Elsevier

Biological Psychiatry

Volume 64, Issue 4, 15 August 2008, Pages 293-301
Biological Psychiatry

Archival Report
Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal

https://doi.org/10.1016/j.biopsych.2008.02.022Get rights and content

Background

Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.

Methods

Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF1) antagonist SSR125543, or the vasopressin 1b (V1b) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.

Results

Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF1 and the V1b antagonists.

Conclusions

Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

Section snippets

Animals

Two-month-old male BALB/c mice were obtained from Taconic (Germantown, New York). All animals were housed in groups of four or five and were maintained under standard laboratory conditions (12/12-hour light/dark cycle: lights on at 8:00 pm, 22 ± 2°C, food and water ad libitum). The treatment of the animals was in accordance with the European Community Council directive 86/609/EEC and with the Guide for Care and Use of Laboratory Animals established by the National Institutes of Health of the

Disruption of Hippocampal Neurogenesis Has No Effect on Sensitivity to Stress

To determine whether loss of neurogenesis alters sensitivity to stress, we compared the responses of irradiated and non-irradiated mice to UCMS. In vehicle-treated mice, UCMS induced a gradual deterioration of coat state that reached significance by 4 weeks after beginning the stress (p < .001) and worsened until the end of the stress procedure (p < .001; Figure 2A). This effect was accompanied by reduced grooming in the splash test (p < .01; Figure 2B) and increased latency to eat in the NSF

Discussion

The UCMS-induced behavioral changes were reversed by several compounds endowed with AD-like properties, such as fluoxetine and imipramine, as well as a CRF1 antagonist (SSR125543) and a V1b antagonist (SSR149415). The x-irradiation of the hippocampus had no effect per se in the UCMS procedure, suggesting that a loss of hippocampal neurogenesis does not induce a depressive-like behavior and does not worsen the deteriorations induced by the UCMS. Nevertheless, irradiation completely abolished the

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