Electrical excitability of the soma of sensory neurons is required for spike invasion of the soma,but not for through-conduction

The cell soma of primary sensory neurons is electrically excitable, and is invaded by action potentials as they pass from the peripheral nerve, past the dorsal root ganglion (DRG) and toward the spinal cord. However, there are virtually no synapses in the DRG, and no signal processing is known to occur there. Why, then, are DRG cell somata excitable? We have constructed and validated an explicit model of the primary sensory neuron and used it to explore the role of electrical excitability of the cell soma in afferent signaling. Reduction and even elimination of soma excitability proved to have no detectable effect on the reliability of spike conduction past the DRG and into the spinal cord. Through-conduction is affected, however, by major changes in neuronal geometry in the region of the t-junction. In contrast to through-conduction, excitability of the soma and initial segment is essential for the invasion of afferent spikes into the cell soma. This implies that soma invasion has a previously unrecognized role in the physiology of afferent neurons, perhaps in the realm of metabolic coupling of the biosynthesis of signaling molecules required at the axon ends to functional demand, or in cell-cell interaction within sensory ganglia. Spike invasion of the soma in central nervous system neurons may play similar roles.     

Properties of slow, cumulative sodium channel inactivation in rat hippocampal CA1 pyramidal neurons.

Sodium channels in the somata and dendrites of hippocampal CA1 pyramidal neurons undergo a form of long-lasting, cumulative inactivation that is involved in regulating back-propagating action potential amplitude and can influence dendritic excitation. Using cell-attached patch-pipette recordings in the somata and apical dendrites of CA1 pyramidal neurons, we determined the properties of slow inactivation on response to trains of brief depolarizations. We find that the amount of slow inactivation gradually increases as a function of distance from the soma. Slow inactivation is also frequency and voltage dependent. Higher frequency depolarizations increase both the amount of slow inactivation and its rate of recovery. Hyperpolarized resting potentials and larger command potentials accelerate recovery from slow inactivation. We compare this form of slow inactivation to that reported in other cell types, using longer depolarizations, and construct a simplified biophysical model to examine the possible gating mechanisms underlying slow inactivation. Our results suggest that sodium channels can enter slow inactivation rapidly from the open state during brief depolarizations or slowly from a fast inactivation state during longer depolarizations. Because of these properties of slow inactivation, sodium channels will modulate neuronal excitability in a way that depends in a complicated manner on the resting potential and previous history of action potential firing.     

Axonal contribution to subthreshold currents inaplysia bursting pacemaker neurons

The contribution of axonal activity to the ionic currents which generate bursting pacemaker activity was studied by using the two-electrode voltage-clamp technique in Aplysia bursting neuron somata in conjunction with intraaxonal voltage recordings. Depolarizing voltage-clamp pulses applied to bursting cell somata triggered axonal action potentials. The voltage-clamp current recording exhibited transient inward current "notches" corresponding to each of the axonal spikes. The addition of 50 microM tetrodotoxin (TTX) to the bathing medium blocked the fast axonal spikes and current notches, revealing a slower axonal spike which was blocked by the replacement of external Ca2+ with Co2+. The inward current evoked by applying a depolarizing voltage-clamp pulse in the soma is distorted by the occurrence of the axonal Ca2+ spike. Elimination of the axonal spike, by injecting hyperpolarizing current into the axon, changes both the time course and the magnitude of the inward current. The axonal Ca2+ spikes are followed by a series of Ca2+-dependent afterpotentials: a rapid postspike hyperpolarization, a depolarizing afterpotential (DAP) and, finally, a long-lasting postburst hyperpolarization. The long-lasting hyperpolarization is not blocked by 50 mM external tetraethyl ammonium, an effective blocker of Ca2+-activated K+ current [IK(Ca)], and does not appear to reverse at EK. Hence, the axonal long-lasting hyperpolarization may not be due to IK(Ca). Somatic voltage-clamp pulses in bursting neurons are followed by a slow inward tail current, which is sometimes coincident with a DAP in the axon. In some cells, the amplitude of the slow inward tail current is greatly reduced if axonal spikes and DAPs are prevented by hyperpolarization of the axon, while, in other cells, elimination of axonal activity has little effect. Therefore, the slow inward tail current is not necessarily an artifact of poor voltage-clamp control over the axonal membrane potential but probably results from the activation of an ionic conductance mechanism located partly in the axon and partly in the soma.     

