Deciphering a neuronal circuit that mediates appetite

Abstract

Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y (NPY), and γ-amino-butyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals1,2. Ablation of these neurons leads to cessation of feeding that is accompanied by Fos activation in most regions where they project3–6. Previous experiments indicate that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABAA receptor signaling in the PBN within a critical adaptation period5. We hypothesized that loss of GABAergic inhibition from AgRP neurons to the PBN leads to abnormal activation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of 5-HT3 receptor signaling in the rostral NTS by either chronic administration of ondansetron or genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Moreover, genetic inactivation of glutamatergic signaling by the NTS onto N-methyl D-aspartate (NMDA)-type glutamate receptors in the PBN prevents starvation. We also demonstrate that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Hence, we identify the PBN as an important hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.

NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus

“…S2). These results suggest that LiCl exerts its protective effect on the PBN by activating vagal afferents to the NTS which then are relayed to the PBN (14).…”

“…Our previous experiments implicated glutamate signaling onto NMDA receptors of PBN neurons as the source of excitation that results in Fos induction and aphagia (14). We hypothesized that acute ablation of AgRP neurons, which could result in a homeostatic increase of PBN excitation, might trigger compensatory changes in the expression profile of the NR2A and NR2B subunits of the NMDA receptor.…”

“…Ablation of AgRP neurons by administration of diphtheria toxin (DT) to mice that express the diphtheria toxin receptor (DTR) selectively in AgRP neurons (Agrp DTR mice) results in aphagia and a fatal loss of body weight caused by the hyperactivity of postsynaptic neurons in the parabrachial nucleus (PBN) as a consequence of losing inhibitory GABAergic signals (11)(12)(13). This anorexic response can be prevented by benzodiazepine potentiation of GABA signaling, by genetic blockade of NMDA glutamate receptor signaling in the PBN, or by reducing glutamatergic input or output from the PBN, including knockdown of NMDA expression in the PBN (14). However, the physiological roles of NMDA receptors in the PBN in modulating appetitive behavior have not been identified.…”

Serotonin controlling feeding and satiety

“…A systemic administration of the 5-HT3 antagonist odansetron attenuated this intestinal effect on brain c-fos expression, suggesting a functional connection of these structures and 5-HT in the efferent control of intestinal disturbances [210]. Caudal serotonergic neurons of the NTS control the excitability of the parabrachial nucleus and inhibit feeding [211]. The parabrachial nucleus is connected to the hypothalamus [212].…”

“…Ablation of hypothalamic AgRP neurons leads to aberrant activation of the parabrachial nucleus and starvation. The parabrachial nucleus has been identified, therefore, as a functional unit that integrates feeding related signals from several brain regions [211,213] and could possibly provide a functional link between hypothalamic and hindbrain mechanisms of 5-HT mediated satiety. 5-HT1B receptor activation in the parabrachial nucleus reduces food intake [214] and the hypophagic effect of fenfluramine in the parabrachial nucleus requires 5-HTB receptor activation [215].…”