基于最大锋电位间隔的爆发检测自适应算法

在各种类型的培养神经元网络、哺乳动物中枢神经系统和切片中,都可以观察到爆发。爆发是空间-时间放电模式的重要特征,它由一系列高频率发放的连续动作电位组成,由于在时间尺度上的复杂性,使其辨识和探测存在许多困难。自适应算法利用爆发外部锋电位间隔超过爆发内部锋电位间隔的累加和识别爆发本身。基于该算法原理,以爆发内部最大锋电位间隔参数作为确定爆发的约束条件,改进爆发检测自适应算法。实验结果表明,改进算法可以有效地避免爆发的漏检和错检,较准确地检测出神经元的爆发活动,确定爆发活动的数目和持续时间等,爆发检测的平均准确率为93.8%,比原自适应算法提高了35.3%。     

Synchronous Ca(2+) oscillation emerges from voltage fluctuations of Ca(2+) stores

Synchronous Ca(2+) oscillation occurs in various cell types to regulate cellular functions. However, the mechanism for synchronization of Ca(2+) increases between cells remains unclear. Recently, synchronous oscillatory changes in the membrane potential of internal Ca(2+) stores were recorded using an organelle-specific voltage-sensitive dye [Yamashita et al. (2006) FEBS J273, 3585-3597], and an electrical coupling model of the synchronization of store potentials and Ca(2+) releases has been proposed [Yamashita (2006) FEBS Lett580, 4979-4983]. This model is based on capacitative coupling, by which transient voltage changes can be synchronized, but oscillatory slow potentials cannot be communicated. Another candidate mechanism is synchronization of action potentials and ensuing Ca(2+) influx through voltage-dependent Ca channels. The present study addresses the question of whether Ca(2+) increases are synchronized by action potentials, and how oscillatory store potentials are synchronized across the cells. Electrophysiological and Ca(2+)-sensitive fluorescence measurements in early embryonic chick retina showed that synchronous Ca(2+) oscillation was caused by releases of Ca(2+) from Ca(2+) stores without any evidence of action potentials in retinal neuroepithelial cells or newborn neurons. High-speed fluorescence measurement of store membrane potential surprisingly revealed that the synchronous oscillatory changes in the store potential were periodic repeats of a burst of high-frequency voltage fluctuations. The burst coincided with a Ca(2+) increase. The present study suggests that synchronization of Ca(2+) release is mediated by the high-frequency fluctuation in the store potential. Close apposition of the store membrane and plasma membrane in an epithelial structure would allow capacitative coupling across the cells.     

α-Calcium calmodulin kinase II modulates the temporal structure of hippocampal bursting patterns

The alpha calcium calmodulin kinase II (α-CaMKII) is known to play a key role in CA1/CA3 synaptic plasticity, hippocampal place cell stability and spatial learning. Additionally, there is evidence from hippocampal electrophysiological slice studies that this kinase has a role in regulating ion channels that control neuronal excitability. Here, we report in vivo single unit studies, with α-CaMKII mutant mice, in which threonine 305 was replaced with an aspartate (α-CaMKII(T305D) mutants), that indicate that this kinase modulates spike patterns in hippocampal pyramidal neurons. Previous studies showed that α-CaMKII(T305D) mutants have abnormalities in both hippocampal LTP and hippocampal-dependent learning. We found that besides decreased place cell stability, which could be caused by their LTP impairments, the hippocampal CA1 spike patterns of α-CaMKII(T305D) mutants were profoundly abnormal. Although overall firing rate, and overall burst frequency were not significantly altered in these mutants, inter-burst intervals, mean number of intra-burst spikes, ratio of intra-burst spikes to total spikes, and mean intra-burst intervals were significantly altered. In particular, the intra burst intervals of place cells in α-CaMKII(T305D) mutants showed higher variability than controls. These results provide in vivo evidence that besides its well-known function in synaptic plasticity, α-CaMKII, and in particular its inhibitory phosphorylation at threonine 305, also have a role in shaping the temporal structure of hippocampal burst patterns. These results suggest that some of the molecular processes involved in acquiring information may also shape the patterns used to encode this information.     

