Methods of simulating the behavior of granule cells in hippocampus based on informon theory

Postulated pathways between neurones in hippocampus are briefly described, as are experiments demonstrating potentiation. It is suggested that variable synapses between the perforant path and granule cells may be acting like informons, and that inhibitory synapses from basket cells to granule cells may be performing the associated function of reinforcement.Methods for simulating the behaviour of a granule/basket cell pair, based on these two hypotheses, are described; it is explained how such a system can be used to predict the behaviour of a population of cells if all granule cells and all basket cells are similarly excited. The limitations of the present simulation are pointed out; suggestions are made for the inclusion of further details in future work.     

Neuronal organization of the accessory olfactory bulb of the lizard Podarcis hispanica: Golgi study

The neuronal organization of the accessory olfactory bulb (AOB), which receives sensory information from the vomeronasal organ, was described in a squamate reptile (Podarcis hispanica) by means of light microscopy. Using the Golgi-impregnation method, seven neuronal types could be distinguished: Periglomerular cells constitute a morphologically heterogeneous population of small neurons located between and around the glomeruli. The mitral cells are diffusely distributed in the AOB. Their cell bodies are usually located within the mitral cell layer, but some of them could be also observed in the plexiform layers. Mitral cells were classified into three subgroups on the basis of their sizes and dendritic tree morphologies. Thus, the “outer mitral cells” have the biggest cell bodies, and their distal secondary dendrites are mainly distributed rostrocaudally in the external plexiform layer. The “inner mitral cells” have large cell bodies, and their secondary dendrites are distributed dorsoventrally and are located deeper than those of the other two subgroups. The third type, the “small mitral cells,” is the smallest one among mitral cells in the AOB, and from their cell bodies, only two main dendritic trunks arise. The granule cells are composed of several categories based on their different cell body locations and dendritic tree morphologies. Thus, the “superficial granule cells” are located exclusively in the external plexiform layer and have small dendritic fields. The “middle granule cells” have fusiform cell bodies—situated in the internal plexiform layer—and present a wide dendritic projection area. Finally, the “deep granule cells” are distributed throughout the granule cell layer and include a great variety of dendritic tree morphologies. The distribution and morphological features of all neuronal types constituting the AOB of Podarcis were compared with those reported on other vertebrates. The results suggest that the lamination pattern and neuronal organization of the AOB in lizards are more similar to that of mammals than to that of the remaining vertebrates.     

Interrelated modification of excitatory and inhibitory synapses in three-layer olivary-cerebellar neural network

The model of three-layer olivary-cerebellar neural network with modifiable excitatory and inhibitory connections between diverse elements is suggested. The same Hebbian modification rules are proposed for Purkinje cells, granule (input) cells, and deep cerebellar nuclei (output) cells. The inverse calcium-dependent modification rules for these cells and hippocampal/neocortical neurones or Golgi cells are conceivably the result of the involvement of cGMP and cAMP in postsynaptic processes. The sign of simultaneous modification of excitatory and inhibitory inputs to a cell is opposite and determined by the variations in pre- and/or postsynaptic cell activity. Modification of excitatory transmission between parallel fibers and Purkinje cells, mossy fibers and granule cells, and mossy fibers and deep cerebellar nuclei cells essentially depends on inhibition effected by stellate/basket cells, Golgi cells and Purkinje cells, respectively. The character of interrelated modifications of diverse synapses in all three layers of the network is influenced by olivary cell activity. In the absence (presence) of a signal from inferior olive, the long-term potentiation (depression) in the efficacy of a synapse between input mossy fiber and output cell can be induced. The results of the suggested model are in accordance with known experimental data.     

Non-associative Potentiation of Perisomatic Inhibition Alters the Temporal Coding of Neocortical Layer 5 Pyramidal Neurons

In the neocortex, the coexistence of temporally locked excitation and inhibition governs complex network activity underlying cognitive functions, and is believed to be altered in several brain diseases. Here we show that this equilibrium can be unlocked by increased activity of layer 5 pyramidal neurons of the mouse neocortex. Somatic depolarization or short bursts of action potentials of layer 5 pyramidal neurons induced a selective long-term potentiation of GABAergic synapses (LTPi) without affecting glutamatergic inputs. Remarkably, LTPi was selective for perisomatic inhibition from parvalbumin basket cells, leaving dendritic inhibition intact. It relied on retrograde signaling of nitric oxide, which persistently altered presynaptic GABA release and diffused to inhibitory synapses impinging on adjacent pyramidal neurons. LTPi reduced the time window of synaptic summation and increased the temporal precision of spike generation. Thus, increases in single cortical pyramidal neuron activity can induce an interneuron-selective GABAergic plasticity effectively altering the computation of temporally coded information.     

