Microglial Refinement of A-Fiber Projections in the Postnatal Spinal Cord Dorsal Horn Is Required for Normal Maturation of Dynamic Touch.

Sensory systems are shaped in postnatal life by the refinement of synaptic connectivity. In the dorsal horn of the spinal cord, somatosensory circuits undergo postnatal activity-dependent reorganization, including the refinement of primary afferent A-fiber terminals from superficial to deeper spinal dorsal horn laminae which is accompanied by decreases in cutaneous sensitivity. Here, we show in the mouse that microglia, the resident immune cells in the CNS, phagocytose A-fiber terminals in superficial laminae in the first weeks of life. Genetic perturbation of microglial engulfment during the initial postnatal period in either sex prevents the normal process of A-fiber refinement and elimination, resulting in an altered sensitivity of dorsal horn cells to dynamic tactile cutaneous stimulation, and behavioral hypersensitivity to dynamic touch. Thus, functional microglia are necessary for the normal postnatal development of dorsal horn sensory circuits. In the absence of microglial engulfment, superfluous A-fiber projections remain in the dorsal horn, and the balance of sensory connectivity is disrupted, leading to lifelong hypersensitivity to dynamic touch.

Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation.

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα- and Aß-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B- and C-) indicated a stronger dependency.Clinical Relevance- Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects.

Filtering property of myelinated internode can change neural information representability and might trigger a compensatory action during demyelination.

In this paper, for the first time, we showed that an Internode Segment (INS) of a myelinated axon acts as a lowpass filter, and its filter characteristics depend on the number of myelin turns. Consequently, we showed how the representability of a neural signal could be altered with myelin loss in pathological conditions involving demyelinating diseases. Contrary to the traditionally held viewpoint that myelin geometry of an INS is optimised for maximising Conduction Velocity (CV) of Action Potential (AP), our theory provides an alternative viewpoint that myelin geometry of an INS is optimised for maximizing representability of the stimuli a fibre is meant to carry. Subsequently, we show that this new viewpoint could explain hitherto unexplained experimentally observed phenomena such as, shortening of INS length during demyelination and remyelination, and non-uniform distribution of INS in the central nervous system fibres and associated changes in diameter of nodes of ranvier along an axon. Finally, our theory indicates that a compensatory action could take place during demyelination up to a certain number of loss of myelin turns to preserve the neural signal representability by simultaneous linear scaling of the length of an INS and the inner radius of the fibre.

Saltatory conduction and intrinsic electrophysiological properties at the nodes of ranvier of Aα/ß-afferent fibers and Aα-efferent fibers in rat sciatic nerves.

Large-diameter myelinated fibers in sciatic nerves are composed of both Aα/ß-afferent fibers and Aα-efferent fibers to convey sensory and motor impulses, respectively, via saltatory conduction for rapid leg responses. Saltatory conduction and electrophysiological properties at the nodes of Ranvier (NRs) of these sciatic nerve fibers have not been directly studied. We used ex vivo sciatic nerve preparations from rats and applied patch-clamp recordings at the NRs of both Aα/ß-afferent fibers and Aα-efferent fibers in the sciatic nerves to characterize their saltatory conduction and intrinsic electrophysiological properties. The velocity and frequency of saltatory conduction in both types of fibers were similar. Resting membrane potentials (RMPs), input resistance, action potential (AP) threshold, and AP rheobase were also not significantly different at the NRs of the two types of fibers in the sciatic nerves. In comparison with Aα/ß-afferent fibers, Aα-efferent fibers in the sciatic nerves show higher amplitude and broader width of APs at their NRs. At the NRs of both types of fibers, depolarizing voltages evoked transient inward currents followed by non-inactivating outward currents, and the inward currents and non-inactivating outward currents at the NRs were not significantly different between the two types of fibers. Using AP-clamp, inward currents during AP upstroke were found to be insignificant difference, but amplitudes of non-inactivating outward currents during AP repolarization were significantly lower at the NRs of Aα-efferent fibers than at the NRs of Aα/ß-afferent fibers in the sciatic nerves. Collectively, saltatory conduction, ionic currents, and intrinsic electrophysiological properties at the NRs of Aα/ß-afferent fibers and Aα-efferent fibers in the sciatic nerves are generally similar, but some differences were also observed.

