EFFECTS OF EXERCISE ON MITOCHONDRIAL FUNCTION, NEUROPLASTICITY AND ANXIO-DEPRESSIVE BEHAVIOR OF MICE A. S. AGUIAR, Jr a,b * E. STRAGIER, c,d D. DA LUZ SCHEFFER, a A. P. REMOR, a P. A. OLIVEIRA, b R. D. PREDIGER, b A. LATINI, a R. RAISMAN-VOZARI, d,e R. MONGEAU c,d AND L. LANFUMEY c,d a Departamento de Bioquı´mica, Universidade Federal de Santa Catarina, UFSC, Centro de Cie ˆncias Biolo ´gicas, CCB, Floriano ´polis, SC 88049-900, Brazil b Departamento de Farmacologia, Universidade Federal de Santa Catarina, UFSC, Centro de Cie ˆncias Biolo ´gicas, CCB, Floriano ´polis, SC 88049-900, Brazil c INSERM UMR 894, Centre de Psychiatrie et Neurosciences, CPN, Paris 75634, France d Universite ´ Pierre et Marie Curie, UPMC, Site Pitie ´-Salpe ˆtrie `re, Paris 75634, France e INSERM UMR 975, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinie `re, CRICM, Paris 75634, France Abstract—The present study was aimed at analyzing the effects of physical exercise on mitochondrial physiology, anxio-depressive-like behaviors and neuroplasticity in mice. Adult C57BL/6J male mice were isolated in home cages equipped or not with free-running wheels. After 6 weeks of exercise, mice were tested in various behavioral paradigms to evaluate anxiety- and depressive-like behaviors. The hippocampi were dissected for neurochemical assays, including mitochondrial activity, monoamines content and the expression of genes involved in energy metabolism and brain-derived neurotrophic factor (BDNF) regulation. Exercise decreased anxiety-like behaviors in the open field and elevated plus maze, and exerted antidepressant-like effects in the tail suspension test. Exercise stimulated brain mitochondrial activity and increased resistance against rotenone, an inhibitor of complex I activity. Furthermore, mRNA expression of Bdnf, Gdnf, Tfam (mitochondrial tran- scription factor A), and Ndufa6 (mitochondrial I subunit) genes, as well as the phosphorylation of cAMP response element-binding protein were increased after exercise. In summary, exercise appears to engage mitochondrial pathways and to potentiate neuroplasticity and might be associated to mood improvement. Ó 2014 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: depression, epigenetic, hippocampus, mitochondria, mood, neurotrophin. INTRODUCTION Although studies on the pathophysiological mechanisms of depression and anxiety have given birth to several hypothesizes, the etiology of those diseases remains mostly unknown. New evidence suggests the impairment of mitochondrial plasticity as one potential mechanism (Moretti et al., 2003; Rezin et al., 2008; Scaini et al., 2010). Indeed, it has been demonstrated that brain cortical inhibition of mitochondrial complexes I, III and IV activities occurs in mice under chronic stress, and this can be recovered following antidepressant treatments (El Idrissi and Trenkner, 1999; Markham et al., 2004). In humans, post-mortem downregulation of mitochondrial complex I subunits was observed in the brain of patients with major depression (Ben-Shachar and Karry, 2008). These dysregulated mitochondrial pathways might result in less efficient mitochondrial activity and compromised ATP synthesis, which can increase neuronal vulner- ability to neurobehavioral changes, including mood disorders. Depression is characterized by a broad range of dysregulations including those impacting the monoamine systems, mostly serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) neurotransmission, in addition to those impacting the activity of hypothalamus–pituitary adrenal (HPA) axis (Lanfumey et al., 2008). More recently, hypotheses pointing out the role of brain neuroplasticity and epigenetic regulations in depression have also been recently proposed (Krishnan and Nestler, 2008; Massart et al., 2012). The neurotrophin hypothesis of depression was supported by evidence showing decreased brain- derived neurotrophic factor (BDNF) mRNA levels, in the hippocampus and the frontal cortex in severely depressed patients (Shimizu et al., 2003; Knable et al., 2004). In turn, antidepressant treatments such as selective serotonin reuptake inhibitors (SSRI) and electroconvulsive therapy, as well as physical exercise (Duman, 1998; Laske et al., 2010), have consistently been reported to enhance the expression of neuroplasticity factors and to improve mood. http://dx.doi.org/10.1016/j.neuroscience.2014.04.027 0306-4522/Ó 2014 IBRO. Published by Elsevier Ltd. All rights reserved. * Corresponding author. Address: Universidade Federal de Santa Catarina, Rod Gov Jorge Lacerda, n° 3201, Ararangua´, SC 88906- 072, Brazil. Tel: +55-48-3721-6250. E-mail addresses: aderbalaguiar@gmail.com, aderbal.aguiar@ufsc. br (A. S. Aguiar Jr). Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; BDNF, brain-derived neurotrophic factor; BSA, bovine serum albumin; CREB, cAMP response element-binding protein; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; DHPG, dihydroxyphenylglycol; EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene glycol tetraacetic acid; EPM, elevated plus maze; HVA, homovanillic acid; MeCP2, methyl-CpG-binding protein 2; NA, noradrenaline; NADH, nicotinamide adenine dinucleotide; PCR, polymerase chain reaction; PMSF, phenylmethanesulfonylfluoride; SSRI, selective serotonin reuptake inhibitors; TBS, Tris-buffered saline; UCP2, uncoupling protein 2. Neuroscience 271 (2014) 56–63 56