Hippocampal Cytogenesis Correlates to Escitalopram-Mediated Recovery in a Chronic Mild Stress Rat Model of Depression

Abstract

From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/ day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.

Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance

“…When we analyze all defeated mice in this study, regardless of susceptibility to stress, there is no difference in BrdU-IR cell survival postdefeat. The lack of decrease in neurogenesis poststress between stressed and control mice is consistent with no change in cell survival 1 day after chronic unpredictable stress in rats (21) and the normal granule cell layer volume reported in many stress studies (23)(24)(25). However, by analyzing the susceptibility to stress through behavioral outcomes, we have uncovered a striking significant increase in surviving BrdU-IR cells in mice specifically susceptible to stress.…”

Involvement of norepinephrine and serotonin system in antidepressant-like effects of hederagenin in the rat model of unpredictable chronic mild stress-induced depression

“…UCMS in rodents has been considered to be the most classic model of depression, as it mimics the role of some environmental stressors that lead to the induction of anxiety or depressive disorders in humans (Surget et al, 2009;Willner, 1997Willner, , 2005. Different classes of antidepressants, such as tricyclic antidepressants, SSRIs, and MAOIs, are effective in treating the UCMS model (Jayatissa et al, 2006). In parallel, chronic treatment with ESC, as well as with HG, at 5 mg/kg ameliorated the anxiety/ depression-like behaviors caused by UCMS exposure, including increase of locomotor activity in the OFT, percentage of time spent in open arm in the EPM to some extent.…”

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…Although this regional dissociation regarding the implication of new neurons in learning and memory processes is not so simple (Snyder et al, 2008), several studies showed selective decreases in neurogenesis in the VH following various stress exposures, which elicit depressive-like behavior in adult rat (Kim et al, 2005;Jayatissa et al, 2006;Lagace et al, 2006). Moreover, prenatal stress induced a selective reduction in neurogenesis in the VH associated with anxious behavior and reversed by agomelatine treatment (Maccari S, unpublished data).…”