Hippocampal CB1 Receptors Control Incidental Associations

Neuron. 2018 Sep 19;99(6):1247-1259.e7. doi: 10.1016/j.neuron.2018.08.014. Epub 2018 Aug 30.

Abstract

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.

Keywords: CB1; GABA; Western immunoblotting; electrophysiology (LTP, I-LTD); endocannabinoids; higher-order associations; hippocampus; incidental learning; mediated learning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • GABAergic Neurons / metabolism
  • Hippocampus / metabolism*
  • Long-Term Synaptic Depression / physiology*
  • Mice
  • Neuronal Plasticity / physiology
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Synapses / physiology*
  • Synaptic Transmission / physiology

Substances

  • Receptor, Cannabinoid, CB1