A cortical attractor network with Martinotti cells driven by facilitating synapses

The population of pyramidal cells significantly outnumbers the inhibitory interneurons in the neocortex, while at the same time the diversity of interneuron types is much more pronounced. One acknowledged key role of inhibition is to control the rate and patterning of pyramidal cell firing via negative feedback, but most likely the diversity of inhibitory pathways is matched by a corresponding diversity of functional roles. An important distinguishing feature of cortical interneurons is the variability of the short-term plasticity properties of synapses received from pyramidal cells. The Martinotti cell type has recently come under scrutiny due to the distinctly facilitating nature of the synapses they receive from pyramidal cells. This distinguishes these neurons from basket cells and other inhibitory interneurons typically targeted by depressing synapses. A key aspect of the work reported here has been to pinpoint the role of this variability. We first set out to reproduce quantitatively based on in vitro data the di-synaptic inhibitory microcircuit connecting two pyramidal cells via one or a few Martinotti cells. In a second step, we embedded this microcircuit in a previously developed attractor memory network model of neocortical layers 2/3. This model network demonstrated that basket cells with their characteristic depressing synapses are the first to discharge when the network enters an attractor state and that Martinotti cells respond with a delay, thereby shifting the excitation-inhibition balance and acting to terminate the attractor state. A parameter sensitivity analysis suggested that Martinotti cells might, in fact, play a dominant role in setting the attractor dwell time and thus cortical speed of processing, with cellular adaptation and synaptic depression having a less prominent role than previously thought.     

Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses

Mossy fibers are the sole excitatory projection from dentate gyrus granule cells to the hippocampus, where they release glutamate, dynorphin, and zinc. In addition, mossy fiber terminals show intense immunoreactivity for the inhibitory neurotransmitter GABA. Fast inhibitory transmission at mossy fiber synapses, however, has not previously been reported. Here, we show that electrical or chemical stimuli that recruit dentate granule cells elicit monosynaptic GABA(A) receptor-mediated synaptic signals in CA3 pyramidal neurons. These inhibitory signals satisfy the criteria that distinguish mossy fiber-CA3 synapses: high sensitivity to metabotropic glutamate receptor agonists, facilitation during repetitive stimulation, and NMDA receptor-independent long-term potentiation. GABAergic transmission from the dentate gyrus to CA3 has major implications not only for information flow into the hippocampus but also for developmental and pathological processes involving the hippocampus.     

Effects of physostigmine and scopolamine on long-term potentiation of hippocampal population spikes in rats

To elucidate an involvement of the cholinergic system in the long-term potentiation phenomenon, effects of physostigmine and scopolamine on population spike and its long-term potentiation in the dentate granule cell layer of anesthetized rats and in the CA1 pyramidal cell layer of rat hippocampal slices were examined. In anesthetized rats, physostigmine (0.01 mg/kg, i.v.) enhanced at a late phase the long-term potentiation induced by tetanic stimulation (15 Hz, 15 s, 7.5 times the threshold for population spike) of the perforant path, while scopolamine (1.0 mg/kg) suppressed it at an early phase. The two drugs did not affect the population spike itself. The time course of the long-term potentiation under the treatment of physostigmine was similar to that induced by stronger tetanic stimulation (10 times the threshold). In hippocampal slices, physostigmine (10(-6)M) showed a tendency to enhance the long-term potentiation induced by tetanic stimulation (15 Hz, 15 s, 5 times the threshold) of the stratum radiatum, with an increase of the population spike itself. Scopolamine (10(-5)M) markedly suppressed the long-term potentiation with a decrease of the population spike itself. From these results, it is suggested that cholinergic modification by physostigmine or scopolamine affects the long-term potentiation phenomenon in the hippocampus under the in vivo and in vitro conditions.     

Electrical characteristics of granule cells of the carp olfactory bulb

Intracellular responses of granule cells and secondary neurons of the carp olfactory bulb to electrical stimulation of the olfactory nerve and olfactory tract were investigated. Synaptic responses of granule cells to both types of stimuli consisted of an early and late EPSP and IPSP. Comparison of responses of the secondary and granule neurons indicated that the granule cells are interneurons of postsynaptic inhibition of secondary neurons. The results suggest that dendro-dendritic and recurrent collateral pathways exist for the activation of granule cells and that inhibitory synapses are located on those dendrites of the secondary neurons that are in contact with endings of olfactory nerve fibers.M. V. Lomonosov State University, Moscow. Translated from Neirofiziologiya, Vol. 7, No. 6, pp. 597–602, November–December, 1975.     

