Systematic Evaluation of Competing Brain Transcriptomic Representations Reveals Reciprocal Patterns Across Heterogeneous Contexts

Abstract

Adaptive and adverse brain states are often assumed to lie on a shared molecular continuum, but this assumption has rarely been evaluated against explicit transcriptomic alternatives. This study aimed to compare two representations of cross-context brain transcriptomic organization: a transcriptome-wide global-axis model and a low-dimensional reciprocal model. We benchmarked these models across a curated cross-study brain cohort spanning exercise, alcohol-related adversity-like contexts, stress, aging, and neurodegeneration, using prespecified intervention-like and adversity-like directional contrast labels rather than assuming homogeneous biological states. We assessed the competing representations using signed-effect correlations, permutation analyses, non-linear fitting, and held-out reconstruction, and we then examined the resulting structure through region-specific human bulk evaluation and exploratory cellular, single-nucleus, spatial, and chromatin projection analyses. These downstream analyses were used to examine localization and biological interpretability and were not treated as independent evaluation of the module 1/module 2 (M1/M2) partition. The combined signed-effect statistics were interpreted as representation-level directional summaries rather than estimates of a homogeneous cross-study biological effect. The global-axis model received limited support: intervention-like and adversity-like signed-effect summaries were only weakly correlated, were not stronger than permutation null expectations, and were not improved by non-linear fitting. Within the selected reciprocal-gene space, a rank-1 latent profile reconstructed held-out genes more accurately than the hard M1/M2 partition, whereas the M1/M2 discretization provided a more interpretable but selection-conditioned directional summary. Human analyses yielded an asymmetric pattern: a significant M1 association was observed only in the hippocampal dataset, whereas M2, the reciprocal index, and the other examined brain regions showed no consistent corresponding effects; leave-one-stratum-out analyses indicated poor cross-stratum reproducibility of the exact gene-level partition. These findings motivate a low-dimensional reciprocal representation as an exploratory framework while emphasizing context dependence, cohort dependence, and heterogeneity.