Dissociating therapeutic effects of exercise and environmental enrichment in mouse models of serotonergic dysfunction

Abstract

Serotonergic (5-HTergic) signaling is implicated in the manifestation of psychiatric disorders and regulates hippocampus-dependent cognitive and emotional processing that can underpin them. Clinical evidence indicates that serotonin 1A receptor (5-HT1AR) and serotonin transporter (5-HTT) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise and environmental enrichment (EE) can change emotionality-related behaviours as well as enhance some aspects of cognition. We aimed to determine the therapeutic effects of exercise versus EE (which does not include running wheels) on constitutive 5-HT1AR and 5-HTT knock-out (KO) mice phenotypes. 5-HT1AR KO mice have an anxiety-like phenotype as well as hippocampus-dependent learning and memory deficits. In addition to increased anxiety-like behaviour, 5-HTT KO mice also have a depression-like phenotype.

The Morris water maze (MWM) is one of the most widely cited behavioural tasks in neuroscience. It measures the capability of the hippocampus to create a viewpoint invariant cognitive map of a distal cue array to find a hidden platform escape goal. Using a Matlab classification algorithm of the search strategy utilised to find the escape during MWM spatial learning, we have shown that increases in the odds of more hippocampus-dependent (allocentric) strategy selection is the key measure indicating the formation of this map to the escape location. Furthermore, using this measure we demonstrated a novel cognitive enhancement due to exercise (but not EE) for the first time. We also showed that 5-HT1AR KO mice had a significant reduction in the likelihood of an allocentric strategy selection. This deficit provides a novel explanation for their impaired long-term memory on the MWM retention probe. Strikingly, we found that these increases in spatial strategy selection through exercise corrected the long-term spatial memory deficits displayed by the 5-HT1AR KO mice.

Assessing emotionality-related behaviours in both models dissociated further therapeutic effects of exercise from EE. Exercise (but not EE) had an antidepressant-like effect in 5-HTT KO mice, rescuing their deficit on the forced-swim test. In contrast, our EE paradigm (but not exercise access) reduced anxiety-like behaviours in both 5-HT1AR and 5-HTT KO mice. Furthermore, we report that 5-HTT KO mice had impaired synaptic plasticity by measuring long term potentiation (LTP) in the hippocampus and exercise also rescued this deficit. Exercise elicited robust increases in adult-born cell survival in wild-type (WT) mice. Exercising 5-HTT KO mice did also have increased adult-born cell survival but had a 3-fold decrease in the level compared to exercising WT mice. LTP and adult neurogenesis are both hypothesised to contribute to antidepressant effects, so our study adds support to the hypothesis that LTP and neurogenesis changes drive the antidepressant-like effect of exercise in 5-HTT KO mice. Surprisingly, in 5-HTT HET mice exercise induced a deficit in LTP compared to WT control mice and there were no exercise-induced increases in adult-born cell survival. 5-HTT HET mice in the standard-housing condition displayed enhanced cognitive flexibility and this behaviour was not present in exercising 5-HTT HET mice.

Prevalent 5-HT1AR or 5-HTT targeted drugs are established treatments in various psychiatric disorders. Functional polymorphisms in both the 5-HT1AR and the 5-HTT genes are associated with increased risk of developing various psychiatric disorders as well as with increased insensitivity to their unique sets of targeted pharmacology. Unfortunately, for this and for other reasons, not all patients have efficacious responses to these established interventions, so novel therapies are required. The therapeutic effects of exercise and EE we uncovered do not seem to require one of either the 5-HT1AR or the 5-HTT, although further mechanistic studies are required to substantiate that conclusion. Therefore, the preclinical evidence contained herein adds support for clinically employing analogous environmental manipulations, such as brief durations of cognitive-behavioural therapy and/or exercise regimes, as viable therapeutic alternatives for such patients.