Origin Of Axons Research Articles

Unveiling the cell biology of hippocampal neurons with dendritic axon origin.

In mammalian axon-carrying-dendrite (AcD) neurons, the axon emanates from a basal dendrite, instead of the soma, to create a privileged route for action potential generation at the axon initial segment (AIS). However, it is unclear how such unusual morphology is established and whether the structure and function of the AIS in AcD neurons are preserved. By using dissociated hippocampal cultures as a model, we show that the development of AcD morphology can occur prior to synaptogenesis and independently of the in vivo environment. A single precursor neurite first gives rise to the axon and then to the AcD. The AIS possesses a similar cytoskeletal architecture as the soma-derived AIS and similarly functions as a trafficking barrier to retain axon-specific molecular composition. However, it does not undergo homeostatic plasticity, contains lesser cisternal organelles, and receives fewer inhibitory inputs. Our findings reveal insights into AcD neuron biology and underscore AIS structural differences based on axon onset.

Increased Interhemispheric Connectivity of a Distinct Type of Hippocampal Pyramidal Cells.

Neurons typically generate action potentials at their axon initial segment based on the integration of synaptic inputs. In many neurons, the axon extends from the soma, equally weighting dendritic inputs. A notable exception is found in a subset of hippocampal pyramidal cells where the axon emerges from a basal dendrite. This structure allows these axon-carrying dendrites (AcDs) a privileged input route. We found that in male mice, such cells in the CA1 region receive stronger excitatory input from the contralateral CA3, compared with those with somatic axon origins. This is supported by a higher count of putative synapses from contralateral CA3 on the AcD. These findings, combined with prior observations of their distinct role in sharp-wave ripple firing, suggest a key role of this neuron subset in coordinating bi-hemispheric hippocampal activity during memory-centric oscillations.

Von Economo neurons as a specialized neuron class of the human cerebral cortex

By studying human cortical cytoarchitecture, von Economo noticed large spindle-shaped-neurons within layer Vb in the anterior-cingulate and fronto-insular cortex. Those neurons had such extremely elongated stick-like or corkscrew-like soma shape that appeared to him as a pathological alteration. Eventually, he realized that this was a specialized-type of neuron which he described as distinct from the main cortical cell populations, including the commonly found spindle cells. Data from recent studies suggest that specialized-stick-corkscrew-neurons may have first developed in the fronto-insular cortex before the division of hominids and Old World monkeys, and that they have become abundant in the anterior-cingulate cortex only in the hominid line. Golgi analysis found that they have distinctive somato-dendritic morphology with a characteristic very distal position of their axon origin. Many additional studies claimed to find cells similar to the specialized cells described by von Economo in other non-primate species, even in functionally unrelated cortical regions and layers. However, these studies did not provide sufficient evidence that the cells they described are indeed distinct from common spindle-shaped-neurons, and that they truly correspond to the specialized-stick-corkscrew-cells described by von Economo. We believe that present evidence primarily supports the presence of specialized-stick-corkscrew-neurons in hominids, with a seeming increase in their number in humans compared to other primates. The functional significance of such neuronal specialization within specific areas of the human cerebral cortex remains to be elucidated.

Somatic Integration of Incoherent Dendritic Inputs in the Gerbil Medial Superior Olive.

