Altered ventilatory and thermoregulatory control in male and female adult Pet-1 null mice

The integrity of the serotonin (5-HT) system is essential to normal respiratory and thermoregulatory control. Male and female transgenic mice lacking central 5-HT neurons (Lmx1b^f/f/p mice) show a 50% reduction in the hypercapnic ventilatory response and insufficient heat generation when cooled (Hodges and Richerson, 2008a; Hodges et al., 2008b). Lmx1b^f/f/p mice also show reduced body temperatures (T_body) and O₂ consumption V̇O2, and breathe less at rest and during hypoxia and hypercapnia when measured below thermoneutrality (24°C), suggesting a role for 5-HT neurons in integrating ventilatory, thermal and metabolic control. Here, the hypothesis that Pet-1 null mice, which retain 30% of central 5-HT neurons, will demonstrate similar deficits in temperature and ventilatory control was tested. Pet-1 null mice had fewer medullary tryptophan hydroxylase-immunoreactive (TPH⁺) neurons compared to wild type (WT) mice, particularly in the midline raphé. Female (but not male) Pet-1 null mice had lower baseline ventilation (V̇E), breathing frequency (f), V̇O2 and T_body relative to female WT mice (P<0.05). In addition, V̇E and V̇E/V̇O2 were decreased in male and female Pet-1 null mice during hypoxia and hypercapnia (P<0.05), but only male Pet-1 null mice showed a significant deficit in the hypercapnic ventilatory response when expressed as % of control (P<0.05). Finally, male and female Pet-1 null mice showed significant decreases in T_body when externally cooled to 4°C. These data demonstrate that a moderate loss of 5-HT neurons leads to a modest attenuation of mechanisms defending body temperature, and that there are gender differences in the contributions of 5-HT neurons to ventilatory and thermoregulatory control.