Our research seeks to uncover the underlying mechanisms of stress resilience. By understanding those mechanisms, we can employ them to develop better treatment strategies for stress-related mental disorders and prevention. Our research has developed a new mouse model with high face validity that allows stratifying a single group of stressed mice into resilience and susceptibility associated phenotypes that are based on the fear circuitry.
Also, we provide evidence for the presence of global resilience mechanisms. Our study on stressed mice revealed that they exhibited characteristics that are indicative of both resilience and susceptibility in humans. Specifically, they show different abilities in threat safety discrimination and responsiveness to extinction, which are key features associated with resilience.
The resilience and susceptibility associated phenotypes that we identified in mice have face validity and are based on the fear circuitry. This circuitry is highly conserved across species and is arguably one of the best studied circuits. In turn, this allows mechanistic investigations that have the potential to contribute to treatment, development, and prevention measures.
We'll use our new model to dig deeper into neurobiological mechanisms of resilience and understand how we can actively promote resilience. In addition, we will employ longitudinal analysis to decipher how individual resilience develops over time. Begin by relocating all chronic socially defeated or CSD-treated and control mice into new cages, mirroring the conditions they first arrived in and letting them rest overnight.
The following morning, sanitize the three-chambered arena using a 5%ethanol solution and set it up beneath the camera ensuring a light condition of 37 lux and full visibility of the entire arena. Similarly, clean the mesh enclosures with 5%ethanol and position them in the designated corners. Define a two-centimeter interaction zone around the boundaries of the mesh enclosures.
For the habituation phase, bring the subject animal into the middle of the arena and allow for a six-minute exploration before returning it to its home cage. Score the duration spent by the animal exploring specifically when the animal's nose is inside the interaction zone. Next, place the CD-1 social target and the novel 129/Sv social target under separate mesh enclosures.
To initiate the testing phase, immediately place the subject animal back at the center of the arena and permit exploration for a period of six minutes. Note the duration the animal interacts with the social targets, again, focusing on the span when the animal's nose is within the interaction zone. Afterward, return all the animals to their individual habitat.
Ensure to clean the arena and mesh enclosures with 5%ethanol solution after assessing each animal. Switch the position of the mesh enclosures between different animals to balance any potential location bias. Calculate the social interaction index as shown.
Based on the social interaction index, divide the mice into the non-avoiders, the indiscriminate-avoiders, and the discriminating-avoiders. A significant difference in the social interaction index with the CD-1 social target between both groups was observed. The discriminating-avoiders and indiscriminate-avoiders subgroups had a social interaction index of less than one with the CD-1 social target, reflecting social avoidance development towards the conditioned stimulus.
The non-avoider subgroup had a social interaction index more than or equivalent to one with the same social target, reflecting impaired aversive conditioned learning with that target. The discriminating-avoiders subgroup showed intact sociability levels towards a safe or neutral stimulus, while the indiscriminate-avoider subgroup showed aversive response generalization. The absence of social preferential bias was reflected in social interaction indices of more than or equivalent to one with both social targets within the control group.
