Zimmermanncortez6285

In this review article, we discuss the effects of traumatic injury on oligodendrocytes in the CNS, the lack of endogenous remyelination, translational studies in rodent models promoting remyelination, and finally human clinical studies on remyelination in the CNS after injury.Dendrites are cellular structures essential for the integration of neuronal information. These elegant but complex structures are highly patterned across the nervous system but vary tremendously in their size and fine architecture, each designed to best serve specific computations within their networks. Recent in vivo imaging studies reveal that the development of mature dendrite arbors in many cases involves extensive remodeling achieved through a precisely orchestrated interplay of growth, degeneration, and regeneration of dendritic branches. Both degeneration and regeneration of dendritic branches involve precise spatiotemporal regulation for the proper wiring of functional networks. In particular, dendrite degeneration must be targeted in a compartmentalized manner to avoid neuronal death. Dysregulation of these developmental processes, in particular dendrite degeneration, is associated with certain types of pathology, injury, and aging. In this article, we review recent progress in our understanding of dendrite degeneration and regeneration, focusing on molecular and cellular mechanisms underlying spatiotemporal control of dendrite remodeling in neural development. We further discuss how developmental dendrite degeneration and regeneration are molecularly and functionally related to dendrite remodeling in pathology, disease, and aging.Early progression in neurodegenerative disease involves challenges to homeostatic processes, including those controlling axonal excitability and dendritic organization. In glaucoma, the leading cause of irreversible blindness, stress from intraocular pressure (IOP) causes degeneration of retinal ganglion cells (RGC) and their axons which comprise the optic nerve. Previously, we discovered that early progression induces axogenic, voltage-gated enhanced excitability of RGCs, even as dendritic complexity in the retina reduces. Here, we investigate a possible contribution of the transient receptor potential vanilloid type 1 (TRPV1) channel to enhanced excitability, given its role in modulating excitation in other neural systems. We find that genetic deletion of Trpv1 (Trpv1-/-) influences excitability differently for RGCs firing continuously to light onset (αON-Sustained) vs. light offset (αOFF-Sustained). Deletion drives excitability in opposing directions so that Trpv1-/- RGC responses with elevated IOP equalize to that of wild-type (WT) RGCs without elevated IOP. Depolarizing current injections in the absence of light-driven presynaptic excitation to directly modulate voltage-gated channels mirrored these changes, while inhibiting voltage-gated sodium channels and isolating retinal excitatory postsynaptic currents abolished both the differences in light-driven activity between WT and Trpv1-/- RGCs and changes in response due to IOP elevation. Tyrphostin B42 research buy Together, these results support a voltage-dependent, axogenic influence of Trpv1-/- with elevated IOP. Finally, Trpv1-/- slowed the loss of dendritic complexity with elevated IOP, opposite its effect on axon degeneration, supporting the idea that axonal and dendritic degeneration follows distinctive programs even at the level of membrane excitability.Different glial cell types are found throughout the central (CNS) and peripheral nervous system (PNS), where they have important functions. These cell types are also involved in nervous system pathology, playing roles in neurodegenerative disease and following trauma in the brain and spinal cord (astrocytes, microglia, oligodendrocytes), nerve degeneration and development of pain in peripheral nerves (Schwann cells, satellite cells), retinal diseases (Müller glia) and gut dysbiosis (enteric glia). These cell type have all been proposed as potential targets for treating these conditions. One approach to target these cell types is the use of gene therapy to modify gene expression. Adeno-associated virus (AAV) vectors have been shown to be safe and effective in targeting cells in the nervous system and have been used in a number of clinical trials. To date, a number of studies have tested the use of different AAV serotypes and cell-specific promoters to increase glial cell tropism and expression. However, true glial-cell specific targeting for a particular glial cell type remains elusive. This review provides an overview of research into developing glial specific gene therapy and discusses some of the issues that still need to be addressed to make glial cell gene therapy a clinical reality.Huntington's disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used. The R6/2 mouse as model of HD was already shown to present major neuropathological changes in the caudate putamen and other brain regions, but recently established biomarkers in HD patients were yet not analyzed in these mice. We therefore performed an in-depth analysis of R6/2 mice to establish new and highly translational readouts focusing on Ctip2 as biological marker for motor system-related neurons and translocator protein (TSPO) as a promising readout for early neuroinflammation. Our results validate already shown pathologies like mutant huntingtin aggregates, ubiquitination, and brain atrophy, but also provide evidence for decreased tyrosine hydroxylase and Ctip2 levels as indicators of a disturbed motor system, while vesicular acetyl choline transporter levels as marker for the cholinergic system barely change. Additionally, increased astrocytosis and activated microglia were observed by GFAP, Iba1 and TSPO labeling, illustrating, that TSPO is a more sensitive marker for early neuroinflammation compared to GFAP and Iba1. Our results thus demonstrate a high sensitivity and translational value of Ctip2 and TSPO as new marker for the preclinical evaluation of new compounds in the R6/2 mouse model of HD.