Spike Failure Research Articles

Design and laboratory evaluation of spring washers as railway baseplate hold-down method to mitigate spike failures

The rising popularity of elastic railroad fasteners for use in timber sleeper tracks, delineated through their wide adoption across the North American freight network, is facing resistance since the derailment data attributes at least 13 derailments in last two decades to spike failures in sleepers leveraging these elastic fasteners. Previous investigations of the spike failure mechanism illustrated that rail baseplate uplift induced by the rail’s wave-action during a train pass reduces friction at the plate-sleeper interface. This loss in friction transfers additional load (e.g., lateral and longitudinal) to spikes and causes the stress levels to exceed the endurance limits. Although installation of spikes with spring washers was suggested to restrain the baseplate uplift, the industry recommended Fe6 washers demonstrate inadequate resiliency (i.e., working range) resulting in failure to maintain the required hold-down load over time. To characterize the appropriate spring washer for spike failure mitigation, this paper presents an overview of the design criteria driven by engineering design standards while accommodating the standard fastener components. Moreover, this study quantifies the load and resiliency demands from spring washers based on spike pullout experiments as well as existing correlations and pertinent studies in the literature. Consequently, the maximum and minimum recommended hold-down installation loads are 22.2 kN (5000 lbs) and 4.5 kN (1000 lbs.), respectively, to protect the sleeper from premature failure while simultaneously reducing spike stress by 70%. To identify a washer that has an adequate working range, static compression experiments were carried out on a set of nine commercial and non-commercial washers. Results indicate that at least two of the washers considered – the Fe19 and polyurethane washer – can achieve working ranges that are 69% and 93% wider, respectively, with a 68% reduced timber stress compared to the baseline Fe6 washer. Results of this work provide insights into the selection of proper spring washer and the magnitude of installation load to mitigate spike failures.

The impact of spike timing precision and spike emission reliability on decoding accuracy

Precisely timed and reliably emitted spikes are hypothesized to serve multiple functions, including improving the accuracy and reproducibility of encoding stimuli, memories, or behaviours across trials. When these spikes occur as a repeating sequence, they can be used to encode and decode a potential time series. Here, we show both analytically and in simulations that the error incurred in approximating a time series with precisely timed and reliably emitted spikes decreases linearly with the number of neurons or spikes used in the decoding. This was verified numerically with synthetically generated patterns of spikes. Further, we found that if spikes were imprecise in their timing, or unreliable in their emission, the error incurred in decoding with these spikes would be sub-linear. However, if the spike precision or spike reliability increased with network size, the error incurred in decoding a time-series with sequences of spikes would maintain a linear decrease with network size. The spike precision had to increase linearly with network size, while the probability of spike failure had to decrease with the square-root of the network size. Finally, we identified a candidate circuit to test this scaling relationship: the repeating sequences of spikes with sub-millisecond precision in area HVC (proper name) of the zebra finch. This scaling relationship can be tested using both neural data and song-spectrogram-based recordings while taking advantage of the natural fluctuation in HVC network size due to neurogenesis.

The Therapeutic Frequency Profile of Subthalamic Nucleus Deep Brain Stimulation in Rats Is Shaped by Antidromic Spike Failure.

The therapeutic mechanisms of subthalamic nucleus (STN) deep brain stimulation (DBS) may depend on antidromic activation of cortex via the hyperdirect pathway. However, hyperdirect pathway neurons cannot reliably follow high-stimulation frequencies, and the spike failure rate appears to correlate with symptom relief as a function of stimulation frequency. We hypothesized that antidromic spike failure contributes to the cortical desynchronization caused by DBS. We measured in vivo evoked cortical activity in female Sprague Dawley rats and developed a computational model of cortical activation from STN DBS. We modeled stochastic antidromic spike failure to determine how spike failure affected the desynchronization of pathophysiological oscillatory activity in cortex. We found that high-frequency STN DBS desynchronized pathologic oscillations via the masking of intrinsic spiking through a combination of spike collision, refractoriness, and synaptic depletion. Antidromic spike failure shaped the parabolic relationship between DBS frequency and cortical desynchronization, with maximum desynchronization at ∼130 Hz. These findings reveal that antidromic spike failure plays a critical role in mediating the dependency of symptom relief on stimulation frequency.SIGNIFICANCE STATEMENT Deep brain stimulation (DBS) is a highly effective neuromodulation therapy, yet it remains uncertain why conventionally used stimulation frequencies (e.g., ∼130 Hz) are optimal. In this study, we demonstrate a potential explanation for the stimulation frequency dependency of DBS through a combination of in vivo experimental measurements and computational modeling. We show that high-frequency stimulation can desynchronize pathologic firing patterns in populations of neurons by inducing an informational lesion. However, sporadic spike failure at these high frequencies limits the efficacy of the informational lesion, yielding a parabolic profile with optimal effects at ∼130 Hz. This work provides a potential explanation for the therapeutic mechanism of DBS, and highlights the importance of considering spike failure in mechanistic models of DBS.

