Interaction between defects in ventilatory and thermoregulatory control in mice lacking 5-HT neurons

We have previously shown that mice with near-complete absence of 5-HT neurons (Lmx1b(f/f/P)) display a blunted hypercapnic ventilatory response (HCVR) and impaired cold-induced thermogenesis, but have normal baseline ventilation (V(E)), core body temperature (T(Core)) and hypoxic ventilatory responses (HVR) at warm ambient temperatures (T(Amb): 30 degrees C). These results suggest that 5-HT neurons are an important site for integration of ventilatory, metabolic and temperature control. To better define this integrative role, we now determine how a moderate cold stress (T(Amb) of 25 degrees C) influences ventilatory control in adult Lmx1b(f/f/P) mice. During whole animal plethysmographic recordings at 25 degrees C, baseline V(E), metabolic rate (V(O2)), and T(Core) of Lmx1b(f/f/P) mice were reduced (P < 0.001) compared to wild type (WT) mice. Additionally, the HCVR was reduced in Lmx1b(f/f/P) mice during normoxic (-33.1%) and hyperoxic (-40.9%) hypercapnia. However, V(E) in Lmx1b(f/f/P) mice was equal to that in WT mice while breathing 10% CO(2), indicating that non-5-HT neurons may play a dominant role during extreme hypercapnia. Additionally, ventilation was decreased during hypoxia in Lmx1b(f/f/P) mice compared to WT mice at 25 degrees C due to decreased T(Core). These data suggest that a moderate cold stress in Lmx1b(f/f/P) mice leads to further dysfunction in ventilatory control resulting from failure to adequately maintain T(Core). We conclude that 5-HT neurons Contribute to the hypercapnic ventilatory response under physiologic, more than during extreme levels of CO(2), and that mild cold stress further compromises ventilatory control in Lmx1b(f/f/P) mice as a result of defective thermogenesis. (C) 2008 Elsevier B.V. All rights reserved.