The potential of exercise to reverse stress induced abnormalities in the rat brain

Thesis (PhD (Biomedical Sciences. Medical Physiology.))--University of Stellenbosch, 2010.ENGLISH ABSTRACT: Adverse experiences during early life causes alterations in the development of the central nervous system structures that may result in abnormal functioning of the brain. It is well known that, in humans, adverse early-life experiences such as social separation, deprivation, maternal neglect and abuse increase the risk of developing psychiatric disorders, such as depression, later in life. We used maternal separation in the rat as a model for early life stress to firstly determine how different brain systems are dysregulated by this stressful experience and additional chronic or acute stress during adulthood. Rat pups were separated from their mothers on postnatal day 2-14 for 3 hours per day while control rats were normally reared. The behavior, stress response, neurotrophin, apoptotic marker and serotonin levels in the ventral hippocampus, striatum and frontal cortex were measured during adulthood. A different group of maternally separated rats were allowed chronic voluntary exercise and similar measurements were done to determine whether exercise was able to normalize the deficits caused by early life stress. Differentially expressed cytosolic proteins of the ventral hippocampus of maternally separated rats versus normally reared rats were also identified. Protein expression levels of maternally separated rats that received chronic voluntary exercise or escitalopram treatment were subsequently determined to unravel the mechanism of therapeutic action for these two interventions. We found that maternal separation increased the baseline corticosterone response of rats and induced a blunted adrenocorticotropin hormone after acute restraint stress. Baseline neurotrophin levels were significantly decreased in the ventral hippocampus. Maternal separation followed by chronic restraint stress during adulthood resulted in increased depressive-like behavior compared to control rats. Maternal separation alone or followed by acute restraint stress during adulthood induced changes in apoptotic marker expression in the striatum and frontal cortex. In rats subjected to maternal separation and chronic restraint stress during adulthood, we found that chronic voluntary exercise decreased their depressive-like behavior and increased brain derived neurotrophin levels in the striatum. Serotonin levels were not affected by maternal separation, but chronic voluntary exercise increased serotonin in the ventral hippocampus of normally reared rats. Maternal separation induced a number of changes in the expression of cytosolic proteins and these stress-induced changes were identified in proteins relating to cytoskeletal structure, neuroplasticity, oxidative stress, energy metabolism, protein metabolism, and cell signaling. Chronic voluntary exercise was able to restore the expression levels of a number of proteins affected by maternal separation that increased the risk for neuronal death. When comparing the efficacy of exercise to that of escitalopram treatment it was evident that, in contrast to exercise, escitalopram targets a different subset of proteins affected by maternal separation, except for a few involved in energy metabolism pathways and neuroprotection. In this study we have shown that chronic voluntary exercise has therapeutic effects in maternally separated rats, decreasing depressive-like behavior, increasing neurotrophin expression and restoring cytosolic protein expression that were dysregulated by early life stress.AFRIKAANSE OPSOMMING: Negatiewe stresvolle ervarings gedurende die vroeë stadium van ‘n mens se lewe veroorsaak veranderinge in die ontwikkeling van breinstrukture en het ‘n nadelige uitwerking op die funksionering van die brein. Dit is bekend dat stresvolle ervarings in kinders, byvoorbeeld sosiale afsondering, verwaarlosing en mishandeling, die risiko vir die ontwikkeling van psigiatriese steurings soos depressie gedurende volwassenheid kan verhoog. In hierdie studie gebruik ons moederlike skeiding van neonatale rotte as ‘n model vir vroeë lewensstres om te bepaal hoe dit verskillende sisteme in die brein negatief beinvloed, en dan ook die effek van addisionele kroniese of akute stres gedurende volwassenheid. Die neonatale rotte is weggeneem van hulle moeders af vanaf dag 2 tot 14 vir 3 ure elke dag terwyl kontrole rotte by hulle moeders gebly het. Die gedrag, stres respons, neurotrofiene, apoptotiese merkers en serotonien vlakke is gemeet in die ventrale hippokampus, frontale korteks en striatum gedurende volwassenheid. Rotte wat van hulle moeders geskei is, is dan toegelaat om vir ses weke in wiele te hardloop om te bepaal of kroniese vrywillige oefening die negatiewe effekte wat veroorsaak is deur stres kan ophef. ‘n Bepaling van sitosoliese proteien uitdrukking in die ventrale hippokampus is ook gedoen om die uitwerking van moederlike skeiding op proteienvlak vas te stel. Hierdie protein data is dan vergelyk met die van gestresde rotte wat kroniese oefening of escitalopram behandeling ontvang het om die meganisme van werking van beide behandelings te bepaal. Ons het gevind dat moederlike skeiding die rustende kortikosteroon vlakke van rotte verhoog terwyl dit adrenokortikotropien vlakke na akute stres inhibeer. Moederlike skeiding het ook die neurotrofien vlakke in die ventrale hippokampus verlaag en addisionele kroniese stres gedurende volwassenheid het ‘n verhoging in depressie-agtige gedrag veroorsaak. Moederlike skeiding alleen, sowel as gevolg deur akute stress gedurende volwassenheid het ook veranderinge in die uitdrukking van apoptotiese merkers in die striatum en frontale korteks veroorsaak. Kroniese vrywillige oefening na moederlike skeiding en addisionele stres gedurende volwassenheid kon depressie-agtige gedrag verlaag en neurotrofienvlakke in die striatum verhoog. Serotonien vlakke was nie beinvloed deur moederlike skeiding nie, maar oefening in kontrole rotte het serotonien verhoog in die ventrale hippokampus. Moederlike skeiding het heelwat veranderinge in die uitdrukking van sitosoliese proteiene van die ventrale hippokampus veroorsaak wat ingedeel kan word in die volgende funksionele kategorieë: sitoskelet, neuroplastisiteit, oksidatiewe stres, energiemetabolisme, proteinmetabolisme en seintransduksie. Oefening kon die uitdrukking van verskeie stres-geïnduseerde veranderinge in proteiene weer herstel terwyl dit wou bleik asof escitalopram se meganisme van werking op ‘n ander vlak geskied. Ons bevindinge bewys dat kroniese vrywillige oefening ‘n goeie behandeling is na vroeë lewenstres en dat dit depressiewe gedrag verminder, neurotrofien vlakke verhoog en sitosoliese proteien skeiding alleen, sowel as gevolg deur akute stress gedurende volwassenheid het ook veranderinge in die uitdrukking van apoptotiese merkers in die striatum en frontale korteks veroorsaak. Kroniese vrywillige oefening na moederlike skeiding en addisionele stres gedurende volwassenheid kon depressie-agtige gedrag verlaag en neurotrofienvlakke in die striatum verhoog. Serotonien vlakke was nie beinvloed deur moederlike skeiding nie, maar oefening in kontrole rotte het serotonien verhoog in die ventrale hippokampus. Moederlike skeiding het heelwat veranderinge in die uitdrukking van sitosoliese proteiene van die ventrale hippokampus veroorsaak wat ingedeel kan word in die volgende funksionele kategorieë: sitoskelet, neuroplastisiteit, oksidatiewe stres, energiemetabolisme, proteinmetabolisme en seintransduksie. Oefening kon die uitdrukking van verskeie stres-geïnduseerde veranderinge in proteiene weer herstel terwyl dit wou bleik asof escitalopram se meganisme van werking op ‘n ander vlak geskied. Ons bevindinge bewys dat kroniese vrywillige oefening ‘n goeie behandeling is na vroeë lewenstres en dat dit depressiewe gedrag verminder, neurotrofien vlakke verhoog en sitosoliese proteien vlakke kan herstel