Original Article

Molecular Psychiatry (2014) 19, 699–709; doi:10.1038/mp.2013.155; published online 17 December 2013

Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis

T Kreisel1, M G Frank2, T Licht3, R Reshef1, O Ben-Menachem-Zidon1, M V Baratta2, S F Maier2 and R Yirmiya1

  1. 1Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel
  2. 2Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA
  3. 3Deparment of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, Jerusalem, Israel

Correspondence: Professor R Yirmiya, Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91005, Israel. E-mail: razyirmiya@huji.ac.il

Received 10 March 2013; Revised 16 September 2013; Accepted 10 October 2013
Advance online publication 17 December 2013

Top

Abstract

The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2–3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

Keywords:

chronic stress; depression; interleukin-1; microglia; minocycline; neurogenesis