海马区锥体神经元轴突高频电刺激对胞体的影响

目的 深部脑刺激（deep brain stimulation,DBS）利用持续的电脉冲高频刺激（high-frequency stimulation,HFS）调控神经元的活动，可望用于治疗更多脑疾病。为了深入了解HFS的作用机制，促进DBS的发展，本文研究轴突HFS在引起轴突阻滞期间神经元胞体的改变。方法 在麻醉大鼠海马CA1区的锥体神经元轴突上施加脉冲频率为100 Hz的1 min逆向高频刺激（antidromic high-frequency stimulation,A-HFS）。为了研究胞体的响应，利用线性垂直排列的多通道微电极阵列，记录刺激位点上游CA1区锥体神经元胞体附近各结构分层上的诱发电位，包括A-HFS脉冲诱发的逆向群峰电位（antidromic population spike,APS）以及A-HFS期间施加的顺向测试脉冲诱发的顺向群峰电位（orthodromic population spike,OPS），并计算诱发电位的电流源密度（current-source density,CSD），用于分析A-HFS期间锥体神经元胞体附近动作电位的生成和传导。结果 锥体神经...     

Axo-axonal coupling. a novel mechanism for ultrafast neuronal communication

We provide physiological, pharmacological, and structural evidence that axons of hippocampal principal cells are electrically coupled, with prepotentials or spikelets forming the physiological substrate of electrical coupling as observed in cell somata. Antidromic activation of neighboring axons induced somatic spikelet potentials in neurons of CA3, CA1, and dentate gyrus areas of rat hippocampal slices. Somatic invasion by these spikelets was dependent on the activation of fast Na(+) channels in the postjunctional neuron. Antidromically elicited spikelets were suppressed by gap junction blockers and low intracellular pH. Paired axo-somatic and somato-dendritic recordings revealed that the coupling potentials appeared in the axon before invading the soma and the dendrite. Using confocal laser scanning microscopy we found that putative axons of principal cells were dye coupled. Our data thus suggest that hippocampal neurons are coupled by axo-axonal junctions, providing a novel mechanism for very fast electrical communication.     

Ultrastructure of orexin-1 receptor immunoreactivities in the spinal cord dorsal horn

The ultrastructural properties of orexin 1-receptor-like immunoreactive (OX1R-LI) neurons in the dorsal horn of the rat spinal cord were examined using light and electron microscopy techniques. At the light microscopy level, the most heavily immunostained OX1R-LI neurons were found in the ventral horn of the spinal cord, while some immunostained profiles, including nerve fibers and small neurons, were also found in the dorsal horn. At the electron microscopy level, OX1R-LI perikarya were identified containing numerous dense-cored vesicles which were more heavily immunostained than any other organelles. Similar vesicles were also found within the axon terminals of the OX1R-LI neurons. The perikarya and dendrites of some of the OX1R-LI neurons could be seen receiving synapses from immunonegative axon terminals. These synapses were found mostly asymmetric in shape. Occasionally, some OX1R-LI axon terminals were found making synapses on dendrites that were OX1R-LI in some cases and immunonegative in others. The synapses made by OX1R-LI axon terminals were found both asymmetric and symmetric in appearance. The results provide solid morphological evidence that OX1R is transported in the dense-cored vesicles from the perikarya to axon terminals and that OX1R-LI neurons in the dorsal horn of the spinal cord have complex synaptic relationships both with other OX1R-LI neurons as well as other neuron types.     

