AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training

Abstract

Two intermingled hypothalamic neuron populations, specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC), positively and negatively influence feeding behavior respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior, and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type-specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency, and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron-mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

“…The different treatment timescales, marked species divergence in GHS-R-1a expression (rat vs. mouse) (38), and detection methods used (in situ hybridization vs. fluorescence) could explain the lower proportion of detected NPY neurons. These numbers were nonetheless within the range of that recently shown to be sufficient to stimulate food intake (∼300 neurons and above) (39). By contrast, labeling of POMC neurons was more surprising given that ghrelin is generally acknowledged to indirectly target this population via GHS-R-1a-expressing presynaptic NPY neurons (25,40).…”

Palatability Can Drive Feeding Independent of AgRP Neurons

“…AgRP neurons represent a critical component of the homeostatic circuitry that respond to decreased nutrient availability by engaging the full sequence of feeding behaviors (Aponte et al, 2011;Carter et al, 2013;Cowley et al, 2003;Cowley et al, 1999;Krashes et al, 2011). Furthermore, ablation of AgRP neurons in adult mice results in profound anorexia (Bewick et al, 2005;Gropp et al, 2005;Luquet et al, 2005;Xu et al, 2005).…”

“…Activation of hypothalamic AgRP neurons promotes robust feeding (Aponte et al, 2011;Krashes et al, 2011). To decipher the contribution of AgRP neurons in hedonic versus nonhedonic regulation of feeding we used a model in which AgRP neurons can be selectively ablated (Joly-Amado et al, 2012;Luquet et al, 2005;Luquet et al, 2007).…”

The role of leptin in diabetes: metabolic effects

“…Future studies are further warranted to better characterise and understand the neurons and neurocircuits that mediate the glucose-lowering and other neuroendocrine effects of leptin in uDM. To facilitate this, new advancements in neuroscience technologies, such as optogenetics and designer receptors exclusively activated by designer drugs (DREADDs), hold promise in the functional mapping and manipulation of discrete populations of cells involved in glycaemic control [54,55], similar to that which has been applied to increase our knowledge of feeding behaviour [56][57][58].…”