A cholinergic basal forebrain feeding circuit modulates appetite suppression

Abstract

Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus1-5, the major centre in the brain that regulates body weight homeostasis6,7. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding8-10 owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.

The menagerie of the basal forebrain: how many (neural) species are there, what do they look like, how do they behave and who talks to whom?

“…Thus, one main function of cholinergic neurons may be to act as a teaching and alerting signal to the cortex in the presence of behaviorally important stimuli. Caudal projections of BF cholinergic neurons whose cell bodies are located in the diagonal band are also reward-related since they modulate appetite [38]. …”

Nucleobindin-2/Nesfatin-1 in the Human Hypothalamus Is Reduced in Obese Subjects and Colocalizes with Oxytocin, Vasopressin, Melanin-Concentrating Hormone, and Cocaine- and Amphetamine-Regulated Transcript

“…Memory and learning have long been appreciated as important influences on food intake and preferences [64]. Recent evidence suggests that impaired cholinergic signaling resulted in hyperphagia and severe obesity, whereas stimulation of cholinergic DBB neurons suppressed food intake in mice [65]. In patients with Alzheimer’s disease, deep brain stimulation of the NBM resulted in nutritional status stabilization in a 1-year period [66].…”

Toward a Wiring Diagram Understanding of Appetite Control

“…As will be discussed later, they likely play an important role in mediating cue-related anticipatory feedforward inhibition of ARC AgRP neurons (Betley et al, 2015; Chen et al, 2015; Mandelblat-Cerf et al, 2015). Finally, it was recently shown that cholinergic neurons in the forebrain suppress appetite (Herman et al, 2016). Strikingly, impairment of their function causes marked hyperphagia and obesity.…”

“…Strikingly, impairment of their function causes marked hyperphagia and obesity. The ability of these cholinergic neurons to control appetite appears to be mediated, at least in part, by projections to the arcuate, where released acetylcholine (Ach) may engage AChRs on ARC POMC neurons and/or possibly ARC Glutamatergic neurons (Herman et al, 2016; Mineur et al, 2011). The function of such forebrain cholinergic regulation is not presently understood.…”

“…These rapid increases are likely driven, in part, by food cue-evoked reduction in activity of inhibitory AgRP inputs to POMC neurons. In addition, long-range inputs such as those from cholinergic neurons in the diagonal band of Broca (Herman et al, 2016) may also contribute to cue-evoked increases in POMC neuron activity, as other basal forebrain cholinergic neurons were shown to be rapidly activated by detection of unexpected food cues (Parikh et al, 2007). …”