Are tuberomammillary histaminergic neurons involved in CO 2-mediated arousal?

Abstract

An increase in arousal in response to hypercapnia [elevated arterial PCO 2 (partial pressure of CO 2) levels] during awake or sleep states is an important component of mechanisms designed to maintain acid–base homeostasis. Since central histaminergic neurons are crucial for maintaining waking states and vigilance, a nonresponsive or dysfunctional histaminergic system could contribute to the lack of arousal in response to hypercapnia in some sleep-related disorders [e.g., sudden infant death syndrome (SIDS) and Ondine's curse]. Therefore, the present study attempted to determine if histaminergic neurons display functional responses to acute exposure to hypercapnic gas (i.e., gas with elevated CO 2 concentrations). Healthy adult male rats were placed in flow cages during the light cycle, or inactive phase, and exposed to either atmospheric air or to environmental CO 2 concentrations increasing from baseline up to 20% CO 2 over a 5-min period. The expression of the protein product of the immediate-early gene c- fos was used as a measure of functional cellular responses within subpopulations of histaminergic neurons. Among the histaminergic subgroups (E1–E5), only the ventral tuberommamillary nucleus (VTMn)/E2 cell group showed significant increases in c-Fos expression following brief exposure to hypercapnic gas. These data are consistent with the hypothesis that histaminergic neuronal cell groups are heterogeneous and are involved in physiological and/or behavioral responses to acute hypercapnic challenge, potentially increasing vigilance during active waking and awakening from sleep during hypercapnic states.