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Compared to many other rodent species, naked mole rats (Heterocephalus glaber) have elevated auditory thresholds, poor frequency selectivity, and limited ability to localize sound. Because the cochlea is responsible for encoding and relaying auditory signals to the brain, we used immunofluorescence and quantitative image analysis to examine cochlear innervation in mature and developing naked mole rats compared to mice (Mus musculus), gerbils (Meriones unguiculatus), and Damaraland mole rats (Fukomys damarensis), another subterranean rodent. In comparison to mice and gerbils, we observed alterations in afferent and efferent innervation as well as their patterns of developmental refinement in naked and Damaraland mole rats. These alterations were, however, not always shared similarly between naked and Damaraland mole rats. Most conspicuously, in both naked and Damaraland mole rats, inner hair cell (IHC) afferent ribbon density was reduced, whereas outer hair cell afferent ribbon density was increased. Naked and Damaraland mole rats also showed reduced lateral and medial efferent terminal density. Developmentally, naked mole rats showed reduced and prolonged postnatal reorganization of afferent and efferent innervation. Damaraland mole rats showed no evidence of postnatal reorganization. Differences in cochlear innervation specifically between the two subterranean rodents and more broadly among rodents provides insight into the cochlear mechanisms that enhance frequency sensitivity and sound localization, maturation of the auditory system, and the evolutionary adaptations occurring in response to subterranean environments. [ABSTRACT FROM AUTHOR]

R5978 --> 761.19 --> IH is a consequence of several clinical conditions such as sleep apnea. Previous work has shown that IH impairs many neurophysiological functions such as hippocampal adult neurogenesis and NMDAr‐dependent synaptic plasticity. While IH produces hippocampal oxidative stress, IH‐dependent changes in hippocampal metabolism may also contribute to impaired neurophysiology. The objective of this study is to understand how IH impacts hippocampal physiology in response to metabolic challenge. We hypothesize that ten days of IH perturbs hippocampal synaptic transmission when metabolically challenged. In vitro recordings of field excitatory post‐synaptic potentials (fEPSPs) from hippocampal slices showed that glucose deprivation (i.e., 30mM Fructose aCSF with 95% O2) caused a complete loss of the fEPSP within 20min; whereas, the fEPSP in control tissue was reduced to 40% of baseline within the same period of time. This difference coincided with a reduction in both maximal and ATP‐linked O2 consumption rates (OCRs) in hippocampal tissue following IH. Despite the reductions in hippocampal OCRs, neither ATP/ADP ratio nor lactate concentrations were different between the two groups. These data indicate that while ATP/ADP levels following IH are sufficiently maintained under basal conditions, metabolic processes fail to support synaptic physiology during glucose deprivation. Our ongoing experiments will further delineate how IH impacts the contribution of glycolytic and oxidative metabolism in the hippocampus. These findings may better define how IH impacts hippocampal responses to metabolic stressors, which could contribute to impairing hippocampal physiology in conditions such as sleep apnea. [ABSTRACT FROM AUTHOR]

R4975 --> 761.24 --> Gaseotransmitters, carbon monoxide (CO) and hydrogen sulfide (H2S), play an important role in maintaining proper function of cardio‐respiratory systems. Previous work has demonstrated that Heme Oxygenase‐2 knock out mice (HO‐2‐/‐) develop a sleep apnea phenotype characterized predominantly by obstructive apneas, which could be normalized by either treating HO‐2‐/‐ with L‐propargylglycine (L‐PAG) an inhibitor of cystathionine gamma‐lysase (CSE) and H2S synthesizing enzyme or in HO‐2+ CSE double null mice. Obstructive apneas are often caused by a loss in upper airway tone, we sought to examine how H2S and CO signaling impacts inspiratory activity from the preBötC and the hypoglossal nucleus (XIIn). We hypothesized that HO‐2 and CSE are involved in the regulation of inspiratory motor output from XIIn. Immunohistochemical analysis revealed many ChAT+ cells of XIIn are positive for HO‐2 and CSE. Biochemical analysis showed elevated H2S abundance in XIIn of HO‐2‐/‐mice. Electrophysiological recordings demonstrated transmission failure from preBötC to XIIn in response to NaHS, a H2S donor or Cr (III) Mesoporphyrin IX chloride (ChrMP459), an inhibitor of HO in brain slices from wild type mice. Furthermore, ChrMP459 reduced inspiratory drive currents received by XIIn neurons and suppressed excitability in XIIn neurons. Brain slices from HO‐2‐/‐mice showed: (1) a larger rate of transmission failure between preBötC and XIIn motor pools; and (2) smaller drive currents from individual XIIn neurons. Brain slices from HO‐2+ CSE double null mice displayed reduced transmission failures from preBötC to XIIn. Furthermore, L‐PAG mitigated transmission failures and increased the magnitude of inspiratory drive currents in XIIn neurons in HO‐2‐/‐mice. These findings demonstrate that HO‐2 and CSE regulate inspiratory drive from XIIn and suggest potential role for gaseotransmitters in regulating upper airway tone. [ABSTRACT FROM AUTHOR]