The initiation of bursts in thalamic neurons and the cortical control of thalamic sensitivity

Thalamic neurons generate high-frequency bursts of action potentials when a low-threshold (T-type) calcium current, located in soma and dendrites, becomes activated. Computational models were used to investigate the bursting properties of thalamic relay and reticular neurons. These two types of thalamic cells differ fundamentally in their ability to generate bursts following either excitatory or inhibitory events. Bursts generated with excitatory inputs in relay cells required a high degree of convergence from excitatory inputs, whereas moderate excitation drove burst discharges in reticular neurons from hyperpolarized levels. The opposite holds for inhibitory rebound bursts, which are more difficult to evoke in reticular neurons than in relay cells. The differences between the reticular neurons and thalamocortical neurons were due to different kinetics of the T-current, different electrotonic properties and different distribution patterns of the T-current in the two cell types. These properties enable the cortex to control the sensitivity of the thalamus to inputs and are also important for understanding states such as absence seizures.     

Ionic mechanisms underlying spontaneous CA1 neuronal firing in Ca2+-free solution

Hippocampal CA1 neurons exposed to zero-[Ca(2+)] solutions can generate periodic spontaneous synchronized activity in the absence of synaptic function. Experiments using hippocampal slices showed that, after exposure to zero-[Ca(2+)](0) solution, CA1 pyramidal cells depolarized 5-10 mV and started firing spontaneous action potentials. Spontaneous single neuron activity appeared in singlets or was grouped into bursts of two or three action potentials. A 16-compartment, 23-variable cable model of a CA1 pyramidal neuron was developed to study mechanisms of spontaneous neuronal bursting in a calcium-free extracellular solution. In the model, five active currents (a fast sodium current, a persistent sodium current, an A-type transient potassium current, a delayed rectifier potassium current, and a muscarinic potassium current) are included in the somatic compartment. The model simulates the spontaneous bursting behavior of neurons in calcium-free solutions. The mechanisms underlying several aspects of bursting are studied, including the generation of triplet bursts, spike duration, burst termination, after-depolarization behavior, and the prolonged inactive period between bursts. We show that the small persistent sodium current can play a key role in spontaneous CA1 activity in zero-calcium solutions. In particular, it is necessary for the generation of an after-depolarizing potential and prolongs both individual bursts and the interburst interval.     

Dynamics of Intrinsic Dendritic Calcium Signaling during Tonic Firing of Thalamic Reticular Neurons

The GABAergic neurons of the nucleus reticularis thalami that control the communication between thalamus and cortex are interconnected not only through axo-dendritic synapses but also through gap junctions and dendro-dendritic synapses. It is still unknown whether these dendritic communication processes may be triggered both by the tonic and the T-type Ca²⁺ channel-dependent high frequency burst firing of action potentials displayed by nucleus reticularis neurons during wakefulness and sleep, respectively. Indeed, while it is known that activation of T-type Ca²⁺ channels actively propagates throughout the dendritic tree, it is still unclear whether tonic action potential firing can also invade the dendritic arborization. Here, using two-photon microscopy, we demonstrated that dendritic Ca²⁺ responses following somatically evoked action potentials that mimic wake-related tonic firing are detected throughout the dendritic arborization. Calcium influx temporally summates to produce dendritic Ca²⁺ accumulations that are linearly related to the duration of the action potential trains. Increasing the firing frequency facilitates Ca²⁺ influx in the proximal but not in the distal dendritic compartments suggesting that the dendritic arborization acts as a low-pass filter in respect to the back-propagating action potentials. In the more distal compartment of the dendritic tree, T-type Ca²⁺ channels play a crucial role in the action potential triggered Ca²⁺ influx suggesting that this Ca²⁺ influx may be controlled by slight changes in the local dendritic membrane potential that determine the T-type channels’ availability. We conclude that by mediating Ca²⁺ dynamic in the whole dendritic arborization, both tonic and burst firing of the nucleus reticularis thalami neurons might control their dendro-dendritic and electrical communications.     

A model of the electrophysiological properties of nucleus reticularis thalami neurons.

