Ben Messaoud, R. | bioRxiv Science

bioRxiv2023

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the following step of wrapping and expansion of myelin membranes. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for demyelinating diseases and neurodevelopmental disorders. SignificanceRemodeling actin cytoskeleton plays a crucial role in myelin formation by oligodendrocytes (OLs). Recent studies have shown that expansion and wrapping of myelin membranes around axons depends on actin depolymerization. However, the molecular mechanisms triggering this key step in myelination are not fully elucidated. Using genetic and pharmacological tools as well as proteomics analyses, we found that PAK1 (P21 Activated Kinase 1) kinase activity is maintained inhibited by NF2/Merlin in OLs to allow actin depolymerization and, consequently, myelin membrane expansion. Pak1 loss-of-function in OLs leads to an increase in myelin thickness in the white matter of adult mice, confirming the role of PAK1 inactivation in myelin membrane expansion.

neuroscience↗

bioRxiv2021

The neural response to the temporal fine structure of continuous musical pieces is not affected by selective attention

Speech and music are spectro-temporally complex acoustic signals that a highly relevant for humans. Both contain a temporal fine structure that is encoded in the neural responses of subcortical and cortical processing centres. The subcortical response to the temporal fine structure of speech has recently been shown to be modulated by selective attention to one of two competing voices. Music similarly often consists of several simultaneous melodic lines, and a listener can selectively attend to a particular one at a time. However, the neural mechanisms that enable such selective attention remain largely enigmatic, not least since most investigations to date have focussed on short and simplified musical stimuli. Here we study the neural encoding of classical musical pieces in human volunteers, using scalp electroencephalography (EEG) recordings. We presented volunteers with continuous musical pieces composed of one or two instruments. In the latter case, the participants were asked to selectively attend to one of the two competing instruments and to perform a vibrato identification task. We used linear encoding and decoding models to relate the recorded EEG activity to the stimulus waveform. We show that we can measure neural responses to the temporal fine structure of melodic lines played by one single instrument, at the population level as well as for most individual subjects. The neural response peaks at a latency of 7.6 ms and is not measurable past 15 ms. When analysing the neural responses elicited by competing instruments, we find no evidence of attentional modulation. Our results show that, much like speech, the temporal fine structure of music is tracked by neural activity. In contrast to speech, however, this response appears unaffected by selective attention in the context of our experiment.

neuroscience↗