miRNA Profiling of the Lateral Habenula in the Chronic Mild Stress Model of Depression

miRNA profilering af den laterale habenula i kronisk mild stress modellen for depression

Jensen, Line

4. term

Medicine with Industrial Specialisation, Master

2012

2012-06-01

54

Depression er en af de største årsager til invaliditet globalt og medfører en øget dødelighed, især på grund af selvmord. Sygdommen er kompleks og involverer flere hjernemekanismer. Selvom behandlingen er forbedret markant de seneste årtier, responderer op til 40 % ikke på førstevalgsbehandling. Årsagen til depression er stadig uklar, men nye fund tyder på, at udtrykket af mikroRNA (miRNA) – små molekyler, der styrer genaktivitet – ændres ved stress i hjernen hos dyr med depressionslignende adfærd og i hjerner fra afdøde patienter med depression. Det peger på, at ændrede miRNA-niveauer kan bidrage til sygdommens udvikling. Ud over den ofte studerede hippocampus har tidligere studier vist øget aktivitet i den laterale habenula (LHb), et lille hjerneområde der påvirker hjernens monoaminerge systemer (som serotonin og dopamin), hos deprimerede patienter og i dyremodeller. Hæmning af LHb kan give antidepressive effekter, og LHb-overaktivitet er forbundet med hæmning af netsystemer, som typisk er nedsat ved depression. Dette peger på en mulig rolle for LHb i udviklingen af egentlig depression (MDD). Formålet med denne undersøgelse var at afklare LHb’s rolle i udvikling og behandling af MDD på miRNA-niveau for at identificere nye sygdomsmål og behandlingsstrategier. Vi søgte samtidig biomarkører for behandlingsresistens og stress-robusthed. Vi brugte den velvaliderede Chronic Mild Stress (CMS)-rottemodel, som fremkalder depressive-lignende adfærd, stress-robusthed og lægemiddelrespons (efter kronisk behandling med escitalopram, et almindeligt antidepressiv). LHb blev isoleret præcist med laser-capture-mikrodissektion, og omfattende miRNA-profiler blev målt med TaqMan Low Density Arrays. Baseret på foruddefinerede udtryksmønstre relateret til depression var miR-130b, miR-205, miR-327, miR-331-5p og miR-336 forbundet med sygdomsdebut og/eller bedring, miR-546 med behandlingsresistens, og miR-331-5p samt miR-409 med stress-robusthed. Da miR-331-5p indgår i både bedring og robusthed, tyder resultaterne på, at dets niveau kan være vigtigt for at bevare en sund tilstand hos rotter udsat for CMS. Det er vanskeligt ud fra disse data at fastslå LHb’s præcise rolle i depression, men flere forudsagte mRNA-mål (identificeret med TargetScan version 6.1) indgår i processer allerede koblet til depression, herunder neuronal plasticitet, neurogenese, synaptisk frigivelse og demethylering (kemiske ændringer, der påvirker genaktivitet). Samlet peger resultaterne på en involvering af LHb i depression, men yderligere studier er nødvendige for at afklare mekanismerne.

Depression is a leading cause of disability worldwide and increases mortality, especially due to suicide. It is a complex disorder involving multiple brain mechanisms. Although treatments have improved over the past decades, up to 40% of patients do not respond to first-line therapy. The causes of depression remain unclear, but emerging evidence shows that microRNAs (miRNAs)—small molecules that help control gene activity—change with stress in the brains of animals with depression-like behavior and in post-mortem brains of depressed patients. This suggests that altered miRNA levels may contribute to the disorder. Beyond the often-studied hippocampus, prior work has found increased activity in the lateral habenula (LHb), a small brain region that influences the brain’s monoamine systems (such as serotonin and dopamine), in depressed patients and animal models. Inhibiting the LHb can produce antidepressant effects, and LHb hyperactivity is linked to inhibition of these systems, a pattern seen in depression. This points to a role for the LHb in major depressive disorder (MDD). Our aim was to examine the LHb’s role in the development and treatment of MDD at the miRNA level to identify new disease targets and treatment strategies, and to search for biomarkers of treatment resistance and stress resilience. We used the well-validated Chronic Mild Stress (CMS) rat model, which produces depression-like behavior, stress resilience, and drug response (after chronic treatment with escitalopram, a common antidepressant). We precisely isolated the LHb using laser capture microdissection and performed large-scale miRNA profiling with TaqMan Low Density Arrays. Based on predefined expression patterns relevant to depression, miR-130b, miR-205, miR-327, miR-331-5p, and miR-336 were associated with the onset and/or recovery from depression; miR-546 was implicated in treatment resistance; and miR-331-5p and miR-409 were linked to stress resilience. Because miR-331-5p is involved in both recovery and resilience, its level may be important for maintaining a healthy state in rats exposed to CMS. It remains difficult to define the LHb’s exact role in depression-related behavior. However, several predicted mRNA targets (identified with TargetScan version 6.1) participate in processes already associated with depression, including neuronal plasticity, neurogenesis, synaptic release, and demethylation (chemical changes that affect gene activity). Together, these findings support an involvement of the LHb in depression, while underscoring the need for further research to clarify the mechanisms.

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