Unexpected benefits of intermittent hypoxia: enhanced respiratory and nonrespiratory motor function.

Intermittent hypoxia (IH) is most often thought of for its role in morbidity associated with sleep-disordered breathing, including central nervous system pathology. However, recent evidence suggests that the nervous system fights back in an attempt to minimize pathology by increasing the expression of growth/trophic factors that confer neuroprotection and neuroplasticity. For example, even modest ("low dose") IH elicits respiratory motor plasticity, increasing the strength of respiratory contractions and breathing. These low IH doses upregulate hypoxia-sensitive growth/trophic factors within respiratory motoneurons but do not elicit detectable pathologies such as hippocampal cell death, neuroinflammation, or systemic hypertension. Recent advances have been made toward understanding cellular mechanisms giving rise to IH-induced respiratory plasticity, and attempts have been made to harness the benefits of low-dose IH to treat respiratory insufficiency after cervical spinal injury. Our recent realization that IH also upregulates growth/trophic factors in nonrespiratory motoneurons and improves limb (or leg) function after incomplete chronic spinal injuries suggests that IH-induced plasticity is a general feature of motor systems. Collectively, available evidence suggests that low-dose IH may represent a safe and effective treatment to restore lost motor function in diverse clinical disorders that impair motor function.

Serotonin refines the locomotor-related alternations in the in vitro neonatal rat spinal cord.

Serotonergic projections from raphe nuclei arrive in the lumbar enlargement of the spinal cord during the late fetal period in the rat, a time window during which the locomotor-related left/right and flexor/extensor coordinations switch from synchrony to alternation. The goal of the present study was to investigate the role played by serotonin (5-HT) in modulating the left/right and flexor/extensor alternations. Fictive locomotion was induced by bath application of N-methyl-D,L-aspartate (NMA) in the in vitro neonatal rat spinal cord preparation. By means of cross-correlation analysis we demonstrate that 5-HT, when added to NMA, improves left/right and flexor/extensor (recorded from the 3rd and 5th lumbar ventral roots, respectively) alternations. This effect was partly reproduced by activation of 5-HT(2A/2C) receptors. We then tested the contribution of endogenous 5-HT to NMA-induced fictive locomotion. Reducing the functional importance of endogenous 5-HT, either by inhibiting its synthesis with daily injections of p-chloro-phenylalanine (PCPA), starting on the day of birth, or by application of ketanserin (a 5-HT(2) receptor antagonist) or SB269970 (a 5-HT(7) receptor antagonist), disorganized the NMA-induced locomotor pattern. This pattern was restored in PCPA-treated animals by adding 5-HT to the bath. Blocking 5-HT(7) receptors disorganized the locomotor-like rhythm even in the absence of electrical activity in the brain stem, suggesting that NMA applied to the spinal cord does not cause 5-HT release by activating a spino-raphe-spinal loop. These results demonstrate that 5-HT is critical in improving the locomotor-related alternations in the neonatal rat.