In 1900, Lord Kelvin addressed an assembly of physicists and claimed, “There is nothing new to be discovered in physics now. All that remains is more and more precise measurement.” Then just 5 years later, Einstein shook up the scientific world with his theory of relativity. Dare I compare this situation to the second paper in my Modern Classic series? No, that would be exaggeration on a disgusting scale. However, hyperbole aside, the findings from today’s paper were a revelation to me and, I’m sure, to many others, and has opened up a new way of thinking about the neuronal control of energy balance.
We saw last time that we can drive voracious feeding in mice by activating AgRP neurones, with DREADD’s or optogenetics. The thinking at the time was that, in a fasted mouse, Ghrelin is high (and satiety hormones such as PYY3-36 are low), so AgRP neurones are actively firing to drive food seeking and consumption. Then as the mouse eats and the balance of hormones switch, the AgRP neurone activity drops, and so does feeding drive. However, this thinking was soon to be upended, when Chen et al. used in vivo photometry recordings to measure the activity of AgRP and POMC neurones in awake behaving animals1.
Photometry is probably my favourite in vivo method, because it allows you to investigate the behaviour of an identified group of neurones in an awake behaving animal. Chen et al. transfected AgRP and POMC neurones with the calcium indicator GCaMP, which closely mimicked the electrical activity of the cell (Figure 1A-E). They then put it into live mice, which allowed them to record the activity of AgRP or POMC neurones in awake behaving animals (Figure 1F-H).
They next showed that Ghrelin injection in their AgRP or POMC photometry recordings caused a rapid increase or decrease, respectively, in activity in those neurone populations. No surprises so far. However, the revelation came when they fasted the animals (to drive up AgRP neurone activity), then presented food (Figure 2). The change in neuronal activity came rapidly after presentation of food. In fact they found, as stated in the name of the paper, that the AgRP and POMC neurone activity was modulated upon sensory detection of food – in fact they had already altered their behaviour before the mice had taken a bite of food (Figure 2H). This shows that the classic theories of AgRP and POMC neurone regulation by hormones and other homeostatic methods are too slow to drive actual feeding. The question then becomes, how do AgRP neurons drive food intake if they are switched off during the time that the animals are actually eating?
Chen et al. go on to show that the degree of response to food presentation is relative to the caloric content of the food, ie. they have a bigger response to peanut butter than to regular chow. There has since been a lot of work to investigate further the control of feeding behaviours by these neurone populations, but I won’t go into detail here. However, it is worthy to note two papers came out soon after the Chen paper, confirming the rapid modulation of AgRP neurones by sensory detection of food, using different methods (Betley et al. used GCaMP and head-mounted miniscopes; Mandelblat-Cerf et al. used optetrode ephys recordings to provide actual spiking data)2,3.
1. Chen et al., Cell 160, 829-841 (2015) Sensory detection of food rapidly modulates arcuate feeding circuits.
2. Betley et al., Nature 521, 180-185 (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal.
3. Mandelblat-Cerf et al., eLife 4, e07122 (2015) Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescale.