Exercise training on the regulation of inhibitory extracellular modulators of plasticity in the central nervous system

Exercise training is well established to enhance neural plasticity and improve learning and memory, which is associated with enhanced neurotrophic factor expression. However, much less is known regarding the modulation of molecules that restrict neural plasticity following exercise training. We hypothesised that exercise training would downregulate the expression of genes involved in the RhoA/ROCK pathway, which is known to restrict neurite outgrowth and dendritic spine plasticity. Adult male Wistar rats underwent six weeks of moderate intensity continuous training (MICT) or high intensity interval training (HIIT) on a motorised treadmill and were compared to sedentary control animals. MICT and HIIT downregulated aggrecan and Nogo-receptor 2 mRNA expression in the hippocampus. Aggrecan is a component of perineuronal nets (PNNs): lattice-like structures that enwrap subsets of neurons, restrict plasticity, and are implicated in learning and memory. PNNs were fluorescently labelled with anti-aggrecan and Wisteria floribunda agglutinin to visualise aggrecan core protein and chondroitin sulphate glycosaminoglycan (CS-GAG) chains, respectively. MICT induced a shift towards a higher proportion of PNNs that expressed aggrecan without WFA labelling, suggesting that MICT modulated CS-GAG expression in hippocampal PNNs. Given these findings, we hypothesised that overexpression of Chst11, a chondroitin 4-sulfotransferase that makes CS-GAGs more inhibitory to plasticity, would impair memory and thus could be used to investigate the causal link between exercise-induced CS-GAG modulation and memory improvements. Hippocampal Chst11 overexpression impaired short-term object recognition memory, which was attenuated by 24 hours in animals that had completed MICT. These results show that exercise training improves recognition memory by modulating CS-GAG expression in hippocampal PNNs. This study provides evidence that exercise training is a non-invasive method of manipulating PNN composition and alleviating cognitive deficits. These adaptations induced by exercise training may have therapeutic value in neurological conditions that display PNN abnormalities, such as Alzheimer’s disease, schizophrenia, epilepsy, and CNS injuries.