Browsing by Author "Gardner, Jennifer J."
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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 Effects of Amyloid β on Recollective Memory: Sex and Hormone Differences(2023) Vera, Edward; Mabry, Steve; Wilson, Nicole; Bradshaw, Jessica L.; Gardner, Jennifer J.; Little, Joel; Rybalchenko, Nataliya; Cunningham, Rebecca L.PURPOSE: Alzheimer’s disease (AD) is linked with increased memory loss and inability to learn new topics. One of the defining neuropathological features of AD is amyloid beta (Aβ) plaques in brain regions, such as the hippocampus. The hippocampus brain region is important for memory and learning. AD risk is elevated in individuals older than 65 years old, especially menopausal women. Menopause is an aging associated endocrine event in which the ovaries stop producing estradiol but continue producing testosterone. Testosterone can be aromatized to estradiol, but aromatase is not functional in women with AD. Therefore, post-menopausal women with AD have more androgens than estrogens than pre-menopausal women and aged men. Androgens can be neuroprotective or neurotoxic depending on the cellular environment. It is unknown what the impact of androgens and sex are on amyloid beta’s effects on the brain, (e.g., hippocampus) and behavior (e.g., memory). We hypothesize that females with the hormonal condition of androgens in the absence of estrogens will exhibit increased recollective memory in response to hippocampal injection of Aβ. METHODS: To investigate the role of androgens and sex on Aβ associated memory impairments, adult male and female Sprague-Dawley rats were gonadectomized to remove circulating sex hormones. A subset of these rats was given either cholesterol or dihydrotestosterone (DHT), which cannot be converted into estrogen. To model AD, rats were injected with 5ug/ul of Aβ oligomer fibrils 1-40 or vehicle shams in the CA1 region of the hippocampus. One week after Aβ hippocampal injections, the rats were assayed for short term and long-term recollective memory via a 1-hour and 24-hour Novel Object behavioral test. The Novel Objective behavioral tests examines recollective memory by quantifying the time spent with a novel object versus the time spent with a known object. Data was quantified with a three-way ANOVA with sex, hormone, and Aβ as independent variables. Tukey’s was used as a post-hoc test. RESULTS: Sex differences were observed between hormone-deficient rats exposed to Aβ. Specifically, males exhibited worse short term recollective memory (1 hour novel object) compared to females. DHT had no effect on recollective memory, regardless of Aβ exposure. No effects were observed in the long-term recollective memory (24-hour novelty test). CONCLUSIONS: Our results indicate that Aβ 's effects on short term recollective memory is influenced by sex chromosomes, as we observed sex differences in the hormone deficient (cholesterol) treated animals. However, DHT did not impact these recollective memory. These results indicate that recollective memory in AD is impacted by the sex chromosomes and not androgens.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 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