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The timing of action potentials arrival at synaptic terminals partially determines integration of synaptic inputs and is important for information processing in the CNS. Therefore, axonal conduction velocity (VC) is a salient parameter, influencing the timing of synaptic inputs. Even small changes in VC may disrupt information coding in networks requiring accurate timing. We recorded compound action potentials in hippocampal slices to measure VC in three mouse models of Alzheimer’s disease. We report an age-dependent reduction in VC in area CA1 in two amyloid-β precursor protein transgenic mouse models, line 41 and APP/PS1, and in a tauopathy model, rTg4510.

A newly introduced term, "axonal conduction block," brought a confusion in the electrodiagnostic diagnosis of Guillain-Barrè syndrome (GBS). I am proposing the term "nodal conduction block" for "axonal conduction block." This unifying concept of nodal conduction block will accommodate both the traditional concept of demyelination as well as the new concept of nodopathy in the "axonal form of GBS,", making the practice of electrodiagnosis much easier.

Myelination increases the conduction velocity in long‐range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement‐related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike‐time arrivals through long‐range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination., Main Points Myelin impairment results in temporal dispersion of axonal conduction in long‐range axons.Low task‐related and high spontaneous activity induced by myelin impairment causes motor learning which is compensated by synchronized optical stimulation

Aims This study determines whether assessment with compound action potentials (CAPs) can distinguish two different forms of cerebral white matter injury at the functional levels. Methods A pure demyelination model was induced in C57/BL6 adult mice by dietary supplementation of cuprizone (0.2%) for 6 weeks. Callosal L‐N5‐(1‐Iminoethyl) ornithine (L‐NIO) hydrochloride (27 mg/mL) was injected into the corpus callosum (CC) to induce a focal white matter stroke (WMS), resulting in both demyelination and axonal injury. White matter integrity was assessed by performing CAP recording, electron microscopy, and immunohistological and luxol fast blue (LFB) staining. Results Immunohistological and electron microscopic analyses confirmed the induction of robust demyelination in CC with cuprizone, and mixed demyelination and axonal damage with L‐NIO. Electrophysiologically, cuprizone‐induced demyelination significantly reduced the amplitude of negative peak 1 (N1), but increased the amplitude of negative peak 2 (N2), of the CAPs compared to the sham controls. However, cuprizone did not affect the axonal conduction velocity. In contrast, the amplitude and area of both N1 and N2 along with N1 axonal conduction velocity were dramatically decreased in L‐NIO‐induced WMS. Conclusions Concertedly, parameters of the CAPs offer a novel functional assessment strategy for cerebral white matter injury in rodent models.

Our understanding of the behaviour of spinal alpha-motoneurons (MNs) in mammals partly relies on our knowledge of the relationships between MN membrane properties, such as MN size, resistance, rheobase, capacitance, time constant, axonal conduction velocity, and afterhyperpolarization duration. We reprocessed the data from 40 experimental studies in adult cat, rat, and mouse MN preparations to empirically derive a set of quantitative mathematical relationships between these MN electrophysiological and anatomical properties. This validated mathematical framework, which supports past findings that the MN membrane properties are all related to each other and clarifies the nature of their associations, is besides consistent with the Henneman's size principle and Rall's cable theory. The derived mathematical relationships provide a convenient tool for neuroscientists and experimenters to complete experimental datasets, explore the relationships between pairs of MN properties never concurrently observed in previous experiments, or investigate inter-mammalian-species variations in MN membrane properties. Using this mathematical framework, modellers can build profiles of inter-consistent MN-specific properties to scale pools of MN models, with consequences on the accuracy and the interpretability of the simulations.Muscles receive their instructions through electrical signals carried by tens or hundreds of cells connected to the command centers of the body. These ‘alpha-motoneurons’ have various sizes and electrical characteristics which affect how they transmit signals. Previous experiments have shown that these properties are linked; for instance, larger motoneurons transfer electrical signals more quickly. The exact nature of the mathematical relationships between these characteristics, however, remains unclear. This limits our understanding of the behaviour of motoneurons from experimental data. To identify the equations linking eight motoneuron properties, Caillet et al. analysed published datasets from experimental studies on cat motoneurons. This approach uncovered simple mathematical associations: in fact, only one characteristic needs to be measured experimentally to calculate all the other properties. The relationships identified were also consistent with previously accepted approaches for modelling motoneuron activity. Caillet et al. then validated this mathematical framework with data from studies on rodents, showing that some of the equations hold true for different mammals. This work offers a quick and easy way for researchers to calculate the characteristics of a motoneuron based on a single observation. This will allow non-measured properties to be added to experimental datasets, and it could help to uncover the diversity of motoneurons at work within a population.

