As you stumble upon this page, deciding whether or not to continue reading, a thought crosses your mind: “I could go for a snack.” What is it that triggers your food-seeking behavior? Many cues can bring on hunger, from the delicious smell of freshly baked cookies, to the mouthwatering description of your favorite dish and the resulting mental imagery. What starts out as a simple thought often leads to action. Are there common brain areas or pathways that are activated to produce the search for food? As the control center for homeostasis in general, the hypothalamus must surely be involved, but is there a particular group of neurons responsible for initiating behavior?
The answer: agouti-related protein, or AGRP-expressing neurons, that are present in the arcuate nucleus (ARC) of the hypothalamus. Dr. Scott Sternson’s group at HHMI’s Janelia Farm Research Campus has shown in previous work that in mice, activating a small subset of AGRP neurons is sufficient to evoke “voracious feeding within minutes.”1 This effect is specifically mediated by projections to the paraventricular hypothalamic nucleus (PVH), a region crucial in coordinating appetite.2 More recently, Dr. Sternson and his team have elucidated this pathway as part of a parallel circuit involving specific subpopulations of AGRP neurons.3
In this most recent study, AGRP neurons were selectively targeted for activation using Cre-dependent expression of channelrhodopsin-2 (ChR2). Multiple axonal projection fields were then photostimulated in independent experiments, showing that some areas elicited feeding behavior while others did not, implicating different roles in the projection areas of AGRP neurons.
Interestingly, these AGRP neurons appear to project to specific areas on a one-to-one basis, with little or no collateralization, as evidenced by further experiments using a glycoprotein-deleted (replication incompetent) rabies virus. Injections in various projection areas remained relatively circumscribed, with local labeling as well as somatic labeling, but little to none seen in other areas.
Dr. Sternson and colleagues further characterized the distinct subpopulations of AGRP neurons, noting that out of an approximate total population of 10,000, almost one third projected to PVH. Areas that did not elicit feeding, on the other hand, formed much smaller subpopulations. Another interesting finding was that the subgroups of AGRP neurons were distributed based on the location of their targets, as illustrated in the diagram below:
Based on these anatomical and functional differences, it was suspected there might be differential regulation of individual AGRP neuron subpopulations as well. Using the immediate early gene product Fos as a marker for activation, Dr. Sternson and colleagues used food deprivation or injection of the hormone ghrelin (which signals energy deficit) to activate AGRP neurons. However, distinct subpopulations appeared to be activated to the same degree regardless of whether or not they elicited feeding. Evidence for differential regulation came with the investigation of the hormone leptin, a negative regulator of AGRP neurons and signal for satiety. It was found that only extrahypothalamic projections expressed the receptor for leptin, making the intrahypothalamic projections insensitive to the hormone’s actions.
Taken together, these findings suggest the existence of a core feeding circuit that can be modulated by several inputs from other areas that are not directly involved in eliciting feeding behavior. Further clarification in terms of the regulation of these circuits may have implications for eating disorders and their treatments. So next time you reach for that cookie, just think for a second about your AGRP neurons. Maybe they caused you to reach in the first place.
Hungry for more? Please join us this Tuesday February 18, 2014 at 4:00PM at the CNCB Large Conference Room to hear from Dr. Scott Sternson about “Circuits and motivational processes for hunger.”
David Adamowicz is a first year student in the UCSD Neurosciences Graduate Program (3rd year MSTP). He is currently working on Parkinson’s disease in the laboratories of Dr. Fred Gage and Dr. Subhojit Roy.
1. Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351–5 (2011).
2. Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–7 (2012).
3. Betley, J. N., Cao, Z. F. H., Ritola, K. D. & Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–50 (2013).