History of winning and hierarchy landscape influence stress susceptibility in mice

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, though gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.

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What it takes to be at the top: The interrelationship between chronic social stress and social dominance

10.1101/2020.06.29.177410 ◽

2020 ◽

Author(s):

Merima Šabanović ◽

He Liu ◽

Vongai Mlambo ◽

Hala Aqel ◽

Dipesh Chaudhury

Keyword(s):

Social Interaction ◽

Social Stress ◽

Social Preference ◽

Social Rank ◽

Social Defeat ◽

Social Defeat Stress ◽

Chronic Social Stress ◽

Hierarchy Formation ◽

Chronic Social Defeat Stress ◽

Stress Susceptibility

AbstractDominance hierarchies of social animal groups are influenced by complex factors such as stress. Stress experienced by an animal prior to social interactions with a conspecific may be a determinant of their future social dynamics. Additionally, long-term occupancy of a specific hierarchical rank can have psychophysiological effects, leading to vulnerability to future stress.The current study aimed to delineate differential effects of stress acting before or after hierarchy formation. Using the chronic social defeat stress (CSDS) paradigm we performed behavioural investigations to determine whether exposure to CSDS before hierarchy formation predicted the new dominance status. Moreover, in another study we investigated whether social rank predicted stress vulnerability.We found that CSDS did not impede the establishment of dominance in new hierarchies as both stress-susceptible (socially avoidant) and –resilient (social) mice were able to attain dominant ranks. In contrast, within newly established hierarchies of stress-naïve mice, the subordinate, but not dominant, mice exhibit significantly greater avoidance of novel social targets. However, following exposure to CSDS, both lowest- and highest-ranked mice exhibit strong susceptibility to stress as measured by decreased interactions with a novel social target.These results suggest that the response to chronic social stress did not determine social rank in new cohorts, but low-status mice in newly established groups exhibited lower sociability to novel social targets. Interestingly, exposure of a hierarchical social group to chronic social stress led to stress-susceptibility in both high- and low-status mice as measured by social interaction.HighlightsStress susceptibility to chronic social defeat did not impede the establishment of dominance in new hierarchies.Subordinate mice exhibit reduced social preference after hierarchy formation.Following chronic social defeat stress, both subordinate and dominant mice exhibit susceptible-like reduction in social interaction, but dominant mice exhibit the greater decrease in social preference as compared to baseline.

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Differential chronic social stress models in male and female mice

European Journal of Neuroscience ◽

10.1111/ejn.15481 ◽

2021 ◽

Author(s):

Orit Furman ◽

Michael Tsoory ◽

Alon Chen

Keyword(s):

Social Stress ◽

Male And Female ◽

Chronic Social Stress ◽

Female Mice ◽

Stress Models

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N6 -Methyladenosine Modification in Chronic Stress Response Due to Social Hierarchy Positioning of Mice

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.705986 ◽

2021 ◽

Vol 9 ◽

Author(s):

Malena dos Santos Guilherme ◽

Theodora Tsoutsouli ◽

Hristo Todorov ◽

Sina Teifel ◽

Vu Thu Thuy Nguyen ◽

...

Keyword(s):

Social Stress ◽

Corticosterone Level ◽

Well Being ◽

Social Hierarchy ◽

Stressful Events ◽

Stress Disorders ◽

Female Mice ◽

New Therapeutic Approaches ◽

The Face ◽

Transcriptomic Changes

Appropriately responding to stressful events is essential for maintaining health and well-being of any organism. Concerning social stress, the response is not always as straightforward as reacting to physical stressors, e.g., extreme heat, and thus has to be balanced subtly. Particularly, regulatory mechanisms contributing to gaining resilience in the face of mild social stress are not fully deciphered yet. We employed an intrinsic social hierarchy stress paradigm in mice of both sexes to identify critical factors for potential coping strategies. While global transcriptomic changes could not be observed in male mice, several genes previously reported to be involved in synaptic plasticity, learning, and anxiety-like behavior were differentially regulated in female mice. Moreover, changes in N6-methyladenosine (m6A)-modification of mRNA occurred associated with corticosterone level in both sexes with, e.g., increased global amount in submissive female mice. In accordance with this, METTL14 and WTAP, subunits of the methyltransferase complex, showed elevated levels in submissive female mice. N6-adenosyl-methylation is the most prominent type of mRNA methylation and plays a crucial role in processes such as metabolism, but also response to physical stress. Our findings underpin its essential role by also providing a link to social stress evoked by hierarchy building within same-sex groups. As recently, search for small molecule modifiers for the respective class of RNA modifying enzymes has started, this might even lead to new therapeutic approaches against stress disorders.