The medial superior olive (MSO) is a binaural nucleus that is specialized in detecting the relative arrival times of sounds at both ears. Excitatory inputs to its neurons originating from either ear are segregated to different dendrites. To study the integration of synaptic inputs both within and between dendrites, we made juxtacellular and whole-cell recordings from the MSO in anesthetized female gerbils, while presenting a "double zwuis" stimulus, in which each ear received its own set of tones, which were chosen in a way that all second-order distortion products (DP2s) could be uniquely identified. MSO neurons phase-locked to multiple tones within the multitone stimulus, and vector strength, a measure for spike phase-locking, generally depended linearly on the size of the average subthreshold response to a tone. Subthreshold responses to tones in one ear depended little on the presence of sound in the other ear, suggesting that inputs from different ears sum linearly without a substantial role for somatic inhibition. The "double zwuis" stimulus also evoked response components in the MSO neuron that were phase-locked to DP2s. Bidendritic subthreshold DP2s were quite rare compared with bidendritic suprathreshold DP2s. We observed that in a small subset of cells, the ability to trigger spikes differed substantially between both ears, which might be explained by a dendritic axonal origin. Some neurons that were driven monaurally by only one of the two ears nevertheless showed decent binaural tuning. We conclude that MSO neurons are remarkably good in finding binaural coincidences even among uncorrelated inputs.SIGNIFICANCE STATEMENT Neurons in the medial superior olive are essential for precisely localizing low-frequency sounds in the horizontal plane. From their soma, only two dendrites emerge, which are innervated by inputs originating from different ears. Using a new sound stimulus, we studied the integration of inputs both within and between these dendrites in unprecedented detail. We found evidence that inputs from different dendrites add linearly at the soma, but that small increases in somatic potentials could lead to large increases in the probability of generating a spike. This basic scheme allowed the MSO neurons to detect the relative arrival time of inputs at both dendrites remarkably efficient, although the relative size of these inputs could differ considerably.

Compartment-specific dendritic information processing in striatal cholinergic interneurons is reconfigured by peptide neuromodulation

Cholinergic interneurons are central hubs of the striatal neuronal network, controlling information processing in a behavioral-state-dependent manner. It remains unknown, however, how such state transitions influence the integrative properties of these neurons. To address this, we made simultaneous somato-dendritic recordings from identified rodent cholinergic interneurons, revealing that action potentials are initiated at dendritic sites because of a dendritic axonal origin. Functionally, this anatomical arrangement ensured that the action potential initiation threshold was lowest at axon-bearing dendritic sites, a privilege efficacy powerfully accentuated at the hyperpolarized membrane potentials achieved in cholinergic interneurons following salient behavioral stimuli. Experimental analysis revealed the voltage-dependent attenuation of the efficacy of non-axon-bearing dendritic excitatory input was mediated by the recruitment of dendritic potassium channels, a regulatory mechanism that, in turn, was controlled by the pharmacological activation of neurokinin receptors. Together, these results indicate that the neuropeptide microenvironment dynamically controls state- and compartment-dependent dendritic information processing in striatal cholinergic interneurons.

Imaging Voltage Globally and in Isofrequency Lamina in Slices of Mouse Ventral Cochlear Nucleus.

The cochlear nuclei (CNs) receive sensory information from the ear and perform fundamental computations before relaying this information to higher processing centers. These computations are performed by distinct types of neurons interconnected in circuits dedicated to the specialized roles of the auditory system. In the present study, we explored the use of voltage imaging to investigate CN circuitry. We tested two approaches based on fundamentally different voltage sensing technologies. Using a voltage-sensitive dye we recorded glutamate receptor-independent signals arising predominantly from axons. The mean conduction velocity of these fibers of 0.27 m/s was rapid but in range with other unmyelinated axons. We then used a genetically-encoded hybrid voltage sensor (hVOS) to image voltage from a specific population of neurons. Probe expression was controlled using Cre recombinase linked to c-fos activation. This activity-induced gene enabled targeting of neurons that are activated when a mouse hears a pure 15-kHz tone. In CN slices from these animals auditory nerve fiber stimulation elicited a glutamate receptor-dependent depolarization in hVOS probe-labeled neurons. These cells resided within a band corresponding to an isofrequency lamina, and responded with a high degree of synchrony. In contrast to the axonal origin of voltage-sensitive dye signals, hVOS signals represent predominantly postsynaptic responses. The introduction of voltage imaging to the CN creates the opportunity to investigate auditory processing circuitry in populations of neurons targeted on the basis of their genetic identity and their roles in sensory processing.

Dendritic axon origin enables information gating by perisomatic inhibition in pyramidal neurons.