OBJECTIVE: To reveal the possible mechanisms underlying post-stimulation block induced by high frequency biphasic stimulation (HFBS). MATERIALS AND METHODS: A new axonal conduction model is developed for unmyelinated axons. This new model is different from the classical axonal conduction model by including both ion concentrations and membrane ion pumps to allow analysis of axonal responses to long-duration stimulation. Using the new model, the post-HFBS block phenomenon reported in animal studies is simulated and analyzed for a wide range of stimulation frequencies (100 Hz – 10 kHz). RESULTS: HFBS can significantly change the Na(+) and K(+) concentrations inside and outside the axon to produce a post-HFBS block of either short-duration (3 seconds) depending on the duration of HFBS. The short-duration block is due to the fast recovery of the Na(+) and K(+) concentrations outside the axon in periaxonal space by diffusion of ions into and from the large extracellular space, while the long-duration block is due to the slow restoration of the normal Na(+) concentration inside the axon by membrane ion pumps. The 100 Hz HFBS requires the minimal electrical energy to achieve the post-HFBS block, while the 10 kHz stimulation is the least effective frequency requiring high intensity and long duration to achieve the block. CONCLUSION: This study reveals two possible ionic mechanisms underlying post-HFBS block of axonal conduction. Understanding these mechanisms is important for improving clinical applications of HFBS block and for developing new nerve block methods employing HFBS.

Saltatory conduction of action potentials along myelinated axons depends on the nodes of Ranvier - small unmyelinated axonal domains where voltage-gated sodium channels are concentrated. Our knowledge of the complex molecular composition of these axonal domains continues to accumulate, although the mechanisms of nodal assembly, which have been elucidated in the PNS, remain only partially understood in the CNS. Besides the key role of the nodes in accelerating conduction, nodal variations are thought to allow the fine tuning of axonal conduction speed to meet information processing needs. In addition, through their multiple glial contacts, nodes seem to be important for neuron-glia interactions. As we highlight in this Review, the disorganization of axonal domains has been implicated in the pathophysiology of various neurological diseases. In multiple sclerosis, for example, nodal and perinodal disruption following demyelination, with subsequent changes in ion channel distribution, leads to altered axonal conduction and integrity. The nodal clusters regenerate concurrently with but also prior to remyelination, allowing the restoration of axonal conduction. In this article, we review current knowledge of the organization and function of nodes of Ranvier in the CNS. We go on to discuss dynamic changes in the nodes during demyelination and remyelination, highlighting the impact of these changes on neuronal physiology in health and disease as well as the associated therapeutic implications.

OBJECTIVES To test the hypothesis that poststimulation block of nerve conduction can be achieved by low-frequency (≤1 kHz) biphasic stimulation (LFBS). MATERIALS AND METHODS A tripolar cuff electrode was placed around the pudendal nerve in cats to deliver LFBS (1 kHz, 500 Hz, and 100 Hz). Two bipolar hook electrodes were placed central and distal to the cuff electrode to induce external urethral sphincter (EUS) contractions. A catheter was inserted into the urethra to record EUS contraction pressure. Pudendal nerve block by LFBS was confirmed by the failure of the central hook electrode stimulation to induce EUS contractions, while the distal hook electrode stimulation still induced contractions. RESULTS Pudendal nerve conduction was completely blocked by LFBS at different frequencies (1 kHz, 500 Hz, and 100 Hz) after terminating LFBS. The post-LFBS block induced at the minimal stimulation intensity and duration was fully reversible within the same time period (10-15 min on average) for the three frequencies. However, the stimulation duration to induce block significantly (p