The cortical evoked potential corresponds with deep brain stimulation efficacy in rats.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) antidromically activates the motor cortex (M1), and this cortical activation appears to play a role in the treatment of hypokinetic motor behaviors (Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Science 324: 354-359, 2009; Yu C, Cassar IR, Sambangi J, Grill WM. J Neurosci 40: 4323-4334, 2020). The synchronous antidromic activation takes the form of a short-latency cortical evoked potential (cEP) in electrocorticography (ECoG) recordings of M1. We assessed the utility of the cEP as a biomarker for STN DBS in unilateral 6-hydroxydopamine-lesioned female Sprague Dawley rats, with stimulating electrodes implanted in the STN and the ECoG recorded above M1. We quantified the correlations of the cEP magnitude and latency with changes in motor behavior from DBS and compared them to the correlation between motor behaviors and several commonly used spectral-based biomarkers. The cEP features correlated strongly with motor behaviors and were highly consistent across animals, whereas the spectral biomarkers correlated weakly with motor behaviors and were highly variable across animals. The cEP may thus be a useful biomarker for assessing the therapeutic efficacy of DBS parameters, as its features strongly correlate with motor behavior, it is consistent across time and subjects, it can be recorded under anesthesia, and it is simple to quantify with a large signal-to-noise ratio, enabling rapid, real-time evaluation. Additionally, our work provides further evidence that antidromic cortical activation mediates changes in motor behavior from STN DBS and that the dependence of DBS efficacy on stimulation frequency may be related to antidromic spike failure.NEW & NOTEWORTHY We characterize a new potential biomarker for deep brain stimulation (DBS), the cortical evoked potential (cEP), and demonstrate that it exhibits a robust correlation with motor behaviors as a function of stimulation frequency. The cEP may thus be a useful clinical biomarker for changes in motor behavior. This work also provides insight into the cortical mechanisms of DBS, suggesting that motor behaviors are strongly affected by the rate of antidromic spike failure during DBS.

Co-expressing fast channelrhodopsin with step-function opsin overcomes spike failure due to photocurrent desensitization in optogenetics: a theoretical study

Objective. A fundamental challenge in optogenetics is to elicit long-term high-fidelity neuronal spiking with negligible heating. Fast channelrhodopsins (ChRs) require higher irradiances and cause spike failure due to photocurrent desensitization under sustained illumination, whereas, more light-sensitive step-function opsins (SFOs) exhibit prolonged depolarization with insufficient photocurrent and fast response for high-fidelity spiking. Approach. We present a novel method to overcome this fundamental limitation by co-expressing fast ChRs with SFOs. A detailed theoretical analysis of ChETA co-expressed with different SFOs, namely ChR2(C128A), ChR2(C128S), stabilized step-function opsin (SSFO) and step-function opsin with ultra-high light sensitivity (SOUL), expressing hippocampal neurons has been carried out by formulating their accurate theoretical models. Main results. ChETA-SFO-expressing hippocampal neurons shows more stable photocurrent that overcomes spike failure. Spiking fidelity in these neurons can be sustained even at lower irradiances of subsequent pulses (77% of initial pulse intensity in ChETA-ChR2(C128A)-expressing neurons) or by using red-shifted light pulses at appropriate intervals. High-fidelity spiking upto 60 Hz can be evoked in ChETA-ChR2(C128S), ChETA-SSFO and ChETA-SOUL-expressing neurons, which cannot be attained with only SFOs. Significance. The present study provides important insights about photostimulation protocols for bi-stable switching of neurons. This new approach provides a means for sustained low-power, high-frequency and high-fidelity optogenetic switching of neurons, necessary to study various neural functions and neurodegenerative disorders, and enhance the utility of optogenetics for biomedical applications.

