Biology subjects

Diaz-Garcia, C. M.

Publications and source records attributed to Diaz-Garcia, C. M..

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↗

bioRxiv2022

The Na+/K+ pump dominates control of glycolysis in hippocampal dentate granule cells

Cellular ATP that is consumed to perform energetically expensive tasks must be replenished by new ATP through the activation of metabolism. Neuronal stimulation, an energetically demanding process, transiently activates aerobic glycolysis, but the precise mechanism underlying this glycolysis activation has not been determined. We previously showed that neuronal glycolysis is correlated with Ca2+ influx, but is not activated by feedforward Ca2+ signaling (Diaz-Garcia, Meyer, et al., 2021). Since ATP-powered Na+ and Ca2+ pumping activities are increased following stimulation to restore ion gradients and are estimated to consume most neuronal ATP, we aimed to determine if they are coupled to neuronal glycolysis activation. By using two-photon imaging of fluorescent biosensors and dyes in dentate granule cell somas of acute mouse hippocampal slices, we observed that production of cytoplasmic NADH, a byproduct of glycolysis, is strongly coupled to changes in intracellular Na+, while intracellular Ca2+ could only increase NADH production if both forward Na+/Ca2+ exchange and Na+/K+ pump activity were intact. Additionally, antidromic stimulation-induced intracellular [Na+] increases were reduced >50% by blocking Ca2+ entry. These results indicate that neuronal glycolysis activation is predominantly a response to an increase in activity of the Na+/K+ pump, which is strongly potentiated by Na+ influx through the Na+/Ca2+ exchanger during extrusion of Ca2+ following stimulation.

neuroscience↗

bioRxiv2021

Metabolic regulation of species-specific developmental rates

Animals display significant inter-specific variation in the rate of embryonic development despite broad conservation of the overall sequence of developmental events. Differences in biochemical reaction speeds, including the rates of protein production and degradation, are thought to be responsible for distinct species-specific rates of development [1-3]. However, the cause of differential biochemical reaction speeds between species remains unknown. Using pluripotent stem cells, we have established an in vitro system that recapitulates the two-fold difference in developmental rate between early mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we showed that mass-specific metabolic rates scale with developmental rate and are therefore elevated in mouse cells compared to human cells. We further showed that reducing these metabolic rates by pharmacologically inhibiting the electron transport chain slows down the segmentation clock. The effect of the electron transport chain on the segmentation clock is mediated by the cellular NAD+/NADH redox balance independent of ATP production and, further downstream, by the global rate of protein synthesis. These findings represent a starting point for the manipulation of developmental rate, which would find multiple translational applications including the acceleration of human pluripotent stem cell differentiation for disease modeling and cell-based therapies.

developmental biology↗

bioRxiv2020

The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle

When neurons engage in intense periods of activity, the consequent increase in energy demand can be counteracted by the coordinated activation of glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. However, the trigger for glycolytic activation is unknown and the role for Ca2+ in the mitochondrial responses has been debated. Using genetically-encoded fluorescent biosensors and NAD(P)H autofluorescence imaging in acute hippocampal slices, here we find that Ca2+ uptake into the mitochondria is responsible for the buildup of mitochondrial NADH, probably through Ca2+ activation of dehydrogenases in the TCA cycle. In the cytosol, we do not observe a role for the Ca2+/calmodulin signaling pathway, or AMPK, in mediating the rise in glycolytic NADH in response to acute stimulation. Calcium, nevertheless, is a major contributor to glycolysis, although not strictly necessary. Aerobic glycolysis in neurons is triggered mainly by the energy demand resulting from either Na+ or Ca2+ extrusion. Impact StatementWhen neurons are stimulated, calcium influx instructs mitochondria to increase energy metabolism, but it is increased energy demand in cytosol rather than Ca2+ signaling that leads to increased neuronal glycolysis.

neuroscience↗