Myelination facilitates rapid axonal conduction thereby enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling myelination after injury and during axon regeneration in the central nervous system (CNS). Previously we discovered multiple molecular pathways and strategies that could promote robust axon regrowth after optic nerve injury. However, regenerated axons remain unmyelinated and the underlying mechanisms were elusive. In this study, we found that in injured optic nerves, oligodendrocyte precursor cells (OPCs) undergo transient proliferation, but fail to differentiate into mature myelination-competent oligodendrocytes, reminiscent of what is observed in human progressive multiple sclerosis. Mechanistically, we showed that both OPC-intrinsic GPR17 signaling and sustained activation of microglia inhibit different stages of OPC differentiation. Importantly, co-manipulation of GPR17 and microglia led to extensive myelination of regenerated axons. The regulatory mechanisms of stage-dependent OPC differentiation uncovered here suggest a translatable strategy for efficient de novo myelination after CNS injury.

The Netrin-1 is a molecule of the 63KD-expressible laminin-dependent molecule secreted by neurons in the midline of the ventricular tube of the vertebrate neuronal tube and is involved in the growth and differentiation of the nervous system as well as angiogenesis as an axonal conduction molecule. The topical use of these adhesives over the past three decades has had a significant effect on reducing the volume of bleeding and accelerating tissue repair and reducing the risk of invasive surgeries and their complications, even in the treatment of hemophilia, it is necessary to use blood and coagulation products This product reduces patient complications and costs. These components are harvested from the stored plasma on the day of operation, and after mixing in the operating position, they coagulate after approximately 10 seconds and cause adhesion, prevent bleeding and neural tissue repair.

Deep brain stimulation (DBS) is effective for treating neurological disorders in clinic. However, the therapeutic mechanisms of high-frequency stimulation (HFS) of DBS have not yet been elucidated. Previous studies have suggested that HFS-induced changes in axon conduction could have important contributions to the DBS effects and desiderate further studies. To investigate the effects of prolonged HFS of afferent axons on the firing of downstream neurons, HFS trains of 100 and 200Hz were applied on the Schaffer collaterals of the hippocampal CA1 region in anaesthetized rats. Single unit activity of putative pyramidal cells and interneurons in the downstream region was analyzed during the late periods of prolonged HFS when the axonal conduction was blocked. The results show that the firing rates of both pyramidal cells and interneurons increased rather than decreased during the period of axon block. However, the firing rates were far smaller than the stimulation frequency of HFS. In addition, the firing pattern of pyramidal cells changed from typical bursts during baseline recordings into regular single spikes during HFS periods. Furthermore, the HFS produced asynchronous firing in the downstream neurons in contrast to the synchronous firing induced by single pulses. Presumably, the HFS-induced block of axonal conduction was not complete. During the period of partial block, individual axons could recover intermittently and independently, and drive the downstream neurons to fire in an asynchronous pattern. This axonal mechanism of HFS provides a novel explanation for how DBS could replace an original pattern of neuronal activity by a HFS-modulated asynchronous firing in the target region thereby generating the therapeutic effects of DBS.

