Sonntag, W. E. | bioRxiv Science

bioRxiv2026

COGNITIVE HETEROGENEITY AND AGING: AN AGE-INDEPENDENT CILIARY GENE PROGRAM TRACKS COGNITIVE RESILIENCE IN MICE

Cognitive decline with age is often viewed as inevitable, yet older animals show striking heterogeneity in functional trajectories, with many preserving cognitive integrity despite physiological decline. The biological basis of this resilience remains poorly understood, partly due to insensitive behavioral testing paradigms. Using an automated home-cage platform and hippocampal RNA sequencing, we integrated behavioral phenotyping with transcriptomic profiling to disentangle molecular programs linked to cognitive performance from chronological age. Behavioral data from 906 C57BL/6 mice across 129 standardized studies, trajectory-based modeling, variance-partitioned correlation, and stability-driven gene prioritization identified a transcriptional signature (271 genes) linked to cognitive state independent of age. Preserved cognition was associated with higher expression of genes governing ciliary structure and motility, neurite organization, and synaptic architecture, while impairment was associated with neuroimmune and metabolic-stress programs. A 38-gene cilia structural module score remained associated with resilience after controlling for age (partial rho = -0.81), with consistent effects across leave-one-out resampling. Because the constituent genes were selected on this same outcome, the module-level magnitude is not an unbiased effect-size estimate; recalibration against a null that reapplies the full selection procedure gave an empirical p of 0.026. This divergence emerged among genetically identical mice, indicating non-genetic, discrete hippocampal molecular signatures underlying individual differences. Cell-type attribution against the Allen Brain Cell Atlas localized the module predominantly to ependymal cells, with 27 of 38 genes ependymal-restricted (median detection 90.2% in ependymal cells versus 1.1% in CA1 glutamatergic neurons) and three genes (Dnah9, Dnai4, Kif9) also detected in CA1. The association was not attributable to ependymal tissue content: the module score was unrelated to Foxj1 expression (rho = -0.016) and the partial correlation was unchanged after adjustment for ependymal and choroid plexus marker panels, indicating that the module reflects how strongly the ciliary program is expressed rather than how many ependymal cells each sample contained. These findings support a conceptual shift: cognitive trajectories appear shaped by intrinsic molecular set points rather than by chronological age, with expression of a motile ciliary program at the cerebrospinal fluid interface, rather than the abundance of the cells carrying it, emerging as a candidate correlate of resilience. This approach offers a generalizable strategy for dissecting functional heterogeneity from aging and identifying pathways for hypothesis-driven tests of resilience across the lifespan.

animal behavior and cognition↗

bioRxiv2021

Adulthood Deficiency of the Insulin-like Growth Factor-1 Receptor in Hippocampal Neurons Impairs Cell Structure and Spatial Learning and Memory in Male and Not Female Mice

Reductions in insulin-like growth factor-1 (IGF-1) are associated with cognitive impairment and increased risk of neurodegenerative disease in advanced age. In mouse models, reduced IGF-1 early-in-life leads to memory impairments and synaptic dysfunction; however, these models are limited by systemic reductions in IGF-1. We hypothesized that IGF-1 continues to promote hippocampal neuron structure and function after development, and as such, the loss of IGF-1 signaling in adult neurons would lead to impaired spatial learning and memory. To test this, the IGF-1 receptor (IGF-1R) was genetically targeted in hippocampal neurons of adult male and female mice. Male mice deficient in neuronal IGF-1R exhibited spatial learning impairments as evidenced by increased pathlength and errors in the radial arm water maze. No differences in learning and memory were observed in female mice. Golgi-Cox staining revealed a reduced number of dendritic boutons of neurons the CA1 region of the hippocampus in male mice. Decreased MAPK and increased ROCK activity were also observed in these tissues. In vitro studies revealed that impaired neurite outgrowth due to inhibited IGF-1R signaling could be rescued by pharmacological inhibitors of ROCK. However, ROCK inhibition in neuronal IGF-1R-deficient mice did not fully rescue learning impairments or bouton numbers. Together, our study highlights that IGF-1 continues to support spatial learning and memory and neuronal structure in adulthood.

neuroscience↗