Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential

Traditionally, neuronal operations in the cerebral cortex have been viewed as occurring through the interaction of synaptic potentials in the dendrite and soma, followed by the initiation of an action potential, typically in the axon. Propagation of this action potential to the synaptic terminals is widely believed to be the only form of rapid communication of information between the soma and axonal synapses, and hence to postsynaptic neurons. Here we show that the voltage fluctuations associated with dendrosomatic synaptic activity propagate significant distances along the axon, and that modest changes in the somatic membrane potential of the presynaptic neuron modulate the amplitude and duration of axonal action potentials and, through a Ca2+-dependent mechanism, the average amplitude of the postsynaptic potential evoked by these spikes. These results indicate that synaptic activity in the dendrite and soma controls not only the pattern of action potentials generated, but also the amplitude of the synaptic potentials that these action potentials initiate in local cortical circuits, resulting in synaptic transmission that is a mixture of triggered and graded (analogue) signals.     

Intracellular calcium stores regulate activity-dependent neuropeptide release from dendrites

Information in neurons flows from synapses, through the dendrites and cell body (soma), and, finally, along the axon as spikes of electrical activity that will ultimately release neurotransmitters from the nerve terminals. However, the dendrites of many neurons also have a secretory role, transmitting information back to afferent nerve terminals. In some central nervous system neurons, spikes that originate at the soma can travel along dendrites as well as axons, and may thus elicit secretion from both compartments. Here, we show that in hypothalamic oxytocin neurons, agents that mobilize intracellular Ca(2+) induce oxytocin release from dendrites without increasing the electrical activity of the cell body, and without inducing secretion from the nerve terminals. Conversely, electrical activity in the cell bodies can cause the secretion of oxytocin from nerve terminals with little or no release from the dendrites. Finally, mobilization of intracellular Ca(2+) can also prime the releasable pool of oxytocin in the dendrites. This priming action makes dendritic oxytocin available for release in response to subsequent spike activity. Priming persists for a prolonged period, changing the nature of interactions between oxytocin neurons and their neighbours.     

Compartmentalized dendritic plasticity and input feature storage in neurons

Although information storage in the central nervous system is thought to be primarily mediated by various forms of synaptic plasticity, other mechanisms, such as modifications in membrane excitability, are available. Local dendritic spikes are nonlinear voltage events that are initiated within dendritic branches by spatially clustered and temporally synchronous synaptic input. That local spikes selectively respond only to appropriately correlated input allows them to function as input feature detectors and potentially as powerful information storage mechanisms. However, it is currently unknown whether any effective form of local dendritic spike plasticity exists. Here we show that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an N-methyl-d-aspartate receptor (NMDAR)-dependent regulation of dendritic Kv4.2 potassium channels. These data suggest that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatio-temporal correlation. We propose that this 'branch strength potentiation' represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.     

NMDA spikes in basal dendrites of cortical pyramidal neurons

Basal dendrites are a major target for synaptic inputs innervating cortical pyramidal neurons. At present little is known about signal processing in these fine dendrites. Here we show that coactivation of clustered neighbouring basal inputs initiated local dendritic spikes, which resulted in a 5.9 +/- 1.5 mV (peak) and 64.4 +/- 19.8 ms (half-width) cable-filtered voltage change at the soma that amplified the somatic voltage response by 226 +/- 46%. These spikes were accompanied by large calcium transients restricted to the activated dendritic segment. In contrast to conventional sodium or calcium spikes, these spikes were mediated mostly by NMDA (N-methyl-D-aspartate) receptor channels, which contributed at least 80% of the total charge. The ionic mechanism of these NMDA spikes may allow 'dynamic spike-initiation zones', set by the spatial distribution of glutamate pre-bound to NMDA receptors, which in turn would depend on recent and ongoing activity in the cortical network. In addition, NMDA spikes may serve as a powerful mechanism for modification of the cortical network by inducing long-term strengthening of co-activated neighbouring inputs.     

Neurophysiology: Hodgkin and Huxley model--still standing?

Action potentials in cortical neurons show a variable threshold and a sudden rise in membrane potential at initiation. Naundorf et al. fail to explain these features using single- or double-compartment Hodgkin-Huxley-style models, suggesting instead that they could arise from cooperative opening of Na+ channels, although there is no direct biological evidence to support this. Here we show that these so-called unique features are to be expected from Hodgkin-Huxley models if the spatial geometry and spike initiation properties of cortical neurons are taken into account--it is therefore unnecessary to invoke exotic channel-gating properties as an explanation.     