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling dispersion of the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs., eLife digest The timing of movements such as posture, balance and speech are coordinated by a region of the brain called the cerebellum. Although this part of the brain is small, it contains a huge number of tiny nerve cells known as granule cells. These cells make up more than half the nerve cells in the human brain. But why there are so many is not well understood. The cerebellum receives signals from sensory organs, such as the ears and eyes, which are passed on as electrical pulses from nerve to nerve until they reach the granule cells. These electrical pulses can have very different repetition rates, ranging from one pulse to a thousand pulses per second. Previous studies have suggested that granule cells are a uniform population that can detect specific patterns within these electrical pulses. However, this would require granule cells to identify patterns in signals that have a range of different repetition rates, which is difficult for individual nerve cells to do. To investigate if granule cells are indeed a uniform population, Straub, Witter, Eshra, Hoidis et al. measured the electrical properties of granule cells from the cerebellum of mice. This revealed that granule cells have different electrical properties depending on how deep they are within the cerebellum. These differences enabled the granule cells to detect sensory signals that had specific repetition rates: signals that contained lots of repeats per second were relayed by granule cells in the lower layers of the cerebellum, while signals that contained fewer repeats were relayed by granule cells in the outer layers. This ability to separate signals based on their rate of repetition is similar to how digital audio files are compressed into an MP3. Computer simulations suggested that having granule cells that can detect specific rates of repetition improves the storage capacity of the brain. These findings further our understanding of how the cerebellum works and the cellular mechanisms that underlie how humans learn and memorize the timing of movement. This mechanism of separating signals to improve storage capacity may apply to other regions of the brain, such as the hippocampus, where differences between nerve cells have also recently been reported.

Recording axonal conduction will be a strong tool to continuously evaluate Na channel expression of cultured neurons. However, little is known about the relationship between ion channel expression and axonal conduction velocity. In this study, we aim to develop a method to evaluate the relationship. A microdevice was developed with photo- and soft-lithography. Cortical neurons were cultured, and activity propagating along axons was recorded. After spike sorting, mixed signal from multiple axons were sorted into clusters of individual axons. Axons were treated with non-selective and subtype specific Na channel blockers, and changes in conduction delay were evaluated. TTX and lidocaine increased conduction delay with a different manner, suggesting that the different affinity and binding kinetics can be detected with the device. Moreover, although Nav 1.2 blocker increased the conduction delay and eventually clocked the conduction at around IC50, the other blockers did not. This result suggests that Nav 1.2 is dominant for the conduction along unmyelinated cortical axons. Overall, our device should be a feasible tool for elucidating Na channel properties by axon-targeted recording.

SUMMARYSequential activation of neurons has been observed during various behavioral and cognitive processes and is thought to play a critical role in their generation. Here, we studied a circuit in the songbird forebrain that drives the performance of adult courtship song. In this region, known as HVC, neurons are sequentially active with millisecond precision in relation to behavior. Using large-scale network models, we found that HVC sequences could only be accurately produced if sequentially active neurons were linked with long and heterogeneous axonal conduction delays. Although such latencies are often thought to be negligible in local microcircuits, we empirically determined that HVC interconnections were surprisingly slow, generating delays up to 22 ms. An analysis of anatomical reconstructions suggests that similar processes may also occur in rat neocortex, supporting the notion that axonal conduction delays can sculpt the dynamical repertoire of a range of local circuits.

Background: 4-AP-3-MeOH, a derivative of 4-aminopyridine, was developed and demonstrated to prevent nerve pulse diffusion due to myelin damage and significantly enhance axonal conduction following nerve injury. Currently, repurposing the existing drug such as 4-AP-3-MeOH to restore motor function is a promising and potential therapy of peripheral nerve injury. However, to evaluate drug effect on sciatic nerve injury is full of challenge. Methods: Sciatic functional index was used to determine and measure the walking track in the stretch injury model. Nerve conductivity was performed by electrical stimulation of a nerve and recording the compound muscle action potential. Myelin thickness and regeneration was imaged and measured with transmission electron microscopy (TEM). Results: In this study, we developed a sciatic nerve injury model to minimize the spontaneous recovery mechanism and found that 4-AP-3-MeOH not only improved walking ability of the animals but also reduced the sensitivity to thermal stimulus. More interesting, 4-AP-3-MeOH enhanced and recovered electric conductivity of injured nerve; our TEM results indicated that the axon sheath thickness was increased and myelin was regenerated, which was an important evidence to support the recovery of injured nerve conductivity with 4-AP-3-MeOH treatment. Conclusions: In summary, our studies suggest that 4-AP-3-MeOH is a viable and promising approach to the therapy of peripheral nerve injury and in support of repurposing the existing drug to restore motor function.

