Biology subjects

Groh, J.

Publications and source records attributed to Groh, J..

4 recordsLinked to original sources

bioRxiv2023

Genetically perturbed myelin as a risk factor for neuroinflammation-driven axon degeneration

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

neuroscience↗

bioRxiv2023

Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed myelinating oligodendrocytes in PLP1 mutant mice

Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.

neuroscience↗

bioRxiv2019

Compensating for a shifting world: A quantitative comparison of the reference frame of visual and auditory signals across three multimodal brain areas

Stimulus locations are detected differently by different sensory systems, but ultimately they yield similar percepts and behavioral responses. How the brain transcends initial differences to compute similar codes is unclear. We quantitatively compared the reference frames of two sensory modalities, vision and audition, across three interconnected brain areas involved in generating saccades, namely the frontal eye fields (FEF), lateral and medial parietal cortex (M/LIP), and superior colliculus (SC). We recorded from single neurons in head-restrained monkeys performing auditory- and visually-guided saccades from variable initial fixation locations, and evaluated whether their receptive fields were better described as eye-centered, head-centered, or hybrid (i.e. not anchored uniquely to head- or eye-orientation). We found a progression of reference frames across areas and across time, with considerable hybrid-ness and persistent differences between modalities during most epochs/brain regions. For both modalities, the SC was more eye-centered than the FEF, which in turn was more eye-centered than the predominantly hybrid M/LIP. In all three areas and temporal epochs from stimulus onset to movement, visual signals were more eye-centered than auditory signals. In the SC and FEF, auditory signals became more eye-centered at the time of the saccade than they were initially after stimulus onset, but only in the SC at the time of the saccade did the auditory signals become predominantly eye-centered. The results indicate that visual and auditory signals both undergo transformations, ultimately reaching the same final reference frame but via different dynamics across brain regions and time. New and NoteworthyModels for visual-auditory integration posit that visual signals are eye-centered throughout the brain, while auditory signals are converted from head-centered to eye-centered coordinates. We show instead that both modalities largely employ hybrid reference frames: neither fully head-nor eye-centered. Across three hubs of the oculomotor network (intraparietal cortex, frontal eye field and superior colliculus) visual and auditory signals evolve from hybrid to a common eye-centered format via different dynamics across brain areas and time.

neuroscience↗

bioRxiv2019

Hemisphere-Specific Properties of the Ventriloquism Aftereffect in Humans and Monkeys

Visual calibration of auditory space requires re-alignment of representations differing in 1) format (auditory hemispheric channels vs. visual maps) and 2) reference frames (head-centered vs. eye-centered). Here, a ventriloquism paradigm from Kop[c]o et al. (J Neurosci, 29, 13809-13814) was used to examine these processes in humans and monkeys for ventriloquism induced within one spatial hemifield. Results show that 1) the auditory representation is adapted even by aligned audio-visual stimuli, and 2) the spatial reference frame is primarily head-centered in humans but mixed in monkeys. These results support the view that the ventriloquism aftereffect is driven by multiple spatially non-uniform processes.\n\nPACS numbers: 43.66.Pn, 43.66.Qp, 43.66.Mk

neuroscience↗