Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress

Nasca, Carla; Ménard, Caroline; Hodes, Georgia E.; Bigio, Benedetta; Peña, Catherine J.; Lorsch, Zachary S.; Zelli, Danielle; Ferris, Anjali; Kana, Veronika; Purushothaman, Immanuel; Dobbin, Josh; Nassim, Marouane; Angelis, Paolo de; Mérad, Miriam; Rasgon, Natalie; Meaney, Michael J.; Nestler, Eric J.; McEwen, Bruce S.; Russo, Scott J.

doi:10.1016/j.biopsych.2019.06.030

Cited by 81 publications

(70 citation statements)

References 45 publications

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“…In this context, there has been a recent push to identify factors that predispose subjects to susceptibility (5,7,8,34). Here, we find that anxiety-like behavior prior to stress predicts poststress anxiety-like behavior, which is consistent with the findings of previous work (8,35). However, neither poststress passive coping nor social interaction deficits were predicted by prestress behavior.…”

Section: Vhip-nac Encodes Vulnerability and Susceptibilitysupporting

confidence: 91%

“…This treatment goal is especially relevant in depression, given that increasing chronicity is accompanied by ever-increasing treatment resistance (2). In this context, there has been a recent push to identify factors that predispose subjects to susceptibility (5,7,8,34). Here, we find that anxiety-like behavior prior to stress predicts poststress anxiety-like behavior, which is consistent with the findings of previous work (8,35).…”

Section: Vhip-nac Encodes Vulnerability and Susceptibilitysupporting

confidence: 90%

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Ventral Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility

Muir

Tse

Iyer

et al. 2020

Biological Psychiatry

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BACKGROUND: Stress is a major risk factor for depression, but not everyone responds to stress in the same way. Identifying why certain individuals are more susceptible is essential for targeted treatment and prevention. In rodents, nucleus accumbens (NAc) afferents from the ventral hippocampus (vHIP) are implicated in stress-induced susceptibility, but little is known about how this pathway might encode future vulnerability or specific behavioral phenotypes. METHODS: We used fiber photometry to record in vivo activity in vHIP-NAc afferents during tests of depressive-and anxiety-like behavior in male and female mice, both before and after a sex-specific chronic variable stress protocol, to probe relationships between prestress neural activity and behavior and potential predictors of poststress behavioral adaptation. Furthermore, we examined chronic variable stress-induced alterations in vHIP-NAc activity in vivo and used ex vivo slice electrophysiology to identify the mechanism of this change. RESULTS: We identified behavioral specificity of the vHIP-NAc pathway to anxiety-like and social interaction behavior. We also showed that this activity is broadly predictive of stress-induced susceptibility in both sexes, while prestress behavior is predictive only of anxiety-like behavior. We observed a stress-induced increase in in vivo vHIP-NAc activity coincident with an increase in spontaneous excitatory postsynaptic current frequency. CONCLUSIONS: We implicate vHIP-NAc in social interaction and anxiety-like behavior and identify markers of vulnerability in this neural signal, with elevated prestress vHIP-NAc activity predicting increased susceptibility across behavioral domains. Our findings indicate that individual differences in neural activity and behavior play a role in predetermining susceptibility to later stress, providing insight into mechanisms of vulnerability.

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Section: Vhip-nac Encodes Vulnerability and Susceptibilitysupporting

confidence: 91%

Section: Vhip-nac Encodes Vulnerability and Susceptibilitysupporting

confidence: 90%

Ventral Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility

Muir

Tse

Iyer

et al. 2020

Biological Psychiatry

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“…Interestingly, only about 20% of those that experience a traumatic event develop clinical PTSD, which demonstrates trauma exposure is necessary, but not sufficient alone, to cause PTSD ( Frans and Rimmö, 2005 ). Given this, there has been a continued interest in determining which psychological or biological factors could determine susceptibility or resilience to PTSD ( Yehuda, 1999 ; Nasca, 2019 ). Understanding that patients with PTSD notably face an increased risk for a number of inflammation-driven diseases ( Bisson, 2019 ; von Känel, 2007 ; Mikuls, 2013 ; O’Donovan, 2015 ; Edmondson and von Känel, 2017 ), investigations into the inflammatory contributions to PTSD have recently garnered significant attention (reviewed exceptionally by Sumner et al .)…”

