The respiratory response to hypoxia reflects the integration of peripheral stimulation of carotid chemoreceptors and the modulation of the respiratory neuronal network by the effects of central hypoxia. The effect of central hypoxia on the net integrated respiratory output is determined by the summation of the inhibitory and excitatory effects of CNS hypoxia. Although the predominant effect of brain hypoxia is to cause a reduction in neuronal excitability, recent work suggests that there may be unique sites within the brain that are directly stimulated by hypoxia. For example, while respiratory premotor ventral respiratory group (VRG) neurons are depressed by hypoxia, sympathoexcitatory and pre-Botzinger respiratory-related neurons in the rostral ventrolateral medulla (RVLM) have been shown to increase their activity in response to local hypoxia. The cellular events that distinguish these two contrasting neuronal responses to hypoxia have not been defined. The studies outlined in this application will investigate the mechanisms underlying these responses in retrogradely labeled (fluorescent latex beads) premotor VRG (hypoxia- depressed) and RVLM (hypoxia-excited) neurons dissociated and cultured from neonatal rats using perforated patch clamp recording techniques to identify the ionic currents that distinguish the different membrane responses of these excited and depressed neurons. Identification of the ionic changes that characterize these neuronal responses to hypoxia will then allow us to explore the cellular mechanisms important for transduction of the hypoxic signal in RVLM oxygen sensing neurons. Since heme oxygenase (HO) has been shown to be an important factor in the oxygen in the oxygen sensing mechanism of excitation of the carotid body and we have found that HO is expressed in the RVLM, we will also test the hypothesis that activation of HO is important for oxygen sensitivity of RVLM neurons. Hypoxic excitation of central cardiorespiratory neurons promotes an effective autoresuscitative response (in the form of intense sympathetic discharge synchronized with respiratory gasping)which may be critical for surviving life-threatening hypoxic events. In fact, failure to gasp has been proposed as a potential cause of sudden infant death syndrome.
| D'Agostino, Dominic; Mazza Jr, Emilio; Neubauer, Judith A (2009) Heme oxygenase is necessary for the excitatory response of cultured neonatal rat rostral ventrolateral medulla neurons to hypoxia. Am J Physiol Regul Integr Comp Physiol 296:R102-18 |
| Mazza, E; Thakkar-Varia, S; Tozzi, C A et al. (2001) Expression of heme oxygenase in the oxygen-sensing regions of the rostral ventrolateral medulla. J Appl Physiol 91:379-85 |
| Mazza Jr, E; Edelman, N H; Neubauer, J A (2000) Hypoxic excitation in neurons cultured from the rostral ventrolateral medulla of the neonatal rat. J Appl Physiol 88:2319-29 |