Quantification of vertical, lateral, and longitudinal fastener demand in broken spike track: Inputs to mechanistic-empirical design

To address a recent challenge related to broken spikes in premium elastic fastening systems that have led to at least ten derailments and require manual walking inspections as well as build upon mechanistic-empirical (M-E) design principles for future fastening system component design, this paper quantifies the vertical, lateral, and longitudinal fastening system loads under revenue service traffic in a curve that has regularly experienced spike fastener fatigue failures. Previous data has indicated that the high rail of Track 3 experienced the most failures at this location. The data from this investigation sheds light into why failures are more predominant at this location than others and how the vertical, lateral, and longitudinal loads cannot be considered independently. Specifically, while the magnitude of the applied loading was the lowest on the high rail of Track 3, the threshold for failure was also the lowest given the operations at this location led to unloading of the high rail, thus indirectly highlighting the importance of friction within a fastening system. The data also show the high rail of Track 3 was subjected to the highest L/V load ratios and was an outlier in the typical lateral load reversals applied likely leading to spike stress reversals and thus a shorter fatigue life. Finally, based upon the data, it is recommended that to mitigate spike failures, as well as similar fastener challenges in other track types (e.g. rail seat deterioration, etc.) railroads should ensure trains operate close to the balance speed and use fastening system that transfer loads through friction. This study also provides novel data for M-E design of fastening systems.

Analytical Elastic Modeling of Rail and Fastener Longitudinal Response

The rail fastening system plays a critical role in maintaining proper railroad track geometry by transferring vertical, lateral, and longitudinal forces from the rails to crossties. Broken spikes in elastic fastening systems have been linked to inadequate transfer of longitudinal loads, posing a safety risk for timber crosstie ballasted track. Longitudinal track demand caused by passing trains has been investigated in previous research, but the magnitude and distribution of longitudinal fastener loads is not well understood or documented. To address these track component failures and improve fastener design, this paper presents a validated analytical model that estimates longitudinal rail seat loads, advancing current formulations to focus specifically on the rail seat. The validated method was used to quantify the distribution and magnitude of longitudinal loads in both the rail and fastening system caused by passing trains. Further, this paper quantifies the effect of track stiffness, number of powered locomotives, and wheel spacing on these distributions and magnitudes. This information provides valuable insight into the specific type of spike failures that have led to at least ten derailments and the requirement of manual walking inspections on multiple North American heavy axle load railroads as detailed in this paper. Further, this method can be used to quantify the longitudinal fastener loads for different track conditions to advance the mechanistic-empirical track design philosophy for elastic fastening systems.

Methods to mitigate railway premium fastening system spike fatigue failures using finite element analysis

Railroad track fasteners work as a system, in conjunction with the sleeper, to maintain gauge, transmit loads, and resist lateral and longitudinal rail movement. Timber sleeper elastic fastening systems have shown benefits by preventing rail rollover derailments and reducing spike killing. However, these systems have experienced broken spike failures leading to at least 10 derailments over the past 20 years. Recent studies focusing on the cause of the failures have indicated that the spikes fail in fatigue and these fatigue failures are driven by the addition of longitudinal loads the spikes carry. Further, due to the nature of the elastic fastener, the wave-action of the rail separates the plate from the sleeper, as opposed to the rail from the plate, thus eliminating the load transferred by friction. This study quantifies the effect of fastening system design changes on spike stress and the load required to exceed the spike endurance limit. Specific design changes investigated in this study include increasing spike cross-sectional area, comparing spike type (cut vs screw), varying the spike load location, controlling the development of friction between the sleeper and plate, varying spike engagement and finally, adjusting the quantity of spikes at a given rail seat. Finite element analysis (FEA) was used to quantify these effects and multiple 3D models were developed and used. Results indicate that the two most effective methods to reduce spike stress and increase the required load to exceed the spike’s endurance limit, and thus mitigate spike fatigue failures, would be to ensure spike engagement between the plate and spikes and develop friction between the plate and sleeper (e.g. add spring washers, etc.). Future fastening system designs can incorporate these, and other findings, to mitigate spike fastener failures to ensure the full value of timber sleeper elastic track fastening systems is realized.

