Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward auto-activation loop in mice.

Synaptic plasticity is identified as innate to hypothalamic feeding circuits in their adaptation to the changing metabolic milieu in control of feeding and obesity. However, less is known about the regulatory principles of the dynamic changes of AgRP perikarya, a crucial region of the neuron gating excitation, and hence, feeding. Here we show that AgRP neurons activated either by food deprivation, ghrelin or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter, GABA, released by AgRP neurons that evoked this astrocytic response, which in turn, resulted in increased glial ensheetment of AgRP perikaryal by glial processes and increased excitability of AgRP neurons. We also identified that astrocyte-derived prostaglandin E2 directly activated, via EP2 receptors, AgRP neurons. Taken together, these observations unmasked a feedforward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding and overfeeding.