2026 ECNP Congress

PS02-2256

Subordination experiences disrupt network adaptivity, biasing negative hippocampal recall

Jonathan Reinwald — N. Danai, C. Nelias, W. Weber-Fahr, W. Kelsch · University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz, Germany

2026 ECNP Congress

Introduction

Individuals differ in how they recall the same negative event, and such cognitive biases can predispose to depression [1]. Such individual differences may emerge even in genetically identical individuals through cumulative individual-by-environment experiences [2]. Social status also modulates depression risk [3], but the connection between everyday rank experiences and negative recall is largely unknown. Competing systems-level hypotheses propose that either adaptive network reconfiguration or retention of pre-existing topology protects against negative events [4,5].

Aims

We tested how social-rank experiences determine the individual adaptivity–stability balance of whole-brain networks during recall of a mild aversive association.

Methods

Twenty-four genetically identical male C57BL/6J mice lived in two semi-naturalistic group habitats (Non-invasive Sensor-rich Maze; NoSeMaze), where individual animals were continuously tracked and social rank was derived from spontaneous tube competitions using David’s scores. After at least two weeks in stable hierarchies, mice underwent awake 9.4 T functional magnetic resonance imaging during odour-guided aversive conditioning. The paradigm comprised pre-conditioning, probabilistic pairing of odour and aversive air-puff, and odour-only recall. Additional cohorts served as no-puff controls (n=24), behavioural learning controls with eyelid recordings (n=9), and haemodynamic-response calibration animals (n=11). Blood oxygenation level-dependent activity was analysed with general linear models and cluster-level family-wise error correction. Task functional connectivity was estimated by beta-series correlation and tested with network-based statistics. Graph-theoretical measures quantified local coupling, long-distance integration, and small-world organisation of the brain network. Rank effects were assessed with Pearson correlations, whole-brain covariate models, decomposition into dominance and subordination components, and bootstrapped mediation analyses.

Results

Mice acquired defensive conditioned eyelid responses that were most persistent at the expected air-puff time. During recall, conditioning engaged a distributed olfactory, prefrontal, insular, striatal, hippocampal, thalamic, and midbrain network (network-based statistics, p<0.05), with stronger functional connectivity than in no-puff controls. Network organisation shifted towards a more locally specialised state, with increased local strength and clustering (permutation tests, p<0.0001), reduced long-distance integration, and stronger segregation. This shift was specific to the expected air-puff time and absent at odour onset. Social rank predicted network adaptation: high-rank mice showed stronger local specialisation and reduced long-distance integration, whereas low-rank mice showed little reconfiguration. Decomposition of rank showed that cumulative subordination, rather than dominance, accounted for weaker network adaptation. At the regional level, whole-brain analysis identified bilateral ventral hippocampal activity as significantly modulated by social rank during negative recall (cluster-defining p<0.01, family-wise error-corrected p<0.05; robust at p<0.001). Low-rank mice showed ventral hippocampal reactivation, whereas high-rank mice showed deactivation. Mediation analysis indicated that network adaptation partly explained the link between social rank and ventral hippocampal recall activity (indirect effect β=0.160, 95% confidence interval 0.04–0.31, p=0.013), accounting for 20% of the total effect.

Conclusions

Everyday subordination experiences may weaken adaptive brain-network reconfiguration during negative recall, leaving ventral hippocampal activity less constrained. This suggests that social experience shapes negative-memory processing through state-dependent network adaptivity rather than through isolated regional activation alone. Although restricted to male mice and one mild aversive paradigm, these findings identify network adaptivity as a candidate mechanism linking social ecology to resilience-related brain function.

References

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  2. Freund J, Brandmaier AM, Lewejohann L, et al. Emergence of individuality in genetically identical mice. Science. 2013;340(6133):756–759.
  3. Larrieu T, Sandi C. Stress-induced depression: is social rank a predictive risk factor? BioEssays. 2018;40(7):e1800012.
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  5. Homberg JR, Jagiellowicz J. A neural model of vulnerability and resilience to stress-related disorders linked to differential susceptibility. Molecular Psychiatry. 2022;27(1):514–524.