Validated computational models predict vagus nerve stimulation thresholds in preclinical animals and humans.

Objective.We demonstrated how automated simulations to characterize electrical nerve thresholds, a recently published open-source software for modeling stimulation of peripheral nerves, can be applied to simulate accurately nerve responses to electrical stimulation.Approach.We simulated vagus nerve stimulation (VNS) for humans, pigs, and rats. We informed our models using histology from sample-specific or representative nerves, device design features (i.e. cuff, waveform), published material and tissue conductivities, and realistic fiber models.Main results.Despite large differences in nerve size, cuff geometry, and stimulation waveform, the models predicted accurate activation thresholds across species and myelinated fiber types. However, our C fiber model thresholds overestimated thresholds across pulse widths, suggesting that improved models of unmyelinated nerve fibers are needed. Our models of human VNS yielded accurate thresholds to activate laryngeal motor fibers and captured the inter-individual variability for both acute and chronic implants. For B fibers, our small-diameter fiber model underestimated threshold and saturation for pulse widths >0.25 ms. Our models of pig VNS consistently captured the range ofin vivothresholds across all measured nerve and physiological responses (i.e. heart rate, Aδ/B fibers, Aγfibers, electromyography, and Aαfibers). In rats, our smallest diameter myelinated fibers accurately predicted fast fiber thresholds across short and intermediate pulse widths; slow unmyelinated fiber thresholds overestimated thresholds across shorter pulse widths, but there was overlap for pulse widths >0.3 ms.Significance.We elevated standards for models of peripheral nerve stimulation in populations of models across species, which enabled us to model accurately nerve responses, demonstrate that individual-specific differences in nerve morphology produce variability in neural and physiological responses, and predict mechanisms of VNS therapeutic and side effects.

Schwann cell stimulation induces functional and structural changes in peripheral nerves.

Signal propagation is the essential function of nerves. Lysophosphatidic acid 18:1 (LPA) allows the selective stimulation of calcium signaling in Schwann cells but not neurons. Here, the time course of slowing and amplitude reduction on compound action potentials due to LPA exposure was observed in myelinated and unmyelinated fibers of the mouse, indicating a clear change of axonal function. Teased nerve fiber imaging showed that Schwann cell activation is also present in axon-attached Schwann cells in freshly isolated peripheral rat nerves. The LPA receptor 1 was primarily localized at the cell extensions in isolated rat Schwann cells, suggesting a role in cell migration. Structural investigation of rat C-fibers demonstrated that LPA leads to an evagination of the axons from their Schwann cells. In A-fibers, the nodes of Ranvier appeared unchanged, but the Schmidt-Lanterman incisures were shortened and myelination reduced. The latter might increase leak current, reducing the potential spread to the next node of Ranvier and explain the changes in conduction velocity. The observed structural changes provide a plausible explanation for the functional changes in myelinated and unmyelinated axons of peripheral nerves and the reported sensory sensations such as itch and pain.

Simulation of nerve fiber based on anti-resonant reflecting optical waveguide.