Cerebellar granule cells (GCs) making up majority of all the neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs. Dynamic clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling to disperse the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.

Background Herniation of the brain through an osseodural defect has been well described in small children as an uncommon occurrence after closed head injury. Pressure from the growing brain has been implicated in progressive enlargement and reshaping of the fracture line. An analogous phenomenon in adults has been observed in the described cases where neurosurgical intervention led to a persistent dural defect. Transcalvarial herniation of the brain through the dural defect resulted in characteristic neurologic and imaging findings producing symptoms disproportionately greater than expected from the extent of the affected brain, accompanied by enlargement of the underlying ventricle and elevation of the bone flap. Disruption of the axonal conduction due to distortion of the axons in the herniated brain is probably responsible for these observations. Case Description A series of 3 cases is described. In all cases, the dural reconstitution at the conclusion of surgery was incomplete. Brain herniation was evident in the postoperative scan. The transcalvarial herniation of the brain was precipitated by either a seizure and resultant brain swelling or persistently raised intracranial tension from a tumor residual. In 2 cases, surgical reexploration resulted in improvement in the neurologic symptoms. Conclusions In symptomatic patients with transcalvarial herniation of the brain, identified on imaging, the neurologic syndrome is quite characteristic. Recognition of this condition and prompt treatment lead to lasting neurologic improvement.

Bimanual motor actions, such as threading a needle, require coordination of the movements of each hand according to the state of the other hand. By connecting homologous cortical regions between the two cerebral hemispheres, the corpus callosum is thought to play a key role in such bimanual coordination. However, direct experimental evidence of the contribution of the corpus callosum to natural behaviors requiring bimanual coordination, such as feeding, is lacking. We investigated the hypothesis that the corpus callosum mediates bimanual movements during food-handling behavior. We first traced the forelimb-related components of the motor corpus callosum in Long-Evans rats, and found that the callosal fiber bundle from the forelimb motor areas passes through the anterior part of the corpus callosum. We then confirmed by electrophysiological recordings that blocking the axonal conduction of fibers in the anterior corpus callosum reduced neural transmission between cortical forelimb areas. The causal role of corpus callosum in bimanual coordination was then tested by analyzing forelimb kinematics during object manipulation, before and after blocking axonal conduction in the anterior corpus callosum. We found the frequency of occurrence of symmetric bimanual movements was reduced by inhibition of anterior corpus callosum. In contrast, asymmetric bimanual movement was increased. Our findings suggest that the anterior corpus callosum coordinates the direction of bimanual movement.

This study aimed at understanding thermal effects on nerve conduction and developing new methods to produce a reversible thermal block of axonal conduction in mammalian myelinated nerves. In 13 cats under α-chloralose anesthesia, conduction block of pudendal nerves ( n = 20) by cooling (5–30°C) or heating (42–54°C) a small segment (9 mm) of the nerve was monitored by the urethral striated muscle contractions and increases in intraurethral pressure induced by intermittent (5 s on and 20 s off) electrical stimulation (50 Hz, 0.2 ms) of the nerve. Cold block was observed at 5–15°C while heat block occurred at 50–54°C. A complete cold block up to 10 min was fully reversible, but a complete heat block was only reversible when the heating duration was less than 1.3 ± 0.1 min. A brief (

Increasing experimental evidence suggests that axonal action potential conduction velocity is a highly adaptive parameter in the adult central nervous system. Yet, the effects of this newfound plasticity on global brain dynamics is poorly understood. In this work, we analyzed oscillations in biologically plausible neuronal networks with different conduction velocity distributions. Changes of 1-2 (ms) in network mean signal transmission time resulted in substantial network oscillation frequency changes ranging in 0-120 (Hz). Our results suggest that changes in axonal conduction velocity may significantly affect both the frequency and synchrony of brain rhythms, which have well established connections to learning, memory, and other cognitive processes., Comment: 4 pages, 5 figures, IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI '19)