Information processing in neuronal networks involves the recruitment of selected neurons into coordinated spatiotemporal activity patterns. This sparse activation results from widespread synaptic inhibition in conjunction with neuron-specific synaptic excitation. We report the selective recruitment of hippocampal pyramidal cells into patterned network activity. During ripple oscillations in awake mice, spiking is much more likely in cells in which the axon originates from a basal dendrite rather than from the soma. High-resolution recordings in vitro and computer modeling indicate that these spikes are elicited by synaptic input to the axon-carrying dendrite and thus escape perisomatic inhibition. Pyramidal cells with somatic axon origin can be activated during ripple oscillations by blocking their somatic inhibition. The recruitment of neurons into active ensembles is thus determined by axonal morphological features.

Morphology and Dendrite-Specific Synaptic Properties of Midbrain Neurons Shape Multimodal Integration.

Multimodal integration facilitates object recognition and response to sensory cues. This depends on spatiotemporal coincidence of sensory information, recruitment of NMDA-type glutamate receptors and inhibitory feedback. Shepherd's crook neurons (SCNs) in the avian optic tectum (TeO) are an ideal model for studying cellular mechanism of multimodal integration. They receive different sensory modalities through spatially segregated dendrites, are important for stimulus selection and have an axon-carrying dendrite (AcD). We performed whole-cell patch-clamp experiments in chicken midbrain slices of both sexes. We emulated visual and auditory input in vitro by stimulating presynaptic afferents electrically. Simultaneous stimulation enhanced responses inversely depending on stimulation amplitude demonstrating the principle of inverse effectiveness. Contribution of NMDA-type glutamate receptors prolonged postsynaptic events for visual inputs only, causing a strong modality-specific difference in synaptic efficacy. We designed a multicompartment model to study the effect of morphological and physiological parameters on multimodal integration by varying the distance between soma and axonal origin and the amount of NMDA receptor (NMDAR) contribution. These parameters changed the preference of the model for one input channel and adjusted the range of input rates at which multimodal enhancement occurred on naturalistic stimulation. Thus, the unique morphology and synaptic features of SCNs shape the integration of input at different dendrites and generates an enhanced multimodal response.SIGNIFICANCE STATEMENT Multimodal integration improves perception and responses to objects. The underlying cellular mechanism depends on a balance between excitation and inhibition, and NMDA-type glutamate receptors that are involved in the multiplicative nature of enhancement following the principle of inverse effectiveness. Based on a detailed analysis of an identified multimodal cell type in the vertebrate midbrain, we studied the influence of cellular morphology and unimodal synaptic properties on multimodal integration. We can show that the combination of cellular morphology and modality-specific synaptic properties including NMDA receptor (NMDAR) contribution is optimal for nonlinear, multimodal enhancement and determines the dynamic response range of the integrating neuron. Our findings mechanistically explain how synaptic properties and cellular morphology of a midbrain neuron contribute to multimodal enhancement.

Single axonal morphology reveals high heterogeneity in spinocerebellar axons originating from the lumbar spinal cord in the mouse.

Among the spinocerebellar projections vital for sensorimotor coordination of limbs and the trunk, the morphology of spinocerebellar axons originating from the lumbar cord has not been well characterized compared to those from thoracic and sacral cords. We reconstructed 26 single spinocerebellar axons labeled by biotinylated dextran injections into the gray matter of the lumbar spinal cord in mice. Axon terminals were mapped with the zebrin pattern of the cerebellar cortex. Reconstructed axons were primarily classified into ipsilaterally and contralaterally ascending axons, arising mainly from the dorsal and ventral horns, respectively. The majority of ipsilateral and contralateral axons took the dorsal-medullary and ventral-pontine pathways, respectively. The axons of both groups terminated mainly in the vermal and medial paravermal areas of lobules II-V and VIII-IXa, often bilaterally but predominantly ipsilateral to the axonal origin, with a weak preference to particular portions of zebrin stripes. The ipsilateral axons originating from the medial dorsal horn in the upper lumbar cord (n=3) had abundant (43-147) mossy fiber terminals and no medullary collaterals. The ipsilateral axons originating from the lateral dorsal horn in the lower lumbar cord (n=9) and the contralateral axons (n=14) showed remarkable morphology variations. The number of their mossy fiber terminals varied from 2 to 172. Their collaterals, observed in 17 axons out of 23, terminated mainly in the medial cerebellar nucleus, nucleus X, and lateral reticular nucleus in various degrees. The results indicated that the lumbar spinocerebellar projection contains highly heterogeneous axonal populations regarding their pathway, branching, and termination patterns.

