Dendritic spikes as a mechanism for cooperative long-term potentiation

Strengthening of synaptic connections following coincident pre- and postsynaptic activity was proposed by Hebb as a cellular mechanism for learning. Contemporary models assume that multiple synapses must act cooperatively to induce the postsynaptic activity required for hebbian synaptic plasticity. One mechanism for the implementation of this cooperation is action potential firing, which begins in the axon, but which can influence synaptic potentiation following active backpropagation into dendrites. Backpropagation is limited, however, and action potentials often fail to invade the most distal dendrites. Here we show that long-term potentiation of synapses on the distal dendrites of hippocampal CA1 pyramidal neurons does require cooperative synaptic inputs, but does not require axonal action potential firing and backpropagation. Rather, locally generated and spatially restricted regenerative potentials (dendritic spikes) contribute to the postsynaptic depolarization and calcium entry necessary to trigger potentiation of distal synapses. We find that this mechanism can also function at proximal synapses, suggesting that dendritic spikes participate generally in a form of synaptic potentiation that does not require postsynaptic action potential firing in the axon.     

中华大蟾蜍胚后原始大脑皮层神经元自发电活动的发育变化

应用微电极电生理技术对中华大蟾蜍(Bufo bufo gargarizans)胚后端脑原始大脑皮层神经元的自发放电活动进行在体胞外记录,探讨其胚后端脑原始大脑皮层神经元自发电活的电生理学特性的发育变化。结果表明原始大脑皮层神经元的自发放电有5种形式。胚后发育的早期为4种放电类型,以簇状放电和连续放电为主;胚后发育的后期为5种放电类型,以簇状和连续簇状放电为主。随着原始大脑皮层的发育,单个放电的动作电位时程缩短,连续单个放电和连续簇状放电频率降低,连续放电、簇状放电和连续簇状放电的持续时间延长。随着端脑原始大脑皮层的发育,神经元的兴奋性逐步提高,神经元电活动形式逐渐呈现多样化。     

A new cellular mechanism for coupling inputs arriving at different cortical layers

Pyramidal neurons in layer 5 of the neocortex of the brain extend their axons and dendrites into all layers. They are also unusual in having both an axonal and a dendritic zone for the initiation of action potentials. Distal dendritic inputs, which normally appear greatly attenuated at the axon, must cross a high threshold at the dendritic initiation zone to evoke calcium action potentials but can then generate bursts of axonal action potentials. Here we show that a single back-propagating sodium action potential generated in the axon facilitates the initiation of these calcium action potentials when it coincides with distal dendritic input within a time window of several milliseconds. Inhibitory dendritic input can selectively block the initiation of dendritic calcium action potentials, preventing bursts of axonal action potentials. Thus, excitatory and inhibitory postsynaptic potentials arising in the distal dendrites can exert significantly greater control over action potential initiation in the axon than would be expected from their electrotonically isolated locations. The coincidence of a single back-propagating action potential with a subthreshold distal excitatory postsynaptic potential to evoke a burst of axonal action potentials represents a new mechanism by which the main cortical output neurons can associate inputs arriving at different cortical layers.     

Acetylcholine induces burst firing in thalamic reticular neurones by activating a potassium conductance

Recent studies have emphasized the role of acetylcholine (ACh) as an excitatory modulator of neuronal activity in mammalian cortex and hippocampus. Much less is known about the mechanism of direct cholinergic inhibition in the central nervous system or its role in regulating neuronal activities. Here we report that application of ACh to thalamic nucleus reticularis (nRt) neurones, which are known to receive a cholinergic input from the ascending reticular system of the brain stem, causes a hyperpolarization due to a relatively small (1-4 nS) increase in membrane conductance to K+. This cholinergic action appears to be mediated by the M2 subclass of muscarinic receptors and acts in conjunction with the intrinsic membrane properties of nucleus reticularis neurones to inhibit single spike activity while promoting the occurrence of burst discharges. Thus, cholinergic inhibitory mechanisms may be important in controlling the firing pattern of this important group of thalamic neurones.     

High-fidelity transmission of sensory information by single cerebellar mossy fibre boutons

Understanding the transmission of sensory information at individual synaptic connections requires knowledge of the properties of presynaptic terminals and their patterns of firing evoked by sensory stimuli. Such information has been difficult to obtain because of the small size and inaccessibility of nerve terminals in the central nervous system. Here we show, by making direct patch-clamp recordings in vivo from cerebellar mossy fibre boutons-the primary source of synaptic input to the cerebellar cortex-that sensory stimulation can produce bursts of spikes in single boutons at very high instantaneous firing frequencies (more than 700 Hz). We show that the mossy fibre-granule cell synapse exhibits high-fidelity transmission at these frequencies, indicating that the rapid burst of excitatory postsynaptic currents underlying the sensory-evoked response of granule cells can be driven by such a presynaptic spike burst. We also demonstrate that a single mossy fibre can trigger action potential bursts in granule cells in vitro when driven with in vivo firing patterns. These findings suggest that the relay from mossy fibre to granule cell can act in a 'detonator' fashion, such that a single presynaptic afferent may be sufficient to transmit the sensory message. This endows the cerebellar mossy fibre system with remarkable sensitivity and high fidelity in the transmission of sensory information.     