Analytical Method to Estimate Railroad Spike Fastener Stress

Previous research indicates that spike fastener fatigue failures have led to at least ten derailments since 2000. Given that railroads continue to install fastening systems that have experienced spike failures, methods to quantify the stress state of the spike must be developed. Common approaches to quantify the effect of key variables include laboratory experimentation, field instrumentation, or finite element model development. However, these approaches may be both time and cost prohibitive. An analytical method based on beam on elastic foundation mechanics, similar to the analysis of laterally loaded piles in deep foundation design, was developed to estimate the spike stresses. The outcome is a laboratory-validated analytical approach that generates estimates of spike stress. This analytical model was used to investigate key design criteria (timber modulus, spike cross-sectional area, and load applied) that could be changed to improve the resiliency of the fastening system to increase railroad safety. Another outcome of this study is the development of an instrumented spike that quantifies the spike demands when installed and loaded within a crosstie.

Intermittent Failure of Spike Propagation in Primary Afferent Neurons during Tactile Stimulation.

Primary afferent neurons convey somatosensory information to the CNS. Low-threshold mechanoreceptors are classified as slow-adapting (SA) or rapid-adapting (RA) based on whether or not they spike repetitively during sustained tactile stimulation; the former are subclassified as Type 1 or 2 based on the regularity of their spiking. Recording in vivo from DRGs of mice, we observed irregular- and regular-spiking units consistent with SA1 and SA2 low-threshold mechanoreceptors, but some units, which we labeled "semiregular," did not fit cleanly into the existing classification scheme. Analysis of their spiking revealed integer-multiple patterning in which spike trains comprised a fundamental interspike interval and multiples thereof. Integer-multiple-patterned spiking was reproduced by randomly removing spikes from an otherwise regular spike train, suggesting that semiregular units represent SA2 units in which some spikes are "missing." We hypothesized that missing spikes arose from intermittent failure of spikes to initiate or to propagate. Intermittent failure of spike initiation was ruled out by several observations: integer-multiple-patterned spiking was not induced by intradermal lidocaine, was independent of stimulus modality (mechanical vs optogenetic), and could not be reproduced in a conductance-based model neuron given constant input. On the other hand, integer-multiple-patterned spiking was induced by application of lidocaine to the DRG, thus pinpointing intermittent failure of spike propagation as the basis for integer-multiple-patterned spiking. Indeed, half of all SA2 units exhibited some missing spikes, mostly at low rate (<5%), which suggests that axons are efficient in using the lowest safety factor capable of producing near-perfect propagation reliability.SIGNIFICANCE STATEMENT The impedance mismatch at axon branch points can impede spike propagation. Reliability of spike propagation across branch points remains an open question and is especially important for primary afferents whose spikes must cross a T-junction to reach the CNS. Past research on propagation reliability has relied almost entirely on simulations and in vitro experiments. Here, recording in vivo, we linked a distinctive pattern of spiking to the intermittent failure of spike propagation at the T-junction. The rarity of failures argues that safety factor is high under physiological conditions, yet the occurrence of such failures argues that safety factor is just high enough to ensure near-perfect reliability, consistent with a good balance between propagation reliability and energy efficiency.

Theoretical optimization of high-frequency optogenetic spiking of red-shifted very fast-Chrimson-expressing neurons.