Synaptic potentials and transfer functions of lamprey spinal neurons

1. Electrotonic and chemical synaptic potentials were measured as a function of frequency of presynaptic action potentials. Over the frequency range from 0.02 to 10 Hz, the electrotonic synaptic potential was constant, while the chemical synaptic potential decreased in magnitude. Above 10 Hz, both synaptic events decreased in magnitude consistent with filtering by the dendritic structures. 2. Electrotonic synaptic transfer functions from 0.5 to 100 Hz were measured for the I1 reticulospinal Müller axon to spinal neuron electrotonic synaptic junction of the lamprey spinal cord using paired recordings from the pre-synaptic terminals and the post-synaptic neurons. In addition to this two-point synaptic transfer function, individual single point impedance functions of both the post-synaptic soma and the pre-synaptic axon terminal were measured. 3. The measured functions were interpreted with a computational model based on a three dimensional reconstruction of a Lucifer yellow filled motoneuron. Simulations of the model for a synaptic location of the I1 synapse were consistent with the measured synaptic transfer functions. 4. Synaptic potentials were simulated for inputs on dendrites near the I1 axon as well as distal dendritic regions. The high frequency filtering increased as the synaptic location was moved from the soma to the periphery, but the potential response on distal dendrites was larger than would have been predicted from the end of the equivalent cylinder of a Rall model that was used to fit soma impedance functions. 5. Electrotonic post-synaptic potentials were enhanced by the activation of a TTX-sensitive negative conductance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Position and size of the axon hillock in various groups of neurons

The origin of the axon was studied in Golgi-Kopsch impregnated specimens prepared from the spinal cord and brain of adult rats. Five types of neurons were sampled: large ventral horn neurons, neurons in the intermediate zone and ventral horn of the spinal cord, antenna-type neurons in the spinal dorsal horn, neurons in the thalamus, and neurons in the hypothalamus. The axon originated from the perikaryon in 76% of the large ventral horn neurons and in 64% of the neurons in the thalamus. In contrast, the axon emerged from one of the dendrites in 75% of the neurons in the intermediate zone and the ventral horn of the spinal cord and in 68% of the neurons in the hypothalamus. In the case of the antenna-type neurons in the spinal dorsal horn, the axon often originated from one of the dendrites, but never from a dorsally oriented dendrite. The mean distance of the axon hillock of dendritic origin was the longest in the neurons in the intermediate zone and the ventral horn of the spinal cord. The size of the axon hillock was proportional to the size of the perikaryon. The impregnated portion of the axon was longest in the large ventral horn neurons.     

Dendritic spikes and activity-dependent synaptic plasticity

Whereas the regenerative nature of action potential conduction in axons has been known since the late 1940s, neuronal dendrites have been considered as passive cables transferring incoming synaptic activity to the soma. The relatively recent discovery that neuronal dendrites contain active conductances has revolutionized our view of information processing in neurons. In many neuronal cell types, sodium action potentials initiated at the axon initial segment can back-propagate actively into the dendrite thereby serving, for the dendrite, as an indicator of the output activity of the neuron. In addition, the dendrites themselves can initiate action-potential-like regenerative responses, so-called dendritic spikes, that are mediated either by the activation of sodium, calcium, and/or N-methyl-D-aspartate receptor channels. Here, we review the recent experimental and theoretical evidence for a role of regenerative dendritic activity in information processing within neurons and, especially, in activity-dependent synaptic plasticity.     

Synaptically activated increases in Ca2+ concentration in hippocampal CA1 pyramidal cells are primarily due to voltage-gated Ca2+ channels.

