Evaluating The Chronic Variable Stress Paradigm as a Model Suitable to Test for Stress Resilience of Mice
Open Access
- Author:
- Botvinov, Julia
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Bernhard Luscher, Thesis Supervisor
Bernhard Luscher, Thesis Honors Advisor
Yingwei Mao, Faculty Reader - Keywords:
- stress resilience
GABA
anxiety
somatostatin
anhedonia - Abstract:
- Major Depressive Disorder (MDD) is one of the most common mental disorders in the United States affecting an estimate of 17.3 million adults in the United States in the year 2017 (NIH, 2019). Currently used antidepressants act with a delay of weeks to months, come with significant side effects, and are ineffective in more than one third of patients, which illustrates the enormous need for better antidepressant therapies. Increasing evidence suggest that defects in GABAergic inhibition may be a core symptom of MDD and that the ability to reverse these defects may determine the efficacy of an antidepressant. Preclinical research by the Lüscher lab, using mice as a model, has shown that enhancing GABAergic inhibition by disinhibition of somatostatin (SST)-positive GABAergic interneurons (SSTCre:γ2f/f mice, which have the γ2 subunit of GABAA receptors deleted selectively from SST neurons) leads to an antidepressant and stress resilient-like phenotype when the mice are exposed to an Uncontrolled Chronic Mild Stress (UCMS) protocol. However, this protocol failed to induce anhedonia and thereby precluded assessment of whether the SSTCre:γ2f/f mice were resilient to stress-induced anhedonia. As part of my thesis, I tested the Chronic Variable Stress (CVS) model as an alternative chronic stress protocol, to examine whether this model is suitable to induce an anxious depressive-like phenotype that includes anhedonia. I then used this model to examine whether SSTCre:γ2f/f mice exhibit resilience not only to CVS induced anxiety, but also anhedonia-like phenotypes. Using pseudo-WT mice, I confirmed that CVS induces anxious behavioral phenotypes in the Novelty Suppressed Feeding Test (for both males and females) and Open Field Test (for males only), as well as anhedonia-like behavior in the Female Urine Sniffing test of males. I have also determined that disinhibition of SST neurons in SSTCre:γ2f/f and SSTCre:γ2f/+ mice results in a CVS induced anxiolytic-like phenotype in the Novelty Suppressed Feeding Test, independent of sex, as well as an anxiolytic phenotype in the Open Field Test in males. Female SSTCre:γ2f/f but not SSTCre:γ2f/+ mice showed CVS induced anxiolysis in the Open Field Test. Moreover, male SSTCre:γ2f/f but not male SSTCre:γ2f/+ mice were resilient to CVS induced anhedonia in the Female Urine Sniffing test (FUST). I conclude that the CVS protocol is sufficient to induce an anxious and depressive-like phenotype in both male and female mice and that both the SSTCre:γ2f/f and SSTCre:γ2f/+ mice exhibit some degree of resilience to CVS-induced behavioral phenotypes. Curiously, I failed to observe CVS induced anhedonia in the sucrose preference test across all genotypes and in both sexes, including pseudo-WT mice. Therefore, additional experimentation will be necessary to assess whether SSTCre:γ2f/f and SSTCre:γ2f/+ mice exhibit resilience to CVS-induced anhedonia, especially in females where the FUST was not applicable. Nevertheless, it appears that deletion of just one copy of the γ2 subunit gene of GABAA receptors from SST cells is sufficient to induce some degree of stress resilience in both male and female mice.