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TNF-α from hippocampal microglia induces working memory deficits by acute stress in mice
Masahiro Ohgidani1, Takahiro A Kato2, Noriaki Sagata1
1Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Abstract:
The role of microglia in stress responses has recently been highlighted, yet the underlying mechanisms of action remain unresolved. The present study examined disruption in working memory due to acute stress using the water-immersion resistant stress (WIRS) test in mice. Mice were subjected to acute WIRS, and biochemical, immunohistochemical, and behavioral assessments were conducted. Spontaneous alternations (working memory) significantly decreased after exposure to acute WIRS for 2h. We employed a 3D morphological analysis and site- and microglia-specific gene analysis techniques to detect microglial activity. Morphological changes in hippocampal microglia were not observed after acute stress, even when assessing ramification ratios and cell somata volumes. Interestingly, hippocampal tumor necrosis factor (TNF)-α levels were significantly elevated after acute stress, and acute stress-induced TNF-α was produced by hippocampal-ramified microglia. Conversely, plasma concentrations of TNF-α were not elevated after acute stress. Etanercept (TNF-α inhibitor) recovered working memory deficits in accordance with hippocampal TNF-α reductions. Overall, results suggest that TNF-α from hippocampal microglia is a key contributor to early-stage stress-to-mental responses.
Insights
Acute stress impairs working memory by increasing hippocampal tumor necrosis factor-alpha (TNF-α) produced by microglia. Inhibiting TNF-α restored memory function, highlighting its role in stress responses.
Area of Science:
- Neuroscience
- Immunology
- Stress Research
Background:
- Microglia's role in stress responses is increasingly recognized but poorly understood.
- Mechanisms linking acute stress to cognitive deficits require elucidation.
Purpose of the Study:
- To investigate the impact of acute stress on working memory in mice.
- To identify the cellular and molecular mechanisms underlying stress-induced working memory impairment, focusing on microglia.
Main Methods:
- Mice were subjected to the water-immersion restraint stress (WIRS) test.
- Behavioral assessments (spontaneous alternations) evaluated working memory.
- Biochemical and immunohistochemical analyses assessed hippocampal tumor necrosis factor-alpha (TNF-α) levels and microglial activity.
- 3D morphological and gene analyses were used to detect microglial activity.
- The effect of Etanercept (a TNF-α inhibitor) on working memory was examined.
Main Results:
- Acute WIRS significantly decreased working memory performance.
- No significant morphological changes were observed in hippocampal microglia after acute stress.
- Hippocampal TNF-α levels significantly increased post-stress, originating from ramified microglia.
- Plasma TNF-α levels did not elevate after acute stress.
- Etanercept treatment restored working memory deficits and reduced hippocampal TNF-α.
Conclusions:
- Hippocampal microglia-derived TNF-α is a critical mediator of early-stage stress-induced cognitive deficits.
- Targeting microglial TNF-α may offer a therapeutic strategy for stress-related mental health conditions.