A detailed theoretical analysis and optimization of high-fidelity, high-frequency firing of the red-shifted very-fast-Chrimson (vf-Chrimson) expressing neurons is presented. A four-state model for vf-Chrimson photocycle has been formulated and incorporated in Hodgkin-Huxley and Wang-Buzsaki spiking neuron circuit models. The effect of various parameters that include irradiance, pulse width, frequency, expression level, and membrane capacitance has been studied in detail. Theoretical simulations are in excellent agreement with recently reported experimental results. The analysis and optimization bring out additional interesting features. A minimal pulse width of 1.7ms at induces a peak photocurrent of 1250pA. Optimal irradiance ( ) and pulse width ( ) to trigger action potential have been determined. At frequencies beyond 200Hz, higher values of expression level and irradiance result in spike failure. Singlet and doublet spiking fidelity can be maintained up to 400 and 150Hz, respectively. The combination of expression level and membrane capacitance is a crucial factor to achieve high-frequency firing above 500Hz. Its optimization enables 100% spike probability of up to 1kHz. The study is useful in designing new high-frequency optogenetic neural spiking experiments with desired spatiotemporal resolution, by providing insights into the temporal spike coding, plasticity, and curing neurodegenerative diseases.

Bifurcation structure of adaptation versus depolarization block

Midbrain dopamine neurons fire in a pacemaker-like fashion in vitro where they are deprived of most afferent input. In vivo, these neurons can emit a burst of action potentials with fast (~50 Hz) frequencies [1]. However, simple somatic depolarization of these neurons does not elicit such rapid firing because the neurons cease firing at levels of depolarizing somatic current injection stronger than those that elicit repetitive firing at about 10 Hz [2]. Here we argue that in the case of simple somatic current injection, firing ceases due to adaptation rather than depolarization block. We hypothesize that the primary adaptation mechanism is the slow inactivation of the fast sodium current [3], which causes the spike threshold to become more depolarized with each spike until spiking fails. We contrast the bifurcation structure of a simple 3 variable model that ceases to fire via this mechanism with a two variable model that fails by going into depolarization block. In both cases, spontaneous firing is characterized by an N shaped voltage nullcline with two stable branches. For the depolarization block, firing ceases when the fixed point moves from the unstable to the stable branch at the knee of the nullcline (Fig.​(Fig.1).1). The action potentials decrease in amplitude both at the peak and the trough, and the resulting stable potential is much more depolarized than the spike threshold for the adaptation case. In contrast, for the adaptation case, only the peaks of the action potential decrease slightly, and the final stable potential is at the spike threshold. As slow inactivation proceeds, the voltage nullcline loses the unstable middle branch, and the two stable branches merge. Spiking fails when the trajectory no longer crosses the unstable middle branch (the spike threshold) because the increasing ISI length allows for more fast inactivation. The two mechanisms can be differentiated experimentally: an additional depolarizing square pulse of current applied just after the last spike should evoke an additional action potential for adaptation, but not depolarization block. Figure 1 Spike Failure via Adaptation. (A) Time course of the membrane potential (top) and slow Na+ channel inactivation, middle), during spike failure after a depolarizing current step (bottom). (B) Phase plane for fast/slow analysis. The N shaped voltage nullcline ...

Shortest Loops are Pacemakers in Random Networks of Electrically Coupled Axons

High-frequency oscillations (HFOs) are an important part of brain activity in health and disease. However, their origins remain obscure and controversial. One possible mechanism depends on the presence of sparsely distributed gap junctions that electrically couple the axons of principal cells. A plexus of electrically coupled axons is modeled as a random network with bi-directional connections between its nodes. Under certain conditions the network can demonstrate one of two types of oscillatory activity. Type I oscillations (100–200 Hz) are predicted to be caused by spontaneously spiking axons in a network with strong (high conductance) gap junctions. Type II oscillations (200–300 Hz) require no spontaneous spiking and relatively weak (low-conductance) gap junctions, across which spike propagation failures occur. The type II oscillations are reentrant and self-sustained. Here we examine what determines the frequency of type II oscillations. Using simulations we show that the distribution of loop lengths is the key factor for determining frequency in type II network oscillations. We first analyze spike failure between two electrically coupled cells using a model of anatomically reconstructed CA1 pyramidal neuron. Then network oscillations are studied by a cellular automaton model with random network connectivity, in which we control loop statistics. We show that oscillation periods can be predicted from the network’s loop statistics. The shortest loop, around which a spike can travel, is the most likely pacemaker candidate. The principle of one loop as a pacemaker is remarkable, because random networks contain a large number of loops juxtaposed and superimposed, and their number rapidly grows with network size. This principle allows us to predict the frequency of oscillations from network connectivity and visa versa. We finally propose that type I oscillations may correspond to ripples, while type II oscillations correspond to so-called fast ripples.

