Biology subjects

Logan, S.

Publications and source records attributed to Logan, S..

4 recordsLinked to original sources

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↗

bioRxiv2025

Bridging Stem Cell Models and Medicine: Integrated 3D Human Cerebral Organoids and Pediatric Serum Reveal Mechanisms and Biomarkers of Anesthetic-Induced Neurotoxicity

BackgroundGeneral anesthetics have been shown to cause acute pathological changes in the developing brain, including neuronal cell death. These effects contribute to long-term cognitive and behavioral impairments observed in animal models. Epidemiological and prospective clinical studies have also reported associations between early-life exposure to anesthesia and neurodevelopmental deficits in children, raising significant concerns about pediatric anesthesia and highlighting the urgent need to understand the molecular mechanisms and biomarkers of anesthetic-induced developmental neurotoxicity (AIDN) using human-relevant models. MethodsThis study employed human induced pluripotent stem cell-derived cerebral organoids that were exposed to varying doses of anesthetic propofol for 1 to 6 hours, including single and repeated exposures. In parallel, serum samples were collected pre- and post-surgery from pediatric patients under 4 years old (n = 10 per group) who underwent either short (<1 hour) or prolonged anesthesia (>3 hours) at the Childrens Hospital of Wisconsin between September 2018 and October 2019. Pathological changes in organoids were assessed using chemical assays, electron microscopy, and western blotting. Brain injury-related proteins in patient serum were quantified via ELISA. Genome-wide expression profiling was conducted on 18,855 mRNAs and 27,427 lncRNAs in organoids and serum using microarray and bioinformatics. ResultsHigher doses, longer duration, and repeated exposures to propofol led to increased apoptosis in organoids. Six-hour exposure induced autophagy as evidenced by LC3-II elevation and led to dysregulation of 553 mRNAs and 792 lncRNAs in organoids, along with their co-expressed signaling networks, affecting pathways related to synaptic integrity, mitochondrial function, and inflammation. ELISA and serum analysis of pediatric patients (<4 years old) exposed to anesthesia (>3 hours) demonstrated elevated brain cell injury-associated proteins (e.g., increased NSE) and brain cell type-specific gene expression changes. Serum findings corroborated organoid data, identifying 21 mRNAs and 12 lncRNAs that were dysregulated in both models and associated with cell injury, neuronal development, inflammation, and learning deficits. ConclusionsThis study represents the first integrative transcriptomic analysis of AIDN using both 3D human cerebral organoids and pediatric patient serum--two complementary, human-relevant models. By identifying consistently dysregulated coding and non-coding RNAs across both platforms, we provide compelling evidence of shared molecular signatures linked to neuronal injury, inflammation, and neurodevelopmental disruption. These findings offer not only mechanistic insights but also lay the groundwork for the development of minimally invasive biomarkers and future therapeutic strategies. This dual-model approach bridges experimental discovery with clinical relevance, advancing the translational understanding of pediatric anesthetic neurotoxicity and supporting efforts to improve long-term neurological outcomes in vulnerable patient populations.

neuroscience↗

bioRxiv2023

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17-estradiol (17-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor is required for the majority of 17-E2-mediated benefits in male mice, but that 17-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor {beta} (ER{beta})-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17-E2-mediated benefits on systemic and hepatic metabolism are ER{beta}-dependent. We found that 17-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ER{beta}KO mice. ER{beta} ablation in male mice attenuated 17-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor {beta}1 (TGF-{beta}1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ER{beta} partially controls 17-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17-E2 likely signals through ER{beta} in HSCs to attenuate pro-fibrotic mechanisms.

physiology↗

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↗