Social trauma engages lateral septum circuitry to occlude social reward

Li, Long; Cuttoli, Romain Durand-de; Aubry, Antonio; Burnett, C. Joseph; Cathomas, Flurin; Parise, Lyonna F.; Chan, Kenny L.; Morel, Carole; Yuan, Chongzhen; Shimo, Yusuke; Lin, Hsiao‐Yun; Wang, Jun; Russo, Scott J.

doi:10.1038/s41586-022-05484-5

Cited by 79 publications

(53 citation statements)

References 61 publications

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“…This approach also used a validated cellular manipulation that causally induces aggression, and it was performed under a behavioral condition that would otherwise not yield aggressive attack behavior (i.e., we used female social partners). Specifically, we expressed an excitatory DREADD (AAV-hsyn-DIO-hM3Dq) in the ESR1+ cells of ventromedial hypothalamus, since it has been shown that direct excitation of these cells induces aggressive behavior towards female mice (Deonaraine et al, 2020; Li et al, 2022; Takahashi et al ., 2017). Experiments were performed in the male F1 offspring of female CD1 strain mice crossed with ESR1-Cre male mice on a C57 strain background.…”

Section: Resultsmentioning

confidence: 99%

A widespread oscillatory network encodes an aggressive internal state

Grossman¹,

Talbot²,

Gallagher³

et al. 2022

Preprint

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Social aggression is an innate behavior that can aid an organism in securing access to resources. Aggression can also disrupt group function and reduce survival under conditions of behavioral pathology. Since many brain regions contribute to multiple social behaviors, expanded knowledge of how the brain encodes distinct social states would enable the development of interventions that suppress aggression, while leaving other social behaviors intact. Here we show that murine aggression is optimally encoded by a brain-wide network. This network is organized by prominent theta (4-11Hz) and beta (14-30Hz) oscillations, leading from orbital frontal cortex and medial dorsal thalamus, and converging on ventral medial hypothalamus and medial amygdala. Activity in this network is coupled to brain-wide cellular firing, and the network is conserved in new mice from multiple genetic backgrounds, and in multiple contexts. Finally, we develop a closed loop stimulation protocol based on network activity levels. This protocol suppressed aggression, but not pro-social behavior. Thus, we defined a causal brain-wide network that selectively encodes aggressive behavior across mice and established a new approach for state specific control of affective behavior.

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Section: Resultsmentioning

confidence: 99%

A widespread oscillatory network encodes an aggressive internal state

Grossman¹,

Talbot²,

Gallagher³

et al. 2022

Preprint

Self Cite

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“…In this study, female mice companionship was given as a social and sexual reward during 21 days of chronic social defeat stress and confirmed the effect of this reward on chronic social defeat stress during sustained stress. The reward used in this study contains both social and sexual reward, in which the social reward is moreand sexual reward is less ( 60 ). However, in clinic, human beings are more social with more social constraints (e.g., ethical).…”

Section: Discussionmentioning

confidence: 99%

Reward enhances resilience to chronic social defeat stress in mice: Neural ECs and mGluR5 mechanism via neuroprotection in VTA and DRN

Shi

Hu²,

Hui³

et al. 2023

Front. Psychiatry

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IntroductionStress often leads to emotional disorders such as depression. The reward might render this effect through the enhancement of stress resilience. However, the effect of reward on stress resilience under different intensities of stress needs more evidence, and its potential neural mechanism has been poorly revealed. It has been reported that the endogenous cannabinoid system (ECs) and downstream metabolic glutamate receptor 5 (mGluR5) are closely related to stress and reward, which might be the potential cerebral mechanism between reward and stress resilience, but there is a lack of direct evidence. This study aims to observe the effect of reward on stress resilience under different intensities of stress and further explore potential cerebral mechanisms underlying this effect.MethodsUsing the chronic social defeat stress model, we applied reward (accompanied by a female mouse) under different intensities of stress in mice during the modeling process. The impact of reward on stress resilience and the potential cerebral mechanism were observed after modeling through behavioral tests and biomolecules.ResultsThe results showed that stronger stress led to higher degrees of depression-like behavior. Reward reduced depression-like behavior and enhanced stress resilience (all p-value <0.05) (more social interaction in the social test, less immobility time in the forced swimming test, etc.), with a stronger effect under the large stress. Furthermore, the mRNA expression levels of CB1 and mGluR5, the protein expression level of mGluR5, and the expression level of 2-AG (2-arachidonoylglycerol) in both ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) were significantly upregulated by reward after modeling (all p-value <0.05). However, the protein expression of CB1 in VTA and DRN and the expression of AEA (anandamide) in VTA did not differ significantly between groups. Intraperitoneal injection of a CB1 agonist (URB-597) during social defeat stress significantly reduced depression-like behavior compared with a CB1 inhibitor (AM251) (all p-value <0.05). Interestingly, in DRN, the expression of AEA in the stress group was lower than that of the control group, with or without reward (all p-value <0.05).DiscussionThese findings demonstrate that combined social and sexual reward has a positive effect on stress resilience during chronic social defeat stress, potentially by influencing the ECs and mGluR5 in VTA and DRN.

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“…However, attributing particular aspects of behavioral control to distinct LS neuronal subpopulations has been challenging due to the incomplete understanding of LS neuronal diversity. Recent studies have focused on several molecularly defined groups of LS neurons to establish their involvement in social behavior 37,38 or context-specific defensive responses 16,17,39,40 . Our research complements these efforts, using a mouse model where Crhr2 -expressing Nkx2.1 -lineage neurons are absent from the lateral septum to assess the role of this subpopulation in the control of innate behavioral responses to stress-related stimuli.…”

Section: Discussionmentioning

confidence: 99%

A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli

García,

Tran,

Peterson

et al. 2023

Preprint

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When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lacking Nkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.

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Social trauma engages lateral septum circuitry to occlude social reward

Cited by 79 publications

References 61 publications

A widespread oscillatory network encodes an aggressive internal state

A widespread oscillatory network encodes an aggressive internal state

Reward enhances resilience to chronic social defeat stress in mice: Neural ECs and mGluR5 mechanism via neuroprotection in VTA and DRN

A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli

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