scholarly journals In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Alison Jane Canty ◽  
Johanna Sara Jackson ◽  
Lieven Huang ◽  
Antonio Trabalza ◽  
Cher Bass ◽  
...  
Keyword(s):  
Nervous System ◽  
Wallerian Degeneration ◽  
Molecular Mechanisms ◽  
Rapid Onset ◽  
Spatiotemporal Dynamics ◽  
Myelinated Fibre ◽  
Mammalian Brain ◽  
Axon Loss ◽  
Synaptic Mechanisms

Abstract Background Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborisation and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons. Results To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started on average 20 times earlier and was executed 3 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed that a nicotinamide adenine dinucleotide (NAD+)-dependent pathway could delay cortical roWD independent of transcription in the damaged neurons, demonstrating further conservation of the molecular mechanisms controlling WD in different areas of the mammalian nervous system. Conclusions Our data illustrate how in vivo time-lapse imaging can provide new insights into the spatiotemporal dynamics and synaptic mechanisms of axon loss and assess therapeutic interventions in the injured mammalian brain.

scholarly journals Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex

2018 ◽  
Author(s):  
A.J. Canty ◽  
J.S. Jackson ◽  
L. Huang ◽  
A. Trabalza ◽  
C. Bass ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Wallerian Degeneration ◽  
Rapid Onset ◽  
Therapeutic Window ◽  
Mammalian Brain ◽  
Axon Degeneration ◽  
Single Axon ◽  
Threshold Length ◽  
Longitudinal Imaging

ABSTRACTDespite the widespread occurrence of axon degeneration in the injured and diseased nervous system, the mechanisms of the degenerative process remain incompletely understood. In particular, the factors that regulate how individual axons degenerate within their native environment in the mammalian brain are unknown. Longitudinal imaging of >120 individually injured cortical axons revealed a threshold length below which injured axons undergo a rapid-onset form of Wallerian degeneration (ROWD). ROWD consistently starts 10 times earlier and is executed 4 times slower than classic Wallerian degeneration (WD). ROWD is dependent on synaptic density, unlike WD, but is independent of axon complexity. Finally, we provide both pharmacological and genetic evidence that a Nicotinamide Adenine Dinucleotide (NAD+)-dependent pathway controls cortical axon ROWD independent of transcription in the damaged neurons. Thus, our data redefine the therapeutic window for intervention to maintain neurological function in injured cortical neurons, and support the use of in vivo optical imaging to gain unique insights into the mechanisms of axon degeneration in the brain.

scholarly journals Foreign body responses in mouse central nervous system mimic natural wound responses and alter biomaterial functions

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Timothy M. OʼShea ◽  
Alexander L. Wollenberg ◽  
Jae H. Kim ◽  
Yan Ao ◽  
Timothy J. Deming ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Foreign Body ◽  
Molecular Mechanisms ◽  
Host Cells ◽  
Peripheral Tissues ◽  
Molecular Delivery ◽  
Wound Responses ◽  
The Central Nervous System

AbstractBiomaterials hold promise for therapeutic applications in the central nervous system (CNS). Little is known about molecular factors that determine CNS foreign body responses (FBRs) in vivo, or about how such responses influence biomaterial function. Here, we probed these factors in mice using a platform of injectable hydrogels readily modified to present interfaces with different physiochemical properties to host cells. We found that biomaterial FBRs mimic specialized multicellular CNS wound responses not present in peripheral tissues, which serve to isolate damaged neural tissue and restore barrier functions. We show that the nature and intensity of CNS FBRs are determined by definable properties that significantly influence hydrogel functions, including resorption and molecular delivery when injected into healthy brain or stroke injuries. Cationic interfaces elicit stromal cell infiltration, peripherally derived inflammation, neural damage and amyloid production. Nonionic and anionic formulations show minimal levels of these responses, which contributes to superior bioactive molecular delivery. Our results identify specific molecular mechanisms that drive FBRs in the CNS and have important implications for developing effective biomaterials for CNS applications.

scholarly journals Neuronal Activity-Dependent Control of Postnatal Neurogenesis and Gliogenesis

2018 ◽  
Vol 41 (1) ◽  
pp. 139-161 ◽  
Author(s):  
Ragnhildur T. Káradóttir ◽  
Chay T. Kuo
Keyword(s):  
Nervous System ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Nervous System Development ◽  
Current Evidence ◽  
Mammalian Brain ◽  
Postnatal Neurogenesis ◽  
Proliferation And Differentiation ◽  
Activity Dependent