Light and optical techniques are widely used for the diagnosis and treatment of neurological diseases as advanced methods. Understanding the optical properties of nervous tissue and nerve cells is vital. Using light sources in these methods raises significant challenges, such as finding the place of light transmission in nerve fibers that could be an appropriate substrate for neural signaling. The myelinated axons are a promising candidate for transmitting neural signals and light due to their waveguide structures. On the other hand, with the emergence of diseases such as multiple sclerosis and disorders within the production and transmission of nerve signals, because of the demyelination, understanding the properties of the myelinated axon as a waveguide is obtaining additional necessity. The present study aims to show that the myelinated axon's refractive index (RI) profile plays an essential role in transmitting the beams in it. According to the nerve fiber, RI profile and its similarity to depressed core fiber with lower RI of the core compared to the cladding, the behaviors of the nerve fiber based on anti-resonant reflecting optical waveguide structure are investigated by taking into account the realistic optical imperfections. Light launching to the myelin sheath and axon is shown by introducing the axon and myelin sheath as a waveguide in the presence of both axon and myelin with bends, myelin sheath variation, and node of Ranvier.

kHz-frequency electrical stimulation selectively activates small, unmyelinated vagus afferents.

BACKGROUND: Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic activation of C-afferents could be used to mechanistically study and treat diseases of peripheral organs in which vagal reflexes are involved, but it has not been achieved. METHODS: We stimulated the vagus in rats and mice using trains of kHz-frequency stimuli. Stimulation effects were assessed using neuronal c-Fos expression, physiological and nerve fiber responses, optogenetic and computational methods. RESULTS: Intermittent kHz stimulation for 30 min activates specific motor and, preferentially, sensory vagus neurons in the brainstem. At sufficiently high frequencies (>5 kHz) and at intensities within a specific range (7-10 times activation threshold, T, in rats; 15-25 × T in mice), C-afferents are activated, whereas larger, A- and B-fibers, are blocked. This was determined by measuring fiber-specific acute physiological responses to kHz stimulus trains, and by assessing fiber excitability around kHz stimulus trains through compound action potentials evoked by probing pulses. Aspects of selective activation of C-afferents are explained in computational models of nerve fibers by how fiber size and myelin shape the response of sodium channels to kHz-frequency stimuli. CONCLUSION: kHz stimulation is a neuromodulation strategy to robustly and selectively activate vagal C-afferents implicated in physiological homeostasis and disease, over larger vagal fibers.

Accurate simulation of cuff electrode stimulation predicting in-vivo strength-duration thresholds.

BACKGROUND: In-silico experiments used to optimize and inform how peripheral nerve based electrode designs perform hold the promise of greatly reducing the guesswork with new designs as well as the number of animals used to identify and prove promising designs. Given adequate realism, in-silico experiments offer the promise of identifying putative mechanisms that further inform exploration of novel stimulation and recording techniques and their interactions with bioelectric phenomena. However, despite using validated nerve fiber models, when applied to the more complex case of an implanted extracellular electrode, the in-silico experiments often do not compare quantitatively with the results of experiments conducted in in-vivo experiments. This suggests that the accuracy/realism of the environment and the lamination of the nerve bundle plays an important role in this discrepancy. This paper describes the sensitivity of in-silico models to the electrical parameter estimates and volume conductor type used. METHODS: In-vivo work was performed on rat vagus nerves (N = 2) to characterize the strength-duration curve for various peaks identified in a compound nerve action potential (CAP) measured via a needle electrode. The vagus nerve has several distinct populations of nerve fiber calibers and types. Recruitment of a fiber caliber/type generates distinct peaks that can be identified, and whose conduction delay correlates to a conduction velocity. Peaks were identified by their recruitment thresholds and associated to their conduction velocities by the conduction delays of their peaks. An in-silico analog of the in-vivo experiment was constructed and experiments were run at the two extreme volume conductor cases: (1) The nerve in-saline, and (2) the nerve in-air. The specifically targeted electrical parameters were extraneural environment (in-air versus saline submersion), the resistivity (ρ) of the epineurium and perineurium, and the relative permittivity (εr ) of those same tissues. A time varying finite element method (FEM) model of the potential distribution vs time was quantified and projected onto a modified McIntyre, Richardson, and Grill (MRG), myelinated spinal nerve, active fiber model in NEURON to identify the threshold of activation as a function of stimulus pulse amplitude versus pulse width versus fiber diameter. The in-silico results were then compared to the in-vivo results. RESULTS: The finite element method simulations spanned two macro environments: in-saline and in-air. For these environments, the resistivities for low and high frequencies as well as two different permittivity cases were used. Between these 8 cases unique cases it was found that the most accurate combination of those variables was the in-air environment for low-frequency resistivity (ρ0 ) and ex-vivo a measured permittivity (εr,measured ) from unpublished ex-vivo experiments in canine vagal nerve, achieving a high degree of convergence (r2  = 0.96). As the in-vivo work was conducted in in-air, the in-air boundary condition test case was convergent with the in-silico results. CONCLUSIONS: The results of this investigation suggest that increasing realism in simulations begets more accurate predictions. Of particular importance are (ρ) and extraneural environment, with reactive electrical parameters becoming important for input waveforms with energy in higher frequencies.

