Effects of HIF-1[alpha] gene deletion in CNS respiratory centers on ventilatory acclimatization to hypoxia

Ventilatory acclimatization to hypoxia (VAH) is a time- dependent increase in normoxic ventilatory drive and the hypoxic ventilatory response (HVR) to acute decreases in inspired PO₂ (PIO₂). Previously, we found that normal VAH in mice depends on Hypoxia Inducible Factor 1-alpha (HIF- 1[alpha]) expression in the central nervous system. HIF- 1[alpha] is a transcription factor that controls the expression of several genes that increase O₂ supply and decrease O₂ metabolism. To define the role of HIF-1[alpha] in VAH with more spatial and temporal precision, we used the Cre-LoxP strategy to delete HIF-1[alpha] in the nucleus tractus solitarii (NTS), which integrates sensory input from carotid body chemoreceptors for respiratory reflexes. We hypothesized that stereotaxic microinjections of Adeno-associated virus expressing Cre recombinase (AAV- Cre) into the NTS of homozygous HIF-1[alpha] floxed adult mice would block normal VAH. Using barometric pressure plethysmography, we measured the HVR in chronically normoxic (CN, PIO₂ = 150 Torr) and chronically hypoxic (CH , PIO₂ = 70 Torr) conscious, unrestrained mice. Microinjections of AAV expressing the LacZ reporter gene (AAV-Lac) were used for controls and localizing AAV infection. There were no differences in the HVR between CN CRE (n=6) and CN LAC (n=6). The HVR decreased in CH CRE (n=9) compared to CH LAC (n=8) because of a significant decrease in ventilation during hypoxia (p < 0.01) with no decrease in normoxic ventilation. Therefore, HIF-1[alpha] expression in the NTS is necessary during CH for normal VA