The role of exercise in depression: Preclinical studies in two distinct animal models

Abstract

Depression er en alvorlig og dehabiliterende psykiatrisk lidelse for de involverede, og beklageligvis er livstidsrisikoen op imod de 20 %. Idet depression er en heterogen sygdom, der manifesterer sig på både psykologiske, adfærdsmæssige og fysiologiske niveauer, komplificerer dette behandlingen. Derudover er det ulykkeligvis kun omkring en tredjedel af patienterne der responderer på konventionel medicinsk behandling, hvormed nye behandlingstrategier for behandlingen af depression er ønskværdigt. Motion er en lovende non-farmakologisk strategi, der eventuelt kunne benyttes som et supplement i behandlingen af depression. Formålet med dette studie var at evaluere det antidepressive potentiale af motion i to forskellige rotte-modeller for depression, en genetisk udviklet depressiv rottestamme, Flinder Sensitive Line (FSL) samt deres kontrol, Flinders Resistant Line (FRL) rotter, samt en immunologisk depressionsmodel hvor Sprague-Dawley rotter blev kronisk behandlet med den pro-inflammatoriske agent lipopolysakkaride (LPS) i 8 uger. Behandlingsforløbene bestod enten af fri adgang til et løbehjul eller behandling med et konventionelt antidepressiva, imipramine (15 mg/kg/dag). Depressions- og angst-ligende adfærd blev efterfølgende evalueret i Forced Swim Test og Elevated Plus Maze. Derudover blev der målt på metabolske markører, ekspressionsniveauer af depressions-relaterede proteiner i hjernen og samt niveauet af brain-derived neurotrophic factor (BDNF) i serum. De sidstnævnte parametre blev kun målt hos FSL-rotterne. Overraskende var vores hovedfund i FSL/FRL-modellen, at ved at have rotterne gående enkeltvis i burene, som var krævet for at opnå det nøjagtige aktivitetsniveau i løbehjulene, ændrede rotte-stammernes karakteriske fænotype sig, dvs at forskellen i depressionsadfærd under FST forsvandt mellem kontrolgrupperne. Derudover influerede den individuelle opbevaring af rotterne også metabolske parametrer. Vi observerede ingen antidepressiv effekt af motion hos FSL rotterne, hvilket kunne skyldes det lave aktivitetsniveau i løbehjulene. Behandling med imipramine viste sig også at være ineffektiv i at mindske depressiv-ligende adfærd hos rotterne, hvorimod kombinationen af både motion og imipramine havde en signifikant antidepressiv effekt på FSL rotterne. Dette kunne tyde på, at motion kunne være et nyttigt supplement til den nuværende medicinske behandling af depression. Vores hovedfund fra den LPS-inducerede depressionsmodel var, at modsat en forventet depressiv adfærd, observederede vi i stedet en vedvarende sygdomsadfærd. LPS forøgede immobiliteten i FST, en effekt som kunne reverseret af både behandling med motion og imipramine, hvilket indikerer at disse behandlingsformer kan have modvirket the inflammatoriske respons fra LPS. Et interessant fund var, at sygdomsadfærden ikke påvirkede rotternes aktivitetsniveau i løbehjulene, hvilket kan forklare de gavnlige effekter fra motion i den LPS-inducerede model, modsat FSL/FRL modellen. Alt i alt, indikerer disse resultater, at motion i visse tilfælde kan benyttes som en alternativ behandlingsform eller som supplement i kombination med et tilgængeligt antidepressiva i behandlingen af depression. Dog vil det være nødvendigt med flere bekræftende studier for at støtte denne hypotese.

Depression is a serious and debilitating psychiatric disease for those affected, and it has a startlingly high lifetime occurrence of approximately 20%. The treatment of depression is complicated by the fact that it is a highly heterogeneous disorder that manifests with symptoms at the psychological, behavioral, and physiological levels. In fact, only about a third of patients respond to conventional antidepressant drug therapy, and novel strategies to treat depression are urgently needed. Physical exercise is a promising non-pharmacological strategy that could serve as a supplementing strategy to current antidepressant treatment. The aim of this study was to evaluate the antidepressant potential of exercise in two distinct rat models of depression, namely a genetic developed depressive rat line, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL) rats, and an immunological model in which Sprague Dawley rats were treated chronically (for 8 weeks) with the pro-inflammatory agent lipopolysaccharide (LPS). Rats were either allowed long-term access to a running wheel, or treated with the conventional antidepressant drug imipramine (15 mg/kg/day) or both. Depression- and anxiety-like behaviours were assessed in the forced swim test (FST) and elevated plus maze (EPM), respectively. In addition, several metabolic markers, the mRNA expression of specific proteins suggested to be involved in depression, and the serum concentration of brain-derived neurotrophic factor (BDNF) were measured. The two last-mentioned measurements were only performed in FSL rats. Surprisingly, our main finding from the FSL/FRL model was that the single housing condition, which was required for the accurate measurement of the running activity of each individual rat, changed the characteristic phenotype of these strains in terms of the difference in immobility in the FST, while also influencing certain metabolic markers. We did not find a significant antidepressant-like effect for exercise in FSL rats, although this may be attributed to the low running activity that was observed in these rats. While imipramine alone was also ineffective as an antidepressant in this experiment, the combined exercise-imipramine treatment displayed significant antidepressant-like effects in FSL rats, suggesting that exercise may be a useful adjunct to current antidepressant drug treatment. Our main finding from the LPS-induced model of depression was that, rather than an expected depression-like state, a prolonged sickness behaviour was observed in these rats. LPS increased immobility in the FST, an effect that was reversed by both the exercise and imipramine treatments, and indicates that these treatments may have counteracted the pro-inflammatory action of LPS. Interestingly, the sickness behaviour did not affect the running activity of these rats, which may explain the apparent beneficial effects of exercise in the LPS-induced model versus the FSL/FRL rat model. Overall, these findings suggest that exercise could serve as an alternative therapy on its own, or in combination with current antidepressants in the treatment of depression. However, several confirmatory studies are required in order to support this theory.

A master thesis from Aalborg University

The role of exercise in depression: Preclinical studies in two distinct animal models

[Motions rolle i depression: Prækliniske studier af to særskilte dyremodeller]