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Combining laser scanning confocal microscopy and electron microscopy to determine sites of synaptic contact between two identified neurons.

Here we report a double labelling method for correlative confocal and electron microscopy (EM) which allows selective characterisation of structural relationships between two single identified neurons in the same preparation. Using the lobster stomatogastric nervous system, we labelled pairs of identified, synaptically-connected neurons by intracellular injection of Lucifer Yellow (LY) in one neuron and a mixture of Rhodamine (Rdh) and Horseradish Peroxidase (HRP) in its partner. First, whole-mounts of LY- and Rdh-stained neurons were visualized using laser scanning confocal microscopy (LSCM) in order to isolate neuropilar regions of possible synaptic contact. Second, after conventional treatment for electron microscopy (LY was revealed with immunogold and HRP with DAB), areas of close appositions were viewed in EM. This technique allowed us to determine all the regions of close contact between two cells, and then to use electron microscopy to determine the presence or absence of synaptic contact within each of these restricted areas. These techniques enabled us to show that there were few areas of apposition and that only an extremely small proportion of these areas was in fact regions of synaptic contact between the two labelled neurons.

Animals↗

Power gain exhibited by motile mechanosensory neurons in Drosophila ears.

In insects and vertebrates alike, hearing is assisted by the motility of mechanosensory cells. Much like pushing a swing augments its swing, this cellular motility is thought to actively augment vibrations inside the ear, thus amplifying the ear's mechanical input. Power gain is the hallmark of such active amplification, yet whether and how much energy motile mechanosensory cells contribute within intact auditory systems has remained uncertain. Here, we assess the mechanical energy provided by motile mechanosensory neurons in the antennal hearing organs of Drosophila melanogaster by analyzing the fluctuations of the sound receiver to which these neurons connect. By using dead WT flies and live mutants (tilB(2), btv(5P1), and nompA(2)) with defective neurons as a background, we show that the intact, motile neurons do exhibit power gain. In WT flies, the neurons lift the receiver's mean total energy by 19 zJ, which corresponds to 4.6 times the energy of the receiver's Brownian motion. Larger energy contributions (200 zJ) associate with self-sustained oscillations, suggesting that the neurons adjust their energy expenditure to optimize the receiver's sensitivity to sound. We conclude that motile mechanosensory cells provide active amplification; in Drosophila, mechanical energy contributed by these cells boosts the vibrations that enter the ear.

Animals↗

Homozygous mutation of focal adhesion kinase in embryonic stem cell derived neurons: normal electrophysiological and morphological properties in vitro.

BACKGROUND: Genetically manipulated embryonic stem (ES) cell derived neurons (ESNs) provide a powerful system with which to study the consequences of gene manipulation in mature, synaptically connected neurons in vitro. Here we report a study of focal adhesion kinase (FAK), which has been implicated in synapse formation and regulation of ion channels, using the ESN system to circumvent the embryonic lethality of homozygous FAK mutant mice. RESULTS: Mouse ES cells carrying homozygous null mutations (FAK-/-) were generated and differentiated in vitro into neurons. FAK-/- ESNs extended axons and dendrites and formed morphologically and electrophysiologically intact synapses. A detailed study of NMDA receptor gated currents and voltage sensitive calcium currents revealed no difference in their magnitude, or modulation by tyrosine kinases. CONCLUSION: FAK does not have an obligatory role in neuronal differentiation, synapse formation or the expression of NMDA receptor or voltage-gated calcium currents under the conditions used in this study. The use of genetically modified ESNs has great potential for rapidly and effectively examining the consequences of neuronal gene manipulation and is complementary to mouse studies.

Animals↗

Neuronal manifestation of two-way connections in conditioning.