Changes in intracellular Ca2+ concentration ([Ca2+]i) in the soma and dendrites of hippocampal CA1 pyramidal neurons were measured using intracellularly injected fura-2. A large component of the [Ca2+]i elevation caused by high frequency stimulation of the Schaffer collaterals was correlated with the Na+ spikes triggered by the excitatory postsynaptic potentials (EPSPs). These spikes were generated in the soma and proximal dendrites and stimulated Ca2+ entry through voltage-gated Ca2+ channels. Suppressing spikes by hyperpolarizing the soma or by injecting QX-314 revealed a smaller nonspike component of Ca2+ entry. A substantial fraction of this component was mediated by the action of the EPSPs on voltage-gated Ca2+ channels, because it persisted in 2-amino-5-phosphonovaleric acid and because it was usually reduced when Ca2+ channel activity was suppressed by hyperpolarization. Ca2+ entry through the N-methyl-D-aspartate receptor channel could not be detected with certainty, perhaps because it was highly localized.     

The generation of action potentials in the terminals of the Schaffer collaterals during long-term potentiation in the CA1 region of the hippocampus]

Experiments were performed in rat hippocampal slices. Activity of individual CA3 pyramidal neurons and field potentials in the CA1 areas were recorded extracellularly. The collision technique was applied to detect the antidromic origin of the background action potentials in the somata of CA3 neurons. Threshold stimulation of terminals of the Schaffer collaterals in the stratum radiatum of the CA1 area was applied to study their excitability during the CA1 long-term potentiation. During the long-term potentiation, antidromic action potentials appeared in the somata of the CA3 neurons. The obtained evidence suggests that the synaptic potentiation is accompanied by an enhancement of axon terminal excitability resulting in generation of the action potentials.     

Morphology and physiology of multiglomerular olfactory projection neurons in the spiny lobster

Whole-cell patch-clamp recording was used to characterize olfactory projection neurons in an isolated brain preparation of the spiny lobster, Panulirus argus. Responses to electrical stimulation of the olfactory afferents were recorded from projection neuron somata using biocytin-filled electrodes. All projection neurons were multiglomerular, innervating up to 80% of all olfactory lobe glomeruli, but the innervation was heterogeneous. Most neurons densely innervated only 3–4 glomeruli; the remaining glomeruli in their dendritic arbor were sparsely innervated, thereby creating two distinct patterns of intraglomerular branching. Projection neurons responded to orthodromic stimulation with an initial depolarization and spiking followed by a 1–3 s hyperpolarization. The inhibitory phase of the response was lower in threshold and longer in latency than the excitatory phase, a response pattern also reported in olfactory projection neurons of insects and vertebrates. The somata of the projection neurons supported voltage-activated currents and TTX-sensitive action potentials, suggesting that the soma, although spatially separated from the axon and dendrites, may play a significant functional role in these cells. Dye coupling between some projection neurons correlated with the presence of multiple amplitude action potentials, suggesting that at least some projection neurons may be coupled via gap junctions.     

Electrical Properties of the Pacemaker Neurons in the Heart Ganglion of a Stomatopod, Squilla oratoria

In the Squilla heart ganglion, the pacemaker is located in the rostral group of cells. After spontaneous firing ceased, the electrophysiological properties of these cells were examined with intracellular electrodes. Cells respond to electrical stimuli with all-or-none action potentials. Direct stimulation by strong currents decreases the size of action potentials. Comparison with action potentials caused by axonal stimulation and analysis of time relations indicate that with stronger currents the soma membrane is directly stimulated whereas with weaker currents the impulse first arises in the axon and then invades the soma. Spikes evoked in a neuron spread into all other neurons. Adjacent cells are interconnected by electrotonic connections. Histologically axons are tied with the side-junction. B spikes of adjacent cells are blocked simultaneously by hyperpolarization or by repetitive stimulation. Experiments show that under such circumstances the B spike is not directly elicited from the A spike but is evoked by invasion of an impulse or electrotonic potential from adjacent cells. On rostral stimulation a small prepotential precedes the main spike. It is interpreted as an action potential from dendrites.     

