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Updated: Jul 9, 2026
The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice
Published on: October 24, 2018
Chronic stress in mice: how gut bacteria influence gene activity in key brain neurons
Wenxia Jiang1,2,3, Yifan Li1,2,3, Jie Yang1,2,3
1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract:
Major depressive disorder (MDD) is a serious mental disorder. Increasing evidence suggests that changes of gut microbiota are involved in pathogenesis of depression, yet the underlying mechanisms remains unknown. Here, chronic unpredictable mild stress (CUMS) mice model was constructed to mimic depression. We characterized the microbial composition and function of control, bedding exchange, and CUMS mice through 16S rRNA gene and metagenomic sequencing. Additionally, single-nucleus RNA sequencing (snRNA-seq) was used to compare the transcriptomic changes in the hypothalamus of these three groups. We found that replacing the bedding of CUMS mice with that of control mice could reverse the depressive-like behaviors. The microbial signatures of bedding exchange group trended towards the control group at the genus level. The abundance of g_norank_f_Muribaculaceae significantly increased in the bedding exchange group compared to CUMS group. Meanwhile, we found that the CUMS mice were characterized by cell-specific transcriptomic changes in hypothalamus. Notably, the transcriptomes of excitatory neurons in the hypothalamus were mainly affected, and these changes could be effectively reversed by bedding exchange treatment. The gene modules analysis revealed that the gut microbiota mainly modulated glyoxylate and dicarboxylate metabolism as well as arginine biosynthesis in hypothalamic excitatory neurons. Our findings provide new insights into the pathogenesis of depression.
Insights
Environmental enrichment, specifically changing bedding, reversed depression-like behaviors in mice. This intervention altered gut microbiota and reversed stress-induced transcriptomic changes in hypothalamic excitatory neurons, suggesting a gut-brain axis connection in depression.
Area of Science:
- Neuroscience
- Microbiology
- Genetics
Background:
- Major depressive disorder (MDD) is a significant mental health condition.
- Gut microbiota alterations are increasingly linked to depression pathogenesis.
- The precise mechanisms underlying this gut-brain connection remain unclear.
Purpose of the Study:
- To investigate the role of gut microbiota in depression using a chronic unpredictable mild stress (CUMS) mouse model.
- To explore the impact of environmental enrichment (bedding exchange) on depressive behaviors and associated biological changes.
- To elucidate the molecular mechanisms linking gut microbiota to hypothalamic function in depression.
Main Methods:
- Construction of a CUMS mouse model to simulate depression.
- 16S rRNA gene and metagenomic sequencing to analyze gut microbial composition and function.
- Single-nucleus RNA sequencing (snRNA-seq) to assess transcriptomic changes in the hypothalamus.
- Behavioral tests to evaluate depressive-like symptoms.
Main Results:
- Bedding exchange reversed depressive-like behaviors in CUMS mice, normalizing microbial signatures.
- The abundance of g_norank_f_Muribaculaceae increased significantly post-bedding exchange.
- CUMS induced cell-specific transcriptomic alterations in the hypothalamus, primarily affecting excitatory neurons.
- Bedding exchange treatment reversed these hypothalamic transcriptomic changes.
Conclusions:
- Gut microbiota modulation through environmental enrichment can alleviate depressive symptoms.
- Gut microbiota influences hypothalamic excitatory neuron function, impacting metabolic pathways like glyoxylate and dicarboxylate metabolism and arginine biosynthesis.
- These findings offer novel insights into the gut-brain axis in depression pathogenesis.