Neuronal characteristics of two-way conditional connections were studied in chronic experiments with alert cats during different types of alimentary conditional reflexes. Single unit and multi-unit activities were chronically recorded in the visual and motor cortex and the lateral hypothalamic nucleus. Cross-correlational analysis of neuronal impulse trains was used to characterize the organization of neuron groups in brain structures involved in the formation of a conditional reflex. The experimental data showed an increase in the number of neuronal two-way connections after learning in all three investigated coordinations: visual-motor, visual-hypothalamic, and motor-hypothalamic. With visual-motor interneuronal coordination, the strengthening of two-way connections was due to the enhancement of connections from the motor to the visual neuron (backward connections); with visual- and motor-hypothalamic coordination, the number of interneuronal connections was equal in both directions. In all investigated coordinations, the analysis of the temporal parameters of the interactions between the neurons of different groups showed a dependence of the conditioning procedure on delays of up to 30 ms and a dependence of the motivational state on the interval range of 90-100 ms. The polyfunctional and polycomponent character of two-way neuronal connections in conditioning can be inferred from these data. Evaluation of the activity of neurons of different brain structures suggests the specific organization of intracortical and cortical-subcortical integrity in learning.

Animals↗

The role of spatio-temporal firing patterns in neuronal development of sensory systems.

The emergence of precise and orderly sets of neuronal connections often depends upon coordinated electrical activity during the early stages of development. In recent years, an increasing number of reports have shown that neurons of immature sensory systems can spontaneously generate electrical activity that occurs synchronously amongst adjacent cells. These patterns of correlated activity seem to be well suited to the role of providing the cues that are necessary for the activity-dependent refinement of the neural connections in the developing visual, auditory and somatosensory pathways.

Aging↗

Polarity and patterning in the neural tube: the origin and function of the floor plate.

Little is known about the cellular and molecular mechanisms that determine neuronal cell fate and the patterning of neuronal connections in the vertebrate central nervous system. In this paper we summarize evidence which indicates that some aspects of neuronal differentiation and axon guidance are regulated by specialized epithelial cells that occupy the medial region of the neural plate and, later, the ventral midline of the spinal cord. This cell group, termed the notoplate/floor plate appears to constitute a distinct compartment within the neural plate that is more closely related in lineage and perhaps also in function to axial mesodermal cells of the underlying notochord than to other neural plate cells. Cells of the notoplate exhibit specialized mechanical and adhesive properties that may contribute to neurulation. At later stages of development, the floor plate appears to guide developing axons in the embryonic spinal cord by releasing a diffusible chemoattractant factor and by virtue of its specialized cell surface properties. The floor plate may also play a role in the determination of cell identity and patterning at earlier stages of neural tube development.

Animals↗

Spontaneous activity and recurrent inhibition in cultured hippocampal networks.

As a model for an integrated neuronal network based on the concept of modular units, we have investigated the occurrence of spontaneous activity and the formation of synaptic circuits in primary cultures of dissociated hippocampal neurons from the embryonic rat. Sodium-dependent action potentials (APs) could be elicited after 1 day in vitro (DIV), whereas spontaneous postsynaptic potentials (PSPs), "miniature" PSPs and APs appeared after 3-6 DIV. The number of cells with spontaneous APs and the rate of APs increased during development of the neuritic network. In addition to a stochastic spike interval distribution, pyramid-shaped neurons could be identified after 10-12 DIV, which fired preferentially at interspike intervals between 20-120 ms and 190-400 ms. This distinctive bimodal interspike interval pattern was sensitive to GABA-A antagonists. Simultaneous recordings of pairs of neurons demonstrated recurrent inhibitory, GABA-ergic synaptic circuits. In addition, a subpopulation of GABAergic neurons could be visualized by immunocytochemistry. These results are discussed in relation to the hypothesis that spontaneous firing of connected neurons is network-driven, based on synaptic "noise" and patterned by recurrent inhibition.

Action Potentials↗

The role of muscarinic acetylcholine receptors in ocular dominance plasticity.