Feedback inhibition controls spike transfer in hybrid thalamic circuits

Sensory information reaches the cerebral cortex through the thalamus, which differentially relays this input depending on the state of arousal. Such 'gating' involves inhibition of the thalamocortical relay neurons by the reticular nucleus of the thalamus, but the underlying mechanisms are poorly understood. We reconstructed the thalamocortical circuit as an artificial and biological hybrid network in vitro. With visual input simulated as retinal cell activity, we show here that when the gain in the thalamic inhibitory feedback loop is greater than a critical value, the circuit tends towards oscillations -- and thus imposes a temporal decorrelation of retinal cell input and thalamic relay output. This results in the functional disconnection of the cortex from the sensory drive, a feature typical of sleep states. Conversely, low gain in the feedback inhibition and the action of noradrenaline, a known modulator of arousal, converge to increase input output correlation in relay neurons. Combining gain control of feedback inhibition and modulation of membrane excitability thus enables thalamic circuits to finely tune the gating of spike transmission from sensory organs to the cortex.     

Spike-timing-dependent synaptic modification induced by natural spike trains

The strength of the connection between two neurons can be modified by activity, in a way that depends on the timing of neuronal firing on either side of the synapse. This spike-timing-dependent plasticity (STDP) has been studied by systematically varying the intervals between pre- and postsynaptic spikes. Here we studied how STDP operates in the context of more natural spike trains. We found that in visual cortical slices the contribution of each pre-/postsynaptic spike pair to synaptic modification depends not only on the interval between the pair, but also on the timing of preceding spikes. The efficacy of each spike in synaptic modification was suppressed by the preceding spike in the same neuron, occurring within several tens of milliseconds. The direction and magnitude of synaptic modifications induced by spike patterns recorded in vivo in response to natural visual stimuli were well predicted by incorporating the suppressive inter-spike interaction within each neuron. Thus, activity-induced synaptic modification depends not only on the relative spike timing between the neurons, but also on the spiking pattern within each neuron. For natural spike trains, the timing of the first spike in each burst is dominant in synaptic modification.     

基于TMAES对GrC神经元放电活动影响的仿真

经颅磁声电刺激（TMAES）是一种新型无创的脑神经调控技术,具有良好的应用前景.该技术利用静磁场和超声波共同作用所产生的磁声电效应,在神经组织中产生感应电流,进而对神经组织实施刺激.作者基于小脑颗粒细胞模型（GrC模型）,建立了突触连接GrC模型,对TMAES刺激下突触连接GrC模型的动作电位进行仿真,分析了动作电位的传播方向.在TMAES神经元的不同突触连接方式下,对比了兴奋性与抑制性对神经元放电的影响.通过改变抑制点的位置分析了抑制作用在TMAES下对神经元放电模式的影响.仿真结果显示,经颅磁声电刺激对GrC模型神经元放电节律具有重要影响.实现了两个神经元突触连接模型在TMAES下的仿真,对进一步发掘和研究神经元的传导及连接模式具有重要意义.     

Correlation between neural spike trains increases with firing rate

Populations of neurons in the retina, olfactory system, visual and somatosensory thalamus, and several cortical regions show temporal correlation between the discharge times of their action potentials (spike trains). Correlated firing has been linked to stimulus encoding, attention, stimulus discrimination, and motor behaviour. Nevertheless, the mechanisms underlying correlated spiking are poorly understood, and its coding implications are still debated. It is not clear, for instance, whether correlations between the discharges of two neurons are determined solely by the correlation between their afferent currents, or whether they also depend on the mean and variance of the input. We addressed this question by computing the spike train correlation coefficient of unconnected pairs of in vitro cortical neurons receiving correlated inputs. Notably, even when the input correlation remained fixed, the spike train output correlation increased with the firing rate, but was largely independent of spike train variability. With a combination of analytical techniques and numerical simulations using 'integrate-and-fire' neuron models we show that this relationship between output correlation and firing rate is robust to input heterogeneities. Finally, this overlooked relationship is replicated by a standard threshold-linear model, demonstrating the universality of the result. This connection between the rate and correlation of spiking activity links two fundamental features of the neural code.     