Morphological plasticity of the tuberoinfundibular dopaminergic neurones in the rat during the oestrous cycle and lactation

The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones are critical with respect to regulating prolactin secretion from the anterior pituitary. Under most physiological conditions, they are stimulated by prolactin to release dopamine into the median eminence which subsequently suppresses further prolactin secretion from the lactotrophs. During lactation, the TIDA neurones are known to undergo both electrophysiological and neurochemical changes that alleviate this negative-feedback, thus allowing circulating prolactin levels to rise. The present study aimed to determine whether TIDA neurone morphology, most notably spine density, is also modified during lactation. This was achieved by stereotaxically injecting the arcuate nucleus of female, tyrosine hydroxylase-promoter driven Cre-recombinase transgenic rats with Cre-dependent adeno-associated virus-expressing Brainbow. This resulted in the highly specifici transfection of between 10% and 30% of the TIDA neurones, thus allowing the morphologies on multiple individual neurones to be examined in a single hypothalamic slice. The transfected neurones exhibited a range of complex forms, including a diversity of soma and location of axonal origin. Neuronal spine counting showed that the density of somatic, but not dendritic, spines was significantly higher during lactation than at any other reproductive stage. There was also a significant fall in somatic spine density across the oestrous cycle from dioestrus to oestrus. Although the functional characteristics of the additional somatic spines have not been determined, if, as might be expected, they represent an increased excitatory input to the TIDA neurones, this could have important physiological implications by perhaps supporting altered neurotransmitter release at their neuroendocrine terminals. Enhanced excitatory input may, for example, favour the release of the opioid peptide enkephalin rather than dopamine, which is potentially significant because the expression of the peptide is known to increase in the TIDA neurones during lactation and, in contrast to dopamine, it stimulates rather than inhibits prolactin secretion from the pituitary.

Kv1.1 contributes to a rapid homeostatic plasticity of intrinsic excitability in CA1 pyramidal neurons in vivo.

In area CA1 of the hippocampus, the selection of place cells to represent a new environment is biased towards neurons with higher excitability. However, different environments are represented by orthogonal cell ensembles, suggesting that regulatory mechanisms exist. Activity-dependent plasticity of intrinsic excitability, as observed in vitro, is an attractive candidate. Here, using whole-cell patch-clamp recordings of CA1 pyramidal neurons in anesthetized rats, we have examined how inducing theta-bursts of action potentials affects their intrinsic excitability over time. We observed a long-lasting, homeostatic depression of intrinsic excitability which commenced within minutes, and, in contrast to in vitro observations, was not mediated by dendritic Ih. Instead, it was attenuated by the Kv1.1 channel blocker dendrotoxin K, suggesting an axonal origin. Analysis of place cells' out-of-field firing in mice navigating in virtual reality further revealed an experience-dependent reduction consistent with decreased excitability. We propose that this mechanism could reduce memory interference.

Origins of Neural Progenitor Cell-Derived Axons Projecting Caudally after Spinal Cord Injury.

SummaryNeural progenitor cells (NPCs) transplanted into sites of spinal cord injury (SCI) extend large numbers of axons into the caudal host spinal cord. We determined the precise locations of neurons in the graft that extend axons into the caudal host spinal cord using AAV9-Cre-initiated retrograde tracing into floxed-TdTomato-expressing NPC grafts. 7,640 ± 630 grafted neurons extended axons to a single caudal host spinal cord site located 2 mm beyond the lesion, 5 weeks post injury. While caudally projecting axons arose from neurons located in all regions of the graft, the majority of caudally projecting graft neurons (53%) were located within the caudal one-third of the graft. Numerous host corticospinal axons formed monosynaptic projections onto caudally projecting graft neurons; however, we find that the majority of host axonal neuronal projections formed by neural progenitor cell interneuronal “relays” across sites of SCI are likely polysynaptic in nature.

