By priming brain circuits, associations between low-salience stimuli often guide future behavioral choices through a process known as mediated or inferred learning. However, the precise neurobiological mechanisms of these incidental associations are largely unknown. Using sensory preconditioning procedures, we show that type 1 cannabinoid receptors (CB1R) in hippocampal GABAergic neurons are necessary and sufficient for mediated but not direct learning. Deletion and re-expression of CB1R in hippocampal GABAergic neurons abolishes and rescues mediated learning, respectively. Interestingly, paired presentations of low-salience sensory cues induce a specific protein synthesis-dependent enhancement of hippocampal CB1R expression and facilitate long-term synaptic plasticity at inhibitory synapses. CB1R blockade or chemogenetic manipulations of hippocampal GABAergic neurons upon preconditioning affect incidental associations, as revealed by impaired mediated learning. Thus, CB1R-dependent control of inhibitory hippocampal neurotransmission mediates incidental associations, allowing future associative inference, a fundamental process for everyday life, which is altered in major neuropsychiatric diseases. Video Abstract: [Figure presented] Busquets-Garcia et al. suggest that cannabinoid CB1 receptors signaling in the hippocampus, a brain structure involved in memory processes, underlines the mammalian ability to associate randomly encountered stimuli, allowing future inferred memories and possibly explaining seemingly ungrounded responses toward certain cues.
CITATION STYLE
Busquets-Garcia, A., Oliveira da Cruz, J. F., Terral, G., Zottola, A. C. P., Soria-Gómez, E., Contini, A., … Marsicano, G. (2018). Hippocampal CB1 Receptors Control Incidental Associations. Neuron, 99(6), 1247-1259.e7. https://doi.org/10.1016/j.neuron.2018.08.014
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