During a critical period of postnatal development neuronal connections in the visual cortex are susceptible to experience-dependent modifications. In normally reared kittens the majority of neurons respond to visual stimulation of either eye. A few days of monocular deprivation, however, are sufficient to render most cortical neurons unresponsive to visual stimuli presented to the deprived eye. Among other factors the cholinergic projection to striate cortex has been identified as having a permissive role in this use-dependent modification of synaptic transmission. In order to analyze further the influence of acetylcholine in cortical plasticity, we tested whether the blockade of muscarinic or nicotinic receptors interfered with ocular dominance plasticity. At four weeks of age kittens had one eyelid sutured closed and osmotic minipumps implanted, which delivered scopolamine (1 nmol/h) or hexamethonium (1 or 10 nmol/h) into the striate cortex of one hemisphere and vehicle solution (saline) into the other. After one week, ocular dominance distributions were determined in area 17 with single unit recording. In the control hemispheres, most neurons became unresponsive to the deprived eye, while in the scopolamine-treated hemispheres most neurons remained binocular. In contrast to the effects of scopolamine, the intracortical infusion of hexamethonium had no effect on ocular dominance plasticity. These results demonstrate that blockade of muscarinic, but not nicotinic receptors renders kitten striate cortex resistant to the effects of monocular deprivation.

Animals↗

Modeling of the H-reflex facilitation during ramp and hold contractions.

Healthy subjects were asked to make a voluntary ramp and hold contraction. The duration of the ramp stage was 500 ms, and the torque increment in this period was set to 15 Nm. The contraction was made from a relaxed and from a 5 Nm background torque situation. Hoffmann (H-) reflexes were elicited during the voluntary contraction, mostly with 100 ms intervals. These experiments showed an increase (facilitation) in the H-reflex before the torque or the EMG started to increase. This facilitation of the H-reflex remained during all the stages of the voluntary movement and declined to normal levels again only at the very end of the hold phase, which lasted for one second. This specific pattern of facilitation during a voluntary contraction was modeled using a modeling language, that is specifically designed to calculate neuronal systems with a high degree of reality (Ekeberg et al., 1991). Our model consisted of a motoneuron pool with 200 neurons connected to an EMG-model of the human soleus muscle and an extra group of higher-level neurons for controlling the amount of decrease of presynaptic inhibition. The model was used to simulate the observed modulation of the H-reflex with both a presynaptic and a postsynaptic mechanism. Simulations showed that a continuous change in the descending control signals is needed to make the model based on postsynaptic mechanism fit with the experimental data, whereas no extra control from the CNS over the excitatory drive to the motoneuron pool is needed when the decrease of presynaptic inhibition mechanism is applied.

Adult↗

Cholera toxin and wheat germ agglutinin conjugates as neuroanatomical probes: their uptake and clearance, transganglionic and retrograde transport and sensitivity.

Horseradish peroxidase (HRP) conjugates of 6 different lectins and cholera toxin (CTHRP) were quantitatively compared with respect to: (a) their behavior at the injection site and (b) their ability to label, by means of transganglionic and retrograde axonal transport, axon terminals and neurons in the medulla of the rat subsequent to injections of each probe into the anterior two thirds of the tongue. HRP conjugates of wheat germ agglutinin (WGHRP) and CTHRP were more sensitive than any of the other lectin-HRP conjugates. Both were far superior to free-HRP (FHRP) in demonstrating these projections and CTHRP was the most sensitive transganglionic and retrograde probe. Additional experiments demonstrated that this superiority was not an artifact of the volume of material injected into the tongue nor of the injection site area or survival time selection. These experiments demonstrated further that CTHRP and WGHRP remain at the injection site approximately twice as long as FHRP and that their removal from or degradation in retrogradely labeled neurons requires approximately twice as much time as that required for FHRP. These observations, together with earlier studies from this laboratory, suggest the following conclusions: (1) CTHRP and WGHRP are superior in sensitivity to FHRP for studies of neuronal connectivity; and (2) HRP conjugates of ligands such as CTHRP and WGHRP are internalized, transported and/or degraded by mammalian neurons in a manner which differs from that of FHRP, a macromolecule for which neuronal plasma membrane 'receptors' are lacking.

