Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury

Delgado, T.; Arefin, T. M.; Pagan, I.; Weekley, B. H.; Rodwell_Bullock, J.; . Chowdhury, M. R.; Crum, A. B.; Maze, I.; Brookes, P. S.; Meeks, J. P.; Johnson, G. V.

doi:10.64898/2026.07.16.738974

bioRxiv · 10.64898/2026.07.16.738974

Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury

Delgado, T.·Arefin, T. M.·Pagan, I.·Weekley, B. H.·Rodwell_Bullock, J.·. Chowdhury, M. R.·Crum, A. B.·Maze, I.·Brookes, P. S.·Meeks, J. P.·Johnson, G. V.

View original source ↗Export metadata ↓

Abstract

Mild traumatic brain injury (mTBI) is the most common form of central nervous system (CNS) injury and is often characterized by persistent neuroinflammation, metabolic dysregulation, and oxidative stress. Repetitive injuries compound these pathologies and lead to multifocal axonal injuries and long-term functional deficits. Despite the prevalence of mTBIs, the cellular mechanisms that facilitate or prevent recovery following injury remain poorly defined. Here, we extend our previous work on the role of the protein transglutaminase 2 (TG2) in CNS injury and we hypothesize that transcriptional regulation by TG2 restricts metabolic versatility in astrocytes following TBI, thereby impairing neuronal energetic support and worsening pathological outcomes. We utilized an established weight-drop model of repetitive mTBI followed by multi-parametric analysis of TBI pathology in complete TG2 knockout (TG2-/-) and wild type mice. At 28 days post-injury, TG2-/- mice showed marked attenuation of TBI pathology, compared to wild type mice, in vulnerable white matter and default mode network (DMN) regions, as assessed by diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and immunohistochemistry. Integrated epigenomic, proteomic, and metabolomic profiling of cortical astrocytes isolated 28 days after injury revealed a pronounced metabolic restriction in wild type astrocytes which was remarkably attenuated in the TG2-/- mice. This rescue was associated with a de-repression of gene networks involved in glutamate recycling, lipid metabolism, and metabolic homeostasis. Together, these studies provide novel mechanistic insights into the metabolic dysregulation that characterizes persistent TBI pathology, and establish a foundation for evaluating TG2 as a therapeutic target for TBI.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Delgado, T., Arefin, T. M., Pagan, I., Weekley, B. H., Rodwell_Bullock, J., . Chowdhury, M. R., Crum, A. B., Maze, I., Brookes, P. S., Meeks, J. P., Johnson, G. V.. 2026-07-21. Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury. https://doi.org/10.64898/2026.07.16.738974

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗

bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗

bioRxiv2026

Why Is Spontaneous Blink Timing Informative? An Adaptive Scheduling Perspective

Spontaneous eye blinks have long been linked to cognitive processing, yet how task demands shape blink timing and its relationship to behavioral performance remains unclear. We examined spontaneous blink behavior in 576 adults performing two variants of the Continuous Performance Task (CPT). Blink occurrence and timing were most strongly modulated by the experimental condition in the more demanding CPT-AX task, whereas their association with response time was stronger in the CPT-X task, where more consistent blink timing predicted faster responses. This dissociation suggests that task structure changes not only blink behavior but also the behavioral relevance of blink timing. These findings are consistent with an adaptive scheduling account of spontaneous blinking and provide a conceptual framework for understanding when and why blink timing contains chronometric information about ongoing cognition.

neuroscience↗