Distribution and three-dimensional structure of AIDS virus envelope spikes

Envelope glycoprotein (Env) spikes on AIDS retroviruses initiate infection of host cells and are therefore targets for vaccine development. Though crystal structures for partial Env subunits are known, the structure and distribution of native Env spikes on virions is obscure. We applied cryoelectron microscopy tomography to define ultrastructural details of spikes. Virions of wild-type human immunodeficiency virus 1 (HIV-1) and a mutant simian immunodeficiency virus (SIV) had approximately 14 and approximately 73 spikes per particle, respectively, with some clustering of HIV-1 spikes. Three-dimensional averaging showed that the surface glycoprotein (gp120) 'head' of each subunit of the trimeric SIV spike contains a primary mass, with two secondary lobes. The transmembrane glycoprotein 'stalk' of each trimer is composed of three independent legs that project obliquely from the trimer head, tripod-like. Reconciling available atomic structures with the three-dimensional whole spike density map yields insights into the orientation of Env spike structural elements and possible structural bases of their functions.     

Topography of acoustic response characteristics in the midbrain inferior colliculus of Kunming mouse

Topography of acoustic response characteristics of the midbrain inferior colliculus(IC)of the Kunming mouse was studied by using extracellular recording techniques.The characteristic frequency(CF)range represented in the different divisions of the IC differed markedly:4-15 kHz in the dorsal cortex(DC),10-70 kHz in the central nucleus(CN),and 4-35kHz in the external cortex(EC).The CF in the CN increased from dorsal and lateral to ventral and medial,higher CFs represented at its ventromedial part and lower CFs at its dorsal part.The isofrequency contours of CFs were incurvate.Minimum thresholds(MT)of the auditory neurons in DC and the central part of CN were lower(about 10dB SPL),but considerably higher in the dorsal and ventral region of EC.Results suggest that each of the divisions in the mouse IC may have different auditory functions.     

Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.     

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.     

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.     

Spike train dynamics predicts theta-related phase precession in hippocampal pyramidal cells

According to the temporal coding hypothesis, neurons encode information by the exact timing of spikes. An example of temporal coding is the hippocampal phase precession phenomenon, in which the timing of pyramidal cell spikes relative to the theta rhythm shows a unidirectional forward precession during spatial behaviour. Here we show that phase precession occurs in both spatial and non-spatial behaviours. We found that spike phase correlated with instantaneous discharge rate, and processed unidirectionally at high rates, regardless of behaviour. The spatial phase precession phenomenon is therefore a manifestation of a more fundamental principle governing the timing of pyramidal cell discharge. We suggest that intrinsic properties of pyramidal cells have a key role in determining spike times, and that the interplay between the magnitude of dendritic excitation and rhythmic inhibition of the somatic region is responsible for the phase assignment of spikes.     

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.     

The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons.

The dendrites of many types of neurons contain voltage-dependent Na+ and Ca2+ conductances that generate action potentials (see ref. 1 for review). The function of these spikes is not well understood, but the Ca2+ entry stimulated by spikes probably affects Ca(2+)-dependent processes in dendrites. These include synaptic plasticity, cytotoxicity and exocytosis. Several lines of evidence suggest that dendritic spikes occur within subregions of the dendrites. To study the mechanism that govern the spread of spikes in the dendrites of hippocampal pyramidal cells, we imaged Ca2+ entry with Fura-2 (ref. 9) and Na+ entry with a newly developed Na(+)-sensitive dye. Our results indicate that Ca2+ entry into dendrites is triggered by Na+ spikes that actively invade the dendrites. The restricted spatial distribution of Ca2+ entry seems to depend on the spread of Na+ spikes in the dendrites, rather than on a limited distribution of Ca2+ channels. In addition, we have observed an activity-dependent process that modulates the invasion of spikes into the dendrites and progressively restricts Ca2+ entry to more proximal dendritic regions.     