A finite element method framework to model extracellular neural stimulation.

Objective.Increasing complexity in extracellular stimulation experiments and neural implant design also requires realistic computer simulations capable of modeling the neural activity of nerve cells under the influence of an electrical stimulus. Classical model approaches are often based on simplifications, are not able to correctly calculate the electric field generated by complex electrode designs, and do not consider electrical effects of the cell on its surrounding. A more accurate approach is the finite element method (FEM), which provides necessary techniques to solve the Poisson equation for complex geometries under consideration of electrical tissue properties. Especially in situations where neurons experience large and non-symmetric extracellular potential gradients, a FEM solution that implements the cell membrane model can improve the computer simulation results. To investigate the response of neurons in an electric field generated by complex electrode designs, a FEM framework for extracellular stimulation was developed in COMSOL.Approach.Methods to implement morphologically- and biophysically-detailed neurons including active Hodgkin-Huxley (HH) cell membrane dynamics as well as the stimulation setup are described in detail. Covered methods are (a) development of cell and electrode geometries including meshing strategies, (b) assignment of physics for the conducting spaces and the realization of active electrodes, (c) implementation of the HH model, and (d) coupling of the physics to get a fully described model.Main results.Several implementation examples are briefly presented: (a) a full FEM implementation of a HH model cell stimulated with a honeycomb electrode, (b) the electric field of a cochlear electrode placed inside the cochlea, and (c) a proof of concept implementation of a detailed double-cable cell membrane model for myelinated nerve fibers.Significance.The presented concepts and methods provide basic and advanced techniques to realize a full FEM framework for innovative studies of neural excitation in response to extracellular stimulation.

Myelinating Schwann cells and Netrin-1 control intra-nervous vascularization of the developing mouse sciatic nerve.

Peripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found, in mice, that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels via the endothelial receptor UNC5B during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during post-natal period.

The ultrastructural study of human cochlear nerve at different ages.

Ultrastructural and molecular changes in the myelin of the cochlear nerve (CN) have been associated with decreased hearing-acuity with increasing age. But most of these are animal studies or with very few human samples. Hence, we studied the ultrastructure of the human CN at different ages. We obtained samples of CN from persons, who at the time of death belonged to young, middle or old age-groups; defined as ≤ 30, 31 to 50, and ≥ 51 years of age, respectively. These were processed for viewing under a transmission electron microscope (TEM). Morphology and morphometry were assessed after blinding the observer. Measurements of diameter (whole nerve fibre, axon), myelin thickness and calculation of G-ratio were made on calibrated images using ImageJ software. K-Means cluster analysis was performed based on total and inner nerve fibre area. Middle and old age CN showed degenerating axons, splitting of myelin sheath and myelin balloons. Between the middle and old age groups there was significant decrease in axon diameter (p<0.001), inner nerve fibre area (p<0.001), myelin thickness (p<0.001), nerve fibre diameter (p<0.001), and G-ratio (p<0.001). By clustering, we identified three distinct populations of myelinated nerve fibres: large, medium and small. The large fibres (by size), seen in the young, disappeared in the old age-group. We were unable to find any unmyelinated nerve fibres in this study. The morphological deterioration CN fibres may be a visible sign of molecular degeneration and contribute to decreased hearing-acuity.

