Takeoka, A. | Search bioRxiv

bioRxiv2022

Electrophysiological signatures reveal spinal learning mechanisms for a lasting sensorimotor adaptation

Neurocircuits within the spinal cord are essential for movement automaticity. However, spinal mechanisms that underlie lasting sensorimotor adjustments remain unclear. Here, we establish a quantitative kinematic framework to characterize a conditioning behavior in which spinal circuits without brain input learn to adapt motor output upon multimodal sensory integration, undergo extinction, and reinforcement of learned behavior with repetitive training. In-vivo Neuropixel spinal cord recordings from awake behaving mice reveal learning phase-tuned single unit activities. In addition, optically identified unit recordings and a loss-of-function experiment demonstrate an essential function of a class of spinal inhibitory interneurons in this learning paradigm. Together, these data reveal neuronal underpinnings that shape lasting sensorimotor adaptation where stable sensory dissemination regulates learning and the existence of neuronal assembly that retains learned behavior.

neuroscience↗

bioRxiv2021

Met/HGFR triggers detrimental reactive microglia in TBI

The complexity of the signaling events, cellular responses unfolding in neuronal, glial and immune cells upon Traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We used array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then to scrutinize the large-scale effects of the perturbation of cMet/HGFR, VEGFR1 and Btk signaling by small molecules. cMet/HGFR emerged as a selective modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of microglial inflammatory mediators, of reactive microglia morphology and of TBI-associated responses in neurons, vessels and brain extracellular matrix. Acute or prolonged cMet/HGFR inhibition ameliorated neuronal survival and motor recovery. Early elevation of HGF itself in the CSF of TBI patients suggest that this mechanism has translational value in human subjects. Our findings identify cMet/HGFR as a modulator of early neuroinflammation in TBI with translational potential and indicate several RTK families as possible additional targets for TBI treatment. SummaryControlling neuroinflammation in neurotrauma is an important but unachieved goal. This study exploits a moderate TBI model and array-based proteomics to identify cMet as a new inducer of reactive microglia. A small-molecule inhibitor of cMet contains microglial reactivity, reduces neuronal and vascular alterations, limits behavioural disturbances and accelerates recovery. HighlightsO_LIMet is activated in microglia upon TBI and drives microglial reactivity. C_LIO_LIA Met inhibitor reduces motor dysfunction upon TBI and promotes recovery. C_LIO_LIBlockade of MET prevents the appearance of a reactive microglia. C_LIO_LIThe cMET inhibitor reduces the sub-acute neuronal loss after TBI. C_LI

neuroscience↗