Structural rearrangements in the membrane penetration protein of a non-enveloped virus

Non-enveloped virus particles (those that lack a lipid-bilayer membrane) must breach the membrane of a target host cell to gain access to its cytoplasm. So far, the molecular mechanism of this membrane penetration step has resisted structural analysis. The spike protein VP4 is a principal component in the entry apparatus of rotavirus, a non-enveloped virus that causes gastroenteritis and kills 440,000 children each year. Trypsin cleavage of VP4 primes the virus for entry by triggering a rearrangement that rigidifies the VP4 spikes. We have determined the crystal structure, at 3.2 A resolution, of the main part of VP4 that projects from the virion. The crystal structure reveals a coiled-coil stabilized trimer. Comparison of this structure with the two-fold clustered VP4 spikes in a approximately 12 A resolution image reconstruction from electron cryomicroscopy of trypsin-primed virions shows that VP4 also undergoes a second rearrangement, in which the oligomer reorganizes and each subunit folds back on itself, translocating a potential membrane-interaction peptide from one end of the spike to the other. This rearrangement resembles the conformational transitions of membrane fusion proteins of enveloped viruses.     

Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current

Neurons in many regions of the mammalian nervous system generate action potentials in two distinct modes: rhythmic oscillations in which spikes cluster together in a cyclical manner, and single spike firing in which action potentials occur relatively independently of one another. Which mode of action potential generation a neuron displays often varies with the behavioural state of the animal. For example, the shift from slow-wave sleep to waking and attentiveness is associated with a change in thalamic neurons from rhythmic burst firing to repetitive single spike activity, and a greatly increased responsiveness to excitatory synaptic inputs. This marked change in firing pattern and excitability is controlled in part by ascending noradrenergic and serotonergic inputs from the brainstem, although the cellular mechanisms of this effect have remained largely unknown. Here we report that noradrenaline and serotonin enhance a mixed Na+/K+ current which is activated by hyperpolarization (Ih) and that this enhancement may be mediated by increases in intracellular concentration of cyclic AMP. This novel action of noradrenaline and serotonin reduces the ability of thalamic neurons to generate rhythmic burst firing and promotes a state of excitability that is conducive to the thalamocortical synaptic processing associated with cognition.     

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.     

多小穗小麦幼胚培养及其无性系变异

三种类型多小穗小麦经幼胚离体培养后，其无性系Ｒ２代的株高、穗长、旗叶长和宽、单株穗数等重要农艺性状发生了不同程度的变异。其中分枝穗类型的９２Ｄ０８６的Ｒ２代除上述各性状发生变异外，穗型、芒、千粒重等也发生了变异。     

Topography and synaptic shaping of direction selectivity in primary auditory cortex

The direction of frequency-modulated (FM) sweeps is an important temporal cue in animal and human communication. FM direction-selective neurons are found in the primary auditory cortex (A1), but their topography and the mechanisms underlying their selectivity remain largely unknown. Here we report that in the rat A1, direction selectivity is topographically ordered in parallel with characteristic frequency (CF): low CF neurons preferred upward sweeps, whereas high CF neurons preferred downward sweeps. The asymmetry of 'inhibitory sidebands', suppressive regions flanking the tonal receptive field (TRF) of the spike response, also co-varied with CF. In vivo whole-cell recordings showed that the direction selectivity already present in the synaptic inputs was enhanced by cortical synaptic inhibition, which suppressed the synaptic excitation of the non-preferred direction more than that of the preferred. The excitatory and inhibitory synaptic TRFs had identical spectral tuning, but with inhibition delayed relative to excitation. The spectral asymmetry of the synaptic TRFs co-varied with CF, as had direction selectivity and sideband asymmetry, and thus suggested a synaptic mechanism for the shaping of FM direction selectivity and its topographic ordering.     

Threshold channels--a novel type of sodium channel in squid giant axon

Sodium channels in nerve and muscle cells are functionally similar across wide phylogenetic boundaries and are usually thought to represent a single, homogeneous population that initiates the action potential at threshold and unerringly transmits it along the surface membrane. In marked contrast, many cell types are known to have several distinct potassium permeability systems. Distinguishable populations of Na channels have been reported in a few cell types, however, including denervated skeletal muscle, embryonic cardiac muscle, Purkinje cell somata and non-myelinated axons at low temperature. We report here that in squid giant axon, in standard experimental conditions, there are two functionally distinct populations of Na channels. The newly discovered population accounts for only a few per cent of the total Na permeability. The channels are selectively activated by small depolarizations and have very slow closing kinetics. Because these channels activate at voltages near the resting potential and tend to stay open for long times, they must dominate behaviour of the axon membrane in the threshold region for action potential initiation.