Afferent Pathways↗

Abnormal cholecystokinin mRNA levels in entorhinal cortex of schizophrenics.

Limbic cortical regions, including anterior cingulate cortex (ACC), prefrontal cortex (PFC) and entorhinal cortex (ERC), have been implicated in the neuropathology of schizophrenia. Glutamate projection neurons connect these limbic cortical regions to each other, as well as to the terminal fields of the striatal/accumbens dopamine neurons. Subsets of these glutamate projection neurons, and of the GABA interneurons in cortex, contain the neuropeptide cholecystokinin (CCK). In an effort to study the limbic cortical glutamate projection neurons and GABA interneurons in schizophrenia, we have measured CCK mRNA with in situ hybridization histochemistry in postmortem samples of dorsolateral (DL)PFC, ACC and ERC of seven schizophrenics, nine non-psychotic suicides and seven normal controls. CCK mRNA is decreased in ERC (especially layers iii vi) and subiculum in schizophrenics relative to controls. Cellular analysis indicates that there is a decrease in density of CCK mRNA in labelled neurons. In so far as ERC CCK mRNA is not reduced in rats treated chronically with haloperidol, this decrease in schizophrenics does not appear to be related to neuroleptic treatment. In contrast, in DLPFC, where schizophrenics do not differ from normals, the suicide victims have elevated CCK mRNA (especially in layers v and vi), and increased cellular density of CCK mRNA, relative to both normals and schizophrenics. These results lend further support for the involvement of ERC and hippocampus in schizophrenia, suggesting that neurons that utilize CCK may be particularly important. Similarly, an increase in CCK mRNA levels in the PFC of suicides adds to a growing body of evidence implicating this structure in this pathological state. In so far as CCK is co-localized with GABA or glutamate in cortical neurons, both of these neuronal populations need to be studied further in schizophrenia and suicide.

Animals↗

Use, disuse, and growth of the brain.

It is well known that across species, the relative size of the cortical area representing a particular sensory surface is proportional to how important that sense is for the animal. Furthermore, we are commonly aware of the observation that the loss of one sense, such as sight, appears to lead to an increase in sensitivity of the remaining senses, although the physiological basis for this is not entirely clear. Now, several studies, including that of Zheng and Purves (11), have suggested that the cortical area devoted to a particular sensory system can be modulated by neuronal activity during development. The fact that use, or disuse, of a sensory organ can lead to significant changes in its area of representation in the developing cortex is intriguing and calls for further investigations aimed at understanding the functional significance and the mechanisms underlying these changes. What remains to be determined is whether enhanced "growth" also means enhanced performance by that sensory system and, if so, whether this is the result of selective changes in neuronal connectivity and/or synaptic efficacy. It is too early to tell, but, whatever the outcome, it is refreshing to consider neuronal growth in the light of enhanced neural activity, in parallel to the results of activity deprivation, to which we are more accustomed.

Aging↗

MOTION-SENSITIVE CELLS: PUTATIVE LARVAL NEURONES INCORPORATED INTO THE OPTIC LOBE OF THE ADULT SWALLOWTAIL BUTTERFLY

Intracellular recordings were made from neurones with large somata situated at the anteromedial edge of the medulla of the swallowtail butterfly Papilio xuthus; the neurones were then filled with Lucifer Yellow. These cells are putative larval visual interneurones incorporated into the adult optic lobe of the butterfly. There are four classes of motion-sensitive neurones. Two have a dendritic arborization in the dorsal half of the medulla and project an axon to the medial protocerebrum or the contralateral medulla. They respond to vertical downward motion with a strong burst of action potentials and their background activities are inhibited by motion in the opposite direction. Variations in position of the dendritic fields suggest that each group of neurones forms a coherent set of cells detecting vertical motion in the dorsal half of the visual field of the eye. The third class of neurones connects the lobula plate to the midbrain and is preferentially sensitive to vertical upward motion. The fourth class of neurones has a dendritic arborization in the lobula. These neurones are tonically excited by a moving grating irrespective of the stimulus orientation and movement direction. The presence of motion-sensitive medulla neurones suggests that the detection of local motion is completed in the distal medulla.