A model of the electrophysiological properties of rodent nucleus reticularis thalami (NRT) neurons of the dorsal lateral thalamus was developed using Hodgkin-Huxley style equations. The model incorporated voltage-dependent rate constants and kinetics obtained from recent voltage-clamp experiments in vitro. The intrinsic electroresponsivity of the model cell was found to be similar to several empirical observations. Three distinct modes of oscillatory activity were identified: 1) a pattern of slow rhythmic burst firing (0.5-7 Hz) usually associated with membrane potentials negative to approximately -70 mV which resulted from the interplay of ITs and IK(Ca); 2) at membrane potentials from approximately -69 to -62 mV, rhythmic burst firing in the spindle frequency range (7-12 Hz) developed and was immediately followed by a tonic tail of single spike firing after several bursts. The initial bursting rhythm resulted from the interaction of ITs and IK(Ca), with a slow after-depolarization due to ICAN which mediated the later tonic firing; 3) with further depolarization of the membrane potential positive to approximately -61 mV, sustained tonic firing appeared in the 10-200-Hz frequency range depending on the amplitude of the injected current. The frequency of this firing was also dependent on the maximum conductance of the leak current, IK(leak), and an interaction between the fast currents involved in generating action potentials, INa(fast) and IK(DR), and the persistent Na+ current, INa(P). Transitions between different firing modes were identified and studied parametrically.     

Linking dynamical and functional properties of intrinsically bursting neurons

Several studies have shown that bursting neurons can encode information in the number of spikes per burst: As the stimulus varies, so does the length of individual bursts.Therepresented stimuli, however, vary substantially among different sensory modalities and different neurons.The goal of this paper is to determine which kind of stimulus features can be encoded in burst length, and how those features depend on the mathematical properties of the underlying dynamical system.We show that the initiation and termination of each burst is triggered by specific stimulus features whose temporal characteristsics are determined by the types of bifurcations that initiate and terminate firing in each burst. As only a few bifurcations are possible, only a restricted number of encoded features exists. Here we focus specifically on describing parabolic, square-wave and elliptic bursters. We find that parabolic bursters, whose firing is initiated and terminated by saddle-node bifurcations, behave as prototypical integrators: Firing is triggered by depolarizing stimuli, and lasts for as long as excitation is prolonged. Elliptic bursters, contrastingly, constitute prototypical resonators, since both the initiating and terminating bifurcations possess well-defined oscillation time scales. Firing is therefore triggered by stimulus stretches of matching frequency and terminated by a phase-inversion in the oscillation. The behavior of square-wave bursters is somewhat intermediate, since they are triggered by a fold bifurcation of cycles of well-defined frequency but are terminated by a homoclinic bifurcation lacking an oscillating time scale. These correspondences show that stimulus selectivity is determined by the type of bifurcations. By testing several neuron models, we also demonstrate that additional biological properties that do not modify the bifurcation structure play a minor role in stimulus encoding. Moreover, we show that burst-length variability (and thereby, the capacity to transmit information) depends on a trade-off between the variance of the external signal driving the cell and the strength of the slow internal currents modulating bursts. Thus, our work explicitly links the computational properties of bursting neurons to the mathematical properties of the underlying dynamical systems.     

Sub-MHz bursts of nanosecond pulses excite neurons at paradoxically low electric field thresholds without membrane damage

Neuromodulation applications of nanosecond electric pulses (nsEP) are hindered by their low potency to elicit action potentials in neurons. Excitation by a single nsEP requires a strong electric field which injures neurons by electroporation. We bypassed the high electric field requirement by replacing single nsEP stimuli with high-frequency brief nsEP bursts. In hippocampal neurons, excitation thresholds progressively decreased at nsEP frequencies above 20–200 kHz, with up to 20–30-fold reduction at sub-MHz and MHz rates. For a fixed burst duration, thresholds were determined by the duty cycle, irrespective of the specific nsEP duration, rate, or number of pulses per burst. For 100-μs bursts of 100-, 400-, or 800-ns pulses, the threshold decreased as a power function when the duty cycle exceeded 3–5 %. nsEP bursts were compared with single “long” pulses whose duration and amplitude matched the duration and the time-average amplitude of the burst. Such pulses deliver the same electric charge as bursts, within the same time interval. High-frequency nsEP bursts excited neurons at the time-average electric field 2–3 times below the threshold for a single long pulse. For example, the excitation threshold of 139 ± 14 V/cm for a single 100-μs pulse decreased to 57 ± 8 V/cm for a 100-μs burst of 100-ns, 0.25-MHz pulses (p < 0.001). Applying nsEP in bursts reduced or prevented the loss of excitability in multiple stimulation attempts. Stimulation by high-frequency nsEP bursts is a powerful novel approach to excite neurons at paradoxically low electric charge while also avoiding the electroporative membrane damage.     

