. Yet, the effects of pregnancy on memory impairment are unclear. We hypothesized that pregnancy would induce maternal cognitive dysfunction that would persist postpartum in a rat model of healthy pregnancy. Methods: To observe recollective memory, the novel object recognition test was performed using Sprague Dawley female rats with different reproductive histories [non-pregnant virgin, late gestation (gestational day 20, term = 22-23 days), postpartum (28 days after birth), and parous non-pregnant (60 days after birth); n = 7-8/group]. Each rat was placed into an empty arena without objects, to allow for adjustments to the open arena. Thirty-minutes after habituation, each rat was given a period of five minutes to explore the arena with two objects of identical size, color, and texture. Upon completion, one hour was given before the animal was placed back in the arena. To test short term recollective memory, each rat was given three minutes to explore two items: one familiar item and a novel item of different size, color, and texture. The latency to which the animal made the initial contact for each object was recorded, and the number of contacts made with the novel object were tallied and compared with overall contacts to each object. Results: Pregnant rats had increased latency to initial contact of the novel object (p < 0.05) compared to virgin females, postpartum dams, and parous non-pregnant dams. Additionally, parous, non-pregnant dams displayed significantly greater contacts with the novel object (p < 0.05) compared to pregnant rats and postpartum dams. Conclusion: Overall, healthy pregnancy results in decreased short term memory recognition that can be repaired over time. Future directions include evaluating the impact of healthy pregnancy on long term memory recognition, examining underlying mechanisms contributing to cerebral impairments during pregnancy, and determining the effects of pregnancy complications on memory impairment.Item Unraveling the Molecular Nexus: Obstructive Sleep Apnea and Glaucoma in a Rat Model(2024-03-21) Donkor, Nina; Mabry, Steve; Wilson, E. Nicole; Gardner, Jennifer J.; Bradshaw, Jessica; Cunningham, Rebecca; Inman, DenisePurpose: Obstructive sleep apnea is a chronic sleep disorder characterized by recurring complete or partial upper airway occlusion. Over the past decade, meta-analyses have established a correlation between this disorder and glaucoma, an ocular neurodegenerative disease, and a leading cause of blindness. However, the link between these pathologies remains elusive. Understanding the mechanisms involved could influence treatment options and reduce the rate of vision loss associated with glaucoma. Using a rat model of sleep apnea, chronic intermittent hypoxia (CIH), we tested the hypothesis that mild sleep apnea initiates morphologic and metabolic changes in the retina that resemble glaucoma. Methods: Rats were randomly assigned to normoxic or CIH groups. The CIH group was exposed to periodic hypoxia during their sleep phase, simulating mild sleep apnea, with oxygen reduction from 21% to 10% and reoxygenation in 6-minute cycles over 8 hours/day for 14 days. The normoxic group experienced similar conditions without changes in oxygen concentration. Subsequently, the eyes were enucleated, and the retina was evaluated for oxidative stress, inflammatory markers, metabolic changes, and hypoxic response modulation using immunohistochemistry and capillary electrophoresis. Results: Immunofluorescence revealed increased expression of 8-OHdG, indicating oxidative stress (nucleic acid damage), as well as the cytokine TNF-α in the CIH group retina compared to controls. No statistically significant differences were observed in HIF-1α protein levels. SIRTUIN-1, a regulator of HIF-1α expression, and the levels of pyruvate dehydrogenase kinase-1 and lactate dehydrogenase-A showed no significant differences between normoxic and CIH groups. Conclusion: The increased oxidative stress and inflammation observed suggest that CIH induces a response in the retina with features shared by early-stage glaucoma. However, the anticipated upregulation of HIF-1α and its targets did not occur, suggesting a greater reduction in oxygen concentration or a longer-term CIH interval may be necessary to observe canonical hypoxic response. Keywords: glaucoma, sleep apnea, chronic intermittent hypoxia, inflammation, oxidative stress