Elsevier

Neuroscience

Volume 150, Issue 2, 5 December 2007, Pages 251-259
Neuroscience

Behavioural neuroscience
Functional implications of decreases in neurogenesis following chronic mild stress in mice

https://doi.org/10.1016/j.neuroscience.2007.09.045Get rights and content

Abstract

Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.

Section snippets

Animals

Male and female mice from the C57BL/6J, BALB/cJ, and DBA/2J inbred strains (abbreviated B6, C, and D2, respectively) were chosen for this study. Breeders were originally obtained from the Jackson Laboratory (Bar Harbor, ME, USA). Each strain was bred for at least two generations in our facility under the following standard conditions: temperature 21±2 °C, photoperiod 12-h light/dark with lights on at 6:00 a.m.; food and water available ad libitum; bedding composed of corncob (Bed-o-Cob ¼″, The

Radial maze

Repeated-measures ANOVA over the last 3 days revealed a significant decrease of errors over time (F(2,284)=10.11, P<0.0001). Strains differed (Fig. 2; F(2,142)=23.06, P<0.0001) and there was an overall increase of errors after UCMS treatment (F(1,142)=6.2, P=0.014). However, this treatment effect depended on strain (Treatment×Strain: F(2,141)=4.81, P=0.01) and sex (Treatment×Sex: F(1,142)=7.24, P=0.008). The learning curve also depended on strain, sex, and treatment, as evidenced by the

Discussion

This study investigated in three different strains of mice the effects of UCMS on neurogenesis and performance in two different learning tasks. The results showed decreases in radial maze learning and the contextual, but not the cued, component of the fear-conditioning task after UCMS confirming an impairment of hippocampal function. The precise effects of UCMS in both tasks were strain dependent given the significant interactions between Strain and Treatment. Thus, there is a differential

Conclusion

In summary, our results demonstrate that sex and genotype obviously are critical factors in determining the sensitivity of brain structures to the deleterious effects of chronic stress. Overall, UCMS leads to decreases in hippocampal neurogenesis and deficits in hippocampal learning tasks in a genotype and sex dependent manner. However, the magnitude of the decrease in neurogenesis predicts neither the size of the learning deficits nor differences in anxiety or depression-like behavior (Mineur

Acknowledgments

We thank Drs. Haley Melikian (BNRI, Worcester, MA, USA) and Jim Crandall (Shriver Center, Waltham, MA, USA) for their expert help with the immunostaining and microscopy procedures and Daniel Prasol (BNRI, Worcester, MA, USA) for technical assistance.

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    Present address: Department of Psychiatry, Yale University School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT 06519, USA (Y. S. Mineur); Centre de Neurosciences Intégratives et Cognitives, Université de Bordeaux I and CNRS, Bat. B2, Avenue des Facultés, 33405 Talence, France (W. E. Crusio).

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