Processing of central and reflex vagal drives by rat cardiac ganglion neurones: an intracellular analysis

Cardiac vagal tone is an important indicator of cardiovascular health, and its loss is an independent risk factor for arrhythmias and mortality. Several studies suggest that this loss of vagal tone can occur at the cardiac ganglion but the factors affecting ganglionic transmission in vivo are poorly understood. We have employed a novel approach allowing intracellular recordings from functionally connected cardiac vagal ganglion cells in the working heart-brainstem preparation. The atria were stabilised in situ preserving their central neural connections, and ganglion cells (n = 32) were impaled with sharp microelectrodes. Cardiac ganglion cells with vagal synaptic inputs (spontaneous, n = 10; or electrically evoked from the vagus, n = 3) were identified as principal neurones and showed tonic firing responses to current injected to their somata. Cells lacking vagal inputs (n = 19, presumed interneurones) were quiescent but showed phasic firing responses to depolarising current. In principal cells the ongoing action potentials and EPSPs exhibited respiratory modulation, with peak frequency in post-inspiration. Action potentials arose from unitary EPSPs and autocorrelation of those events showed that each ganglion cell received inputs from a single active preganglionic source. Peripheral chemoreceptor, arterial baroreceptor and diving response activation all evoked high frequency synaptic barrages in these cells, always from the same single preganglionic source. EPSP amplitudes showed frequency dependent depression, leading to more spike failures at shorter inter-event intervals. These findings indicate that rather than integrating convergent inputs, cardiac vagal postganglionic neurones gate preganglionic inputs, so regulating the proportion of central parasympathetic tone that is transmitted on to the heart.

Morphological and Functional Continuum Underlying Heterogeneity in the Spiking Fidelity at the Calyx of Held SynapseIn Vitro

Reliable neuronal spiking is critical for a myriad of computations performed by neural circuits. This is particularly evident for sound localization cues in the auditory brainstem circuits that detect timing and intensity differences of sounds arriving at two ears. The calyx of Held-principal neuron synapse in the medial nucleus of the trapezoid body (MNTB) in this circuit is traditionally viewed as a reliable relay, which converts contralateral excitatory inputs to inhibitory outputs to ipsilateral superior olive neurons that code interaural timing and intensity differences. However, recent studies demonstrated large variability in the incidence of postsynaptic spike failures at this synapse, challenging the view that this synapse is a fail-safe relay. Using combined imaging and paired recordings in mature (P16-P19) mouse brainstem slices, we show that spike failure rates of MNTB neurons are strongly correlated with differences in gross morphology of the calyx terminal and quantal properties under standard in vitro- and in vivo-like conditions. MNTB neurons innervated by calyces with simple morphologies (mainly digits) express strong short-term synaptic depression and a high incidence of spike failures after high-frequency stimulation. Conversely, MNTB neurons innervated by structurally complex calyces (digits and numerous bouton-like swellings) exhibit initial facilitation followed by slow depression and very few spike failures. Our results indicate that the calyx of Held-MNTB synapse is likely organized as a structural and functional continuum, in that correlated heterogeneities in calyx morphology and short-term plasticity serve as a filter for regulating the inhibition delivered to superior olive neurons during sound localization.

Reservoirs of Stability: Dynamic Flux Tubes in Cortical Circuits

Reservoirs of Stability: Dynamic Flux Tubes in Cortical Circuits

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin–Huxley and reduced Morris–Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g Na /g L , acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g Na /g L just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its “pathological” attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g Na and g L after demyelination. The KCNK family of g L potassium channels may be an important target for new drugs to treat the symptoms of demyelination.

