SARS-CoV-2 induces acute neurological signs while Calcitonin Gene-Related Peptide (CGRP) signaling blockade reduces interleukin 6 (IL-6) release and weight loss in mouse models

Rahman, S. M.; Buchholz, D. W.; Imbiakha, B.; Jaeger, M. C.; Leach, J.; Osborn, R. M.; Birmingham, A. O.; Dewhurst, S.; Aguilar, H. C.; Luebke, A. E.

doi:10.1101/2023.10.23.563669

bioRxiv · 10.1101/2023.10.23.563669

SARS-CoV-2 induces acute neurological signs while Calcitonin Gene-Related Peptide (CGRP) signaling blockade reduces interleukin 6 (IL-6) release and weight loss in mouse models

Rahman, S. M.·Buchholz, D. W.·Imbiakha, B.·Jaeger, M. C.·Leach, J.·Osborn, R. M.·Birmingham, A. O.·Dewhurst, S.·Aguilar, H. C.·Luebke, A. E.

View original source ↗Export metadata ↓

Abstract

COVID-19 can result in neurological symptoms such as fever, headache, dizziness, and nausea. However, neurological signs of SARS-CoV-2 infection have been hardly assessed in mouse models. Here, we infected two commonly used wildtype mice lines (C57BL/6 and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including motion- related dizziness. We then evaluated whether the Calcitonin Gene-Related Peptide (CGRP) receptor antagonist, olcegepant, used in migraine treatment could mitigate acute neuroinflammatory and neurological responses to SARS-COV-2 infection. We infected wildtype C57BL/6J and 129/SvEv mice, and a 129 CGRP-null mouse line with a mouse-adapted SARS- CoV-2 virus, and evaluated the effect of CGRP receptor antagonism on the outcome of that infection. First, we determined that CGRP receptor antagonism provided protection from permanent weight loss in older (>12 m) C57BL/6J and 129 SvEv mice. We also observed acute fever and motion-induced dizziness in all older mice, regardless of treatment. However, in both wildtype mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels by half, with virtually no IL-6 release in mice lacking CGRP. These findings suggest that migraine inhibitors such as those blocking CGRP signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic and/or endemic coronaviruses. ImportanceCOVID-19 can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. Here, we first infected two commonly used wildtype mice lines (C57BL/6 and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including motion-related dizziness. Further, we showed that migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes of infection.

Source connections

Published article ↗

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Rahman, S. M., Buchholz, D. W., Imbiakha, B., Jaeger, M. C., Leach, J., Osborn, R. M., Birmingham, A. O., Dewhurst, S., Aguilar, H. C., Luebke, A. E.. 2023-10-24. SARS-CoV-2 induces acute neurological signs while Calcitonin Gene-Related Peptide (CGRP) signaling blockade reduces interleukin 6 (IL-6) release and weight loss in mouse models. https://doi.org/10.1101/2023.10.23.563669

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗

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↗