The endocannabinoid system regulates the moderate exercise-induced enhancement of learning and memory in mice.

Abstract

Exercise has been reported to enhance cognitive functions via mechanism(s) yet to be fully understood. The endogenous cannabinoid system (ECS) is involved in regulating cognitive function, including learning and memory. This system may also be involved in enhancing learning and memory after exercise. The objective of this study is to explore whether and how ECS participates in the enhancement of learning and memory after exercise. In this study, a treadmill exercise training model was established. Wild-type C57BL/6J mice and those deficient in the cannabinoid receptor 1 (CB1R) coding gene, Cnr1, specifically in the glutamatergic neurons, γ-aminobutyric acid (GABA) neurons or glial cells were randomly grouped for 4 weeks' moderate treadmill exercise. The Morris water maze was used to evaluate the spatial learning and memory abilities of mice in each group. The expression of brain-derived neurotrophic factor (BDNF) and CB1R in hippocampus was detected by western blot. The dendritic spine density of pyramidal cells in the hippocampal CA1 region was analyzed by quantitative Golgi staining. This study consisted of eight single-factor inter-subject designs, and each batch of experiments was divided into two groups. Corresponding experimental items and data analysis were carried out according to the experimental objectives. CB1R antagonist administration or CB1R knockout in glutamatergic neurons eliminated the effect of exercise on learning and memory, and counteracted exercise-elicited upregulation of BDNF in the hippocampus; CB1R-specific knockout on GABAergic neurons and glial cells did not affect the moderate exercise-induced enhancement of learning and memory. In addition, the results of Golgi staining showed that exercise increased dendritic spine density in hippocampal neurons, which was abolished by specific CB1R depletion in glutamatergic neurons. The ECS, particularly CB1R signaling in glutamatergic neurons, mediates the enhancement of learning and memory by exercise, which involves increased BDNF production and dendritic spine density.