The addition of new neurons and oligodendroglia in the postnatal and adult mammalian brain presents distinct forms of gray and white matter plasticity. Substantial effort has been devoted to understanding the cellular and molecular mechanisms controlling postnatal neurogenesis and gliogenesis, revealing important parallels to principles governing the embryonic stages. While during central nervous system development, scripted temporal and spatial patterns of neural and glial progenitor proliferation and differentiation are necessary to create the nervous system architecture, it remains unclear what driving forces maintain and sustain postnatal neural stem cell (NSC) and oligodendrocyte progenitor cell (OPC) production of new neurons and glia. In recent years, neuronal activity has been identified as an important modulator of these processes. Using the distinct properties of neurotransmitter ionotropic and metabotropic channels to signal downstream cellular events, NSCs and OPCs share common features in their readout of neuronal activity patterns. Here we review the current evidence for neuronal activity-dependent control of NSC/OPC proliferation and differentiation in the postnatal brain, highlight some potential mechanisms used by the two progenitor populations, and discuss future studies that might advance these research areas further.

scholarly journals SUMO Represses Transcriptional Activity of the Drosophila SoxNeuro and Human Sox3 Central Nervous System–specific Transcription Factors

2005 ◽  
Vol 16 (6) ◽  
pp. 2660-2669 ◽  
Author(s):  
Jean Savare ◽  
Nathalie Bonneaud ◽  
Franck Girard
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Acceptor Site ◽  
Hmg Box ◽  
Sumo Modification

Sry high mobility group (HMG) box (Sox) transcription factors are involved in the development of central nervous system (CNS) in all metazoans. Little is known on the molecular mechanisms that regulate their transcriptional activity. Covalent posttranslational modification by small ubiquitin-like modifier (SUMO) regulates several nuclear events, including the transcriptional activity of transcription factors. Here, we demonstrate that SoxNeuro, an HMG box-containing transcription factor involved in neuroblast formation in Drosophila, is a substrate for SUMO modification. SUMOylation assays in HeLa cells and Drosophila S2 cells reveal that lysine 439 is the major SUMO acceptor site. The sequence in SoxNeuro targeted for SUMOylation, IKSE, is part of a small inhibitory domain, able to repress in cis the activity of two adjacent transcriptional activation domains. Our data show that SUMO modification represses SoxNeuro transcriptional activity in transfected cells. Overexpression in Drosophila embryos of a SoxN form that cannot be targeted for SUMOylation strongly impairs the development of the CNS, suggesting that SUMO modification of SoxN is crucial for regulating its activity in vivo. Finally, we present evidence that SUMO modification of group B1 Sox factors was conserved during evolution, because Sox3, the human counterpart of SoxN, is also negatively regulated through SUMO modification.

scholarly journals Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Samuel Teo ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Model Systems ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Wnt Ligands

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.

scholarly journals Adult Mouse Retina Explants: From ex vivo to in vivo Model of Central Nervous System Injuries

2020 ◽  
Vol 13 ◽  
Author(s):  
Julia Schaeffer ◽  
Céline Delpech ◽  
Floriane Albert ◽  
Stephane Belin ◽  
Homaira Nawabi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Axon Regeneration ◽  
Ex Vivo ◽  
Mouse Retina ◽  
In Vivo Model ◽  
Cns Regeneration ◽  
Single Axon

In mammals, adult neurons fail to regenerate following any insult to adult central nervous system (CNS), which leads to a permanent and irreversible loss of motor and cognitive functions. For a long time, much effort has been deployed to uncover mechanisms of axon regeneration in the CNS. Even if some cases of functional recovery have been reported, there is still a discrepancy regarding the functionality of a neuronal circuit upon lesion. Today, there is a need not only to identify new molecules implicated in adult CNS axon regeneration, but also to decipher the fine molecular mechanisms associated with regeneration failure. Here, we propose to use cultures of adult retina explants to study all molecular and cellular mechanisms that occur during CNS regeneration. We show that adult retinal explant cultures have the advantages to (i) recapitulate all the features observed in vivo, including axon regeneration induced by intrinsic factors, and (ii) be an ex vivo set-up with high accessibility and many downstream applications. Thanks to several examples, we demonstrate that adult explants can be used to address many questions, such as axon guidance, growth cone formation and cytoskeleton dynamics. Using laser guided ablation of a single axon, axonal injury can be performed at a single axon level, which allows to record early and late molecular events that occur after the lesion. Our model is the ideal tool to study all molecular and cellular events that occur during CNS regeneration at a single-axon level, which is currently not doable in vivo. It is extremely valuable to address unanswered questions of neuroprotection and neuroregeneration in the context of CNS lesion and neurodegenerative diseases.

scholarly journals Neuronal hibernation following hippocampal demyelination

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Selva Baltan ◽  
Safdar S. Jawaid ◽  
Anthony M. Chomyk ◽  
Grahame J. Kidd ◽  
Jacqueline Chen ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Mammalian Brain ◽  
Gene Transcript ◽  
Ca1 Neurons

AbstractCognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca2+-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.

scholarly journals Excitatory and inhibitory receptors utilize distinct post- and trans-synaptic mechanisms in vivo

