Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus.

Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30 did not affect paired-pulse facilitation, IH30 suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30 increased the number of proliferating Sox2+ neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30 increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.SIGNIFICANCE STATEMENT Individuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.

Stage-dependent effects of intermittent hypoxia influence the outcome of hippocampal adult neurogenesis.

Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer's disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.

A HIF1a-Dependent Pro-Oxidant State Disrupts Synaptic Plasticity and Impairs Spatial Memory in Response to Intermittent Hypoxia.

Sleep apnea causes cognitive deficits and is associated with several neurologic diseases. Intermittent hypoxia (IH) is recognized as a principal mediator of pathophysiology associated with sleep apnea, yet the basis by which IH contributes to impaired cognition remains poorly defined. Using a mouse model exposed to IH, this study examines how the transcription factor, hypoxia inducible factor 1a (HIF1a), contributes to disrupted synaptic physiology and spatial memory. In wild-type mice, impaired performance in the Barnes maze caused by IH coincided with a loss of NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) in area CA1 and increased nuclear HIF1a within the hippocampus. IH-dependent HIF1a signaling caused a two-fold increase in expression of the reactive oxygen species (ROS) generating enzyme NADPH oxidase 4 (NOX4). These changes promoted a pro-oxidant state and the downregulation of GluN1 within the hippocampus. The IH-dependent effects were not present in either mice heterozygous for Hif1a (HIF1a+/-) or wild-type mice treated with the antioxidant manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP). Our findings indicate that HIF1a-dependent changes in redox state are central to the mechanism by which IH disrupts hippocampal synaptic plasticity and impairs spatial memory. This mechanism may enhance the vulnerability for cognitive deficit and lower the threshold for neurologic diseases associated untreated sleep apnea.

Respiratory rhythm generation, hypoxia, and oxidative stress-Implications for development.

Encountered in a number of clinical conditions, repeated hypoxia/reoxygenation during the neonatal period can pose both a threat to immediate survival as well as a diminished quality of living later in life. This review focuses on our current understanding of central respiratory rhythm generation and the role that hypoxia and reoxygenation play in influencing rhythmogenesis. Here, we examine the stereotypical response of the inspiratory rhythm from the preBötzinger complex (preBötC), basic neuronal mechanisms that support rhythm generation during the peri-hypoxic interval, and the physiological consequences of inspiratory network responsivity to hypoxia and reoxygenation, acute and chronic intermittent hypoxia, and oxidative stress. These topics are examined in the context of Sudden Infant Death Syndrome, apneas of prematurity, and neonatal abstinence syndrome.

Chronic Intermittent Hypoxia Differentially Impacts Different States of Inspiratory Activity at the Level of the preBötzinger Complex.

The preBötzinger complex (preBötC) is a medullary brainstem network crucially involved in the generation of different inspiratory rhythms. In the isolated brainstem slice, the preBötC reconfigures to produce different rhythms that we refer to as "fictive eupnea" under baseline conditions (i.e., carbogen), and "fictive gasping" in hypoxia. We recently demonstrated that fictive eupnea is irregular following exposure to chronic intermittent hypoxia (CIH). However, it is unknown how CIH impacts fictive gasping. To address this, brain slices containing the preBötC were prepared from control and CIH exposed mice. Electrophysiological recordings of rhythmogenesis were obtained during the perihypoxic interval. We examined how CIH affects various dynamic aspects of the rhythm characterized by: (1) the irregularity score (IrS), to assess burst-to-variability; (2) the fluctuation value (χ), to quantify the gain of oscillations throughout the time series; and (3) Sample Entropy (sENT), to characterize the pattern/structure of oscillations in the time series. In baseline conditions, CIH increased IrS of amplitude (0.21 ± 0.2) and χ of amplitude (0.34 ± 0.02) but did not affect sENT of amplitude. This indicated that CIH increased burst-to-burst irregularity and the gain of amplitude fluctuations but did not affect the overall pattern/structure of amplitude oscillations. During the transition to hypoxia, 33% of control rhythms whereas 64% of CIH-exposed rhythms showed no doubling of period, suggesting that the probability for stable rhythmogenesis during the transition to hypoxia was greater following CIH. While 29% of control rhythms maintained rhythmicity throughout hypoxia, all slices from CIH exposed mice exhibited rhythms throughout the hypoxic interval. During hypoxia, differences in χ for amplitude were no longer observed between groups. To test the contribution of the persistent sodium current, we examined how riluzole influenced rhythmogenesis following CIH. In networks exposed to CIH, riluzole reduced the IrS of amplitude (-24 ± 14%) yet increased IrS of period (+49 ± 17%). Our data indicate that CIH affects the preBötC, in a manner dependent on the state of the oxygenation. Along with known changes that CIH has on peripheral sensory organs, the effects of CIH on the preBötC may have important implications for sleep apnea, a condition characterized by rapid transitions between normoxia and hypoxia.

Chronic Intermittent Hypoxia Alters Local Respiratory Circuit Function at the Level of the preBötzinger Complex.

Chronic intermittent hypoxia (CIH) is a common state experienced in several breathing disorders, including obstructive sleep apnea (OSA) and apneas of prematurity. Unraveling how CIH affects the CNS, and in turn how the CNS contributes to apneas is perhaps the most challenging task. The preBötzinger complex (preBötC) is a pre-motor respiratory network critical for inspiratory rhythm generation. Here, we test the hypothesis that CIH increases irregular output from the isolated preBötC, which can be mitigated by antioxidant treatment. Electrophysiological recordings from brainstem slices revealed that CIH enhanced burst-to-burst irregularity in period and/or amplitude. Irregularities represented a change in individual fidelity among preBötC neurons, and changed transmission from preBötC to the hypoglossal motor nucleus (XIIn), which resulted in increased transmission failure to XIIn. CIH increased the degree of lipid peroxidation in the preBötC and treatment with the antioxidant, 5,10,15,20-Tetrakis (1-methylpyridinium-4-yl)-21H,23H-porphyrin manganese(III) pentachloride (MnTMPyP), reduced CIH-mediated irregularities on the network rhythm and improved transmission of preBötC to the XIIn. These findings suggest that CIH promotes a pro-oxidant state that destabilizes rhythmogenesis originating from the preBötC and changes the local rhythm generating circuit which in turn, can lead to intermittent transmission failure to the XIIn. We propose that these CIH-mediated effects represent a part of the central mechanism that may perpetuate apneas and respiratory instability, which are hallmark traits in several dysautonomic conditions.