Characterization of mouse stress models on allostatic overload of the HPA axis and depressive-like behavior
Author
Pretzmann, Freja
Term
4. term
Publication year
2021
Abstract
Depression er udbredt og vanskelig at behandle, hvilket understreger behovet for robuste dyremodeller til at undersøge sygdommens mekanismer. Denne afhandling undersøger, om tre stressparadigmer i hanmus kan fremkalde allostatisk overbelastning af HPA-aksen og en depressiv-lignende fænotype. Der blev anvendt et kronisk stress (CS) paradigme baseret på kronisk mild stress kombineret med jetlag, et 14-dages gentaget fikseringsstress (RRS14) og et afbrudt RRS (iRRS) med cyklusser af 3 dages stress og 48 timers hvile over 20 dage. Efter stress blev adfærd undersøgt med Elevated Plus Maze, diurnal og akut lokomotorisk aktivitet, gravning og redebygning, mens biologiske mål omfattede basale og akutte corticosteronniveauer samt genudtryk i hjernen (bl.a. ur- og inflammationsgener) ved RT-PCR og ELISA. CS og iRRS øgede signifikant basal corticosteron, mens RRS14 gav en akut stigning under fiksering. CS ændrede motiveret adfærd og søvnrytme med vedvarende diurnal forstyrrelse og opregulering af ur-gener i hjernen. CS og RRS14 tenderede til øget lokomotorisk aktivitet, mens iRRS reducerede den. Desuden var Il-1β opreguleret akut i RRS14 og 48 timer efter sidste stress i iRRS, hvilket peger på neuroinflammation. Samlet set tyder resultaterne på, at CS og iRRS inducerer allostatisk overbelastning af HPA-aksen, at CS fremkalder en depressiv-lignende fænotype og forstyrrer døgnrytmen, og at begge RRS-paradigmer udløser neuroinflammation.
Depression is common and difficult to treat, highlighting the need for robust animal models to probe underlying mechanisms. This thesis evaluates whether three stress paradigms in male mice can induce allostatic overload of the HPA axis and a depressive-like phenotype. The paradigms included a chronic stress (CS) model based on chronic mild stress combined with jetlag, a 14-day repeated restraint stress (RRS14), and an interrupted RRS (iRRS) with cycles of 3 days of stress and 48 hours of rest over 20 days. Post-stress assessments comprised the Elevated Plus Maze, diurnal and acute locomotor activity, burrowing, and nest building, alongside biological measures of basal and acute corticosterone and brain gene expression (including clock and inflammatory genes) using RT-PCR and ELISA. CS and iRRS significantly increased basal corticosterone, whereas RRS14 produced an acute rise during restraint. CS altered motivated behavior and sleep rhythm, showing persistent diurnal disruption and upregulation of clock genes in the brain. CS and RRS14 tended to increase locomotor activity, while iRRS decreased it. Il-1β was upregulated acutely in RRS14 and 48 hours after the last stress in iRRS, indicating neuroinflammation. Overall, the findings suggest that CS and iRRS induce allostatic overload of the HPA axis, CS elicits a depressive-like phenotype and circadian disruption, and both RRS paradigms trigger neuroinflammation.
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