Metabotropic glutamate receptor 1 activity generates persistent, N‐methyl‐d‐aspartate receptor‐dependent depression of hippocampal pyramidal cell excitability

Metabotropic glutamate receptors (mGluRs) are involved in many forms of neuronal plasticity. In the hippocampus, they have well-defined roles in long-lasting forms of both synaptic and intrinsic plasticity. Here, we describe a novel form of long-lasting intrinsic plasticity that we call (S)-3,5-dihydroxyphenylglycine (DHPG)-mediated long-term depression of excitability (DHPG-LDE), and which is generated following transient pharmacological activation of group I mGluRs. In extracellular recordings from hippocampal slices, DHPG-LDE was expressed as a long-lasting depression of antidromic compound action potentials (cAPs) in CA1 or CA3 cells following a 4-min exposure to the group I mGluR agonist (S)-DHPG. A similar phenomenon was also seen for orthodromic fibre volleys evoked in CA3 axons. In single-cell recordings from CA1 pyramids, DHPG-LDE was manifest as persistent failures in antidromic action potential generation. DHPG-LDE was blocked by (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), an antagonist of mGluR1, but not 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 inhibitor. Although insensitive to antagonists of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and gamma-aminobutyric acid(A) receptors, DHPG-LDE was blocked by antagonists of N-methyl-D-aspartate (NMDA) receptors. Similarly, in single-cell recordings, DHPG-mediated antidromic spike failures were eliminated by NMDA receptor antagonism. Long after (S)-DHPG washout, DHPG-LDE was reversed by mGluR1 antagonism. A 4-min application of (S)-DHPG also produced an NMDA receptor-dependent persistent depolarization of CA1 pyramidal cells. This depolarization was not solely responsible for DHPG-LDE, because a similar level of depolarization elicited by raising extracellular K(+) increased the amplitude of the cAP. DHPG-LDE did not involve HCN channels or protein synthesis, but was eliminated by blockers of protein kinase C or tyrosine phosphatases.

Activity-Dependent Control of Neuronal Output by Local and Global Dendritic Spike Attenuation

Neurons possess elaborate dendritic arbors which receive and integrate excitatory synaptic signals. Individual dendritic subbranches exhibit local membrane potential supralinearities, termed dendritic spikes, which control transfer of local synaptic input to the soma. Here, we show that dendritic spikes in CA1 pyramidal cells are strongly regulated by specific types of prior input. While input in the linear range is without effect, supralinear input inhibits subsequent spikes, causing them to attenuate and ultimately fail due to dendritic Na(+) channel inactivation. This mechanism acts locally within the boundaries of the input branch. If an input is sufficiently strong to trigger axonal action potentials, their back-propagation into the dendritic tree causes a widespread global reduction in dendritic excitability which is prominent after firing patterns occurring in vivo. Together, these mechanisms control the capability of individual dendritic branches to trigger somatic action potential output. They are invoked at frequencies encountered during learning, and impose limits on the storage and retrieval rates of information encoded as branch excitability.

Escape Behavior Elicited by Single, Channelrhodopsin-2-Evoked Spikes in Zebrafish Somatosensory Neurons

Somatosensory neurons in teleosts and amphibians are sensitive to thermal, mechanical, or nociceptive stimuli [1, 2]. The two main types of such cells in zebrafish--Rohon-Beard and trigeminal neurons--have served as models for neural development [3-6], but little is known about how they encode tactile stimuli. The hindbrain networks that transduce somatosensory stimuli into a motor output encode information by using very few spikes in a small number of cells [7], but it is unclear whether activity in the primary receptor neurons is similarly efficient. To address this question, we manipulated the activity of zebrafish neurons with the light-activated cation channel, Channelrhodopsin-2 (ChR2) [8, 9]. We found that photoactivation of ChR2 in genetically defined populations of somatosensory neurons triggered escape behaviors in 24-hr-old zebrafish. Electrophysiological recordings from ChR2-positive trigeminal neurons in intact fish revealed that these cells have extremely low rates of spontaneous activity and can be induced to fire by brief pulses of blue light. Using this technique, we find that even a single action potential in a single sensory neuron was at times sufficient to evoke an escape behavior. These results establish ChR2 as a powerful tool for the manipulation of neural activity in zebrafish and reveal a degree of efficiency in coding that has not been found in primary sensory neurons.