Since the discovery of the pre-Bötzinger Complex (preBötC) as a crucial region for generating the main respiratory rhythm, our understanding of its cellular and molecular aspects has rapidly increased within the last few decades. It is now apparent that preBötC is a highly flexible neuronal network that reconfigures state-dependently to produce the most appropriate respiratory output in response to various metabolic challenges, such as hypoxia. However, the responses of the preBötC to hypoxic conditions can be varied based on the intensity, pattern, and duration of the hypoxic challenge. This review discusses the preBötC response to hypoxic challenges at the cellular and network level. Particularly, the involvement of preBötC in the classical biphasic response of the respiratory network to acute hypoxia is illuminated. Furthermore, the article discusses the functional and structural changes of preBötC neurons following intermittent and sustained hypoxic challenges. Accumulating evidence shows that the preBötC neural circuits undergo substantial changes following hypoxia and contribute to several types of the respiratory system\'s hypoxic ventilatory responses.

Acute, intermittent hypoxia (AIH) induces ventilatory long-term facilitation (vLTF) in awake, freely behaving rats under poikilocapnic and isocapnic experimental conditions. Establishing pre-clinical methods for vLTF induction that more closely align with successful protocols in humans and anesthetized rats would minimize dissonance in experimental findings and improve translational aspects of vLTF. Here, we tested several levels of low-dose CO2 supplementation during and after AIH to determine 1) the lowest amount of inspired CO2 that would maintain isocapnia in rats during a vLTF protocol, and 2) the net impact of supplemental CO2 on vLTF expression. Rats received one of four levels of inspired CO2 (0%, 0.5%, 1% or 2%) administered during AIH and for the 60 min following AIH to quantify vLTF. Our findings indicated that 2% inspired CO2 was sufficient to maintain isocapnia across the AIH protocol and reveal significant vLTF. These findings provide evidence-based support for using 2% supplemental CO2 during and after AIH when assessing vLTF in rats.

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Phosphorylation of the MAPK family member extracellular signal-regulated kinase (ERK) is required to induce long-term synaptic plasticity, but little is known about its persistence. We examined ERK activation by three protocols that induce long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse - the standard protocol (five 5-min pulses of 5-HT with interstimulus intervals (ISIs) of 20 min), the enhanced protocol (five pulses with irregular ISIs, which induces greater and longer-lasting LTF) and the two-pulse protocol (two pulses with ISI 45 min). Immunofluorescence revealed complex ERK activation. The standard and two-pulse protocols immediately increased active, phosphorylated ERK (pERK), which decayed within 5 h. A second wave of increased pERK was detected 18 h post-treatment for all protocols. This late phase was blocked by inhibitors of protein kinase A, TrkB and TGF-β. These results suggest that complex interactions among kinase pathways and growth factors contribute to the late increase of pERK. ERK activity returned to basal 24 h after the standard or two-pulse protocols, but remained elevated 24 h for the enhanced protocol. This 24-h elevation was also dependent on PKA and TGF-β, and partly on TrkB. These results begin to characterize long-lasting ERK activation, plausibly maintained by positive feedback involving growth factors and PKA, that appears essential to maintain LTF and LTM. Because many processes involved in LTF and late LTP are conserved among Aplysia and mammals, these findings highlight the importance of examining the dynamics of kinase cascades involved in vertebrate long-term memory.

Two-trial learning in Aplysia reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory. Extracellularly regulated kinase (ERK) activity is essential for intertrial interactions, but the mechanism remains unresolved. A combination of immunochemical and optogenetic tools reveals unexpected complexity of ERK signaling during the induction of long-term synaptic facilitation by two spaced pulses of serotonin (5-hydroxytryptamine, 5HT). Specifically, dual ERK phosphorylation at its activating TxY motif is accompanied by dephosphorylation at the pT position, leading to a buildup of inactive, singly phosphorylated pY-ERK. Phosphorylation and dephosphorylation occur concurrently but scale differently with varying 5HT concentrations, predicting that mixed two-trial protocols involving both \"strong\" and \"weak\" 5HT pulses should be sensitive to the precise order and timing of trials. Indeed, long-term synaptic facilitation is induced only when weak pulses precede strong, not vice versa. This may represent a physiological mechanism to prioritize memory of escalating threats.

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short- and long-term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2 ) and 40% carbon dioxide (CO2 ) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2 ). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V.E. ), tidal volume (V.T. ), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short-term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long-term facilitation following AIH in either group.

Widespread appreciation that neuroplasticity is an essential feature of the neural system controlling breathing has emerged only in recent years. In this chapter, we focus on respiratory motor plasticity, with emphasis on the phrenic motor system. First, we define related but distinct concepts: neuromodulation and neuroplasticity. We then focus on mechanisms underlying two well-studied models of phrenic motor plasticity: (1) phrenic long-term facilitation following brief exposure to acute intermittent hypoxia; and (2) phrenic motor facilitation after prolonged or recurrent bouts of diminished respiratory neural activity. Advances in our understanding of these novel and important forms of plasticity have been rapid and have already inspired translation in multiple respects: (1) development of novel therapeutic strategies to preserve/restore breathing function in humans with severe neurological disorders, such as spinal cord injury and amyotrophic lateral sclerosis; and (2) the discovery that similar plasticity also occurs in nonrespiratory motor systems. Indeed, the realization that similar plasticity occurs in respiratory and nonrespiratory motor neurons inspired clinical trials to restore leg/walking and hand/arm function in people living with chronic, incomplete spinal cord injury. Similar application may be possible to other clinical disorders that compromise respiratory and non-respiratory movements.

