Fear circuit–based neurobehavioral signatures mirror resilience to chronic social stress in mouse

Abstract

Consistent evidence from human data points to successful threat–safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat–safety discrimination and conditioned learning: the Discriminating-avoiders , characterized by successful social threat–safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders , showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat–safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.

Naturalistic housing condition promotes behavioral flexibility and increases resilience to stress in rats.

“…knowledge, this is the first study that evaluated the effects of NE in stress resilience. Although here EE was not effective to promote resilience others have shown that it can also be effective (Ayash et al, 2023;Lehmann & Herkenham, 2011). An alternative interpretation is that NE caused a deficit in fear learning, but even if that were the case, a disruption of fear acquisition could still be taken to promote resilience.…”

Chronic Social Defeat Stress Gives Rise to Social Avoidance Through Fear Learning

“…In addition, some studies show that defeated C57BL/6 mice fail to avoid mice of another strain that either physically resemble them (i.e. Black Swiss mice) [19] or are physically distinct (i.e., 129/Sv) [20, 21], supporting the view that they specifically learned to fear mice that look like the aggressor. The finding that C57BL/6 mice avoid a conspecific after being defeated by other C57BL/6 mice is in line with this interpretation [22].…”

“…Extinction of social avoidance has been considered previously in studies that re-exposed defeated C57BL/6J mice to the CD-1 by placing them in a familiar aggressor’s home cage (15 minutes/day) for 16 days [20, 21]. During this time, animals were separated by a mesh wall, which is the same way they were housed after being attacked on each day of CSDS, as it provides psychological stress caused by continuous exposure to the CD-1.…”

“…While this extinction procedure exposes mice to the CD-1 and contextual cues associated with threat (i.e., aggressor’s home cage) in the absence of an attack, it also re-exposes them to psychological stress, potentially minimizing the acquisition of extinction. This may be why only a subset of susceptible mice exhibited extinction, as measured by increases in the social interaction index [21]. In our study, we extinguished animals by repeatedly placing them in an arena that was never associated with threat and measuring daily changes in interaction with the CD-1, allowing us to visualize extinction learning over the course of 7 days of testing.…”

Characterization of transcriptional profiles associated with stress-induced neuronal activation in Arc-GFP mice

“…The potential involvement of oligodendrocytes, as highlighted also by our study, might suggest a more important pathway that has not been considered previously and which might require further investigation. Other recent studies have challenged the previous notions of resilience and susceptibility to chronic social defeat stress, highlighting a more intricate behavioral and neurobiological response to stress [58,59]. The integration of these modi ed interaction test approaches and the subclassi cation of animals, along with the strategy of sorting and analyzing AN, holds promise for providing a more comprehensive understanding of the intricate behavioral states and the dynamics within speci c activated cell populations during complex stress-related responses.…”