ReviewHow the enriched get richer? Experience-dependent modulation of microRNAs and the therapeutic effects of environmental enrichment
Introduction
Stimulating environments, those rich in opportunities for cognitive, social and physical engagement, are well known to be of benefit in delaying the onset and slowing the progression of psychiatric and neurodegenerative disorders (Burrows and Hannan, 2016; Hannan, 2014; Rogers et al., 2019; Tillerson et al., 2003; Van Dellen et al., 2000). While the exact biochemical mechanisms underlying these effects remain poorly understood, animal studies have revealed that modified housing conditions can have long-lasting effects on many biological processes, including neuroplasticity (Kempermann, 2019; Pedersen and Hoffman-Goetz, 2000; Vivar et al., 2013), the stress response (via the hypothalamic-pituitary-adrenal (HPA) axis) (Pang et al., 2019; Shilpa et al., 2017; Wassouf and Schulze-Hentrich, 2019) and the immune system (Scarola et al., 2019; Svensson et al., 2015). In recent years, scientists have begun to investigate the connection between stimulating environments, voluntary physical activity (exercise) and the regulation of gene expression in both the brain and peripheral systems. In particular, research has highlighted the important role of experience-dependent modulations to microRNAs (miRNAs) in these effects. miRNAs, as will be discussed in detail below, constitute a substantial class of small non-coding RNAs that are heavily involved in the regulation of gene expression at the post-transcriptional level.
Notably, changes in blood miRNA concentrations have the potential to provide biomarkers at early disease stages, even prior to the onset of symptoms (Arshad et al., 2017; Atif and Hicks, 2019; Backes et al., 2016). Accordingly, miRNAs—which are precisely regulated to exhibit network, site and cell-type-specific expression—have the potential to become therapeutic targets used in the personalised treatment of neurological and psychiatric disorders (Avci and Baran, 2014; S. W. L. Lee et al., 2019). This review will explore the established preclinical rodent literature that has investigated the effects of enriched environments on miRNAs, in both healthy controls and in animal models of relevance to the study of human brain dysfunction.
Section snippets
Environmental enrichment and physical exercise
In early works, environmental enrichment (EE) in rodents was achieved by providing animals with a ‘combination of [complex] inanimate and social stimulation’ (Rosenzweig et al., 1978, p. 564). This description was subsequently expanded, and now EE may be thought of as any enhancement to animal welfare through the provision of sensory and/or motor stimulation. This can be accomplished through the introduction of novel stimuli and resources that promote cognitive engagement and facilitate innate
microRNAs: discovery, biogenesis and function
microRNAs (miRNAs or miRs) constitute a class of small non-coding RNAs (sncRNAs), approximately 22 nucleotides in length, that regulate post-transcriptional gene expression in multi-cellular animals, protozoa and flora (Fabian et al., 2010). They were discovered in 1993, by a group studying developmental gene expression of the Caenorhabditis elegans (roundworm). Although likely unaware of the magnitude of their discovery, these researchers noted the presence of a small untranslated RNA species,
Experience-dependent modulation of miRNA expression in healthy controls
An active lifestyle has a multitude of well-documented benefits to physical health, emotional well-being and the body's biochemical composition, including modulations of key miRNAs. For example, a recent study found miRNAs in the nucleus accumbens to be differentially expressed when comparing high- vs low-activity inbred mice under standard housing conditions. RT-qPCR validation of these results showed a downregulation of miR-466d-3p and an upregulation of miR-342-5p in high-activity mice (
Mood and anxiety disorders
Affective disorders are highly prevalent, with major depressive disorder (MDD, depression) a significant contributor to the global burden of disease and a leading cause of human disability. Indeed, more than 300 million people of all ages suffered from depression worldwide at the time of writing (World Health Organization, 2019). Exercise is known to have beneficial effects on depressive- and anxiety-like behaviours through various biological means (including a modulation of neurogenesis,
General comments and concluding remarks
Exercise and enriched environments provide an exciting and often readily accessible therapy for neurological and psychiatric disorders. A deepened understanding of experience-dependent molecular and cellular adaptations has evolved dramatically in recent years with the emergence of next-generation sequencing technology. ‘Big data’ bioinformatic approaches have given rise to transformative transcriptomic insights that have opened new avenues to understanding disease pathology and treatment
Declaration of competing interest
The authors have no conflict of interest to report.
Acknowledgements
This work was supported by an ARC Discovery Early Career Research Award (TR). AJH is an NHMRC Principal Research Fellow. The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government's Operational Infrastructure Support Grant.
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Contributed equally (joint first author).