Convergent energy state-dependent antagonistic signalling by CART and NPY modulates the plasticity of forebrain neurons to regulate feeding in zebrafish

Dynamic re-configuration of circuit function subserves the flexibility of innate behaviours tuned to physiological states. Internal energy stores adaptively regulate feeding-associated behaviours by integrating opposing hunger and satiety signals at the level of neural circuits. Across vertebrate lineages, the neuropeptides CART and NPY have potent anorexic and orexic functions, respectively, and show energy state-dependent expression in interoceptive neurons. However, how the antagonistic activities of these peptides modulate circuit plasticity remains unclear. Using behavioural, neuroanatomical and activity analysis in adult zebrafish of both sexes, along with pharmacological interventions, we show that CART and NPY activities converge on a population of neurons in the dorsomedial telencephalon (Dm). While CART facilitates glutamatergic neurotransmission at the Dm, NPY dampens the response to glutamate. In energy-rich states, CART enhances NMDA receptor (NMDAR) function by PKA/PKC mediated phosphorylation of the NR1 subunit of the NMDAR complex. Conversely, starvation triggers NPY-mediated reduction in phosphorylated NR1 via calcineurin activation and inhibition of cAMP production leading to reduced responsiveness to glutamate. Our data identify convergent integration of CART and NPY inputs by the Dm neurons to generate nutritional state-dependent circuit plasticity that is correlated with the behavioural switch induced by the opposing actions of satiety and hunger signals.SIGNIFICANCE STATEMENT:Internal energy needs reconfigure neuronal circuits to adaptively regulate feeding behaviour. Energy state-dependent neuropeptide release can signal energy status to feeding-associated circuits and modulate circuit function. CART and NPY are major anorexic and orexic factors, respectively, but the intracellular signalling pathways utilised by these peptides to alter circuit function remain uncharacterised. We show that CART and NPY-expressing neurons from energy state interoceptive areas project to a novel telencephalic region, Dm, in adult zebrafish. CART increases the excitability of Dm neurons while NPY opposes CART activity. Antagonistic signalling by CART and NPY converge onto NMDA-receptor function to modulate glutamatergic neurotransmission. Thus opposing activities of anorexic CART and orexic NPY reconfigure circuit function to generate flexibility in feeding behaviour.