Dynamic encoding of natural luminance sequences by LGN bursts

In the lateral geniculate nucleus (LGN) of the thalamus, visual stimulation produces two distinct types of responses known as tonic and burst. Due to the dynamics of the T-type Ca ²⁺ channels involved in burst generation, the type of response evoked by a particular stimulus depends on the resting membrane potential, which is controlled by a network of modulatory connections from other brain areas. In this study, we use simulated responses to natural scene movies to describe how modulatory and stimulus-driven changes in LGN membrane potential interact to determine the luminance sequences that trigger burst responses. We find that at low resting potentials, when the T channels are de-inactivated and bursts are relatively frequent, an excitatory stimulus transient alone is sufficient to evoke a burst. However, to evoke a burst at high resting potentials, when the T channels are inactivated and bursts are relatively rare, prolonged inhibitory stimulation followed by an excitatory transient is required. We also observe evidence of these effects in vivo, where analysis of experimental recordings demonstrates that the luminance sequences that trigger bursts can vary dramatically with the overall burst percentage of the response. To characterize the functional consequences of the effects of resting potential on burst generation, we simulate LGN responses to different luminance sequences at a range of resting potentials with and without a mechanism for generating bursts. Using analysis based on signal detection theory, we show that bursts enhance detection of specific luminance sequences, ranging from the onset of excitatory sequences at low resting potentials to the offset of inhibitory sequences at high resting potentials. These results suggest a dynamic role for burst responses during visual processing that may change according to behavioral state.     

Interval analysis of bursting discharges in aplysia neurons

Time intervals of 12 records of bursting discharges in Aplysia neurons were analysed by digital computer to determine the interrelations between the burst period, the interburst interval and the burst duration. The effects of membrane potential changes on the parameters of bursting discharges were examined also. A low correlation was found between burst duration and burst period in the majority of cases, and this was interpreted as an indication of probable independence between the mechanisms governing these parameters. Also, a specific temporal organization of interspike intervals seems to be present in each type of neuron. The results suggest that the mechanism governing the burst period is characterized by a slow membrane potential oscillation resembling that observed in bursting neurons when actions potentials are blocked by tetrodotoxin. The burst duration would be determined by the response of the neuron to suprathreshold depolarization.     

Thalamic T-type Ca2+ channels and NREM sleep

T-type Ca2+ channels play a number of different and pivotal roles in almost every type of neuronal oscillation expressed by thalamic neurones during non-rapid eye movement (NREM) sleep, including those underlying sleep theta waves, the K-complex and the slow (<1 Hz) sleep rhythm, sleep spindles and delta waves. In particular, the transient opening of T channels not only gives rise to the 'classical' low threshold Ca2+ potentials, and associated high frequency burst of action potentials, that are characteristically present during sleep spindles and delta waves, but also contributes to the high threshold bursts that underlie the thalamic generation of sleep theta rhythms. The persistent opening of a small fraction of T channels, i.e. I(Twindow), is responsible for the large amplitude and long lasting depolarization, or UP state, of the slow (<1 Hz) sleep oscillation in thalamic neurones. These cellular findings are in part matched by the wake-sleep phenotype of global and thalamic-selective CaV3.1 knockout mice that show a decreased amount of total NREM sleep time. T-type Ca2+ channels, therefore, constitute the single most crucial voltage-dependent conductance that permeates all activities of thalamic neurones during NREM sleep. Since I(Twindow) and high threshold bursts are not restricted to thalamic neurones, the cellular neurophysiology of T channels should now move away from the simplistic, though historically significant, view of these channels as being responsible only for low threshold Ca2+ potentials.     