Journal Article↗

Fine structure and synaptic connections of identified neurons in the rat fascia dentata.

A survey is given of the synaptic connections of identified neurons in the rat fascia dentata based on our own Golgi/electron microscopic and light and electron microscopic immunocytochemical findings as well as on results obtained from the literature. The report largely deals with the dominating cell type in the region, the dentate granule cell. Of the various types of hilar cells, the GABAergic neurons, particularly the inhibitory basket cells, are taken into account. Differences in fine structure between granule cells and basket cells as well as mutual synaptic connections between these two types of dentate neurons are elaborated. This survey may provide a basis for further neurophysiological and pharmacological studies on these cells.

Animals↗

Model circuit of spiking neurons generating directional selectivity in simple cells.

1. We here consider the property of directional selectivity (DS) in simple cells of layer 4 of cat area 17 as an instance of a receptive field (RF) transformation between two monosynaptically connected neuron populations: the afferent geniculate (lateral geniculate nucleus, LGN) cells and their target, layer 4 simple cells. We have studied this particular RF transformation because the large set of experimental data available allowed us to restrain the synaptic organization of our model layer 4 circuitry. 2. The one-compartment, spiking model neurons of the layer 4 circuitry are excitatory (adapting) or inhibitory (nonadapting). They all have simple-cell RFs composed of two spatially separated ON and OFF subregions. The sequence of the subregions across the neurons' RFs, which is determined by the geniculocortical inputs they receive, varies independently from their preferred direction of stimulus motion, which is determined by spatial asymmetries in their corticocortical inputs. 3. Synaptic transmission in the model layer 4 circuitry is mediated via non-N-methyl-D-aspartate (non-NMDA) receptors (geniculocortical excitation), via NMDA receptors (corticocortical excitation), and via gamma-aminobutyric acid-A receptors (corticocortical inhibition). Excitatory and inhibitory cortical neurons receive the same afferents. However, excitatory neurons form efferent synapses exclusively with neurons having the same RF characteristics, and preferentially with those having the same RF position. Inhibitory neurons form synapses preferentially with neurons having different RF characteristics or adjacent RF positions. 4. By comparing the neurons' numerically computed responses to visual stimuli with those of actual simple cells, the topology of the corticocortical connections has been constrained. The experimental responses to stationary and moving, and to bar as well as grating, stimuli are consistently reproduced with a single constant parameter setting. 5. Subsequently, the model has been analyzed from a system-theoretic approach and has been manipulated in order to find the components critical for its proper functioning. Variations on the model have been simulated for evaluating the performance of alternative connection schemes. 6. Spatially opponent inhibition between model simple cells with antagonistic RF subregions is necessary for the restoration of linearity lost at the LGN output. It hyperpolarizes model simple cells when the contrast polarity of an efficient stimulus is reversed and prevents, particularly in directionally nonselective cells, a frequency doubling of the responses to sine wave gratings of low spatial frequencies. 7. Directionally opponent inhibition between model simple cells preferring opposite directions of motion is necessary for the generation of genuine DS (a ratio of firing rates > 2 for opposite directions of motion). 8. The corticocortical excitatory polysynaptic feedback loops in the model are able to provide the time delays needed to generate DS, and even to preserve DS at very low speeds. The strength spatial extension, and time course of this corticocortical feedback excitation, together with the dynamics of the geniculate afferents and the width of the RF, determine the tuning of model simple cells in the temporal and velocity domain. 9. The present model generates directionally selective responses to stimulus motion over distances smaller than the width of a single subregion and as small as the spacing between the afferent geniculate RFs. The direction-selective mechanism acts uniformly across the entire width of a subregion. Thus the position invariance of DS arises in the present model at the same level as DS itself. The same holds for the stimulus polarity (light vs. dark) invariance of DS. Consequently, there is no need for highly hierarchical models in which all these characteristics accumulate in simple cells by pooling from lower-order subunits or neurons.