The ASHA recommends including electrophysiological measures in an auditory processing disorder (APD) assessment battery, but few audiologists do so, potentially because of limited published evidence for its utility.This study compared the auditory brainstem responses (ABRs) of children with APD with age-matched children and adults.This study retrospectively examined the records of 108 children suspected of APD (sAPD) who had click-evoked ABRs recorded as part of their clinical assessment. Twenty adults and 22 typically developing (TD) children were recruited as controls.Click-evoked ABRs were recorded at slow (13.3 clicks/sec) and faster (57.7 clicks/sec) stimulation rates. ABRs were analyzed using typical clinical measures (latencies and interpeak intervals for waves I, III, and V) and using a model proposed by Ponton et al that offered a more detailed analysis of axonal conduction time and synaptic transmission delay.Both clinical measures and the Ponton model analysis showed no significant differences between TD children and adults. Children sAPD showed absolute latencies that were significantly prolonged when compared with adults but not when compared with TD children. But individual children sAPD showed clinically significant delays (>2 standard deviations of TD children’s data). Examination of responses delineating axonal versus synaptic transmission showed significant delays in synaptic transmission in the group of children sAPD in comparison to TD children and adults. These results suggest that a significant portion of children with listening difficulties showed evidence of reduced or atypical brainstem functioning. Examining the responses for axonal and synaptic delays revealed evidence of a synaptic pattern of abnormalities in a significant portion (37.03%) of children sAPD. Such observations could provide objective evidence of factors potentially contributing to listening difficulties that are frequently reported in children identified with APD.Children sAPD often showed abnormalities in the ABR, suggesting a neurophysiologic origin of their reported difficulties, frequently originating at or before the first synapse. This study provides supportive evidence for the value of click-evoked ABRs in comprehensive auditory processing assessment batteries.

We study dynamics of a spiking network of synaptically connected bistable neuronal oscillators. We find that delays in axonal conduction result in the emergence of coexisting states with high and low activity levels (up and down states). In the network, where cellular bistability is present, propagation delays and noise play a crucial role in the emergence of transitions between the states.

This feature article focuses on the discrepancy between the distribution of axon diameters within the primate corticospinal tract, determined neuroanatomically, and the distribution of axonal conduction velocities within the same tract, determined electrophysiologically. We point out the importance of resolving this discrepancy for a complete understanding of corticospinal functions, and discuss the various explanations for the mismatch between anatomy and physiology.

Myelination of axons by oligodendrocytes is a key feature of the remarkably fast operating CNS. Oligodendrocytes not only tune axonal conduction speed but are also suggested to maintain long-term axonal integrity by providing metabolic support to the axons they ensheath. However, how myelinating oligodendrocytes impact axonal energy homeostasis remains poorly understood and difficult to investigate. Here, we provide a method of how to study electrically active myelinated axons expressing genetically encoded sensors by combining electrophysiology and two-photon imaging of acutely isolated optic nerves. We show that intravitreal adeno-associated viral (AAV) vector delivery is an efficient tool to achieve functional sensor expression in optic nerve axons, which is demonstrated by measuring axonal ATP dynamics following AAV-mediated sensor expression. This novel approach allows for fast expression of any optical sensor of interest to be studied in optic nerve axons without the need to go through the laborious process of producing new transgenic mouse lines. Viral-mediated biosensor expression in myelinated axons and the subsequent combination of nerve recordings and sensor imaging outlines a powerful method to investigate oligodendroglial support functions and to further interrogate cellular mechanisms governing axonal energy homeostasis under physiological and pathological conditions., Frontiers in Cellular Neuroscience, 12, ISSN:1662-5102