Detection of bursts in neuronal spike trains by the mean inter-spike interval method

Bursts are electrical spikes firing with a high frequency, which are the most important property in synaptic plasticity and information processing in the central nervous system. However, bursts are difficult to identify because bursting activities or patterns vary with physiological conditions or external stimuli. In this paper, a simple method automatically to detect bursts in spike trains is described. This method auto-adaptively sets a parameter (mean inter-spike interval) according to intrinsic properties of the detected burst spike trains, without any arbitrary choices or any operator judgment. When the mean value of several successive inter-spike intervals is not larger than the parameter, a burst is identified. By this method, bursts can be automatically extracted from different bursting patterns of cultured neurons on multi-electrode arrays, as accurately as by visual inspection. Furthermore, significant changes of burst variables caused by electrical stimulus have been found in spontaneous activity of neuronal network. These suggest that the mean inter-spike interval method is robust for detecting changes in burst patterns and characteristics induced by environmental alterations.     

Stable propagation of synchronous spiking in cortical neural networks

The classical view of neural coding has emphasized the importance of information carried by the rate at which neurons discharge action potentials. More recent proposals that information may be carried by precise spike timing have been challenged by the assumption that these neurons operate in a noisy fashion--presumably reflecting fluctuations in synaptic input and, thus, incapable of transmitting signals with millisecond fidelity. Here we show that precisely synchronized action potentials can propagate within a model of cortical network activity that recapitulates many of the features of biological systems. An attractor, yielding a stable spiking precision in the (sub)millisecond range, governs the dynamics of synchronization. Our results indicate that a combinatorial neural code, based on rapid associations of groups of neurons co-ordinating their activity at the single spike level, is possible within a cortical-like network.     

Role of experience and oscillations in transforming a rate code into a temporal code

In the vast majority of brain areas, the firing rates of neurons, averaged over several hundred milliseconds to several seconds, can be strongly modulated by, and provide accurate information about, properties of their inputs. This is referred to as the rate code. However, the biophysical laws of synaptic plasticity require precise timing of spikes over short timescales (<10 ms). Hence it is critical to understand the physiological mechanisms that can generate precise spike timing in vivo, and the relationship between such a temporal code and a rate code. Here we propose a mechanism by which a temporal code can be generated through an interaction between an asymmetric rate code and oscillatory inhibition. Consistent with the predictions of our model, the rate and temporal codes of hippocampal pyramidal neurons are highly correlated. Furthermore, the temporal code becomes more robust with experience. The resulting spike timing satisfies the temporal order constraints of hebbian learning. Thus, oscillations and receptive field asymmetry may have a critical role in temporal sequence learning.     

神经系统识别爆发性锋电位序列的机制讨论

讨论神经系统识别爆发型锋电位序列信息的机制,认为序列的信息存储在爆发锋电位组内间隔和组间间隔2个时间变量中,建立了一个神经回路,通过突触传递过程中的易化、反馈调节机制以及时间依赖的学习机制等突触可塑性机制,给出了神经系统识别爆发性锋电位序列信息的一种可能机制,其中包括分解机制和整合机制两部分.首先通过神经元选择性响应的动力学性质,将锋电位序列的信息分解,并将每组锋电位内部间隔的信息通过不同神经元学习存储.通过突触延迟时间的动力学调整,将2组锋电位之间的时间间隔学习、存储在回路中.经过多次学习训练,神经回路对输入信号形成特定的突触连接结构以及时空响应输出模式,实现对爆发性锋电位序列信息的识别.     

Histamine and noradrenaline decrease calcium-activated potassium conductance in hippocampal pyramidal cells

Ample evidence exists for histaminergic and noradrenergic projections to the hippocampus. Both amines exert neurotransmitter or modulator actions on principal neurones in the CA 1 and in the dentate area. A number of mechanisms have been proposed for these actions, including increased potassium conductance, increased chloride conductance and electrogenic pump stimulation, and reduction of the anomalous inward rectification. Action potentials, and particularly bursts of spikes, in CA 1 pyramidal cells, are followed by an afterhyperpolarization (AHP) which consists of two components. The late AHP depends on a calcium-activated potassium conductance gK+ (Ca2+), and has recently been shown to be increased by dopamine. We report here a rapid and reversible decrease of the late AHP component following a burst of sodium spikes or a calcium spike, during perfusion with micromolar concentrations of histamine and noradrenaline. This effect is mediated by H2 receptors and beta-receptors, respectively, and occurred in the absence of changes in the calcium spike. By such a mechanism histamine and noradrenaline can profoundly potentiate the excitatory impact of depolarizing signals.     

