Neuropsychopharmacology. 2009 May;34(6):1363-80. Epub 2008 Jun 4.

Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal.

Surget A, Wang Y, Leman S, Ibarguen-Vargas Y, Edgar N, Griebel G, Belzung C, Sibille E.

Source

U930 FRE CNRS 2448, INSERM and Université François Rabelais, Tours, France.

Abstract

Gene microarrays may enable the elucidation of neurobiological changes underlying the pathophysiology and treatment of major depression. However, previous studies of antidepressant treatments were performed in healthy normal rather than 'depressed' animals. Since antidepressants are devoid of mood-changing effects in normal individuals, the clinically relevant rodent transcriptional changes could remain undetected. We investigated antidepressant-related transcriptome changes in a corticolimbic network of mood regulation in the context of the unpredictable chronic mild stress (UCMS), a naturalistic model of depression based on socio-environmental stressors. Mice subjected to a 7-week UCMS displayed a progressive coat state deterioration, reduced weight gain, and increased agonistic and emotion-related behaviors. Chronic administration of an effective (fluoxetine) or putative antidepressant (corticotropin-releasing factor-1 (CRF1) antagonist, SSR125543) reversed all physical and behavioral effects. Changes in gene expression differed among cingulate cortex (CC), amygdala (AMY) and dentate gyrus (DG) and were extensively reversed by both drugs in CC and AMY, and to a lesser extent in DG. Fluoxetine and SSR125543 also induced additional and very similar molecular profiles in UCMS-treated mice, but the effects of the same drug differed considerably between control and UCMS states. These studies established on a large-scale that the molecular impacts of antidepressants are region-specific and state-dependent, revealed common transcriptional changes downstream from different antidepressant treatments and supported CRF1 targeting as an effective therapeutic strategy. Correlations between UCMS, drug treatments, and gene expression suggest distinct AMY neuronal and oligodendrocyte molecular phenotypes as candidate systems for mood regulation and therapeutic interventions.

PMID:: 18536703; [PubMed - indexed for MEDLINE]
PMCID:: PMC2669699

Free PMC Article

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Figure 2

UCMS-induced changes in physical state and behavior are reversed by chronic treatment with fluoxetine or SSR125543. (a) UCMS induced a significant deterioration of the coat state, as demonstrated by increasing coat state scores (see Materials and methods). Drug treatments initiated in the third week of UCMS exposure reversed this deterioration after 2 weeks of SSR125543 treatment and after 4 weeks of fluoxetine treatment (ANOVA: environment, week 1, F_1,104=9.34, P<0.01; weeks 2–7 F_1,104>35.06, P<0.001; treatment, week 4, F_2,104=6.39, P<0.01, weeks 5–7, F_2,104>15.8, P<0.001; environment × treatment: weeks 4–7, F_2,104>6.39, P<0.01). (b) UCMS significantly disrupted the normal gain in body weight, starting at the fifth week of UCMS regimen. The progressive reversal of UCMS effect on weight gain by fluoxetine and SSR125543 exposure became significant in the last week of UCMS (ANOVA: environment, weeks 4–7, F_1,104>10, P<0.001; treatment, week 7, F_2,104=5.34, P<0.01). n=18–19 mice per group. Post hoc Tukey test: ^#P<0.05 and ^###P<0.001 for UCMS/vehicle mice vs control/vehicle mice; *P<0.05, **P<0.01 and ***P<0.001 for UCMS/treated group vs UCMS/vehicle group. (c) The latency to begin eating in the NSF test was increased by UCMS. This effect was reversed by both fluoxetine and SSR125543 treatments (ANOVA: environment, F_1,65=5.79, P<0.05; treatment, F_2,65=8.49, P<0.001; environment × treatment, F_2,65=3.89, P<0.05). (d) UCMS induced a significant decrease in the latency to attack the intruder in the R/I test, while both fluoxetine and SSR125543 treatment reversed this effect. (ANOVA: environment × treatment, F_2,65=4.75, P<0.05). n=11–12 mice per group. Post hoc Tukey test: ^##P<0.01 for UCMS/vehicle mice vs control/vehicle mice; *^P<0.05, **P<0.01 and ***P<0.001 for UCMS/drug-treated group vs UCMS/vehicle group. Data represent mean±SEM.

Corticolimbic Transcriptome Changes are State-Dependent and Region-Specific in a Rodent Model of Depression and of Antidepressant Reversal

Neuropsychopharmacology. Neuropsychopharmacology;34(6):1363-1380.