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Delineating neural circuitry of STress REsilience and Stress Susceptibility using DREADD combined with fMRI technique (STRESS-DREADD)

Subject Area Biological Psychiatry
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 415098680
 
Final Report Year 2023

Final Report Abstract

Chronic unpredictable mild stress (CUMS) in rodents is commonly utilized to model depressionlike symptoms in rats, representing currently the most reliable and effective model for the disease. Surprisingly, despite its extensive use in preclinical neuroscience, nearly 97% of CUMS studies have focused on male rodents, with very few examining females. This lack of female studies in CUMS animal models is of specific importance, as the prevalence of depression is almost twice as high in women compared to men. Our comprehensive study explores the impact of chronic stress especially in female rats, encompassing both behavioral and neuroimaging aspects to address this knowledge gap. We evaluated signs of depression in CUMS rats through various behavioral tests, including their activity levels, immobility in a swimming test, anxious behavior in a maze, and their preference for sugar. Afterward, we used MRI scans to further study their brain activity and chemistry. Traditional CUMS studies in male rats mostly propagate sucrose preference as the key indicator of a depressive-like state, primarily reflecting anhedonia. Surprisingly, our study in female rats revealed that sucrose preference remained unchanged, while significant stress-induced changes could be observed in most of the other behavioral tests. Thus, our results highlight that a more diverse evaluation strategy, involving complementary tests that explore different depressionrelated symptoms like inactivity, anxiety, anhedonia, and despair, provides a more thorough understanding of stress-induced depressive-like behaviors in animal models. As a result, we recommend incorporating such multifaceted behavioral assessments, especially when testing novel treatment options. This is crucial because different treatments may impact specific dimensions of depression that might not be adequately captured by simplistic behavioral tests. Furthermore, our research revealed that the CUMS procedure affected various aspects of brain function in female rats, with a particular focus on the prefrontal cortex. Our approach examined stress effects on brain volume, functional brain networks, and metabolites, showing changes in prefrontal glutamate levels, as well as reductions in striatal and prefrontal volume. Additionally, there was a decrease in the prefrontal cortex's control over the ventral striatum, which is a crucial brain region associated with reward processing. Again, when assessing potential treatment options for depression in this animal model, it is essential to incorporate a comprehensive neuroimaging evaluation to capture potential effects on various brain domains. For instance, the influences of drugs on brain network connectivity and brain metabolites might be missed when solely focusing on changes in brain volume. In summary, our study contributes to a better understanding of how chronic stress affects brain function, especially in female rodents. It emphasizes the significance of conducting multimodal assessments, involving both behavior and neuroimaging, to gain a complete understanding of depression-like symptoms. This holistic approach is essential when testing potential treatment options for depression.

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