Median amplitude and frequency analysis of sensory nerve responses to intraepidermal stimulation.

BACKGROUND: In clinical practice, small myelinated sensory fibers conveying pain and other sensations, Aδ-fibers, cannot be examined with available nerve conduction study techniques. NEW METHOD: Equipment available in clinical neurophysiology laboratories is used to record from human sensory nerves multiple averaged responses to non-painful stimulation of intraepidermal nerves. Ten averaged responses are analyzed in all possible pair combinations with an algorithm applied to a 0.45 ms period of amplitude and frequency (power spectrum). The median of the algorithms is compared to control data to identify potentials generated as response to intraepidermal stimulation. RESULTS: Median analysis of the algorithm applied to amplitude and frequency of multiple record pairs identifies potentials with conduction velocities of Aδ-fibers. The analysis of frequency (power spectrum) adds data to the analysis of amplitude. Median analysis of multiple record pairs yields more data than analysis of one pair of alternate averages with the same algorithms. COMPARISON WITH EXISTING METHOD(S): At present, analysis of one pair of alternate average records with an algorithm is the only method to identify Aδ-fiber generated potentials. Median analysis of the same algorithm applied to the amplitude of multiple record pairs increases the number of Aδ-fiber generated potentials identified. Neither median analysis of amplitude nor frequency of multiple records pairs has ever been used for conduction studies of nerve fibers, including Aδ-fibers. CONCLUSIONS: Stimulation, recording and data analysis methods used in this study can be applied in the clinical EMG laboratory to identify the conduction velocities of Aδ-fibers in human sensory nerves.

Age is associated with reduced urethral pressure and afferent activity in rat.

Age-related changes in the lower urinary tract (LUT) can affect the coordination of reflexes and increase the incidence of bladder disorders in elderly. This study examines the age-related loss of urethral signaling capability by measuring the afferent activity directly. We find that less urethral pressure develops in response to fluid flow in old rats compared to young rats and that pressure and flow evoke less urethral afferent activation. These findings are consistent with our previous study demonstrating that the urethra-to-bladder reflex, which is required for efficient voiding, becomes weaker with age. We measured the pudendal afferent response in young (4-7 months) and old (18-24 months) rats to fluid flow in the urethra across a range of flow rates. We used paraffin embedding and hematoxylin and eosin staining to quantify age-related changes in the sensory branch of the pudendal nerve. Urethral afferent signaling in response to the same urethral flow rates was weaker in older animals. That is, the sensitivity of urethra afferents to flow decreased with age, and higher flow rates were required in older animals to recruit urethra afferents. There was also a reduction in the myelin thickness of pudendal afferents in old rats, which is a possible contributing factor to the sensory activity. Furthermore, the same flow rates evoked less pressure in the urethras of old animals, indicating there is an age-related change of the urethral tissue that reduces the pressure stimulus to which these afferents respond. These results help characterize the underlying changes in LUT system with age.

The plasticity of nerve fibers: the prolonged effects of polarization of afferent fibers.