Action Potentials↗

Neurotrophic regulation of retinal ganglion cell synaptic connectivity: from axons and dendrites to synapses.

This review highlights important events during the morphological development of retinal ganglion cells (RGCs), focusing on mechanisms that control axon and dendritic arborization as a means to understand synaptic connectivity with special emphasis on the role of neurotrophins during structural and functional development of RGCs. Neurotrophins and their receptors participate in the development of visual connectivity at multiple levels. In the visual system, neurotrophins have been shown to exert various developmental influences, from guiding the morphological differentiation of neurons to controlling the functional plasticity of visual circuits. This review article examines the role of neurotrophins, and in particular of BDNF, during the morphological development of RGCs, and discusses potential interactions between activity and neurotrophins during development of neuronal connectivity.

Animals↗

A quantitative analysis of the local connectivity between pyramidal neurons in layers 2/3 of the rat visual cortex.

This study provides a detailed quantitative estimate for local synaptic connectivity between neocortical pyramidal neurons. A new way of obtaining such an estimate is presented. In acute slices of the rat visual cortex, four layer 2 and four layer 3 pyramidal neurons were intracellularly injected with biocytin. Axonal and dendritic arborizations were three-dimensionally reconstructed with the aid of a computer-based camera lucida system. In a computer experiment, pairs of pre- and postsynaptic neurons were formed and potential synaptic contacts were calculated. For each pair, the calculations were carried out for a whole range of distances (0 to 500 microm) between the presynaptic and the postsynaptic neuron, in order to estimate cortical connectivity as a function of the spatial separation of neurons. It was also differentiated whether neurons were situated in the same or in different cortical layers. The data thus obtained was used to compute connection probabilities, the average number of contacts between neurons, the frequency of specific numbers of contacts and the total number of contacts a dendritic tree receives from the surrounding cortical volume. Connection probabilities ranged from 50% to 80% for directly adjacent neurons and from 0% to 15% for neurons 500 microm apart. In many cases, connections were mediated by one contact only. However, close neighbors made on average up to 3 contacts with each other. The question as to whether the method employed in this study yields a realistic estimate of synaptic connectivity is discussed. It is argued that the results can be used as a detailed blueprint for building artificial neural networks with a cortex-like architecture.

Animals↗

Integrity of lateral and feedbackward connections in visual processing in children with pervasive developmental disorder.

Enhanced visual detail processing in subjects with pervasive developmental disorder (PDD) has been related to impairments in feature integration. The functional integrity of two types of neuronal connections involved in visual feature integration, namely horizontal and feedbackward connections, were tested. Sixteen children with PDD and 17 age- and IQ-matched control children (mean age 13.3 years) were included. In a texture segregation task the difference in ERP response to homogeneous and checkered visual stimuli was determined. Additionally, in a contour integration task subjects had to point out a contour consisting of colinearly aligned Gabor signals in backgrounds increasing in noise. Children with PDD showed a normal performance on the contour integration task, suggesting that neurons in the primary visual cortex of children with PDD can effectively integrate the activity of local detectors that process different aspects of the same object information by making use of long-range lateral connections. The amplitude of ERP activity related to texture segregation was also not different between the PDD and control groups, indicating functional visual feedback mechanisms between V1 and higher order areas in subjects with PDD. However, a difference in latency of texture-segmentation related activity between the groups was noted. This effect did not reach significance, which could be due to the small N of the study. Therefore, the data need replication in a study with larger samples before more definitive conclusions can be drawn.

Adolescent↗