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Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways

Scientific Reports ◽

10.1038/s41598-021-90521-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

F. Quessy ◽

T. Bittar ◽

L. J. Blanchette ◽

M. Lévesque ◽

B. Labonté

Keyword(s):

Molecular Interactions ◽

Life Stress ◽

Social Stress ◽

Cognitive Strategies ◽

Social Defeat ◽

Social Defeat Stress ◽

Male And Female ◽

Female Mice ◽

Males And Females ◽

Dopaminergic Pathways

AbstractOur ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidence suggests that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical dopaminergic pathways. Yet, the molecular interactions underlying these changes are still poorly understood, and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and mesocortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of activity-dependent markers pERK and c-fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Our results show that social stress decreases the density of TH+ dopaminergic axonal projections in the deep layers of the mPFC in susceptible but not resilient male and female mice. Consistently, our analyses suggest that pERK expression is decreased in the mPFC but increased in the NAc following CSDS in males and females, with no change in c-fos expression in both sexes. Overall, our findings indicate that social defeat stress impacts the mesolimbic and mesocortical pathways by altering the molecular interactions regulating somatic and axonal plasticity in males and females.

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Activation of Npas1-neurons in the Ventral Pallidum Mediates Stress Susceptibility

10.1101/2021.10.27.466188 ◽

2021 ◽

Author(s):

Gessynger Morais-Silva ◽

Hyungwoo Nam ◽

Rianne Campbell ◽

Mahashweta Basu ◽

Marco Pagliusi ◽

...

Keyword(s):

Social Stress ◽

Brain Regions ◽

Lateral Septum ◽

Ventral Pallidum ◽

Heterogeneous Structure ◽

Social Stressors ◽

Lateral Habenula ◽

Electrophysiological Properties ◽

Gray Area ◽

Stress Susceptibility

Background: Altered activity of the ventral pallidum (VP) underlies disrupted motivation after stress exposure. The VP is a very heterogeneous structure comprised of many different neuron types with distinct electrophysiological properties and projections. Neuronal PAS 1-positive (Npas1+) VP neurons are thought to send projections to brain regions critical for stress response. In this study, we evaluated how activity of VP Npas1+ neurons affect emotional behaviors and responses to social stress. Methods: We used a chemogenetic approach to manipulate VP Npas1+ neurons during social defeat stress (SDS) and behavioral tasks related to anxiety and motivation in Npas1-Cre mice. We employed a similar approach in females using the chronic witness defeat stress (CWDS). Finally, to characterize VP Npas1+ neuron circuitry and molecular identity we evaluated the projection targets of the VP Npas1+ neurons and performed RNA-seq on ribosome-associated mRNA from VP Npas1+ neurons. Results: Chemogenetic activation of VP Npas1+ neurons increased susceptibility to a subthreshold (S)SDS and anxiety-like behavior in the elevated plus maze and open field. Inhibition of VP Npas1+ neurons enhanced resilience to chronic (C)SDS and CWDS. We identified VP Npas1+ projections to the nucleus accumbens (NAc), ventral tegmental area (VTA), medial and lateral habenula (LHb), lateral hypothalamus (LH), thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas1+ neurons displayed distinct transcriptomes representing distinct biological processes. Conclusions: Activity, of VP Npas1+ neurons, modulates susceptibility to social stressors and anxiety-like behavior. These outcomes could be related to their projections to brain regions that modulate reward and aversion.

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Modulating chronic stress

eLife ◽

10.7554/elife.63996 ◽

2020 ◽

Vol 9 ◽

Author(s):

Debra A Bangasser ◽

Evelyn Ordoñes Sanchez

Keyword(s):

Chronic Stress ◽

Social Rank ◽

Male And Female ◽

Female Mice

Social rank differentially influences how male and female mice respond to chronic stress.

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Sex-specific retinal anomalies induced by chronic social stress in mice

10.1101/2020.09.28.317230 ◽

2020 ◽

Author(s):

E Arsenault ◽

AA Lavigne ◽

S Mansouri ◽

K Francis ◽

TP Bittar ◽

...

Keyword(s):

Stress Response ◽

Social Stress ◽

Social Defeat ◽

Major Depressive ◽

Male And Female ◽

Retinal Activity ◽

Female Mice ◽

Chronic Social Defeat Stress ◽

Before And After ◽

The Brain

AbstractMajor depressive disorder (MDD) is one of the most common consequences of chronic stress. Still, there is currently no reliable biomarker to detect individuals at risk to develop MDD. Recently, the retina emerged as an effective way to approach the brain and investigate psychiatric disorders with the use of the electroretinogram (ERG). In this study, cones and rods ERGs were performed in male and female mice before and after chronic social defeat stress (CSDS). Mice were then divided as susceptible or resilient to stress. Significant results were only observed in rods ERGs. In males, susceptible mice showed prolonged a-wave implicit times at baseline that were shortened after CSDS. The a-wave was also decreased in both susceptible and resilient male mice after CSDS. In females, rod a-waves were shorter in susceptible than in control mice after CSDS resulting from the latter demonstrating delayed a-waves. Baseline ERGs were able to predict – to some extent – the expression of susceptibility and resilience before stress exposition in male and female mice. Overall, our findings suggest that retinal activity is a presumptive biomarker of stress response and that the ERG could potentially serve as a predicting tool of the stress response in mice.

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