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Taisuke Miyazaki ◽  
Megumi Morimoto-Tomita ◽  
Coralie Berthoux ◽  
Kotaro Konno ◽  
Yoav Noam ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Ectopic Expression ◽  
Inhibitory Neurons ◽  
Mammalian Brain ◽  
Neurotransmitter Receptors ◽  
Presynaptic Terminals ◽  
Postsynaptic Receptors ◽  
A Cell ◽  
Synaptic Mechanisms

Ionotropic neurotransmitter receptors at postsynapses mediate fast synaptic transmission upon binding of the neurotransmitter. Post- and trans-synaptic mechanisms through cytosolic, membrane, and secreted proteins have been proposed to localize neurotransmitter receptors at postsynapses. However, it remains unknown which mechanism is crucial to maintain neurotransmitter receptors at postsynapses. In this study, we ablated excitatory or inhibitory neurons in adult mouse brains in a cell-autonomous manner. Unexpectedly, we found that excitatory AMPA receptors remain at the postsynaptic density upon ablation of excitatory presynaptic terminals. In contrast, inhibitory GABAA receptors required inhibitory presynaptic terminals for their postsynaptic localization. Consistent with this finding, ectopic expression at excitatory presynapses of neurexin 3alpha, a putative trans-synaptic interactor with the native GABAA receptor complex, could recruit GABAA receptors to contacted postsynaptic sites. These results establish distinct mechanisms for the maintenance of excitatory and inhibitory postsynaptic receptors in the mature mammalian brain.

scholarly journals Is the commonly used UV filter benzophenone-3 a risk factor for the nervous system?

2021 ◽  
Author(s):  
Agnieszka Wnuk ◽  
Małgorzata Kajta
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Cells ◽  
Industrial Applications ◽  
Mammalian Brain ◽  
Human Environment ◽  
Developmental Abnormalities ◽  
Increased Risk ◽  
Wide Range ◽  
And Function

Benzophenone-3 (2-hydroxy-4-methoxybenzophenone, oxybenzone, or BP-3) is one of the most frequently used UV radiation absorbents, which are commonly referred to as sunscreen filters. Its widespread use in industrial applications provides protection against the photodegradation of a wide range of products but at the same time creates the risk of human exposure to benzophenone-3 unbeknownst to the individuals exposed. Topically applied benzophenone-3 penetrates individual skin layers, enters the bloodstream, and is excreted in the urine. In addition, benzophenone-3 easily crosses the placental barrier, which creates the risk of exposure to this substance in the prenatal period. Despite the widespread use and occurrence of benzophenone-3 in the human environment, little knowledge of the mechanisms underlying the effect of benzophenone-3 on the nervous system was available until recently. Only the most recent research, including studies by our group, has enabled the identification of new molecular mechanisms through which benzophenone-3 affects embryonic neuronal cells and the developing mammalian brain. Benzophenone-3 has been shown to induce neurotoxicity and apoptotic processes and inhibit autophagy in embryonic neuronal cells. Benzophenone-3 also alters expression and impairs function of receptors necessary for the proper development and function of the nervous system. The most worrying finding seems to be that benzophenone-3 contributes to an increased risk of developmental abnormalities and/or epigenetically based degeneration of neuronal cells by changing the epigenetic status of neuronal cells.

scholarly journals Regulation of solute and water balance and cell volume in the central nervous system.

1992 ◽  
Vol 3 (1) ◽  
pp. 12-27
Author(s):  
K Strange
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Molecular Mechanisms ◽  
Mammalian Brain ◽  
Ionic Balance ◽  
Total Brain Volume ◽  
Disease States ◽  
The Central Nervous System ◽  
Physiological Problem

The mammalian brain is composed of four distinct fluid compartments: blood, cerebral spinal fluid, interstitial fluid surrounding glial cells and neurons, and intracellular fluid. Maintenance of the ionic and osmotic composition and volume of these fluids is crucial for the normal functioning of the brain. Small changes in intracellular or extracellular solute composition can dramatically alter neuronal signaling and information processing. Because of the rigid confines of the skull and complex brain architecture, changes in total brain volume can cause devastating neurological damage. As a result, it is not surprising to find that the composition and volume of brain intracellular and extracellular fluids are controlled tightly under both normal conditions and in various disease states. Osmotic and ionic balance in the central nervous system is regulated by solute and water transport across the blood-brain barrier, the choroid plexus, and the plasma membrane of glial cells and neurons. Despite its clinical and physiological significance, however, little is known about the underlying cellular and molecular mechanisms by which the central nervous system's osmotic and ionic balance is maintained. In this review, the current understanding of osmoregulation in the mammalian brain and its role in various disease processes such as hyponatremia, renal failure, and hypernatremia will be summarized. A detailed understanding of brain osmoregulatory processes represents a fundamental physiological problem and is required for the treatment of numerous disease states, particularly those encountered in the practice of nephrology.

Sign in / Sign up

Export Citation Format

Share Document