Different stress coping strategies of 129Sv and C57/Bl6 mouse strains – evidence from behavioural, pharmacological, metabolomics and gene expression studies
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2022-12-21
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Abstrakt
Prekliinilistes uuringutes on kõige laialdasemalt kasutatavaks mudelorganismiks laborihiir (Mus musculus domesticus). Põhjuseks on asjaolu, et hiired on inimestega geneetiliselt ja bioloogiliselt piisavalt sarnased. Kõige levinumad hiireliinid biomeditsiinilistes uuringutes on C57/Bl6 (Bl6) ja 129Sv. Käesolev doktoritöö annab ülevaate kahe hiireliini – 129Sv ja Bl6 – erinevustest, mis aitab teadlastel paremini valida konkreetse uurimisülesande lahendamiseks vajalikku hiireliini.
Käitumiskatsed näitasid Bl6 hiirte suuremat liikumisaktiivsust. Seejärel vaadeldi ühekordse ja korduva amfetamiini manustamise mõju liikumisaktiivsusele. Amfetamiini rakendatakse prekliinilistes uuringutes psühhootiliste seisundite alusmehhanismide uurimise vahendina. Tulemusena leiti, et Bl6 hiired, kes said amfetamiini ühekordselt, liikusid võrreldes 129Sv hiirtega palju rohkem. Korduv amfetamiini manustamine suurendas liikumisaktiivsust palju enam 129Sv liinis. Tõsi, mitte kõigil 129Sv hiirtel, sest pooltel grupi loomadel jäi läbitud distants samale tasemele ühekordse manustamisega. Ka inimpopulatsioonis ilmneb sarnane mõju erinevus – osal tekib amfetamiini võimsama analoogi metamfetamiini mõjul sõltuvus, teistel aga kujuneb raske psühhoos.
Metaboloomika uuringud näitasid, et Bl6 hiirtel on motoorse testiga kohanemisel eelkõige aktiveerunud suhkrutega seotud metabolismirajad, kuid 129Sv hiirtel domineeris rasvade metabolism.
Arvestades hiirte käitumuslikku reageerimist amfetamiinile ja geeniekspressiooni tulemusi, võib järeldada, et Bl6 hiirte ajustruktuurides on dopaminergilise süsteemi aktiivsus suurem kui 129Sv hiirtel. Valguekspressiooni uuringute põhjal võivad EGF, ERBB1 ja GRIN1 olla need otsmikukoore biomarkerid, mis on seotud parema kohanemisega Bl6 hiirtel.
Kokkuvõttes võib väita, et Bl6 hiireliin näib olevat sobivam uimastisõltuvuse mehhanismide uurimiseks ning 129Sv hiireliin pakub paremaid võimalusi depressiooni- ja psühhoosilaadsete seisundite selgitamiseks.
The most widely used animal model in preclinical studies is the laboratory mouse (Mus musculus domesticus) because they are similar to humans, both genetically and biologically. The most common mouse strains in biomedical applications are C57/Bl6 (Bl6) and 129Sv. The dissertation provides an overview of the differences between the two strains - 129Sv and Bl6 - which would allow researchers to better choose the line required to solve a specific research task. The study showed higher behavioral activity of Bl6 line. Thereafter, the effect of amphetamine on locomotor activity was evaluated. Amphetamine treatment is applied in preclinical settings to investigate the basic mechanisms of psychotic conditions. Bl6 mice receiving acute (one time injection of) amphetamine displayed significantly higher motor activity compared to 129Sv mice. However, repeated administration of amphetamine elevated activity more in the 129Sv line, but not in all animals, as in half of the mice the activity remained the same as in acute administration group. A similar effect is present in human population where methamphetamine causes in some individuals addiction, but others develop psychosis. The metabolomic studies revealed that in adaptation to the environment, Bl6 mice use glucosis-related pathways whereas the 129Sv line tends to favor lipid metabolism. Based on the behavioural response of mice to amphetamine and the gene expression studies, it was concluded that the activity of the dopaminergic system in the brain of Bl6 mice is higher than that of 129Sv mice. Furthermore, studies of protein expression suggested that EGF, ERBB1 and GRIN1 in the frontal cortex may be the biomarkers related with better environmental adaptation. In conclusion, the Bl6 mouse line seems to be more suitable for elucidating the mechanisms of drug dependence, and 129Sv mice offer better opportunities to investigate depression and psychosis-like conditions.
The most widely used animal model in preclinical studies is the laboratory mouse (Mus musculus domesticus) because they are similar to humans, both genetically and biologically. The most common mouse strains in biomedical applications are C57/Bl6 (Bl6) and 129Sv. The dissertation provides an overview of the differences between the two strains - 129Sv and Bl6 - which would allow researchers to better choose the line required to solve a specific research task. The study showed higher behavioral activity of Bl6 line. Thereafter, the effect of amphetamine on locomotor activity was evaluated. Amphetamine treatment is applied in preclinical settings to investigate the basic mechanisms of psychotic conditions. Bl6 mice receiving acute (one time injection of) amphetamine displayed significantly higher motor activity compared to 129Sv mice. However, repeated administration of amphetamine elevated activity more in the 129Sv line, but not in all animals, as in half of the mice the activity remained the same as in acute administration group. A similar effect is present in human population where methamphetamine causes in some individuals addiction, but others develop psychosis. The metabolomic studies revealed that in adaptation to the environment, Bl6 mice use glucosis-related pathways whereas the 129Sv line tends to favor lipid metabolism. Based on the behavioural response of mice to amphetamine and the gene expression studies, it was concluded that the activity of the dopaminergic system in the brain of Bl6 mice is higher than that of 129Sv mice. Furthermore, studies of protein expression suggested that EGF, ERBB1 and GRIN1 in the frontal cortex may be the biomarkers related with better environmental adaptation. In conclusion, the Bl6 mouse line seems to be more suitable for elucidating the mechanisms of drug dependence, and 129Sv mice offer better opportunities to investigate depression and psychosis-like conditions.
Kirjeldus
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Märksõnad
neuropsychiatry, animal experimentation, animal models, laboratory mouse, stress tolerance, metabolomics, gene expression, amphetamine, pharmacological effect, behaviour modifications