Frequency-dependent interaction of ultrashort E-fields with nociceptor membranes and proteins

We examined the influence of ultrashort pulses (USP) on sensory neurons. Single and high frequency bursts of 12 ns E‐fields were presented to rat skin nociceptors that expressed distinct combinations of voltage‐sensitive proteins. A single E‐field pulse produced action potentials in all nociceptor subtypes at a critical threshold (E_c) of 403 V/cm. When configured into high frequency bursts, USP charge integrated to reduce the action potential threshold in a frequency and burst duration‐dependent manner with E_c as low as 16 V/cm (4000 Hz, 25 ms burst). There was no evidence of electroporation at field intensities near the E_c for nociceptor activation. USP bursts activated a late, persistent Ca⁺⁺ flux that was identified as a dantrolene‐sensitive Ca⁺⁺‐induced Ca⁺⁺ release (CICR). Influx of Ca⁺⁺ into the cell was required for the CICR and resulted in a reduction of the single pulse E_c by about 50%. Bioelectromagnetics 32:148–163, 2011. © 2010 Wiley‐Liss, Inc.     

The nodal origin of intrinsic bursting

The output of cortical neurons in the form of bursts of action potentials was thought to be controlled solely by the dendrites. In this issue of Neuron, Maarten Kole reveals that axonal sodium channels at the first node of Ranvier are essential for neuronal burst firing.     

Sympathetic activity and the underlying action potentials in sympathetic nerves: a simulation

Understanding the relationship between activity recorded in sympathetic nerves and the action potentials of the axons that contribute to that activity is important for understanding the processing of sympathetic activity by the central nervous system. Because this relationship cannot be determined experimentally and is difficult to predict analytically, we simulated the summed action potentials of 300 axons. This simulation closely resembled actual sympathetic activity and permitted us to know how many action potentials contributed to each burst of simulated sympathetic activity and the durations and amplitudes of each burst. We used these simulated data to examine a statistical method (cluster analysis) that has been used to identify and quantify bursts of sympathetic activity. Simulation indicated that the integrals of bursts, whether determined directly from the simulation or by integrating bursts detected by cluster analysis, were linearly correlated to the number of action potentials contributing to bursts. The variances of samples of the simulated signal were also linearly correlated to the number of action potentials. The amplitudes of bursts of sympathetic activity were less well correlated to the number of underlying action potentials. A linear relationship existed between the average number of action potentials contributing to simulated bursts and the integral of the amplitude spectra obtained by Fourier transform of the simulated activity. Finally, simulated experiments indicated that relatively brief recordings might be sufficient to detect statistically significant changes in sympathetic activity.     

Decreased Response to Acetylcholine during Aging of Aplysia Neuron R15

How aging affects the communication between neurons is poorly understood. To address this question, we have studied the electrophysiological properties of identified neuron R15 of the marine mollusk Aplysia californica. R15 is a bursting neuron in the abdominal ganglia of the central nervous system and is implicated in reproduction, water balance, and heart function. Exposure to acetylcholine (ACh) causes an increase in R15 burst firing. Whole-cell recordings of R15 in the intact ganglia dissected from mature and old Aplysia showed specific changes in burst firing and properties of action potentials induced by ACh. We found that while there were no significant changes in resting membrane potential and latency in response to ACh, the burst number and burst duration is altered during aging. The action potential waveform analysis showed that unlike mature neurons, the duration of depolarization and the repolarization amplitude and duration did not change in old neurons in response to ACh. Furthermore, single neuron quantitative analysis of acetylcholine receptors (AChRs) suggested alteration of expression of specific AChRs in R15 neurons during aging. These results suggest a defect in cholinergic transmission during aging of the R15 neuron.     