Myelin damage is a hallmark of spinal cord injury (SCI), and potassium channel blocker (PCB) is proven effective to restore axonal conduction and regain neurological function. Aiming to improve this therapy beyond the U.S. Food and Drug Administration-approved 4-aminopyridine (4-AP), we have developed multiple new PCBs, with 4-aminopyridine-3-methanol (4-AP-3-MeOH) being the most potent and effective. The current study evaluated two PCBs, 4-AP-3-MeOH and 4-AP, in parallel in both ex vivo and in vivo rat mechanical SCI models. Specifically, 4-AP-3-MeOH induced significantly greater augmentation of axonal conduction than 4-AP in both acute and chronic injury. 4-AP-3-MeOH had no negative influence on the electrical responsiveness of rescued axons whereas 4-AP-recruited axons displayed a reduced ability to follow multiple stimuli. In addition, 4-AP-3-MeOH can be applied intraperitoneally at a dose that is at least 5 times higher (5 mg/kg) than that of 4-AP (1 mg/kg) in vivo. Further, 5 mg/kg of 4-AP-3-MeOH significantly improved motor function whereas both 4-AP-3-MeOH (1 and 5 mg/kg) and, to a lesser degree, 4-AP (1 mg/kg) alleviated neuropathic pain-like behavior when applied in rats 2 weeks post-SCI. Based on these and other findings, we conclude that 4-AP-3-MeOH appears to be more advantageous over 4-AP in restoring axonal conduction because of the combination of its higher efficacy in enhancing the amplitude of compound action potential, lesser negative effect on axonal responsiveness to multiple stimuli, and wider therapeutic range in both ex vivo and in vivo application. As a result, 4-AP-3-MeOH has emerged as a strong alternative to 4-AP that can complement the effectiveness, and even partially overcome the shortcomings, of 4-AP in the treatment of neurotrauma and degenerative diseases where myelin damage is implicated.

The sensation of gentle touch of the mammalian hairy skin is mediated by morphologically and physiologically distinct classes of low-threshold mechanoreceptors (LTMs) which are classified, according to their axonal conduction velocities, into Aβ-, Aδ- and C-LTMs. Although Aδ-LTMs (D-hair cells) were first described about five decades ago, and have been found in hairy skin of every species examined including humans, it is commonly assumed that all Aδ-fiber neurons are nociceptors. This view is endorsed by many textbooks. This article reviews the evidence that Aδ-LTMs exist in substantial proportions in different species, and that their peripheral and central axonal endings, molecular markers, receptive, electrophysiological and cytochemical properties are distinct from those of Aδ-high-threshold mechanoreceptors (Aδ-HTMs). A brief overview of some of the ion channels and markers that are expressed by the two populations of primary afferent neurons is also provided. Failure to recognize the existence and properties of Aδ-LTMs might lead/have led to misinterpretations of data. Aβ-LTMs and C-LTMs have been reviewed elsewhere and are not subject of this review.

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS) that is associated with progressive neurodegeneration. To better understand the dynamics of disease progression in individuals with MS, and to personalise treatment strategies, the development of quantitative in-vivo biomarkers is critical. Magnetic resonance imaging (MRI) is an essential technique that has been successfully embedded in the formal diagnostic criteria for MS since 2001. Conventional MRI techniques facilitate the demonstration of lesion dissemination in both space and time. Furthermore, conventional MRI metrics derived from quantitative analysis can predict disability progression in clinical trials. However, these imaging metrics are often criticised for their weak correlations with clinical outcomes at the individual level; and lack of specificity for the underlying pathological process(es). Despite successes in large group studies, the transition of quantitative neuroimaging to clinical practice as a tool for both monitoring disease progression and guiding therapeutic strategy has progressed slowly. In this thesis, a refined analysis framework that improves the specificity and clinical validity of MRI metrics, is described and evaluated. Specifically, multi-modal approaches that integrate advanced diffusion imaging and conventional structural metrics are investigated; and a potential composite biomarker of MS disease progression is proposed.

Microelectrode array (MEA) recordings of the ex vivo flat-mounted retina enable the functional analysis of the retinal output. The electrical activity of a large portion of retinal ganglion cells (RGCs) is recorded simultaneously in response to various light stimuli. Analysis of the recorded time series of action potentials reveals physiological parameters such as firing rate, time latency, receptive field size, axonal conduction velocity. These parameters change during retinal diseases.