Past social trauma is encoded by a population of stress/threat-responsive brain cells that grow to be hyperactivated during subsequent interaction with non-threatening social targets. As a consequence, previously rewarding social targets are actually perceived as social threats, which promotes generalized social avoidance and impaired social reward processing that may contribute to psychiatric disorders, in response to a study conducted by researchers on the Brain and Body Research Center at Mount Sinai and published November 30 in Nature.

In humans, studies have shown that social trauma impairs brain reward function to the extent that social interaction is not any longer rewarding, resulting in severe social avoidance. In rodents, chronic social defeat stress, a model of social trauma, has been used to grasp the brain circuit mechanisms underlying stress susceptibility versus resilience, yet little is understood regarding its impact on social reward. Previous studies have assessed social interaction with an adult mouse just like those used as aggressors to induce the social trauma. Social avoidance under these circumstances likely reflects fear or submissive behavior, relatively than altered social reward.

To raised understand how traumatic social experience affects social reward, we tested social interaction and social preference with a same-sex juvenile mouse that, under control conditions, is rewarding. We found that, following chronic social defeat stress, a subset of female and male mice termed susceptible avoid social interactions with juvenile mice and don’t develop context-dependent social reward following encounters with them.”

Long Li, PhD, Instructor of Neuroscience on the Icahn School of Medicine at Mount Sinai and lead creator of the study

Within the study, adult female and male mice underwent chronic social defeat stress, wherein they were repeatedly subordinated by aggressive mice, followed by social interaction testing, where an experimental mouse is placed in a cage with a bigger aggressive mouse behind a barrier and the period of time spent interacting is measured. The mice were classified as resilient or prone to the stressor based on their social interaction behavior. This was followed by an extra social interaction test called resident-intruder test wherein a 4-6-week-old (juvenile) same-sex mouse was introduced into the topics’ homecage and allowed to freely interact. This was then followed by a social conditioned place preference test wherein the topic mice were conditioned with the juvenile mice to evaluate their preference for rewarding social targets. Throughout the resident-intruder test, control and resilient mice exhibited similar social behaviors towards the juvenile, including the quantity of lively interaction (approach, close following, and sniffing). Mice in these groups rarely withdrew from social contact with the juvenile and freely approached and investigated them. Conversely, stress-susceptible mice exhibited much less lively social investigation, an extended delay before the primary social bout (“latency”), and significantly more social avoidance. Moreover, social investigation time, social avoidance, and latency to analyze correlated with social interaction ratios during testing with an aggressive adult mouse. These results show that susceptible mice not only exhibit avoidance towards aggressive adult male mice, but additionally to non-threatening same-sex juvenile mice.

To discover the potential brain regions involved in heightened social threat, advanced histological and imaging techniques were used to discover a population of stress/threat responsive lateral septum neurotensin (NTLS) neurons which are activated by juvenile social interactions only in susceptible mice, but not in resilient or unstressed control mice.

Lastly the team used optogenetic and chemogenetic strategies to either activate or inhibit NTLS neurons and their downstream connections.

“What was so surprising is that when NTLS neurons were activated in a social threat context, they inhibited centers within the brain that encode details about social rewards,” said Scott Russo, PhD, Professor of Neuroscience and Director of the Center for Affective Neuroscience and Brain Body Research Center. “So ultimately we consider that when mice experience social trauma their ability to experience social reward is occluded by these NTLS cells.”

These findings provide a vital foundation for understanding the neural mechanisms underlying post-trauma social reward processing. The Mount Sinai team is planning studies in humans to check the relevance of lateral septum circuitry in mediating social threat perception and reward sensitivity in victims of trauma.

Source:

Mount Sinai Health System

Journal reference:

Li, L., et al. (2022) Social trauma engages lateral septum circuitry to occlude social reward. Nature. doi.org/10.1038/s41586-022-05484-5.