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

Abstract

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 Garcia III et al. Hypoxia Differentially Affects Inspiratory Rythmogenesis 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.

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…This conclusion is based on the observation that CB lesioning abolishes many of the detrimental consequences associated with obstructive sleep apnoea (Semenza & Prabhakar, 1985;Prabhakhar & Semenza, 2016). CIH leads to an upregulation of haem oxygenase 1 (Sunderram et al 2016) and to an increased desynchronization of the inspiratory neurons within the preBötC Garcia et al 2017). Incompletely synchronized preBötC bursts fail to evoke a population burst within the XII motor nucleus , which could contribute to a pharyngeal collapse ).…”

“…; Garcia et al . ). Incompletely synchronized preBötC bursts fail to evoke a population burst within the XII motor nucleus (Garcia et al .…”

Interdependent feedback regulation of breathing by the carotid bodies and the retrotrapezoid nucleus

“…Chronic intermittent hypoxia (CIH), an animal model of OSA (Fletcher, 2001) sometimes produces a persistent increase in breathing rate and amplitude in rats (Reeves & Gozal, 2006) and may even elicit a permanent state of active expiration (Zoccal et al 2008). CIH also modifies the discharge characteristics and hypoxic sensitivity of the preBötzinger complex in slices, denoting some persistent changes in cellular properties or a circuit configuration (Garcia et al 2017). Animal models in which resting ventilation is elevated or disrupted at rest (CIH, heart failure) may present with a level of carotid body afferent activity considerably higher than in the human disease they are designed to mimic.…”

“…CIH also modifies the discharge characteristics and hypoxic sensitivity of the preBötzinger complex in slices, denoting some persistent changes in cellular properties or a circuit configuration (Garcia et al . ). Animal models in which resting ventilation is elevated or disrupted at rest (CIH, heart failure) may present with a level of carotid body afferent activity considerably higher than in the human disease they are designed to mimic.…”

Prebiotic administration modulates gut microbiota and faecal short-chain fatty acid concentrations but does not prevent chronic intermittent hypoxia-induced apnoea and hypertension in adult rats

“…However, exposure to CIH elicits cardiorespiratory and autonomic disturbances in guinea-pigs with hypoxia-insensitive carotid bodies [ 13 , 14 ], revealing that sites beyond the carotid bodies can contribute to the manifestation of CIH-induced cardiorespiratory and autonomic disturbances. It is known that CIH-induced plasticity also occurs at other key sites of the cardiorespiratory control circuit, including the nucleus tractus solitarius (NTS), pre-Bötzinger complex, ponto-medullary network and paraventricular nucleus of the hypothalamus [15] , [16] , [17] , [18] , [19] , [20] . More recently, studies have described effects of CIH on other peripheral sites including the gut microbiota [ 12 , 14 , [21] , [22] , [23] , [24] , [25] , [26] ].…”