Individual Oligodendrocytes Show Bias for Inhibitory Axons in the Neocortex

Reciprocal communication between neurons and oligodendrocytes is essential for the generation and localization of myelin, a critical feature of the CNS. In the neocortex, individual oligodendrocytes can myelinate multiple axons; however, the neuronal origin of the myelinated axons has remained undefined and, while largely assumed to be from excitatory pyramidal neurons, it also includes inhibitory interneurons. Thisraises the question of whether individual oligodendrocytes display bias for the class of neurons that they myelinate. Here, we find that different classes of cortical interneurons show distinct patterns ofmyelin distribution starting from the onset of myelination, suggesting that oligodendrocytes can recognize the class identity of individual types of interneurons that they target. Notably, we show that some oligodendrocytes disproportionately myelinate the axons of inhibitory interneurons, whereas others primarily target excitatory axons or show no bias. These results point toward very specific interactions between oligodendrocytes and neurons and raise the interesting question of why myelination is differentially directed toward different neuron types.

Extracellular waveforms reveal an axonal origin of spikelets in pyramidal neurons.

Spikelets are small spike-like membrane depolarizations measured at the soma whose origin in pyramidal neurons is still unresolved. We investigated the mechanism of spikelet generation using detailed models of pyramidal neurons. We simulated extracellular waveforms associated with action potentials and spikelets and compared these with experimental data obtained by Chorev and Brecht ( J Neurophysiol 108: 1584-1593, 2012) from hippocampal pyramidal neurons in vivo. We considered spikelets originating in the axon of a single cell as well as spikelets generated in two cells coupled with gap junctions. We found that in both cases the experimental data can be explained by an axonal origin of spikelets: in the single-cell case, action potentials are generated in the axon but fail to activate the soma. Such spikelets can be evoked by dendritic input. Alternatively, spikelets resulting from axoaxonal gap junction coupling with a large (greater than several hundred μm) distance between the somata of the coupled cells are also consistent with the data. Our results demonstrate that a cell firing a somatic spikelet generates a detectable extracellular potential that is different from the action potential-correlated extracellular waveform generated by the same cell and recorded at the same location. This, together with the absence of a refractory period between action potentials and spikelets, implies that spikelets and action potentials generated in one cell may easily get misclassified in extracellular recordings as two different cells, albeit they both constitute the output of a single pyramidal neuron. NEW & NOTEWORTHY We addressed the origin of spikelets, using compartmental models of pyramidal neurons. Comparing our simulation results with published extracellular spikelet recordings revealed an axonal origin of spikelets. Our results imply that action potential- and spikelet-associated extracellular waveforms may easily get misclassified as two different cells, albeit they both constitute the output of a single pyramidal cell.

Distinct kinetics of inhibitory currents in thalamocortical neurons that arise from dendritic or axonal origin.

Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN) transfer visual information from retina to primary visual cortex. This information is modulated by inhibitory input arising from local interneurons and thalamic reticular nucleus (TRN) neurons, leading to alterations of receptive field properties of thalamocortical neurons. Local GABAergic interneurons provide two distinct synaptic outputs: axonal (F1 terminals) and dendritic (F2 terminals) onto dLGN thalamocortical neurons. By contrast, TRN neurons provide only axonal output (F1 terminals) onto dLGN thalamocortical neurons. It is unclear if GABAA receptor-mediated currents originating from F1 and F2 terminals have different characteristics. In the present study, we examined multiple characteristics (rise time, slope, halfwidth and decay τ) of GABAA receptor-mediated miniature inhibitory postsynaptic synaptic currents (mIPSCs) originating from F1 and F2 terminals. The mIPSCs arising from F2 terminals showed slower kinetics relative to those from F1 terminals. Such differential kinetics of GABAAR-mediated responses could be an important role in temporal coding of visual signals.

Expression patterns of ion channels and structural proteins in a multimodal cell type of the avian optic tectum.

