Pinho, J. | bioRxiv Science

bioRxiv2026

Endocannabinoid-dopamine interactions mediate incidental associations in the hippocampus

Reinforced conditioning allows individuals predicting future events with high confidence. However, many daily behaviours rely on unreinforced connections of neutral stimuli, called Incidental Associations (IAs), which enhance predictive capacity in unstable environments and are observed across species. IAs can be studied through sensory preconditioning paradigms, where two neutral stimuli (S1/S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. As a result, subjects present a direct response to the S1 stimulus, but also display mediated responses to the S2 stimulus never explicitly reinforced, indicating IA formation during preconditioning. Our previous work demonstrated that type-1 cannabinoid receptors (CB1 receptors) in the hippocampus are essential for this IA formation. As dopamine signaling is also important for this process, we investigate the role of interactions between these dopamine-cannabinoid systems in IA memory formation in the hippocampus. Extending our previous work on odor-taste association, using light-sound association we showed that global CB1 receptor knock-out or specific hippocampal CB1 receptor deletion also blocked mediated responses to sound (S2) while direct response to light (S1) was unaltered. Focusing on dopamine, we then found hippocampal dopaminergic activity is enhanced during paired presentations of S1 and S2 and that blockade of dopamine D1 receptor during preconditioning S1-S2 associations abolished mediated response to S2. Interestingly, mice lacking CB1 receptors specifically in D1-receptor-expressing cells (D1-CB1-KO) failed to show mediated responses for either light-sound or odor-taste associations, identifying this CB1 receptor population as critical for IA formation. Enhanced activation of CB1 receptors, through either increase of endocannabinoids (using degradation enzyme inhibition) or exogenous stimulation by cannabis-derived Delta-9-tetrahydrocannabinol (THC), was able to promote the formation of IAs under insufficient conditions. The effect of endogenous CB1 activation, but not THC, was blocked in D1-CB1-KO mice indicating that IA-facilitation by endogenous and exogenous receptor activation rely on different mechanisms. Overall, these data uncover new mechanisms underlying unreinforced associative learning.

neuroscience↗

bioRxiv2021

Social and asocial learning in zebrafish are encoded by a shared brain network that is differentially modulated by local activation

Group living animals can use social and asocial cues to predict the presence of a reward or a punishment in the environment through associative learning. The degree to which social and asocial learning share the same mechanisms is still a matter of debate, and, so far, studies investigating the neuronal basis of these two types of learning are scarce and have been restricted to primates, including humans, and rodents. Here we have used a Pavlovian fear conditioning paradigm in which a social (fish image) or an asocial (circle image) conditioned stimulus (CS) have been paired with an unconditioned stimulus (US=food), and we have used the expression of the immediate early gene c-fos to map the neural circuits associated with social and asocial learning. Our results show that the learning performance is similar with social (fish image) and asocial (circle image) CSs. However, the brain regions involved in each learning type are distinct. Social learning is associated with an increased expression of c-fos in olfactory bulbs, ventral zone of ventral telencephalic area, ventral habenula and ventromedial thalamus, whereas asocial learning is associated with a decreased expression of c-fos in dorsal habenula and anterior tubercular nucleus. Using egonetworks, we further show that each learning type has an associated pattern of functional connectivity across brain regions. Moreover, a community analysis of the network data reveals four segregated functional submodules, which seem to be associated with different cognitive functions involved in the learning tasks: a generalized attention module, a visual response module, a social stimulus integration module and a learning module. Together, these results suggest that, although there are localized differences in brain activity between social and asocial learning, the two learning types share a common learning module and social learning also recruits a specific social stimulus integration module. Therefore, our results support the occurrence of a common general-purpose learning module, that is differentially modulated by localized activation in social and asocial learning.

animal behavior and cognition↗