Cerebral oxidative metabolism and effects of chronic variable stress in animal models of human affective styles
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2010-10-12
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Käesolevas väitekirjas vaadeldakse kaht püsivatel käitumuslikel fenotüüpidel põhinevat ja üht geneetilist loomkatsemudelit, mis on mõeldud afektiivsete protsesside kaudu haavatavamate katseloomade väljavalimiseks või tekitamiseks. Emotsionaalselt haavatavamad loomad võimaldavad valiidsemalt reprodutseerida inimese depressioonilaadset seisundit. Esimene kahel polaarsel käitumisfenotüübil põhinev loomkatsemudel on uudiskastis vähe- ja palju-uudistavad rotid ja teine on eksperimentaatori-poolse manuaalse stimulatsiooni ehk kõdistamise poolt esilekutsutud 50-kHz sagedusel esitatud ultrahelihäälitsuste hulga põhjal eristatud vähe ja palju 50-kHz sagedusel häälitsevad rotid. Kolmadaks mudeliks oli heterosügootne hiire nokautmudel, kus hiirel oli välja lülitatud vesikulaarse glutamaadi transporteri 1 (VGLUT1) geeni üks kahest alleelist. Selline manipulatsioon suurendab glutamaadi/gamma-aminovõihappe suhet kesknärvisüsteemis ja sellist endofenotüüpi on leitud ka meeleoluhäretega inimestel. Kõigis kolmes mudelis rakendati loomadele kroonilist muutlikku stressi depressiooni-laadse afektiivse seisundi esilekutsumiseks ning mõõdeti oksüdatiivset ajumetabolismi tsütokroom c oksüdaasi histokeemia abil. Vähe 50-kHz-häälitsevad isasrotid osutusid läbitestitud käitumuslikest fenotüüpidest stressi poolt enim haavatavateks. Kroonilise muutliku stressi tagajärjel arenes neil anhedoonia ning nad eelistasid passiivseid toimetulekustrateegiaid, lisaks esines neil rohkem stressijärgseid ajumetabolismi regionaalseid muutusi. Väheuudistavad rotid olid teiseks käitumuslikuks fenotüübiks, kellel esinesid mõned paljulubavad stressijärgsed käitumise muutused, kuid mitte nii selgelt, nagu vähe 50-kHz-häälitsevatel isastel. VGLUT1 geeni osalise nokaudiga hiirtel suurenes samuti anhedoonia kroonilise muutliku stressi tagajärjel ning mitmes käitumiskatses paistsid nad abitumad kui geneetiliselt muundamata hiired. Emaste rottide kroonilise muutliku stressi taluvusvõime oli käitumiskatsetes suurem võrreldes isastega ning neil esines ka vähem stressijärgseid ajumetabolismi regionaalseid
Two animal models of affective vulnerability based on the selection for stable behavioural phenotypes and one based on the genetic manipulation are discussed in the thesis. Use of animals exhibiting affective vulnerability adds validity to models of human mood disorders. The first animal model was based on the selection in the exploratory box test for rats with low and high exploratory phenotype. In the second animal model, the selection for opposing behavioural phenotypes was based on the number 50-kHz ultrasonic vocalisations (USVs) emitted upon manual playful stimulation of a juvenile rat by experimenter or 'tickling'. Heterozygous knockout of the vesicular glutamate transporter 1 (VGLUT1) in mice was the third animal model, in which one of VGLUT1 gene alleles was inactivated. Partial VGLUT1 gene inactivation increases glutamate to GABA ratio in the central nervous system - an endophenotype of human mood disorders observed in some clinical samples. In all three models, a chronic variable stress (CVS) was employed to elicit depressive-like state in the experimental subjects, and their cerebral oxidative metabolism was measured via cytochrome c oxidase histochemistry - a biomarker for long-term neuronal energy demand. From the presented behavioural phenotypes, low 50-kHz USV emitting male rats seem to be the most vulnerable to stressful stimulation. They co-express symptoms of anhedonia and passive coping strategies and show discrete changes in cerebral oxidative metabolism. Low exploratory (LE) male rats is another behavioural phenotype that showed some promising stress-associated changes in behaviour, however, behavioural profile of LE-rats is more ambiguous, and there was no unique changes in brain metabolic activity to CVS regimen. Female rats demonstrated a better stress-tolerance and had fewer CVS-associated changes in cytochrome c oxidase activity than male rats.
Two animal models of affective vulnerability based on the selection for stable behavioural phenotypes and one based on the genetic manipulation are discussed in the thesis. Use of animals exhibiting affective vulnerability adds validity to models of human mood disorders. The first animal model was based on the selection in the exploratory box test for rats with low and high exploratory phenotype. In the second animal model, the selection for opposing behavioural phenotypes was based on the number 50-kHz ultrasonic vocalisations (USVs) emitted upon manual playful stimulation of a juvenile rat by experimenter or 'tickling'. Heterozygous knockout of the vesicular glutamate transporter 1 (VGLUT1) in mice was the third animal model, in which one of VGLUT1 gene alleles was inactivated. Partial VGLUT1 gene inactivation increases glutamate to GABA ratio in the central nervous system - an endophenotype of human mood disorders observed in some clinical samples. In all three models, a chronic variable stress (CVS) was employed to elicit depressive-like state in the experimental subjects, and their cerebral oxidative metabolism was measured via cytochrome c oxidase histochemistry - a biomarker for long-term neuronal energy demand. From the presented behavioural phenotypes, low 50-kHz USV emitting male rats seem to be the most vulnerable to stressful stimulation. They co-express symptoms of anhedonia and passive coping strategies and show discrete changes in cerebral oxidative metabolism. Low exploratory (LE) male rats is another behavioural phenotype that showed some promising stress-associated changes in behaviour, however, behavioural profile of LE-rats is more ambiguous, and there was no unique changes in brain metabolic activity to CVS regimen. Female rats demonstrated a better stress-tolerance and had fewer CVS-associated changes in cytochrome c oxidase activity than male rats.
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