The midbrain is an important subcortical area involved in distinct functions such as multimodal integration, movement initiation, bottom-up, and top-down attention. Our group is particularly interested in cellular computation of multisensory integration. We focus on the visual part of the avian midbrain, the optic tectum (TeO, counterpart to mammalian superior colliculus). This area has a layered structure with the great advantage of distinct input and output regions. In chicken, the TeO is organized in 15 layers where visual input targets the superficial layers while auditory input terminates in deeper layers. One specific cell type, the Shepherd's crook neuron (SCN), extends dendrites in both input regions. The characteristic feature of these neurons is the axon origin at the apical dendrite. The molecular identity of this characteristic region and thus, the site of action potential generation are of particular importance to understand signal flow and cellular computation in this neuron. We present immunohistochemical data of structural proteins (NF200, Ankyrin G, and Myelin) and ion channels (Pan-Nav , Nav 1.6, and Kv 3.1b). NF200 is strongly expressed in the axon. Ankyrin G is mainly expressed at the axon initial segment (AIS). Myelination starts after the AIS as well as the distribution of Nav channels on the axon. The subtype Nav 1.6 has a high density in this region. Kv 3.1b is restricted to the soma, the primary neurite and the axon branch. The distribution of functional molecules in SCNs provides insight into the information flow and the integration of sensory modalities in the TeO of the avian midbrain.

Heterogeneity of the Axon Initial Segment in Interneurons and Pyramidal Cells of Rodent Visual Cortex.

The microdomain that orchestrates action potential initiation in neurons is the axon initial segment (AIS). It has long been considered to be a rather homogeneous domain at the very proximal axon hillock with relatively stable length, particularly in cortical pyramidal cells. However, studies in other brain regions paint a different picture. In hippocampal CA1, up to 50% of axons emerge from basal dendrites. Further, in about 30% of thick-tufted layer V pyramidal neurons in rat somatosensory cortex, axons have a dendritic origin. Consequently, the AIS is separated from the soma. Recent in vitro and in vivo studies have shown that cellular excitability is a function of AIS length/position and somatodendritic morphology, undermining a potentially significant impact of AIS heterogeneity for neuronal function. We therefore investigated neocortical axon morphology and AIS composition, hypothesizing that the initial observation of seemingly homogeneous AIS is inadequate and needs to take into account neuronal cell types. Here, we biolistically transfected cortical neurons in organotypic cultures to visualize the entire neuron and classify cell types in combination with immunolabeling against AIS markers. Using confocal microscopy and morphometric analysis, we investigated axon origin, AIS position, length, diameter as well as distance to the soma. We find a substantial AIS heterogeneity in visual cortical neurons, classified into three groups: (I) axons with somatic origin with proximal AIS at the axon hillock; (II) axons with somatic origin with distal AIS, with a discernible gap between the AIS and the soma; and (III) axons with dendritic origin (axon-carrying dendrite cell, AcD cell) and an AIS either starting directly at the axon origin or more distal to that point. Pyramidal cells have significantly longer AIS than interneurons. Interneurons with vertical columnar axonal projections have significantly more distal AIS locations than all other cells with their prevailing phenotype as an AcD cell. In contrast, neurons with perisomatic terminations display most often an axon originating from the soma. Our data contribute to the emerging understanding that AIS morphology is highly variable, and potentially a function of the cell type.

The Mesoaccumbens Pathway: A Retrograde Labeling and Single-Cell Axon Tracing Analysis in the Mouse

Neurons in the ventral tegmental area (VTA) that innervate the nucleus accumbens (Acb) constitute the so-called mesoaccumbens system. Increased activity by these neurons is correlated with the expectation and achievement of reward. The mesoaccumbens projection neurons are regarded as a central node in the brain networks that regulate drive and hedonic experience, and their dysregulation is a common pathophysiological step in addictive behaviors as well as major depression. Despite previous anatomical studies that have analyzed the origin of the mesoaccumbens axons within the VTA, regarded as a unit, the exact contributions of the various cytoarchitectural subdivisions of the VTA to this innervation is still unexplored; understanding these contributions would help further our understanding of their precise anatomical organization. With the aim of deciphering the contribution of the various VTA subdivisions to accumbal innervation, the present study has used retrograde tracer microinjections in the Acb to map the location within the various VTA subdivisions of neurons targeting either the shell or core compartments of the Acb in mice. Furthermore, the dopaminergic nature of these projections has also been analyzed using tyrosine-hydroxylase immunohistochemistry. We demonstrate here that small territories of the Acb core and shell are innervated simultaneously by many VTA subdivisions, contributing dopaminergic as well as non-dopaminergic axons to the accumbal innervation. In fact, single VTA subdivisions harbor both dopaminergic and non-dopaminergic neurons that project to the same accumbal territory. The most medial VTA subnuclei, like the caudal linear nucleus, project abundantly to medial aspects of the Acb core, whereas more lateral territories of the Acb are preferentially targeted by neurons located in the parabrachial pigmented and paranigral nuclei. Overall, about half of the mesoaccumbens neurons are putatively dopaminergic in mice. Anterograde single-cell labeling (Sindbis-pal-eGFP vector) of a limited sample of neurons revealed that mesoaccumbens neurons form profuse terminal arborizations to cover large volumes of either the Acb core or shell, and, unlike other VTA projection neuron populations, they do not branch to other striatal or extrastriatal structures. These anatomical observations are consistent with reports of an intense response in many Acb neurons after stimulation of very few VTA cells.

