Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.

Members of the myocyte enhancer factor 2 (MEF2) gene family are expressed in a dynamic pattern during development of the CNS of pre- and postnatal mice. The four MEF2 genes, Mef2A, -B, -C, -D, encode transcription factors belonging to the MADS (MCM1-agamous-deficiens-serum response factor) superfamily of DNA binding proteins. MEF2 factors have previously been shown to be positive regulators of gene expression in terminally differentiated muscle cells. To begin to determine the role of MEF2 factors in CNS development, we used in situ hybridization with gene-specific cRNA probes to define the expression patterns of each of the four Mef2 mRNAs in the developing and mature mouse CNS. Mef2C mRNA was first detected in a ventral portion of the telencephalon at 11.5 d postcoitum (p.c.). By 13.5 d p.c., each of the four Mef2 genes were expressed in overlapping yet distinct patterns in regions of the frontal cortex, midbrain, thalamus, hippocampus, and hindbrain. Temporal and spatial patterns of embryonic Mef2 gene expression appeared to follow gradients of neuron maturation and suggested that the onset of Mef2 gene expression coincides with withdrawal from the cell cycle and initiation of neuronal differentiation. This correlation is particularly striking for Purkinje cells in the cerebellum. Since the molecular mechanisms that regulate neuron differentiation are unknown, we propose that the MEF2 factors are likely to play an important role in this process.

We tested two hypotheses: 1) that the spontaneous enhancement of phrenic motor output below a C2 spinal hemisection (C2HS) is associated with plasticity in ventrolateral spinal inputs to phrenic motoneurons; and 2) that phrenic motor recovery in anesthetized rats after C2HS correlates with increased capacity to generate inspiratory volume during hypercapnia in unanesthetized rats. At 2 and 4 wk post-C2HS, ipsilateral phrenic nerve activity was recorded in anesthetized, paralyzed, vagotomized, and ventilated rats. Electrical stimulation of the ventrolateral funiculus contralateral to C2HS was used to activate crossed spinal synaptic pathway phrenic motoneurons. Inspiratory phrenic burst amplitudes ipsilateral to C2HS were larger in the 4- vs. 2-wk groups (P<0.05); however, no differences in spinally evoked compound phrenic action potentials could be detected. In unanesthetized rats, inspiratory volume and frequency were quantified using barometric plethysmography at inspired CO2 fractions between 0.0 and 0.07 (inspired O2 fraction 0.21, balance N2) before and 2, 3, and 5 wk post-C2HS. Inspiratory volume was diminished, and frequency enhanced, at 0.0 inspired CO2 fraction (P<0.05) 2-wk post-C2HS; further changes were not observed in the 3- and 5-wk groups. Inspiratory frequency during hypercapnia was unaffected by C2HS. Hypercapnic inspiratory volumes were similarly attenuated at all time points post-C2HS (P<0.05), thereby decreasing hypercapnic minute ventilation (P<0.05). Thus increases in ipsilateral phrenic activity during 4 wk post-C2HS have little impact on the capacity to generate inspiratory volume in unanesthetized rats. Enhanced crossed phrenic activity post-C2HS may reflect plasticity associated with spinal axons not activated by our ventrolateral spinal stimulation.

We tested the hypothesis that unanesthetized rats exhibit ventilatory long-term facilitation (LTF) after intermittent, but not continuous, hypoxia. Minute ventilation (VE) and carbon dioxide production (VCO(2)) were measured in unanesthetized, unrestrained male Sprague-Dawley rats via barometric plethysmography before, during, and after exposure to continuous or intermittent hypoxia. Hypoxia was either isocapnic [inspired O(2) fraction (FI(O(2))) = 0.08--0.09 and inspired CO(2) fraction (FI(CO(2))) = 0.04] or poikilocapnic (FI(O(2)) = 0.11 and FI(CO(2)) = 0.00). Sixty minutes after intermittent hypoxia, VE or VE/VCO(2) was significantly greater than baseline in both isocapnic and poikilocapnic conditions. In contrast, 60 min after continuous hypoxia, VE and VE/VCO(2) were not significantly different from baseline values. These data demonstrate ventilatory LTF after intermittent hypoxia in unanesthetized rats. Ventilatory LTF appeared similar in its magnitude (after accounting for CO(2) feedback), time course, and dependence on intermittent hypoxia to phrenic LTF previously observed in anesthetized, vagotomized, paralyzed rats.

1. This study was designed to test the hypothesis that perinatal suppression of peripheral arterial chemoreceptor inputs attenuates the hypoxic ventilatory response in adult rats. Perinatal suppression of peripheral chemoreceptor activity was achieved by exposing rats to hyperoxia throughout the first month of life. 2. Late-gestation pregnant rats were housed in a 60% 02 environment, exposing the pups to hyperoxia from several days prior to birth until they were returned to normoxia on postnatal day 28. These perinatally treated rats were then reared to adulthood (3-5 months old) in normoxia. In addition to the mother rats, adult male rats were also exposed to hyperoxia, creating an adult-treated control group. Two to four months after the hyperoxic exposure, treated rats were compared with untreated male rats of similar age. 3. A whole-body, flow-through plethysmograph was used to measure hypoxic and hypercapnic ventilatory responses of the unanaesthetized adult rats. In moderate hypoxia (arterial oxygen partial pressure, Pa02 -48 mmHg), VE (minute ventilation) and the ratio VE/VGO2(ventilation relative to CO2 production) increased by 16-7 + 4 0 and 35-4 + 3 4%, respectively, in perinatal-treated rats (means + S.E.M.), but increased more in untreated control rats (51-4 + 2-8 and 83-1 + 4.3%; both P < 10-6).4. In contrast to the impaired hypoxic ventilatory response, ventilatory responses to hypercapnia (5 % C02) were similar between untreated control and perinatal-treated rats. 5. Impaired hypoxic responsiveness was unique to the perinatal-treated rats since hypoxic ventilatory responses were not attenuated in adult-treated rats. 6. The results indicate that ventilatory responses to hypoxaemia are greatly attenuated in adult rats that had experienced hyperoxia during their first month of life, and suggest that normal hypoxic ventilatory control mechanisms are susceptible to developmental plasticity.