Introduction: Resting minute ventilation and ventilation during and following hypoxia may be enhanced following daily exposure to mild intermittent hypoxia (MIH). In contrast, resting systolic blood pressure (SBP) is reduced following daily exposure to MIH. However, it is presently unknown if the reduction in resting SBP following daily exposure, is coupled with reduced SBP responses during and after acute exposure to MIH. Methods: Participants with obstructive sleep apnea (OSA) and hypertension (n = 10) were exposed to twelve 2-min bouts of MIH (oxygen saturation-87%)/day for 15 days. A control group (n = 6) was exposed to a sham protocol during which compressed air (i.e., FIO2 = 0.21) was inspired in place of MIH. Results: The hypoxic ventilatory response (HVR) and hypoxic systolic blood pressure response (HSBP) increased from the first to the last hypoxic episode on the initial (HVR: 0.08 ± 0.02 vs. 0.13 ± 0.02 L/min/mmHg, p = 0.03; HSBP: 0.13 ± 0.04 vs. 0.37 ± 0.06 mmHg/mmHg, p < 0.001) and final (HVR: 0.10 ± 0.01 vs. 0.15 ± 0.03 L/min/mmHg, p = 0.03; HSBP: 0.16 ± 0.03 vs. 0.41 ± 0.34 mmHg/mmHg, p < 0.001) day. The magnitude of the increase was not different between days (p ≥ 0.83). Following exposure to MIH, minute ventilation and SBP was elevated compared to baseline on the initial (MV: 16.70 ± 1.10 vs. 14.20 ± 0.28 L/min, p = 0.01; SBP: 167.26 ± 4.43 vs. 151.13 ± 4.56 mmHg, p < 0.001) and final (MV: 17.90 ± 1.25 vs. 15.40 ± 0.77 L/min, p = 0.01; SBP: 156.24 ± 3.42 vs. 137.18 ± 4.17 mmHg, p < 0.001) day. The magnitude of the increases was similar on both days (MV: 3.68 ± 1.69 vs. 3.22 ± 1.27 L/min, SBP: 14.83 ± 2.64 vs. 14.28 ± 1.66 mmHg, p ≥ 0.414). Despite these similarities, blood pressure at baseline and at other time points during the MIH protocol was reduced on the final compared to the initial day (p ≤ 0.005). Conclusion: The ventilatory and blood pressure responses during and following acute MIH were similar on the initial and final day of exposure. Alternatively, blood pressure was down regulated, while ventilation was similar at all time points (i.e., baseline, during and following MIH) after daily exposure to MIH.

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Acute intermittent hypoxia (AIH) elicits long-term facilitation (LTF) of respiration. Although LTF is observed when CO2 is elevated during AIH in awake humans, the influence of CO2 on corticospinal respiratory motor plasticity is unknown. Thus, we tested the hypotheses that acute intermittent hypercapnic-hypoxia (AIHH): (1) enhances cortico-phrenic neurotransmission (reflecting volitional respiratory control); and (2) elicits ventilatory LTF (reflecting automatic respiratory control). Eighteen healthy adults completed four study visits. Day 1 consisted of anthropometry and pulmonary function testing. On Days 2, 3 and 4, in a balanced alternating sequence, participants received: AIHH, poikilocapnic AIH, and normocapnic-normoxia (Sham). Protocols consisted of 15, 60 s exposures with 90 s normoxic intervals. Transcranial (TMS) and cervical (CMS) magnetic stimulation were used to induce diaphragmatic motor-evoked potentials and compound muscle action potentials, respectively. Respiratory drive was assessed via mouth occlusion pressure (P0.1 ), and minute ventilation measured at rest. Dependent variables were assessed at baseline and 30-60 min after exposures. Increases in TMS-evoked diaphragm potential amplitudes were observed following AIHH vs. Sham (+28 ± 41%, P = 0.003), but not after AIH. No changes were observed in CMS-evoked diaphragm potential amplitudes. Mouth occlusion pressure also increased after AIHH (+21 ± 34%, P = 0.033), but not after AIH. Ventilatory LTF was not observed after any treatment. We demonstrate that AIHH elicits central neural mechanisms of respiratory motor plasticity and increases resting respiratory drive in awake humans. These findings may have important implications for neurorehabilitation after spinal cord injury and other neuromuscular disorders compromising breathing. KEY POINTS: The occurrence of respiratory long-term facilitation following acute exposure to intermittent hypoxia is believed to be dependent upon CO2 regulation - mechanisms governing the critical role of CO2 have seldom been explored. We tested the hypothesis that acute intermittent hypercapnic-hypoxia (AIHH) enhances cortico-phrenic neurotransmission in awake healthy humans. The amplitude of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation was increased after AIHH, but not the amplitude of compound muscle action potentials evoked by cervical magnetic stimulation. Mouth occlusion pressure (P0.1 , an indicator of neural respiratory drive) was also increased after AIHH, but not tidal volume or minute ventilation. Thus, moderate AIHH elicits central neural mechanisms of respiratory motor plasticity, without measurable ventilatory long-term facilitation in awake humans.