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

T. Kreisel; M. G. Frank; T. Licht; R. Reshef; O. Ben-Menachem-Zidon; M. V. Baratta; S. F. Maier; R. Yirmiya

doi:10.1038/mp.2013.155

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

T. Kreisel, M. G. Frank, T. Licht, R. Reshef, O. Ben-Menachem-Zidon, M. V. Baratta, S. F. Maier, R. Yirmiya^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

527 Scopus citations

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.

Original language	English
Pages (from-to)	699-709
Number of pages	11
Journal	Molecular Psychiatry
Volume	19
Issue number	6
DOIs	https://doi.org/10.1038/mp.2013.155
State	Published - Jun 2014

Bibliographical note

Funding Information:
We thank Dr Steffen Jung, the Weizmann Institute, Israel, for the CX3CR1-GFP mice, Ms Laura Benhamou, Mr Mattan Mittelman and Ms Brittany M Thompson for their help with various aspects of the experiments and Ms Zehava Cohen for help in preparation of the figures. This research was supported by grants from the ISRAEL SCIENCE FOUNDATION (Grant number 206/12) and the ISRAEL SCIENCE FOUNDATION–FIRST Program (Grant number 1357/13) to RY.

Keywords

chronic stress
depression
interleukin-1
microglia
minocycline
neurogenesis

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title = "Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis",

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.",

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note = "Funding Information: We thank Dr Steffen Jung, the Weizmann Institute, Israel, for the CX3CR1-GFP mice, Ms Laura Benhamou, Mr Mattan Mittelman and Ms Brittany M Thompson for their help with various aspects of the experiments and Ms Zehava Cohen for help in preparation of the figures. This research was supported by grants from the ISRAEL SCIENCE FOUNDATION (Grant number 206/12) and the ISRAEL SCIENCE FOUNDATION–FIRST Program (Grant number 1357/13) to RY.",

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

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