Social trauma engages lateral septum circuitry to occlude social reward

Long Li, Romain Durand- de Cuttoli, Antonio V. Aubry, C. Joseph Burnett, Flurin Cathomas, Lyonna F. Parise, Kenny L. Chan, Carole Morel, Chongzhen Yuan, Yusuke Shimo, Hsiao-yun Lin, Jun Wang and Scott J. Russo ()
Additional contact information
Long Li: Icahn School of Medicine at Mount Sinai
Romain Durand- de Cuttoli: Icahn School of Medicine at Mount Sinai
Antonio V. Aubry: Icahn School of Medicine at Mount Sinai
C. Joseph Burnett: Icahn School of Medicine at Mount Sinai
Flurin Cathomas: Icahn School of Medicine at Mount Sinai
Lyonna F. Parise: Icahn School of Medicine at Mount Sinai
Kenny L. Chan: Icahn School of Medicine at Mount Sinai
Carole Morel: Icahn School of Medicine at Mount Sinai
Chongzhen Yuan: Icahn School of Medicine at Mount Sinai
Yusuke Shimo: Icahn School of Medicine at Mount Sinai
Hsiao-yun Lin: Icahn School of Medicine at Mount Sinai
Jun Wang: Icahn School of Medicine at Mount Sinai
Scott J. Russo: Icahn School of Medicine at Mount Sinai

Nature, 2023, vol. 613, issue 7945, 696-703

Abstract: Abstract In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.

Date: 2023
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DOI: 10.1038/s41586-022-05484-5

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