The Journal of neuroscience : the official journal of the Society for Neuroscience
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To define the importance of iron storage in oligodendrocyte development and function, the ferritin heavy subunit (Fth) was specifically deleted in oligodendroglial cells. Blocking Fth synthesis in Sox10 or NG2-positive oligodendrocytes during the first or the third postnatal week significantly reduces oligodendrocyte iron storage and maturation. The brain of Fth KO animals presented an important decrease in the expression of myelin proteins and a substantial reduction in the percentage of myelinated axons. ⋯ We have also tested the consequences of disrupting Fth iron storage in oligodendrocyte progenitor cells (OPCs) after demyelination. We have found that Fth deletion in NG2-positive OPCs significantly delays the remyelination process in the adult brain. Therefore, Fth iron storage is essential for early oligodendrocyte development as well as for OPC maturation in the demyelinated adult brain.
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We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE2) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. ⋯ SIGNIFICANCE STATEMENT High-molecular-weight-hyaluronan (HMWH) is used to treat osteoarthritis and other pain syndromes. In this study we demonstrate that attenuation of inflammatory hyperalgesia by HMWH is mediated by its action at cluster of differentiation 44 (CD44) and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1), phospholipases (phospholipases Cε and Cγ1), and phosphoinositide 3-kinase, in nociceptors. These findings contribute to our understanding of the antihyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.
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In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. ⋯ Efficient clearance of myelin after injury by Schwann cells is important for axonal regrowth and remyelination, which is one reason why the PNS is significantly better at recovery compared with the CNS. Improved understanding of myelin clearance allows for the identification of pathways that are potentially accessible to increase myelin clearance and improve remyelination and recovery. Finally, this paper clarifies the role of calcineurin in Schwann cells and myelination.
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Several lines of inquiry have separately identified beta oscillations, synchrony, waveform shape, and phase-amplitude coupling as important but sometimes inconsistent factors in the pathophysiology of Parkinson's disease. What has so far been lacking is a means by which these neurophysiological parameters are interrelated and how they relate to clinical symptomatology. To clarify the relationship among oscillatory power, bursting, synchrony, and phase-amplitude coupling, we recorded local field potentials/electrocorticography from hand motor and premotor cortical area in human subjects with c (N = 10) and Parkinson's disease (N = 22) during deep brain stimulator implantation surgery (14 females, 18 males). ⋯ Here, simultaneous recordings from motor cortices show that increases in network beta synchrony anticipate episodes of beta bursting. We furthermore identify beta bursting as being associated with changes in waveform shape and increases in phase-amplitude coupling. Our results identify network synchrony as a driver of various pathophysiological observations reported in the literature and account for inconsistencies in the literature by virtue of the temporally variable nature of the phenomenon.
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Drug-resistant focal epilepsy is a large-scale brain networks disorder characterized by altered spatiotemporal patterns of functional connectivity (FC), even during interictal resting state (RS). Although RS-FC-based metrics can detect these changes, results from RS functional magnetic resonance imaging (RS-fMRI) studies are unclear and difficult to interpret, and the underlying dynamical mechanisms are still largely unknown. To better capture the RS dynamics, we phenomenologically extended the neural mass model of partial seizures, the Epileptor, by including two neuron subpopulations of epileptogenic and nonepileptogenic type, making it capable of producing physiological oscillations in addition to the epileptiform activity. ⋯ To identify local and network processes behind the RS-functional connectivity (FC) spatiotemporal patterns, we systematically manipulated the local excitability and the global coupling in the virtual human epileptic patient brain network models (BNMs), complemented by the analysis of the impact of interictal spikes and fitting to the neuroimaging data. Our results suggest that a global shift of the dynamic working point of the brain model, coupled with locally hyperexcitable node dynamics of the epileptogenic networks, provides a mechanistic explanation of the epileptic processes during the interictal RS period. These, in turn, are associated with the changes in FC.