Effect of intracellular injection of cyclic amp on electrical characteristics of identified neurons in Helix pomatia

The effect of intracellular iontophoretic injection of cyclic AMP on electrical activity of neurons RPa1, RPa3, LPa2, LPa3, and LPl1 in the corresponding ganglia ofHelix pomatia was investigated. Injection of cyclic AMP into neuron LPl1 was found to cause the appearance of rhythmic activity (if the neuron was originally "silent"), an increase in the frequency of spike generation (if the neuron had rhythmic activity), and a decrease in amplitude of waves of membrane potential, in the duration of the interval between bursts, and in the number of action potentials in the burst (if the neuron demonstrated bursting activity). In the remaining "silent" neurons injection of cyclic AMP led to membrane depolarization. Injection of cyclic AMP into neurons whose membrane potential was clamped at the resting potential level evoked the development of an inward transmembrane current (cyclic AMP current), the rate of rise and duration of which increased proportionally to the size and duration of the injection. Theophylline in a concentration of 1 mM led to an increase in the amplitude and duration of the cyclic AMP current by about 50%. It is concluded that a change in the cyclic AMP concentration within the nerve cell may modify the ionic permeability of its membrane and, correspondingly, its electrical activity.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 12, No. 5, pp. 517–525, September–October, 1980.     

Intracellular electrophysiology of mammalian peptidergic neurons in rat hypothalamic slices

The magnocellular neuropeptidergic cells (MNCs) of the paraventricular and supraoptic nuclei have been a model for biochemical and physiological studies of peptidergic neurons in the mammalian brain, but nearly all the electrophysiological studies of these vasopressinergic and oxytocinergic neuroendocrine cells are based on extracellular recordings. This paper reviews recent literature on electrophysiological properties of neurons in the magnocellular nuclei in which the rat in vitro slice preparation and intracellular recording were used. Spontaneously occurring action potentials and synaptic potentials (excitatory and inhibitory) have been observed in hypothalamic slices. The spike patterns have included slow and irregular firing, short rapid bursts of inactivating spikes, and slow phasic discharge with prolonged active and silent periods. Some studies have shown that increased osmolality causes neuronal firing, but this area is controversial. Intracellular injections of lucifer yellow have shown that some MNCs are dye-coupled and electron microscopic observations with the freeze-fracture technique have revealed occasional gap junctions, thus suggesting that some MNCs are electrotonically coupled. Both excitatory and inhibitory postsynaptic potentials have been evoked with extracellular stimulation. Therefore, action potentials, synaptic potentials, burst discharges, and probably electrotonic coupling have been found with intracellular recording in mammalian neuroendocrine cells. Future studies with intracellular recording and staining followed by immunohistochemical identification of cells should provide significant new information on the membrane physiology and synaptic pharmacology of vasopressinergic and oxytocinergic cells.     

Modulation of electrical activity of neuron RPa2 ofHelix pomatia

Neuron RPa2 ofHelix pomatia can generate rhythmic (beating) or periodic (bursting) activity. A spontaneous switch from beating to bursting activity takes place in the course of tens of minutes. Similar changes in electrical activity can be induced by the addition of the water-soluble fraction obtained from a homogenate of snail ganglia to the experimental chamber. Artificial polarization of the membrane of neuron RPa2 by asteady inward current leads to an increase in the duration of intervals between bursts and to a decrease in the number of action potentials in the burst. With an increase in amplitude of the polarizing current, action potential generation ceases completely, but generation of waves of membrane potential persists. If the voltage on the neuron membrane is clamped, periodic fluctuations of membrane current disappear. It is suggested that action potential generation by neurons RPa2 is determined by the properties of the potential-dependent conductance of its membrane, i.e., that it is endogenous in origin and can be regulated by compounds acting on the membrane. These compounds, secreted by other neurons, resemble neurotransmitters or neurohormones.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 13, No. 4, pp. 406–412, July–August, 1981.     

Contributions of T-type calcium channel isoforms to neuronal firing

Low voltage-activated (LVA) T-type calcium channels play critical roles in the excitability of many cell types and are a focus of research aimed both at understanding the physiological basis of calcium channel-dependent signaling and the underlying pathophysiology associated with hyperexcitability disorders such as epilepsy. These channels play a critical role towards neuronal firing in both conducting calcium ions during action potentials and also in switching neurons between distinct modes of firing. In this review the properties of the CaV3.1, CaV3.2 and CaV3.3 T-type channel isoforms is discussed in relation to their individual contributions to action potentials during burst and tonic firing states as well their roles in switching between firing states.