R4558 --> Deaths related to synthetic opioids have increased six‐fold over the past 20 years. In comparison to the expansive foundation of literature investigating circuit and cellular level mechanisms involved with acute opioid induced respiratory depression (OIRD), very little is known about how chronic opioid use remodels respiration. Similarly, the understanding of tolerance to the euphoric and analgesic effects of opioids has been well studied, yet tolerance to the respiratory side effects of chronic opioid use has been largely ignored. One reason that this gap in knowledge may exist is that the rates of tolerance to the analgesic and euphoric effects of opioids appear to emerge faster than respiratory tolerance to opioids. The goal of this ongoing work is to investigate the mechanisms by which chronic fentanyl use influences the control of breathing and the development of tolerance to its depressive respiratory effects. Here, we introduce an adult mouse model of chronic opioid use. In this model, the synthetic opioid, fentanyl (0.7 mg/kg) was administered for up to ten days. Breathing was assessed prior to, during and after OIRD using unrestrained whole body plethysmography. Our preliminary findings indicate that after five days of fentanyl administration, the magnitude of OIRD is approximately 50% less (n=5) as compared to ORID during the first day of fentanyl. Moreover, assessing the hypoxic chemoreflex after five days of chronic fentanyl treatment reveals that the hypoxic ventilatory response (outside of the window of OIRD). In 2 of 5 subjects, pronounced periodic breathing emerged during baseline conditions after the fifth day of fentanyl administration. These results are consistent with phenotypes observed in individuals who chronically use opioids and/or receive treatment for chronic opioid use and suggest that chronic fentanyl use perturbs respiratory control outside of the immediate window of OIRD. Thus, our model can be used to examine the mechanisms that that drive pharmacodynamic changes to opioids and promote respiratory‐related morbidities associated with chronic fentanyl use. [ABSTRACT FROM AUTHOR]

R4831 --> Intermittent Hypoxia (IH) is a well‐recognized trait of untreated sleep apnea. We have recently demonstrated that mitigating oxidative stress induced by IH prevents impairments to hippocampal NMDAr‐dependent LTP, hippocampal adult neurogenesis, spatial learning and memory. As these processes are also dependent on metabolic activity, the changes of metabolism caused by IH could also contribute to the impairment of synaptic plasticity and adult neurogenesis. The objective of this on‐going study is to assess mitochondrial respiration in hippocampal tissue after ten days of IH (IH10). We assessed hippocampal mitochondrial respiration using Seahorse XF24 Extracellular Flux Analyzer technology. The tissue biopsies (Diameter: 1mm, thickness: 350 μm) were prepared from hippocampal brain slices originating from control mice or mice exposed to IH10. Preliminary experiments indicate that the basal O2 consumption rate (OCR) tended to decrease in IH10 (control: 202 ± 15 pmol/min, n=8 vs. IH: 126 ± 39 pmol/min n=4, P=0.05) and maximal OCR induced by FCCP was decreased in IH10 (control: 278 ± 29 pmol/min vs. IH10: 126 ± 39 pmol/min, P<0.05). These findings suggest IH impaired mitochondrial function in the hippocampus. ATP‐linked OCR induced by oligomycin and proton leak were not altered by IH10. Interestingly, the proportion of non‑mitochondrial OCR in control was smaller than IH10 (control: 13 ± 1 % vs. IH10: 20 ± 5 %, P<0.05). Such a difference in non‐mitochondrial OCR may reflect a state favoring enhanced reactive oxygen species production independent of mitochondrial origin. In conclusion, our study provides greater insights into the molecular basis by which untreated sleep apnea accelerates neurodegeneration in conditions such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

R4346 --> Arias et al. (eNeuro, 2020) recently demonstrated that intermittent hypoxia (IH), a principal outcome of sleep apnea, increases hippocampal oxidative stress that in turn, contributes to IH‑mediated deficits in spatial memory and NMDAr‐dependent LTP. These phenomena were mitigated in hemizygous HIF1a mice indicating that IH‐dependent HIF1a signaling plays a central role in mediating neurophysiological changes associated with impaired spatial memory. However, it remains unclear where such signaling originates. As glutamatergic synaptic communication in the hippocampus and cortex is critical for learning and memory, we sought to determine whether hemizygosity of HIF1a among glutamatergic neurons could mediate the impact of IH on hippocampal synaptic plasticity and spatial memory. To address this, we generated Vglut1‐HIF1a+/‐ mice using Cre/LoxP recombination technology. Vglut1‑HIF1a+/‐ mice were exposed to either room air (control) or ten days of IH (IH10). In the hippocampus of wild‐type mice, IH10 decreased expression of the obligatory NMDAr subunit, GluN1. This correlated with deficient induction of NMDAr‐dependent synaptic plasticity. IH10 also increased hippocampal oxidative stress and caused a two‐fold increase in hippocampal expression of the pro‐oxidant enzyme, NADPH oxidase 4 (NOX4). In contrast to the effects in wild type mice, IH10 neither increased oxidative stress nor increased NOX4 expression in the hippocampus of Vglut1‐HIF1a+/‐ mice. IH10 did not suppress GluN1 expression or impair hippocampal NMDAr‐dependent synaptic plasticity in Vglut1‐HIF1a+/‐ mice. In conclusion, our findings show that hemizygosity of HIF1a in vGlut1+ cells mitigate IH‐dependent changes to hippocampal synaptic plasticity and protein expression. Thus, HIF1a signaling in vGlut1+ glutamatergic neurons appear to be a significant contributor for perturbing NMDAr‐dependent synaptic plasticity and the molecular profile of the hippocampus following IH. [ABSTRACT FROM AUTHOR]