Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size

Ingestive behavior is controlled by a complex interplay between signals conveying availability of (1) potentially ingestible food in the environment, (2) digestible food in the alimentary canal, (3) circulating fuels and (4) stored fuels. Each of these four classes of signals interact with specific sensors and neural circuits whose integrated output determines when food intake is initiated and when it is stopped. Because the final common path responsible for oromotor control is contained within complex neural pattern generators within the brainstem and is intimately linked to sensory information from the alimentary canal, at least part of the integration between the four classes of signals is thought to take place at the level of the caudal brainstem. Here we show that CCK, representing a class 2, or direct signal, and MC4-melanocortin receptor activity, representing a second order class 3/4, or indirect signal, converge in the nucleus of the solitary tract where they modulate activity of the mitogen-activated, extracellular-signal regulated kinases 1 and 2 (ERK) pathway to determine the level of satiation. Blockade of this signaling pathway attenuates suppression of deprivation-induced food intake by intraperitoneal CCK and fourth ventricular MTII injection. Additional findings suggest that specific ERK-phosphorylation sites on ion channels and enzymes involved in catecholamine synthesis of NTS neurons may be involved in ERK-mediated satiation and meal termination. Longer-term downstream effects of ERK activation might involve CREB-mediated gene transcription known to produce plasticity changes in neurocircuitry that could determine inter-meal intervals and the size of future meals.