High dendritic expression of Ih in the proximity of the axon origin controls the integrative properties of nigral dopamine neurons

The hyperpolarization-activated cation current Ih is expressed in dopamine neurons of the substantia nigra, but the subcellular distribution of the current and its role in synaptic integration remain unknown. We used cell-attached patch recordings to determine the localization profile of Ih along the somatodendritic axis of nigral dopamine neurons in slices from young rats. Ih density is higher in axon-bearing dendrites, in a membrane area close to the axon origin, than in the soma and axon-lacking dendrites. Dual current-clamp recordings revealed a similar contribution of Ih to the waveform of single excitatory postsynaptic potentials throughout the somatodendritic domain. The Ih blocker ZD7288 increased the temporal summation in all dendrites with a comparable effect in axon- and non-axon dendrites. The strategic position of Ih in the proximity of the axon may influence importantly transitions between pacemaker and bursting activities and consequently the downstream release of dopamine. Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The hyperpolarization-activated cation current Ih present in the dendrites of some pyramidal neurons affects their membrane and integration properties, synaptic plasticity and higher functions such as memory. A gradient of increasing h-channel density towards distal dendrites has been found to be responsible for the location independence of excitatory postsynaptic potential (EPSP) waveform and temporal summation in cortical and hippocampal pyramidal cells. However, reports on other cell types revealed that smoother gradients or even linear distributions of Ih can achieve homogeneous temporal summation. Although the existence of a robust, slowly activating Ih current has been repeatedly demonstrated in nigral dopamine neurons, its subcellular distribution and precise role in synaptic integration are unknown. Using cell-attached patch-clamp recordings, we find a higher Ih current density in the axon-bearing dendrite than in the soma or in dendrites without axon in nigral dopamine neurons. Ih is mainly concentrated in the dendritic membrane area surrounding the axon origin and decreases with increasing distances from this site. Single EPSPs and temporal summation are similarly affected by blockade of Ih in axon- and non-axon-bearing dendrites. The presence of Ih close to the axon is pivotal to control the integrative functions and the output signal of dopamine neurons and may consequently influence the downstream coding of movement.

Motor unit firing pattern: evidence for motoneuronal or axonal discharge origin?

In neuromuscular diseases, a fasciculation origin is disputed. In some reports, it was suggested that motor unit firing pattern alone is evidence for motoneuronal or axonal fasciculations; namely interspike intervals of approximately 5 ms (doublet intervals) provide evidence for the axonal firing. To clarify the reliability of the suggestion, we compared doublet intervals originated in motoneurons and their axons in healthy humans. For this aim, the H-reflex and M-response of single motor units were elicited during gentle voluntary muscle contractions. Peri-stimulus time histograms allowed reliable judgment about a doublet origin: motoneuronal (at the H-reflex latency) or axonal (at the M-response latency). Significant difference between motoneuronal and axonal doublet intervals was absent. It was concluded that doublet interval alone cannot be the reliable criterion for an axonal firing origin; additional evidences are needed for this conclusion, for example, the appearance of the F-wave. The approach may be used as an additional estimation of mechanisms underlying motor unit diseases.