Pacemaker Potentials for the Periodic Burst Discharge in the Heart Ganglion of a Stomatopod, Squilla oratoria

From somata of the pacemaker neurons in the Squilla heart ganglion, pacemaker potentials for the spontaneous periodic burst discharge are recorded with intracellular electrodes. The electrical activity is composed of slow potentials and superimposed spikes, and is divided into four types, which are: (a) "mammalian heart" type, (b) "slow generator" type, (c) "slow grower" type, and (d) "slow deficient" type. Since axons which are far from the somata do not produce slow potentials, the soma and dendrites must be where the slow potentials are generated. Hyperpolarization impedes generation of the slow potential, showing that it is an electrically excitable response. Membrane impedance increases on depolarization. Brief hyperpolarizing current can abolish the plateau but brief tetanic inhibitory fiber stimulation is more effective for the abolition. A single stimulus to the axon evokes the slow potential when the stimulus is applied some time after a previous burst. Repetitive stimuli to the axon are more effective in eliciting the slow potential, but the depolarization is not maintained on continuous stimulation. Synchronization of the slow potential among neurons is achieved by: (a) the electrotonic connections, with periodic change in resistance of the soma membrane, (b) active spread of the slow potential, and (c) synchronization through spikes.     

A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons

Pyramidal neurons in the cerebral cortex span multiple cortical layers. How the excitable properties of pyramidal neuron dendrites allow these neurons to both integrate activity and store associations between different layers is not well understood, but is thought to rely in part on dendritic backpropagation of action potentials. Here we demonstrate that the sign of synaptic plasticity in neocortical pyramidal neurons is regulated by the spread of the backpropagating action potential to the synapse. This creates a progressive gradient between LTP and LTD as the distance of the synaptic contacts from the soma increases. At distal synapses, cooperative synaptic input or dendritic depolarization can switch plasticity between LTD and LTP by boosting backpropagation of action potentials. This activity-dependent switch provides a mechanism for associative learning across different neocortical layers that process distinct types of information.     

Variability of adaptational properties of an excitable neuron membrane

This investigation was made on a preparation of stretch receptors of molting crayfish. We made intracellular recordings of potentials from the soma of a slowly-adapting neuron, and extracellular recordings from the nerve trunk. After strychnine had been added to the physiological solution surrounding the preparation, additional rhythmic activity was recorded from the nerve trunk, with corresponding depolarizational oscillations in the membrane potential of the soma of the slowly-adapting neuron. The additional rhythmic activity had a competitive relationship to the action potentials lying along the axon of the slowly-adapting neuron, the rhythm frequency increasing as the prolonged action potentials arose in the soma of that neuron. The depolarizational oscillations in the soma did not change sign as its membrane potential decreased. Analysis of the above phenomenon led to the conclusion that within the axon membrane of a slowly-adapting neuron there appears a section that spontaneously generates rhythmic action potentials. The results of the investigation indicate that there may be wide variations in the adaptational properties of the neuron membrane.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 1, No. 3, pp. 309–314, November–December, 1969.     

Electrophysiology of Supramedullary Neurons in Spheroides maculatus : I. Orthodromic and antidromic responses

