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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/3188 |
| Date | 03 1900 |
| Creators | Marais, Lelanie |
| Contributors | Daniels, W. M. U., Stein, D. J, Janse van Rensburg, S., University of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. Medical Physiology. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | Unknown |
| Type | Thesis |
| Rights | University of Stellenbosch |
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