Elsevier

Biological Psychiatry

Volume 54, Issue 10, 15 November 2003, Pages 1035-1040
Biological Psychiatry

Original article
Reduced cell proliferation in the dentate gyrusis not correlated with the development of learned helplessness

https://doi.org/10.1016/S0006-3223(03)00527-4Get rights and content

Abstract

Background

A plethora of indirect findings suggests that mood disorders may be caused by or result in structural changes in the brain, namely decreased hippocampal cell proliferation.

Methods

To test for these hypotheses, we used a rat model of depression, learned helplessness. Moderate unpredictable and inescapable foot shocks induced learned helplessness only in a portion of the rats. Rats that showed helpless behavior were compared to those behaving normally after inescapable shock. Proliferating cells in the dentate gyrus were labeled with BrdU (bromodeoxyuridine).

Results

Helpless behavior appeared before the decrease of dentate gyrus cell proliferation was maximal. Cell proliferation was decreased to the same extent in animals that developed helplessness as those that were not helpless. Furthermore, immobilization stress, which reduced the rate of cell proliferation, did not induce learned helplessness.

Conclusion

These results are in line with reports that the rate of dentate gyrus cell proliferation is acutely down-regulated by stress, but the development of helpless behavior does not correlate with this process. Further studies will have to clarify if during learned helpless behavior neurogenesis is impaired by altered differentiation or survival of cells.

Introduction

Current ideas concerning the induction and maintenance of a depressive episode suggest that changes in the modulatory aminergic and peptidergic systems converge in altered second messenger signaling and lead to changes in gene transcription, resulting in decreased plasticity. Specifically, it was proposed that as a part of impairments in the structural plasticity, a stress-induced decrease in dentate gyrus neurogenesis might be critically involved in the development of depressive episodes Duman et al 1999, Duman 2002, Gage 2000, Jacobs et al 2000, Kempermann 2002, Manji et al 2001, Nestler et al 2002. There is extensive evidence that neurogenesis in the dentate gyrus continues through adulthood in mammalian species and that the newly formed neurons form functional connections and participate in learning Kaplan and Hinds 1977, Kornack and Rakic 1999, Kuhn et al 1996, Shors et al 2001, van Praag et al 2002. Dentate gyrus cell proliferation and neurogenesis decrease as a result of serotonin depletion, stress hormones, or stress Brezun and Daszuta 1999, Fuchs and Gould 2000, Gould et al 1997, Gould et al 1998, Gould and Tanapat 1999, Tanapat et al 1998, Tanapat et al 2001, Cameron and Gould 1994. Vice versa, antidepressant treatment, lithium, and electroconvulsive treatment were reported to increase dentate gyrus cell proliferation and neurogenesis Chen et al 2000, Czeh et al 2001, D’Sa and Duman 2002, Duman et al 1999, Madsen et al 2000, Malberg et al 2000, Scott et al 2000. This led to the hypothesis that dentate gyrus neurogenesis might play a major role in the pathophysiology of major depression Gage 2000, Jacobs et al 2000, Kempermann 2002. To test for this hypothesis, we examined dentate gyrus cell proliferation in an animal model of depression, rats with learned helplessness. The model shows excellent face validity and is pharmacologically specific Alexopoulos et al 1993, Dess and Chapman 1990, Greenberg et al 1989, Seligman and Beagley 1975, Sherman et al 1982. In helpless animals, a cascade of changes in the norepinephrine (NE) and serotonin (5HT) systems and second messenger signaling have been demonstrated Edwards et al 1991, Martin et al 1990, as well as the importance of brain-derived neurotrophic factor (BDNF) (Shirayama et al 2002, Siuciak et al 1997, Vollmayr et al 2001. Thus, the model is appropriate to look at a downstream effect like neurogenesis.

Section snippets

Animal behavior

Animals were treated in accordance with the European Communities Council Directive of 24 November 1986, and the procedures were approved by the Regierungspraesidium Karlsruhe. A total of 200 male Sprague-Dawley rats (270 g to 330 g body weight) (Janvier, France) were used. As a behavioral control, 20 rats underwent only the test of learned helplessness without previous inescapable shock or restraint stress. Eight rats were injected with bromodeoxyuridine (BrdU) without any stressful experience.

Results

In our initial experiment, we looked at the rate of cell proliferation in animals that developed helpless behavior compared to those that did not following equivalent stress exposure. Using inescapable foot shock, in our procedure, about 20% of the animals exposed to inescapable stress will exhibit helpless behavior (Vollmayr and Henn 2001). Animals that are not helpless following exposure to unpredictable and inescapable foot shock show behaviors identical to animals never exposed to

Discussion

It was proposed that a stress-induced decrease in dentate gyrus neurogenesis might be an important causal factor in the development of depressive episodes Gage 2000, Jacobs et al 2000, Kempermann 2002. The experiments described here tested this hypothesis in a stress model of depression with clear established behavioral and biochemical markers of a changed affective state. Learned helplessness can be detected as early as 24 hours after inescapable stress and lasts for more than 7 days. This

Acknowledgements

Financial support provided to BV: German Research Foundation VO 621/3-1, and to PG: German Research Foundation GA 427/4-2.

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