Hypoxia And Cold Adaptive Mechanisms Of Plateau Pika In Qinghai Tibetan Plateau

Qinghai-Tibetan Plateau(QTP), the average altitude is 4500 m, which is the largest and highest altitude on earth. Coldness, dry and lower oxygen air pressure with the intensive UV light is the main environmental feature of the plateau, which impaired the respirational and cardiovascular functions, as well as posed the physiological challenges to the populations moved from the sea level. However, the native mammals are survival and well adaptive to this harsh conditions in the highland of QTP.The plateau pika(Ochotona curzoniae) is a species native to the Qinghai-Tibetan Plateau. Both cold and hypoxia are significant challenges to life in the Plateau, but plateau pika are well-adapted to both. Numerous studies have demonstrated that pika have evolved adaptive mechanisms to deal with these challenges, such as high resting metabolic rates(RMR) and non-shivering thermogenesis(NST) for warmth, and lower rates of oxygen consumption to deal with hypoxia. Evidence indicates that with increased altitude, pika increase fat accumulation, and that low temperatures at high altitude may be the primary environmental driving force for these adaptive phenotypes. Therefore, the plateau pika is a good animal model to study energy expenditure in general and the adipose mechanisms involved in adaptation to cold exposure.In this study, we continuously move forward of our research steps into the deeper and broad view, with the standing on the shoulders of the previous evidence. Two aspects of the adaptive features, both the coldness and hypoxic tolerant abilities are integrated to reveal the molecular mechanisms to against the hostile conditions in plateau pika.Part I Central modulations of Hypoxic Ventilatory responses in plateau pika, the role of glutamate and serotoninAim: The plateau Pika(Ochotona curzoniae) is a small lagomorph living on high altitude Tibetan Chinese plateaus and is therefore considered to be fully adapted to high altitude. We have previously studied the hypoxic ventilatory response(HVR) and the long-term ventilatory adaptation to hypoxia in this animal. We have shown that plateau Pika have developed specific adaptations with changes in ventilatory pattern as compared to low altitude or high altitude acclimatized rats, even if the ventilatory response to hypoxia was not statistically different between species. These adaptations are mainly due to an increase in tidal volume and inspiratory time in Pikas leading to a better ventilatory efficiency. We used pharmacological approach to test the influence of NMDA(memantine) and non-NMDA receptors(DNQX), nitric oxide(NO, L-NAME) and serotonin(fluoxetine) on ventilatory parameters and hypoxic ventilatory response in the adapted high altitude ‘Plateau Pika’.Methods: Ventilatory parameters were measured before and after drug injections using a whole body plethysmographic method in conscious pikas at their natural living altitude(4100m, PIO2-86 mm Hg) and after a hypoxic challenge(6800m, PIO2-57 mm Hg).Results: Tidal volume(Vt), respiratory frequency and minute ventilation(Vi) were increased and total time(Ttot) and inspiratory time(Ti) were decreased after hypoxic challenge(vehicle) whereas the Ti/Ttot ratio remained unchanged. Memantine or DNQX had no effect on HVR in pikas. At PIO2-57, L-NAME induced an increase in the Ti/Ttot ratio(0.59±0.03 vs 0.56±0.03, p<0.05) as compared to vehicle. The increase in VE and Vt observed with vehicle at PIO2-57 as compared to PIO2-86 were inhibited after fluoxetine injection.Conclusions: Ventilatory adaptation at Pikas usual living altitude seems to be independent of the NMDA/NO, non-NMDA and serotonin pathways. However, AMPA receptors stimulation and serotonin accumulation at the synaptic level seem to limit the ventilatory response to acute hypoxia whereas NMDA receptors stimulation and NO synthesis have minor effect in our model of mammals adapted to hypoxia.Part II Intermittent cold exposure results in visceral adipose tissue “browning” in the Plateau PikaObject The plateau pika has developed tolerance to cold and hypoxia in order to adapt to living in the extreme environment of the Qinghai-Tibetan Plateau. One mammalian mechanism for cold adaptation is thermogenesis by brown adipose tissue(BAT), but it is not known the degree to which pika exploit this mechanism nor how it may be modified by the additional stresses of high altitude.Methods Intermittent Cold Exposure(ICE) is an approachable method to study cold adaptation in rodents. To investigate the role of adipose tissue in the adaptation of pika to cold temperatures, we have studied pika during ICE.Results We find that pika kept in warm temperatures has little classical brown fat, but “browning” of white adipose tissues is observed rapidly upon cold exposure. This is demonstrated by the increased expression of several markers of brown fat differentiation including uncoupling protein 1(UCP-1). Surprisingly, this occurs mainly in visceral rather than epididymal adipose tissue. In addition, ICE increases the expression of several general adipose differentiation markers at both the m RNA and protein levels. These substantial changes in the distribution of fat are accomplished without changes in weight or blood levels of glucose and triglycerides, suggesting that the adaptable changes are coordinated and self-compensated.Conclusion Together, our results demonstrate that ICE promotes recruitment of BAT in pika, and unlike small mammals in at lower altitudes, pika can activate visceral WAT to adapt to cold stress without major changes overall energy balance.