Energy homeostasis is of paramount importance for health and survival during periods of duress and this must occur at both the cellular and organismal level. Starvation is therefore often accompanied by compensatory behaviours that are triggered to increase the probability of encountering a food source. But how hunger results in changes in the activity of neural circuits to elicit specific adaptive behavioural responses is just beginning to be elucidated. AMP-activated protein kinase (AMPK) is a metabolic sensor that has also emerged as a key modulator of behavioral responses to food availability, although the mechanisms by which this kinase affects such outcomes remain unclear. We observed a locomotory defect in starved AMPK-deficient C. elegans larvae, which reflects their inability to appropriately respond to resource depletion. We observed that AMPK is expressed in key neurons involved in the various locomotory responses associated with reduced food availability, while reconstitution of AMPK within these neurons completely rescues the locomotory defects of AMPK mutants. Using a combination of classic genetic analysis, optogenetic approaches and calcium imaging techniques, we discovered that although AMPK is not required for the essential aspects of neural function, it plays a key role in the regulation of the neuronal activity in starved animals, which in turn ensures appropriate behavioral outcomes in response to acute energy stress. Furthermore, we observed that this effect of AMPK is partly mediated by regulating the levels of AMPA-type glutamate receptor GLR-1, which ultimately modulates synaptic strength under conditions of starvation. Overall, our study suggests that besides its well-known function in metabolic control at the cellular level, AMPK also acts at the organismal level as a molecular trigger required to modulate neuronal activity to elicit adaptive behavioral outputs in response to starvation.
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