Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal.
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.
Surget
Alexandre
A
U930 FRE CNRS 2448, INSERM and Université François Rabelais, Tours, France.
Wang
Yingjie
Y
Leman
Samuel
S
Ibarguen-Vargas
Yadira
Y
Edgar
Nicole
N
Griebel
Guy
G
Belzung
Catherine
C
Sibille
Etienne
E
D000339:Affect / Q000187:drug effects / Q000502:physiology; D000378:Agonistic Behavior / Q000187:drug effects / Q000502:physiology; D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020869:Gene Expression Profiling; D006179:Gyrus Cinguli / Q000187:drug effects / Q000503:physiopathology; D006846:Hydrocarbons, Halogenated / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology; D013843:Thiazines / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
D000928:Antidepressive Agents; D006846:Hydrocarbons, Halogenated; C502407:SSR125543; D013843:Thiazines; D005473:Fluoxetine; D003346:Corticotropin-Releasing Hormone