Animals must express the appropriate behavior that meets their most pressing physiological needs and their environmental context. However, it is currently unclear how alternative behavioral options are evaluated and appropriate actions are prioritized. Here, we describe how fruit flies choose between feeding and courtship; two behaviors necessary for survival and reproduction. We show that sex- and food-deprived male flies prioritize feeding over courtship initiation, and manipulation of food quality or the animal's internal state fine-tunes this decision. We identify the tyramine signaling pathway as an essential mediator of this decision. Tyramine biosynthesis is regulated by the fly's nutritional state and acts as a satiety signal, favoring courtship over feeding. Tyramine inhibits a subset of feeding-promoting tyramine receptor (TyrR)-expressing neurons and activates P1 neurons, a known command center for courtship. Conversely, the perception of a nutritious food source activates TyrR neurons and inhibits P1 neurons. Therefore, TyrR and P1 neurons are oppositely modulated by starvation, via tyramine levels, and food availability. We propose that antagonistic co-regulation of neurons controlling alternative actions is key to prioritizing competing drives in a context- dependent manner.

Interpreting sensory information requires its integration with the current behavior of the animal. However, how motor-related circuits influence sensory information processing is incompletely understood. Here, we report that current locomotor state directly modulates the activity of BAG CO2 sensory neurons in Caenorhabditis elegans. By recording neuronal activity in animals freely navigating CO2 landscapes, we found that during reverse crawling states, BAG activity is suppressed by tyraminergic corollary discharge signaling. We provide genetic evidence that tyramine released from the RIM reversal interneurons extrasynaptically activates the inhibitory chloride channel LGC-55 in BAG. Disrupting this pathway genetically leads to excessive behavioral responses to CO2 stimuli. Moreover, we find that LGC-55 signaling cancels out perception of self-produced CO2 and O2 stimuli when animals reverse into their own gas plume in ethologically relevant aqueous environments. Our results show that sensorimotor integration involves corollary discharge signals directly modulating chemosensory neurons.

Pentameric ligand-gated ion channels (LGICs) play conserved, critical roles in both excitatory and inhibitory synaptic transmission and can be activated by diverse neurochemical ligands. We have performed a characterization of orphan channels from the nematode C. elegans, identifying five new monoamine-gated LGICs with diverse functional properties and expression postsynaptic to aminergic neurons. These include polymodal anion channels activated by both dopamine and tyramine, which may mediate inhibitory transmission by both molecules in vivo. Intriguingly, we also find that a novel serotonin-gated cation channel, LGC-50, is essential for aversive olfactory learning of pathogenic bacteria, a process known to depend on serotonergic neurotransmission. Remarkably, the redistribution of LGC-50 to neuronal processes is modulated by olfactory conditioning, and lgc-50 point mutations that cause misregulation of receptor membrane expression interfere with olfactory learning. Thus, the intracellular trafficking and localization of these receptors at synapses may represent a molecular cornerstone of the learning mechanism.

Nutrient deprivation can lead to dramatic changes in feeding behavior, including acceptance of foods that are normally rejected. In flies, this behavioral shift depends in part on reciprocal sensitization and desensitization of sweet and bitter taste, respectively. However, the mechanisms for bitter taste modulation remain unclear. Here, we identify a set of octopaminergic/tyraminergic neurons, named OA-VLs, that directly modulate bitter sensory neuron output in response to starvation. OA-VLs are in close proximity to bitter sensory neuron axon terminals and show reduced tonic firing following starvation. We find that octopamine and tyramine potentiate bitter sensory neuron responses, suggesting that starvation-induced reduction in OA-VL activity depotentiates bitter taste. Consistent with this model, artificial silencing of OA-VL activity induces a starvation-like reduction in bitter sensory neuron output. These results demonstrate that OA-VLs mediate a critical step in starvation-dependent bitter taste modulation, allowing flies to dynamically balance the risks associated with bitter food consumption against the threat of severe starvation.