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Restraint to Induce Stress in Mice and Rats
Published on: December 6, 2024
Regulatory T cells administration reduces anxiety-like behavior in mice submitted to chronic restraint stress
Yamila Cepeda1,2, Roberto Elizondo-Vega2, Camila Garrido1,2
1Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción, Chile.
Background:
Major depression disorder (MDD) and anxiety are common mental disorders that significantly affect the quality of life of those who suffer from them, altering the person's normal functioning. From the biological perspective, the most classical hypothesis explaining their occurrence relies on neurotransmission and hippocampal excitability alterations. However, around 30% of MDD patients do not respond to medication targeting these processes. Over the last decade, the involvement of inflammatory responses in depression and anxiety pathogenesis has been strongly acknowledged, opening the possibility of tackling these disorders from an immunological point of view. In this context, regulatory T cells (Treg cells), which naturally maintain immune homeostasis by suppressing inflammation could be promising candidates for their therapeutic use in mental disorders.
Methods:
To test this hypothesis, C57BL/6 adult male mice were submitted to classical stress protocols to induce depressive and anxiety-like behavior; chronic restriction stress (CRS), and chronic unpredictable stress (CUS). Some of the stressed mice received a single adoptive transfer of Treg cells during stress protocols. Mouse behavior was analyzed through the open field (OFT) and forced swim test (FST). Blood and spleen samples were collected for T cell analysis using cell cytometry, while brains were collected to study changes in microglia by immunohistochemistry.
Results:
Mice submitted to CRS and CUS develop anxiety and depressive-like behavior, and only CRS mice exhibit lower frequencies of circulating Treg cells. Adoptive transfer of Treg cells decreased anxiety-like behavior in the OFT only in CRS model, but not depressive behavior in FST in neither of the two models. In CRS mice, Treg cells administration lowered the number of microglia in the hippocampus, which increased due this stress paradigm, and restored its arborization. However, in CUS mice, Treg cells administration increased microglia number with no significant effect on their arborization.
Conclusion:
Our results for effector CD4+ T cells in the spleen and microglia number and morphology in the hippocampus add new evidence in favor of the participation of inflammatory responses in the development of depressive and anxiety-like behavior and suggest that the modulation of key immune cells such as Treg cells, could have beneficial effects on these disorders.
Insights
Regulatory T cells (Treg cells) show potential in treating depression and anxiety. Treg cell therapy reduced anxiety-like behaviors and modulated microglia in a chronic restriction stress mouse model, suggesting immune system involvement in mental health.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Major depressive disorder (MDD) and anxiety significantly impact quality of life.
- Traditional treatments targeting neurotransmission are ineffective for ~30% of MDD patients.
- Inflammatory responses and regulatory T cells (Treg cells) are increasingly recognized for their role in mental health disorders.
Purpose of the Study:
- To investigate the therapeutic potential of Treg cells in stress-induced depressive and anxiety-like behaviors in mice.
- To explore the immunological mechanisms underlying these behaviors.
Main Methods:
- Mice were subjected to chronic restriction stress (CRS) or chronic unpredictable stress (CUS) to induce behavioral changes.
- Adoptive transfer of Treg cells was administered during stress protocols.
- Behavioral tests (OFT, FST), T cell analysis (flow cytometry), and microglia assessment (immunohistochemistry) were performed.
Main Results:
- Both CRS and CUS induced anxiety and depressive-like behaviors.
- Treg cell transfer reduced anxiety-like behavior in the CRS model only.
- Treg cells modulated hippocampal microglia in CRS mice, reducing their number and restoring arborization, but increased microglia in CUS mice.
Conclusions:
- Inflammatory responses, particularly involving T cells and microglia, contribute to depressive and anxiety-like behaviors.
- Modulating Treg cells may offer a novel therapeutic strategy for mental disorders.
- The effects of Treg cells are context-dependent, varying between different stress models.