The review surveys various aspects of the plasticity of nerve fibers, in particular the prolonged increase in their excitability evoked by polarization, focusing on a long-lasting increase in the excitability of myelinated afferent fibers traversing the dorsal columns of the spinal cord. We review the evidence that increased axonal excitability 1) follows epidurally applied direct current (DC) as well as relatively short (5 or 10 ms) current pulses and synaptically evoked intrinsic field potentials; 2) critically depends on the polarization of branching regions of afferent fibers at the sites where they bifurcate and give off axon collaterals entering the spinal gray matter in conjunction with actions of extrasynaptic GABAA membrane receptors; and 3) shares the feature of being activity-independent with the short-lasting effects of polarization of peripheral nerve fibers. A comparison between the polarization evoked sustained increase in the excitability of dorsal column fibers and spinal motoneurons (plateau potentials) indicates the possibility that they are mediated by partly similar membrane channels (including noninactivating type L Cav++ 1.3 but not Na+ channels) and partly different mechanisms. We finally consider under which conditions transspinally applied DC (tsDCS) might reproduce the effects of epidural polarization on dorsal column fibers and the possible advantages of increased excitability of afferent fibers for the rehabilitation of motor and sensory functions after spinal cord injuries.NEW & NOTEWORTHY This review supplements previous reviews of properties of nerve fibers by surveying recent experimental evidence for their long-term plasticity. It also extends recent descriptions of spinal effects of DC by reviewing effects of polarization of afferent nerve fibers within the dorsal columns, the mechanisms most likely underlying the long-lasting increase in their excitability and possible clinical implications.

Progression and regression of nerve fibre pathology and dysfunction early in diabetes over 5 years.

It has traditionally been suggested that the early development of diabetic sensorimotor polyneuropathy (DSPN) is characterized by predominant and progressive injury to small nerve fibres followed by large fibre impairment. We alternatively hypothesized that small and large fibre damage due to DSPN in type 1 and type 2 diabetes could develop in parallel and may not only be progressive but also reversible. Participants from the German Diabetes Study baseline cohort with recent-onset type 1/type 2 diabetes (n = 350/570) and age-matched glucose-tolerant control individuals (Control 1/Control 2: n = 114/190) were assessed using nerve conduction studies, thermal detection thresholds, vibration perception thresholds, neuropathy symptom scores, neuropathy disability scores and intraepidermal nerve fibre density (IENFD) in skin biopsies (type 1/type 2 diabetes: n = 102/226; Control 1/Control 2: n = 109/208). Subsets of participants with type 1/type 2 diabetes were followed for 5 years (n = 184/307; IENFD subset: n = 18/69). DSPN was defined by the Toronto Consensus criteria. At baseline, DSPN was present in 8.1% and 13.3% of the type 1 and type 2 diabetes groups, respectively. The most frequently abnormal tests in the lower limbs below or above the 2.5th and 97.5th centiles of the controls were the IENFD (13.7%) and individual nerve conduction studies (up to 9.4%) in type 1 diabetes participants and IENFD (21.8%), malleolar vibration perception thresholds (17.5%), and individual nerve conduction studies (up to 11.8%) in those with type 2 diabetes, whereas thermal detection threshold abnormalities did not differ between the control and diabetes groups. After 5 years, the highest progression rates from the normal to the abnormal range in type 2 diabetes participants were found for IENFD (18.8%) by -4.1 ± 2.8 fibres/mm, malleolar vibration perception threshold (18.6%) by 9.1 ± 20.2 µm and nerve conduction studies (15.0%) by 3.7 ± 1.5 points, while vice versa the highest regression rates were observed for neuropathy disability scores (11.2%) by -3.1 ± 1.3 points, sural nerve amplitudes (9.1%) by 4.7 ± 3.0 µV, IENFD (8.7%) by 1.4 ± 1.3 fibres/mm, and neuropathy symptom scores (8.2%) by -5.8 ± 1.6 points. In type 1 diabetes participants, no major progression was seen after 5 years, but subclinical DSPN regressed in 10.3%. These findings point to early parallel damage to both small and large nerve fibres in well-controlled recent-onset type 2 and, to a lesser extent, type 1 diabetes. After 5 years, peripheral nerve morphology and function and clinical measures progress to the abnormal range in type 2 diabetes, but initial nerve alterations are also reversible to a meaningful degree.

Model-based signal processing enables bidirectional inferring between local field potential and spikes evoked by noxious stimulation.