Temporal integration by a slowly inactivating K+ current in hippocampal neurons

A central aspect of neuronal function is how each nerve cell translated synaptic input into a sequence of action potentials that carry information along the axon, coded as spike frequency. When transduction from a graded depolarizing input to spikes is studied by injecting a depolarizing current, there is often a remarkably long delay to the first action potential, both in mammalian and molluscan neurons. Here, I report that the delayed excitation in rat hippocampal neurons is due to a slowly inactivating potassium current, ID. ID co-exists with other voltage-gated K+ currents, including a fast A current and a slow delayed rectifier current. As ID activates in the subthreshold range, and takes tens of seconds to recover from inactivation, it enables the cell to integrate separate depolarizing inputs over long times. ID also makes the encoding properties of the cell exceedingly sensitive to the prevailing membrane potential.     

Integration of quanta in cerebellar granule cells during sensory processing

To understand the computations performed by the input layers of cortical structures, it is essential to determine the relationship between sensory-evoked synaptic input and the resulting pattern of output spikes. In the cerebellum, granule cells constitute the input layer, translating mossy fibre signals into parallel fibre input to Purkinje cells. Until now, their small size and dense packing have precluded recordings from individual granule cells in vivo. Here we use whole-cell patch-clamp recordings to show the relationship between mossy fibre synaptic currents evoked by somatosensory stimulation and the resulting granule cell output patterns. Granule cells exhibited a low ongoing firing rate, due in part to dampening of excitability by a tonic inhibitory conductance mediated by GABA(A) (gamma-aminobutyric acid type A) receptors. Sensory stimulation produced bursts of mossy fibre excitatory postsynaptic currents (EPSCs) that summate to trigger bursts of spikes. Notably, these spike bursts were evoked by only a few quantal EPSCs, and yet spontaneous mossy fibre inputs triggered spikes only when inhibition was reduced. Our results reveal that the input layer of the cerebellum balances exquisite sensitivity with a high signal-to-noise ratio. Granule cell bursts are optimally suited to trigger glutamate receptor activation and plasticity at parallel fibre synapses, providing a link between input representation and memory storage in the cerebellum.     

Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated.

At excitatory synapses in the central nervous system, the number of glutamate molecules released from a vesicle is much larger than the number of postsynaptic receptors. But does release of a single vesicle normally saturate these receptors? Answering this question is critical to understanding how the amplitude and variability of synaptic transmission are set and regulated. Here we describe the use of two-photon microscopy to image transient increases in Ca2+ concentration mediated by NMDA (N-methyl-D-aspartate) receptors in single dendritic spines of CA1 pyramidal neurons in hippocampal slices. To test for NMDA-receptor saturation, we compared responses to stimulation with single and double pulses. We find that a single release event does not saturate spine NMDA receptors; a second release occurring 10 ms later produces approximately 80% more NMDA-receptor activation. The amplitude of spine NMDA-receptor-mediated [Ca2+] transients (and the synaptic plasticity which depends on this) may thus be sensitive to the number of quanta released by a burst of action potentials and to changes in the concentration profile of glutamate in the synaptic cleft.     

Sodium and calcium action potential in pituitary cells

Several endocrine cells or their neoplastic derivatives generate action potentials similar to those seen in neurones, and in the adrenal chromaffin cell such regenerative potentials depend primarily on a sodium mechanism. Kidokoro has described action potentials in the GH3 rat pituitary cell line which seem to depend on a calcium mechanism. We have re-investigated the action potential in GH3 cells and found that it results from combined Na and Ca mechanisms in physiological conditions. In addition, we have recorded similar electrical excitability from two human pituitary tumours grown in vitro.     

Whisker movements evoked by stimulation of single pyramidal cells in rat motor cortex

Neuronal activity in the motor cortex is understood to be correlated with movements, but the impact of action potentials (APs) in single cortical neurons on the generation of movement has not been fully determined. Here we show that trains of APs in single pyramidal cells of rat motor cortex can evoke long sequences of small whisker movements. For layer-5 pyramids, we find that evoked rhythmic movements have a constant phase relative to the AP train, indicating that single layer-5 pyramids can reset the rhythm of whisker movements. Action potentials evoked in layer-6 pyramids can generate bursts of rhythmic whisking, with a variable phase of movements relative to the AP train. An increasing number of APs decreases the latency to onset of movement, whereas AP frequency determines movement direction and amplitude. We find that the efficacy of cortical APs in evoking whisker movements is not dependent on background cortical activity and is greatly enhanced in waking rats. We conclude that in vibrissae motor cortex sparse AP activity can evoke movements.