This series of three papers presents data on a system of neurons, the large supramedullary cells (SMC) of the puffer, Spheroides maculatus, in terms of the physiological properties of the individual cells, of their afferent and efferent connections, and of their interconnections. Some of these findings are verified by available anatomical data, but others suggest structures that must be sought for in the light of the demonstration that these cells are not sensory neurons. Analysis on so broad a scale was made possible by the accessibility of the cells in a compact cluster on the dorsal surface of the spinal cord. Simultaneous recordings were made intracellularly and extracellularly from individual cells or from several, frequently with registration of the afferent or efferent activity as well. The passive and active electrical properties of the SMC are essentially similar to those of other neurons, but various response characteristics have been observed which are related to different excitabilities of different parts of the neuron, and to specific anatomical features. The SMC produce spikes to direct stimuli by intracellular depolarization, or by indirect synaptic excitation from many afferent paths, including tactile stimulation of the skin. Responses that were evoked by intracellular stimulation of a single cell cause an efferent discharge bilaterally in many dorsal roots, but not in the ventral. Sometimes several distinct spikes occurred in the same root, and behaved independently. Thus, a number of axons are efferent from each neuron. They are large unmyelinated fibers which give rise to the elevation of slowest conduction in the compound action potential of the dorsal root. A similar component is absent in the ventral root action potential. Antidromic stimulation of the axons causes small potentials in the cell body, indicating that the antidromic spikes are blocked distantly to the soma, probably in the axon branches. The failure of antidromic invasion is correlated with differences in excitability of the axons and the neurite from which they arise. As recorded in the cell body, the postsynaptic potentials associated with stimulation of afferent fibers in the dorsal roots or cranial nerves are too small to discharge the soma spike. The indirect spike has two components, the first of which is due to the synaptically initiated activity of the neurite and which invades the cell body. The second component is then produced when the soma is fired. The neurite impulse arises at some distance from the cell body and propagates centrifugally as well as centripetally. An indirect stimulus frequently produces repetitive spikes which are observed to occur synchronously in all the cells examined at one time. Each discharge gives rise to a large efferent volley in each of the dorsal roots and cranial nerves examined. The synchronized responses of all the SMC to indirect stimulation occur with slightly different latencies. They are due to a combination of excitation by synaptic bombardment from the afferent pathways and by excitatory interconnections among the SMC. Direct stimulation of a cell may also excite all the others. This spread of activity is facilitated by repetitive direct excitation of the cell as well as by indirect stimulation.     

Role of an A-Type K+ Conductance in the Back-Propagation of Action Potentials in the Dendrites of Hippocampal Pyramidal Neurons

Action potentials elicited in the axon actively back-propagate into the dendritic tree. During this process their amplitudes can be modulated by internal and external factors. We used a compartmental model of a hippocampal CA1 pyramidal neuron to illustrate how this modulation could depend on (1) the properties of an A-type K⁺ conductance that is expressed at high density in hippocampal dendrites and (2) the relative timing of synaptic activation. The simulations suggest that the time relationship between pre- and postsynaptic activity could help regulate the amplitude of back-propagating action potentials, especially in the distal portion of the dendritic tree.     

神经元对于高频电刺激的动态响应

深部脑刺激(deep brain stimulation,DBS)在许多神经系统疾病的临床治疗上都展现出良好的应用前景,然而,其作用机制尚不明确.常规DBS采用高频刺激(high frequency stimulation,HFS)的脉冲序列,这种窄脉冲最容易激活神经元结构中的轴突部分,通过轴突的投射,将HFS的作用传播至下游神经元.因此,为了探讨DBS的作用机制,并鉴于海马脑区是治疗癫痫和痴呆症等疾病的重要靶点,我们研究了海马区轴突HFS对于下游神经元的作用.对麻醉大鼠的海马CA1区传入神经通路Schaffer侧支施加1 min的100 Hz高频刺激,记录并提取下游CA1区锥体神经元和中间神经元的单元锋电位.计算锋电位的发放率,以及它们与刺激脉冲之间的锁相值(phase-locking value,PLV)和潜伏期,以定量分析HFS期间神经元动作电位发放的变化趋势.结果显示,在传入轴突上施加HFS时,初期会诱发下游神经元群体同步产生动作电位(即群峰电位).在HFS后期(群峰电位消失之后),两类神经元的单元锋电位发放仍然持续,并且发放率较稳定.但是,锋电位与刺激脉冲之间的锁相性逐渐减弱、潜伏期逐渐延长.而且,与中间神经元相比较,锥体神经元锋电位的锁相性更弱、潜伏期更长.这些结果表明,持续的轴突HFS可以诱导下游神经元产生非同步的活动,高频脉冲刺激引起的不完全轴突传导阻滞可能是导致该现象产生的主要原因.本文的研究为揭示脑刺激的作用机制提供了重要信息.