Biology subjects

Stieger, K.

Publications and source records attributed to Stieger, K..

4 recordsLinked to original sources

bioRxiv2026

Astrocyte modulation of neural activity during intracortical microstimulation

Electrical manipulation of neural circuits has advanced our understanding of brain function, but the mechanisms that shape neural activity during stimulation remain incompletely understood. This gap reflects a persistent neuron-centric view of stimulation that overlooks the regulatory influence of glial cells, especially for long duration stimuli. Here we investigated whether astrocytes actively shape the brains response to different patterns of stimulation. Using two-photon and mesoscale calcium imaging of the visual cortex in awake mice, we bidirectionally manipulated astrocyte calcium signaling during intracortical microstimulation (ICMS) via chemogenetic (hM3Dq) and optogenetic (melanopsin) tools. We show that astrocytes respond to stimulation in a pattern-dependent way and shape ongoing neural activity rather than simply following it. Near the electrode, neurons responded to astrocyte modulation in mixed directions, some increasing and some decreasing. Instead of uniformly raising or lowering activity, changing astrocyte calcium pulled neuronal responses toward an intermediate state, with the direction determined by each neurons starting response and its distance from the electrode. Our results identify astrocyte calcium as a source of this shaping during electrical stimulation, and highlight the need to incorporate neuron-glia dynamics into the design of therapeutic neurostimulation.

bioengineering↗

bioRxiv2026

The Onset of Breathing at Birth Switches Off Regenerative Capacity

Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO2 exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO2 exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK), which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO2 inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO2 inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO2/pH signaling shapes the regenerative capacity across life and pointing to a potential CO2-based strategy for promoting tissue regeneration.

neuroscience↗

bioRxiv2026

Mitochondrial COX4I2 drives pericyte-dependent inflammation and emphysema

Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic inflammation, emphysema, and mild pulmonary hypertension (PH). Oxidative/nitrosative stress are key drivers, but specific mitochondrial mechanisms remain unclear. We show increased expression of the regulatory mitochondrial cytochrome c oxidase subunit 4 isoform 2 (COX4I2) in an early murine model and human COPD. After 8 months of cigarette smoke exposure, Cox4i2-/- mice were completely protected from emphysema but not from PH, associated with reduced nitrosative stress, inflammation, and apoptosis. Using a novel Cox4i2 reporter mouse and in situ hybridization of human lungs, COX4I2 was detected in precapillary ACTA2+ cells and capillary pericytes. COX4I2 promotes mitochondrial reactive oxygen species (mtROS) production in these cells, thereby enhancing neutrophil migration and alveolar type II cell apoptosis, and modulates angiogenesis. In contrast to Cox4i2-/-, mitochondria-targeted antioxidant MitoQ reversed emphysema and PH, suggesting pericyte-specific regulation of COPD pathologies and mtROS inhibition as a therapeutic approach in COPD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/703513v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@83bca4org.highwire.dtl.DTLVardef@d5ebaborg.highwire.dtl.DTLVardef@632d1borg.highwire.dtl.DTLVardef@1267a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Microglia surveillance is directed toward neuron activation during sustained intracortical microstimulation

Intracortical microstimulation (ICMS) is a widely used tool for neuroprostheses, but its long-term efficacy is often limited by biofouling and neuroinflammatory responses at the electrode-tissue interface. Microglia orchestrate neuroinflammation and regulate synaptic plasticity, and low-frequency stimulation has been shown to promote anti-inflammatory microglial phenotypes. We therefore examined, over the first three days post-implantation, how 10-Hz ICMS influences microglial-neuronal interactions in vivo using two-photon imaging in Cx3cr1-GFP/jRGECO1a mice. A one-hour session of 10-Hz ICMS did not induce overt morphological activation of microglia but increased their process motility, directing extensions toward both the electrode and neurons exhibiting elevated calcium activity. By post-implantation Day 2, microglial extensions were significantly biased toward neurons whose {Delta}F/F surpassed a 3 standard deviation threshold after stimulation onset (74.26{degrees} {+/-} 11.83{degrees}) but shifted away from those same neurons after 40 min of continuous stimulation (116.99{degrees} {+/-} 9.19{degrees}) (p = 0.001732), suggesting a dynamic, homeostatic response to sustained neuronal calcium elevations. Although multi-day electrode insertion accelerated microglial motility and polarization toward the device, 10-Hz ICMS alone did not alter microglial branching or soma shape. Microglial contact frequency scaled with neuronal adaptation profiles: depressed neurons received the most contacts immediately post-implant (1.15 {+/-} 0.3 contacts; p = .0460). These findings reveal stimulus-associated, neuron-dependent surveillance behaviors of microglia during early post-implantation ICMS and implicate them as active participants in short-term modulation of cortical circuits.

bioengineering↗