The conserved endocannabinoid anandamide modulates olfactory sensitivity to induce hedonic feeding in C. elegans.

The ability of cannabis to increase food consumption has been known for centuries. In addition to producing hyperphagia, cannabinoids can amplify existing preferences for calorically dense, palatable food sources, a phenomenon called hedonic amplification of feeding. These effects result from the action of plant-derived cannabinoids that mimic endogenous ligands called endocannabinoids. The high degree of conservation of cannabinoid signaling at the molecular level across the animal kingdom suggests hedonic feeding may also be widely conserved. Here, we show that exposure of Caenorhabditis elegans to anandamide, an endocannabinoid common to nematodes and mammals, shifts both appetitive and consummatory responses toward nutritionally superior food, an effect analogous to hedonic feeding. We find that anandamide's effect on feeding requires the C. elegans cannabinoid receptor NPR-19 but can also be mediated by the human CB1 cannabinoid receptor, indicating functional conservation between the nematode and mammalian endocannabinoid systems for the regulation of food preferences. Furthermore, anandamide has reciprocal effects on appetitive and consummatory responses to food, increasing and decreasing responses to inferior and superior foods, respectively. Anandamide's behavioral effects require the AWC chemosensory neurons, and anandamide renders these neurons more sensitive to superior foods and less sensitive to inferior foods, mirroring the reciprocal effects seen at the behavioral level. Our findings reveal a surprising degree of functional conservation in the effects of endocannabinoids on hedonic feeding across species and establish a new system to investigate the cellular and molecular basis of endocannabinoid system function in the regulation of food choice.

Egr1 Is Necessary for Forebrain Dopaminergic Signaling during Social Behavior.

Finding the link between behaviors and their regulatory molecular pathways is a major obstacle in treating neuropsychiatric disorders. The immediate early gene (IEG) EGR1 is implicated in the etiology of neuropsychiatric disorders, and is linked to gene pathways associated with social behavior. Despite extensive knowledge of EGR1 gene regulation at the molecular level, it remains unclear how EGR1 deficits might affect the social component of these disorders. Here, we examined the social behavior of zebrafish with a mutation in the homologous gene egr1 Mutant fish exhibited reduced social approach and orienting, whereas other sensorimotor behaviors were unaffected. On a molecular level, expression of the dopaminergic biosynthetic enzyme, tyrosine hydroxylase (TH), was strongly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus. These neurons are connected with basal forebrain (BF) neurons associated with social behavior. Chemogenetic ablation of around 30% of TH-positive neurons in this preoptic region reduced social attraction to a similar extent as the egr1 mutation. These results demonstrate the requirement of Egr1 and dopamine signaling during social interactions, and identify novel circuitry underlying this behavior.

Choice-Selective Neurons in the Auditory Cortex and in Its Striatal Target Encode Reward Expectation.

Learned behavioral responses to sounds depend largely on the expected outcomes associated with each potential choice. Where and how the nervous system integrates expectations about reward with auditory sensory information to drive appropriate decisions is not fully understood. Using a two-alternative choice task in which the expected reward associated with each sound varied over time, we investigated potential sites along the corticostriatal pathway for the integration of sound signals, behavioral choice, and reward information in male mice. We found that auditory cortical neurons encode not only sound identity, but also the animal's choice and the expected size of reward. This influence of reward expectation on sound- and choice-related activity was further enhanced in the major striatal target of the auditory cortex: the posterior tail of the dorsal striatum. These results indicate that choice-specific information is integrated with reward signals throughout the corticostriatal pathway, potentially contributing to adaptation in sound-driven behavior.SIGNIFICANCE STATEMENT Learning and maintenance of sensory-motor associations require that neural circuits keep track of sensory stimuli, choices, and outcomes. It is not clear at what stages along the auditory sensorimotor pathway these signals are integrated to influence future behavior in response to sounds. Our results show that the activity of auditory cortical neurons and of their striatal targets encodes the animals' choices and expectation of reward, in addition to stimulus identity. These results challenge previous views of the influence of motor signals on auditory circuits and identifies potential loci for integration of task-related information necessary for updating auditory decisions in changing environments.