| Hindbrain 'sensing' of glucoprivation activates central neural mechanisms that enhance systemic glucose availability, but the critical molecular variable(s) that is(are) linked to detection of local metabolic insufficiency remain(s) unclear. Recent studies support the metabolic coupling of neurons and glia in the brain via intercellular trafficking of the glycolytic product, lactate, as a substrate for neuronal oxidative respiration. The current studies investigated the hypothesis that lactate insufficiency may be monitored by local metabolically 'sensitive' neurons as an indicator of CNS energy imbalance. Using complementary in vivo models for experimental manipulation of lactate availability within the caudal hindbrain, we evaluated the effects of hindbrain lactate manipulation on physiological and neuroanatomical parameters, including immediate-early gene expression in the nucleus tractus solitarius (NTS) and forebrain structures that integrate sensory input from metabolic sensors and coordinate motor responses to energy shortages stasis. The present data show that lactate manipulation in hindbrain alters blood glucose levels and elicits cfos gene expression in discrete metabolically-sensitive areas in the hindbrain and forebrain. Furthermore, the current studies demonstrate that pharmacological reduction of lactate uptake in the caudal hindbrain stimulates food consumption in a dose dependent manner and that this behavioral response is correlated with widespread neuronal genomic activation in principal forebrain metabolic loci. Dual-label immunofluorescence histochemistry for cytoplasmic tyrosine hydroxylase (TH) reveals that pharmacological suppression of lactate trafficking in the caudal hindbrain causes genomic activation of NTS/AP catecholaminergic neurons. We have observed that chemical lesioning of NTS catecholaminergic neurons attenuates 4CIN-induced hyperglycemia, an outcome that implicates these neurons in the transduction of hindbrain lactoprivic signaling of physiological compensatory responses. These studies, taken together, provide key evidence that lactate is a critical monitored variable in caudal hindbrain detection of cellular energy imbalance resulting from systemic glucoprivation, and will serve as a solid platform for extended efforts in the field of CNS energetics. |
