Abstract
Agouti-related-peptide (AgRP) neurons—interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)—are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.DOI: http://dx.doi.org/10.7554/eLife.07122.001
Highlights
The homeostatic drive to feed is at least partially driven by agouti-related-peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC)
Because the only ARC neurons currently known to be inhibited by AgRP neurons are POMC neurons
Because AgRP neurons are densely packed in the ARC (Figure 1A), we used tetrodes with high impedance that allowed for isolation of large spike waveforms (Figure 1B) from neurons proximal to the tetrodes (4–8 bundles of 4 wires,
Summary
The homeostatic drive to feed is at least partially driven by agouti-related-peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC). These neurons have privileged access to slow hormonal signals of energy balance, such as ghrelin and leptin (Willesen et al, 1999, Morton and Schwartz, 2001, Zigman and Elmquist, 2003, Varela and Horvath, 2012, Wang et al, 2014), and receive long-range glutamatergic, GABAergic, and peptidergic synaptic inputs from multiple central brain nuclei, including the paraventricular and dorsomedial hypothalamus (Krashes et al, 2014) Both opto- and pharmaco-genetic activation of AgRP neurons drive intense feeding in ad libitum-fed mice (Aponte et al, 2011, Krashes et al, 2011), while loss-of-function experiments in food-restricted mice lead to a reduction in food consumption (Gropp et al, 2005, Luquet et al, 2005, Krashes et al, 2011). Previous attempts to directly record spiking activity of AgRP neurons have been restricted to in vitro approaches, due to the technical challenges of extracellular electrophysiological recordings in the ARC in living animals, and the fact that AgRP neurons are intermingled with pro-opiomelanocortin (POMC) neurons with opposing effects on food intake (Varela and Horvath, 2012, Zhan et al, 2013)
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