BACKGROUND: Recording spontaneous and evoked activities by means of unitary extracellular recordings and local field potential (LFP) are key understanding the mechanisms of neural coding. The LFP is one of the most popular and easy methods to measure the activity of a population of neurons. LFP is also a composite signal known to be difficult to interpret and model. There is a growing need to highlight the relationship between spiking activity and LFP. Here, we hypothesized that LFP could be inferred from spikes under evoked noxious conditions. METHOD: Recording was performed from the medullary dorsal horn (MDH) in deeply anesthetized rats. We detail a process to highlight the C-fiber (nociceptive) evoked activity, by removing the A-fiber evoked activity using a model-based approach. Then, we applied the convolution kernel theory and optimization algorithms to infer the C-fiber LFP from the single cell spikes. Finally, we used a probability density function and an optimization algorithm to infer the spikes distribution from the LFP. RESULTS: We successfully extracted C-fiber LFP in all data recordings. We observed that C-fibers spikes preceded the C-fiber LFP and were rather correlated to the LFP derivative. Finally, we inferred LFP from spikes with excellent correlation coefficient (r = 0.9) and reverse generated the spikes distribution from LFP with good correlation coefficients (r = 0.7) on spikes number. CONCLUSION: We introduced the kernel convolution theory to successfully infer the LFP from spikes, and we demonstrated that we could generate the spikes distribution from the LFP.

Different sensitivity of action potential generation to the rate of depolarization in vagal afferent A-fiber versus C-fiber neurons.

This study demonstrates that the action potential discharge in vagal afferent A-fiber neurons is about 20 times more sensitive to the rate of membrane depolarization compared to C-fiber neurons. The sensitivity of action potential generation to the depolarization rate in vagal sensory neurons is independent of the intensity of current stimuli but nearly abrogated by inhibiting the D-type potassium channel. These findings help better understand the mechanisms that control the activation of vagal afferent nerves.

Intravital Imaging of Neocortical Heterotopia Reveals Aberrant Axonal Pathfinding and Myelination around Ectopic Neurons.

Neocortical heterotopia consist of ectopic neuronal clusters that are frequently found in individuals with cognitive disability and epilepsy. However, their pathogenesis remains poorly understood due in part to a lack of tractable animal models. We have developed an inducible model of focal cortical heterotopia that enables their precise spatiotemporal control and high-resolution optical imaging in live mice. Here, we report that heterotopia are associated with striking patterns of circumferentially projecting axons and increased myelination around neuronal clusters. Despite their aberrant axonal patterns, in vivo calcium imaging revealed that heterotopic neurons remain functionally connected to other brain regions, highlighting their potential to influence global neural networks. These aberrant patterns only form when heterotopia are induced during a critical embryonic temporal window, but not in early postnatal development. Our model provides a new way to investigate heterotopia formation in vivo and reveals features suggesting the existence of developmentally modulated, neuron-derived axon guidance and myelination factors.

Conduction Velocity Along the Local Axons of Parvalbumin Interneurons Correlates With the Degree of Axonal Myelination.

Parvalbumin-containing (PV+) basket cells in mammalian neocortex are fast-spiking interneurons that regulate the activity of local neuronal circuits in multiple ways. Even though PV+ basket cells are locally projecting interneurons, their axons are myelinated. Can this myelination contribute in any significant way to the speed of action potential propagation along such short axons? We used dual whole cell recordings of synaptically connected PV+ interneurons and their postsynaptic target in acutely prepared neocortical slices from adult mice to measure the amplitude and latency of single presynaptic action potential-evoked inhibitory postsynaptic currents. These same neurons were then imaged with immunofluorescent array tomography, the synapses between them identified and a precise map of the connections was generated, with the exact axonal length and extent of myelin coverage. Our results support that myelination of PV+ basket cells significantly increases conduction velocity, and does so to a degree that can be physiologically relevant.