Section: Introductionmentioning

confidence: 99%

Peripheral inflammation is strongly linked to elevated zero maze behavior in repeated social defeat stress

Elkhatib

Moshfegh

Watson

et al. 2020

Brain, Behavior, and Immunity

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Post-traumatic stress disorder (PTSD) is a psychiatric illness that results in an increased risk for a variety of inflammatory diseases. The exact etiology of this increased risk is unknown, and thus several animal models have been developed to investigate the neuroimmune interactions of PTSD. Repeated social defeat stress (RSDS) is an established preclinical model of psychological trauma that recapitulates certain behavioral and inflammatory aspects of human PTSD. Furthermore, RSDS has been utilized to subgroup animals into susceptible and resilient populations based on one specific behavioral phenotype ( i.e. , social interaction). Herein, we conducted an extensive investigation of circulating inflammatory proteins after RSDS and found significant elevations in various cytokines and chemokines after exposure to RSDS. When categorizing animals into either susceptible or resilient populations based on social interaction, we found no inflammatory or other behavioral differences between these subgroups. Furthermore, correlative analyses found no significant correlation between social interaction parameters and inflammation. In contrast, parameters from the elevated zero maze (EZM) demonstrated significant associations and clustering to five circulating cytokines. When animals were subdivided into susceptible and resilient populations solely based upon combined EZM performance, significant inflammatory differences were evident between these groups. Strikingly, these circulating inflammatory proteins displayed a stronger predictive ability of EZM performance compared to social interaction test performance. These findings provide new insights into inflammatory markers associated with RSDS, and the utility of EZM to effectively group RSDS-exposed mice into populations with differential levels of peripheral inflammation.

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“…Until recentlyborrowing from groundbreaking advancement of other organ systems -mechanistic dissection of disordered affect has targeted singular neurotransmitter systems, brain regions, or genes. This approach enabled the understanding of the individual building blocks of brain function and continues to be supported by novel theories involving global mechanism of affect disruption, implicating for example the immune sys-tem and the gut microbiome (2,3). However, the mysteries of the brain, a structure with idiosyncratic and interconnected architecture, are unlikely to be revealed solely on the basis of this type of sledgehammer approach.…”

Section: The Era Of Circuit Mappingmentioning

confidence: 99%

MouseCircuits.org: An online repository to guide the circuit era of disordered affect

Anderson¹,

Dumitriu²

2020

Preprint

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Affective disorders rank amongst the most disruptive and prevalent psychiatric diseases, resulting in enormous societal and economic burden, and immeasurable personal costs. Novel therapies are urgently needed but have remained elusive. The era of circuit-mapping in rodent models of disordered affect, ushered in by recent technological advancements allowing for precise and specific neural control, has reenergized the hope for precision psychiatry. Here, we present a novel whole-brain cumulative network and critically access the progress made todate on circuits mediating affective-like behaviors in rodents to seek unifying principles of this cumulative data. We identified 106 original manuscripts in which optogenetics or chemogenetics were used to dissect behaviors related to fear-like, depressive-like or anxiety-like behaviors in rodents. Focusing on the 60 manuscripts that investigated pathways rather than regions, we identified emergent themes. We found that while a few pathways have been validated across similar behaviors and multiple labs, the data is mostly disjointed, with evidence of bidirectional effects of several pathways. Additionally, there is a need for analysis informed by observation prior to perturbation. Given the complex nature of brain connectivity, we argue that the compartmentalized viewpoint that develops as a consequence of fragmented pathway-specific manipulations does not readily lend itself to an integrative picture. To address this, we launched an interactive online consortium, MouseCircuits.org, an open-source platform for consolidated circuit data. This tool aims to support the shared vision of informed circuit dissection that ultimately leads to prevention and treatment of human disorders.

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Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress

Cited by 81 publications

References 45 publications

Ventral Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility

Ventral Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility

Peripheral inflammation is strongly linked to elevated zero maze behavior in repeated social defeat stress

MouseCircuits.org: An online repository to guide the circuit era of disordered affect

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