This proposal hypothesizes that intermittent hypoxia elicits unique, serotonin-dependent mechanisms of plasticity in the central neural control of breathing. These forms of plasticity are unique since they are elicited by intermittent hypoxia, but not by an equivalent duration of sustained hypoxia. The PI proposes to investigate cellular and molecular mechanisms of two specific forms of plasticity elicited by intermittent hypoxia: 1) long term facilitation (LTF) of phrenic motor output following three brief hypoxic episodes; and 2) enhanced LTF in rats previously exposed to chronic intermittent hypoxia. A working model has been developed suggesting that, although these forms of plasticity differ in time course and in their requirement for gene transcription, they are initiated by the same events. The PI postulates that the common initiating event is repeated activation of serotonergic 5-HT2A receptors on phrenic motoneurons that increases intracellular kinase activity. As a result, glutamatergic receptors associated with descending respiratory drive and the gene transcription factor cyclic AMP response element binding protein (CREB) are phosphorylated, leading to LTF and enhanced LTF, respectively.
Five specific aims are proposed to test the hypotheses that: 1) phrenic LTF requires spinal 5-HT2A receptor activation; 2) chronic intermittent (but not sustained) hypoxia enhances LTF; 3) enhanced LTF is associated with gene transcription regulated by CREB; 4) serotonergic 5-HT7 receptor induction is necessary for enhanced LTF; and 5) brain derived neurotrophic factor (BDNF) induction is necessary for enhanced LTF. A multidisciplinary approach will be used to test key elements of the model.
| Johnson, Rebecca A; Mitchell, Gordon S (2013) Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders. Respir Physiol Neurobiol 189:419-28 |
| Baker-Herman, T L; Bavis, R W; Dahlberg, J M et al. (2010) Differential expression of respiratory long-term facilitation among inbred rat strains. Respir Physiol Neurobiol 170:260-7 |
| Nakamura, A; Olson Jr, E B; Terada, J et al. (2010) Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats. J Appl Physiol (1985) 109:323-31 |
| Baker-Herman, Tracy L; Mitchell, Gordon S (2008) Determinants of frequency long-term facilitation following acute intermittent hypoxia in vagotomized rats. Respir Physiol Neurobiol 162:8-17 |
| Bavis, Ryan W; Johnson, Rebecca A; Ording, Kari M et al. (2006) Respiratory plasticity after perinatal hypercapnia in rats. Respir Physiol Neurobiol 153:78-91 |
| Mitchell, Gordon S; Babb, Tony G (2006) Layers of exercise hyperpnea: modulation and plasticity. Respir Physiol Neurobiol 151:251-66 |
| Zabka, A G; Mitchell, G S; Behan, M (2005) Ageing and gonadectomy have similar effects on hypoglossal long-term facilitation in male Fischer rats. J Physiol 563:557-68 |
| Fuller, David D; Baker-Herman, Tracy L; Golder, Francis J et al. (2005) Cervical spinal cord injury upregulates ventral spinal 5-HT2A receptors. J Neurotrauma 22:203-13 |
| Golder, Francis J; Zabka, Andrea G; Bavis, Ryan W et al. (2005) Differences in time-dependent hypoxic phrenic responses among inbred rat strains. J Appl Physiol 98:838-44 |
| Baker-Herman, Tracy L; Fuller, David D; Bavis, Ryan W et al. (2004) BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7:48-55 |
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