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.

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Hyperpolarization-activated channels (I h or HCN channels) are widely expressed in principal neurons in the central nervous system. However, I h in inhibitory GABAergic interneurons is less well characterized. We examined the functional properties of I h in fast-spiking basket cells (BCs) of the dentate gyrus, using hippocampal slices from 17-to 21-day-old rats. Bath application of the I h channel blocker ZD 7288 at a concentration of 30 μM induced a hyperpolarization of 5.7 ± 1.5 mV, an increase in input resistance and a correlated increase in apparent membrane time constant. ZD 7288 blocked a hyperpolarization-activated current in a concentration-dependent manner (IC 50 , 1.4 μM). The effects of ZD 7288 were mimicked by external Cs + . The reversal potential of I h was −27.4 mV, corresponding to a Na + to K + permeability ratio (P Na /P K ) of 0.36. The midpoint potential of the activation curve of I h was −83.9 mV, and the activation time constant at −120 mV was 190 ms. Single-cell expression analysis using reverse transcription followed by quantitative polymerase chain reaction revealed that BCs coexpress HCN1 and HCN2 subunit mRNA, suggesting the formation of heteromeric HCN1/2 channels. ZD 7288 increased the current threshold for evoking antidromic action potentials by extracellular stimulation, consistent with the expression of I h in BC axons. Finally, ZD 7288 decreased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal granule cells, the main target cells of BCs, to 70 ± 4% of the control value. In contrast, the amplitude of mIPSCs was unchanged, consistent with the presence of I h in inhibitory terminals. In conclusion, our results suggest that I h channels are expressed in the somatodendritic region, axon and presynaptic elements of fast-spiking BCs in the hippocampus.

Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from αCaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGT was associated with impaired satiety. These results identify O-GlcNAcylation in αCaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior.