Biology subjects

Steiner, S. C.

Publications and source records attributed to Steiner, S. C..

3 recordsLinked to original sources

bioRxiv2026

A Role for Astrocyte Metabolism in Species-Specific Neuronal Development

Human neurons develop more slowly than non-human primate (NHP) neurons, a phenomenon called neoteny, but research has primarily focused on neuron-intrinsic drivers. We hoped to further elucidate any species-specific divergence in function and the astrocytes role in influencing species-specific neurodevelopment rate. In this study, we identified a delayed onset of gliogenesis in human versus NHP organoid models. Transcriptomic and 13C metabolic flux analyses of iPSC-derived astrocytes revealed distinct metabolic profiles: NHP astrocytes exhibit increased serine and glycine synthesis, whereas human astrocytes show elevated lactate secretion, suggesting a change in the metabolic role of astrocytes across primate evolution. We then assessed the impact of these different species astrocytes on neuronal development. We observed an increase in electrophysiological maturation and a change in transcriptomic neuronal development trajectory in human neurons cultured with rhesus astrocyte conditioned media as opposed to human astrocyte conditioned media. Human astrocyte secretomes were enriched for synaptogenic and axon-growth proteins, which could indicate they play a greater role in supporting structural complexity and dendritic arborization over rapid maturation when compared to NHP astrocytes. Finally, chemical inhibition of PHGDH demonstrated that these changes in neuronal differentiation are partially mediated by the different metabolic roles that astrocytes play in humans versus NHPs. Collectively, our results reveal a cell-extrinsic role for astrocyte metabolism in shaping human-specific neurodevelopmental timing and trajectories. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/737608v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@ad88f4org.highwire.dtl.DTLVardef@fa5cf5org.highwire.dtl.DTLVardef@ecf0eborg.highwire.dtl.DTLVardef@1bcf078_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia

While Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for late-onset Alzheimers disease, its mechanistic role in the brain-resident macrophage, microglia, remains elusive. Microglia are important in the clearance of pathology in disease, heavily relying on lysosome functionality; therefore, we sought to understand the impact of APOE4 on microglial function. APOE44 microglia have been shown to have lipid accumulation, yet the mechanisms leading to this accumulation are unknown. Using induced pluripotent stem cell-derived microglia, we found that the APOE4 haplotype resulted in transcriptional state shifts in microglia, suppressing activated-response microglia (ARMs) and promoting a G2 senescent-like state. We found that APOE44 microglia accumulate cholesterol esters and provide less lipid support to fibroblast-induced neurons, decreasing their synaptic connections. APOE44 microglia secrete significantly less lipoproteins, leading to the accumulation of lipoproteins within the cells including the lysosomes. APOE44 microglia exhibit impaired lysosomal acidification and degradation capacity. Further, our results elucidated that APOE44 microglia are proinflammatory and shift away from fatty acid oxidation towards glycolysis, due to dysfunctional mitochondria. Taken together, our findings indicate that a loss-of-function in lipoprotein secretion drives intracellular lipid accumulation, including within lysosomes, ultimately disrupting the lysosome-endoplasmic reticulum-mitochondrial axis. This drives a proinflammatory and metabolically compromised microglial phenotype with impaired neuro-supportive functions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/724612v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@18d6a2org.highwire.dtl.DTLVardef@b3644dorg.highwire.dtl.DTLVardef@17e3716org.highwire.dtl.DTLVardef@1529caf_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Multiple sequential prediction errors during reward processing in the human brain

Recent developments in reinforcement learning, cognitive control, and systems neuroscience highlight the complimentary roles in learning of valenced reward prediction errors (RPEs) and non-valenced salience prediction errors (PEs) driven by the magnitude of surprise. A core debate in reward learning focuses on whether valenced and non-valenced PEs can be isolated in the human electroencephalogram (EEG). Here, we combine behavioral modeling and single-trial EEG regression revealing a sequence of valenced and non-valenced PEs in an interval timing task dissociating outcome valence, magnitude, and probability. Multiple regression across temporal, spatial, and frequency dimensions revealed a spatio-tempo-spectral cascade from valenced RPE value represented by the feedback related negativity event-related potential (ERP) followed by non-valenced RPE magnitude and outcome probability effects indexed by subsequent P300 and late frontal positivity ERPs. The results show that learning is supported by a sequence of multiple PEs evident in the human EEG.

neuroscience↗