title: Chronic mild stress and imipramine treatment elicit opposite changes in behavior and in gene expression in the mouse prefrontal cortex.
abstract: Many studies suggest that the prefrontal cortex (PFC) is a target limbic region for stress response because a dysfunction here is linked to anhedonia, a decrease in reactivity to rewards, and to anxiety. It is suggested that stress-induced persistent molecular changes in this brain region could bring some light on the mechanisms perpetuating depressive episodes. In order to address this issue, here we have studied the long-term PFC gene expression pattern and behavioral effects induced by a chronic mild stress (CMS) model and antidepressant treatment in mice. CMS was applied to mice for six weeks and imipramine (10mg/kg, i.p.) or saline treatment was administered for five weeks starting from the third week of CMS. Mice were sacrificed one month after CMS and following two weeks after the discontinuation of drug treatment and the PFC was dissected and prepared for gene (mRNA) and protein expression studies. Using the same experimental design, a separate group of mice was tested for anhedonia, recognition memory, social interaction and anxiety. CMS induced a long-term altered gene expression profile in the PFC that was partially reverted by imipramine. Specifically, the circadian rhythm signaling pathway and functions such as gene expression, cell proliferation, survival and apoptosis as well as neurological and psychiatric disorders were affected. Of these, some changes of the circadian rhythm pathway (Hdac5, Per1, and Per2) were validated by RT-PCR and western-blot. Moreover, CMS induced long-lasting anhedonia that was reverted by imipramine treatment. Impaired memory, decreased social interaction and anxiety behavior were also induced by chronic stress. We have identified in the PFC molecular targets oppositely regulated by CMS and imipramine that could be relevant for chronic depression and antidepressant action. Among these, a possible candidate for further investigation could be the circadian rhythm pathway.
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Erburu
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Cajaleon
authors.affiliation: Bioinformatics Unit, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Guruceaga
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Venzala
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Muñoz-Cobo
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Beltrán
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Puerta
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. Electronic address: rtordera@unav.es.
authors.forename: R M
authors.initials: RM
authors.lastname: Tordera
mesh_terms: D059445:Anhedonia / Q000187:drug effects; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D007099:Imipramine / Q000494:pharmacology*; D007398:Interpersonal Relations; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D013315:Stress, Psychological / Q000235:genetics* / Q000523:psychology*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D012333:RNA, Messenger; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D007099:Imipramine
keywords: Anhedonia; Chronic mild stress; Circadian rhythm; Depression; Hdac5; Imipramine; Microarray; Prefrontal cortex