Long-term potentiation and olfactory memory formation in the carp (<Emphasis Type="Italic">Cyprinus carpio</Emphasis> L.) olfactory bulb

Long-term potentiation of synaptic transmission is considered to be an elementary process underlying the cellular mechanism of memory formation. In the present study we aimed to examine whether or not the dendrodendritic mitral-to-granule cell synapses in the carp olfactory bulb show plastic changes after their repeated activation. It was found that: (1) the dendrodendritic mitral-to-granule cell synapses showed three types of plasticity after tetanic electrical stimulation applied to the olfactory tract—long-term potentiation (potentiation lasting >1 h), short-term potentiation (potentiation lasting <1 h) and post-tetanic potentiation (potentiation lasting <10 min); (2) Long-term potentiation was generally induced when both the dendrodendritic mitral-to-granule cell synapses and centrifugal fiber-to-granule cell synapses were repeatedly and simultaneously activated; (3) long-term enhancement (>1 h) of the odor-evoked bulbar response accompanied the electrically-induced LTP, and; (4) repeated olfactory stimulation enhanced dendrodendritic mitral-to-granule cell transmission. Based on these results, it was proposed that long-term potentiation (as well as olfactory memory) occurs at the dendrodendritic mitral-to-granule cell synapses after strong and long-lasting depolarization of granule cells, which follows repeated and simultaneous synaptic activation of both the peripheral and deep dendrites (or somata).     

Quantitative Organization of GABAergic Synapses in the Molecular Layer of the Mouse Cerebellar Cortex

In the cerebellar cortex, interneurons of the molecular layer (stellate and basket cells) provide GABAergic input to Purkinje cells, as well as to each other and possibly to other interneurons. GABAergic inhibition in the molecular layer has mainly been investigated at the interneuron to Purkinje cell synapse. In this study, we used complementary subtractive strategies to quantitatively assess the ratio of GABAergic synapses on Purkinje cell dendrites versus those on interneurons. We generated a mouse model in which the GABA_A receptor α1 subunit (GABA_ARα1) was selectively removed from Purkinje cells using the Cre/loxP system. Deletion of the α1 subunit resulted in a complete loss of GABA_AR aggregates from Purkinje cells, allowing us to determine the density of GABA_AR clusters in interneurons. In a complementary approach, we determined the density of GABA synapses impinging on Purkinje cells using α-dystroglycan as a specific marker of inhibitory postsynaptic sites. Combining these inverse approaches, we found that synapses received by interneurons represent approximately 40% of all GABAergic synapses in the molecular layer. Notably, this proportion was stable during postnatal development, indicating synchronized synaptogenesis. Based on the pure quantity of GABAergic synapses onto interneurons, we propose that mutual inhibition must play an important, yet largely neglected, computational role in the cerebellar cortex.     

Interrelated modification of excitatory and inhibitory synaptic connections in the olivary-cerebellar neuronal network

The model of simultaneous interrelated modification in the efficacy of synaptic inputs to different neurons of the olivary-cerebellar network is developed. The model is based on the following features of the network: simultaneous activation of the input layer (granule) cells and the output layer (deep cerebellar nuclei) cells by mossy fibers; simultaneous activation of Purkinje cells and cerebellar cells of the input and output layers by climbing fibers and their collaterals; the existence of local feedback excitatory, inhibitory, and disinhibitory circuits. The rise (decrease) of posttetanic Ca2+ concentration in reference to the level produced by previous stimulation causes the decrease (increase) in cGMP-dependent protein kinase G activity, and increase (decrease) inprotein phosphatase 1 activity. Subsequent dephosphorylation (phosphorylation) of ionotropic receptors results in simultaneous LTD (LTP) of the excitatory input together with the LTP (LTD) of the inhibitory input to the same neuron. The character of interrelated modifications of synapses at different cerebellar levels strongly depends on the olivary cell activity. In the presence (absence) of the signal from the inferior olive LTD (LTP) of the output cerebellar signal can be induced.     

Fine Structure of the Tunic of Ciona intestinalis L. II. Tunic morphology,cell distribution and their functional importance

Ciona intestinalis L. tunic architecture and cell distribution were investigated with the electron microscope. The observations showed that the ascidian covering is formed by a thin outer cuticle, a subcuticle of variable width and a large single layer of ground substance. “Large granule”, morula, phagocyte and granulocyte are the cellular types encountered; they appear mainly in highly vacuolated states and are distributed throughout the whole tunic. The “large granule” cells, however, are mainly seen in the cuticle layer and the morula cells appear mostly in the outer zone of the ground substance. The role of these cells in tunic construction, repair and regeneration as well as their scavenging function are discussed.     

Probabilistic secretion of quanta in the central nervous system: granule cell synaptic control of pattern separation and activity regulation.

The implications of probabilistic secretion of quanta for the functioning of neural networks in the central nervous system have been explored. A model of stochastic secretion at synapses in simple networks, consisting of large numbers of granule cells and a relatively small number of inhibitory interneurons, has been analysed. Such networks occur in the input to the cerebellum Purkinje cells as well as to hippocampal CA3 pyramidal cells and to pyramidal cells in the visual cortex. In this model the input axons terminate on granule cells as well as on an inhibitory interneuron that projects to the granule cells. Stochastic secretion at these synapses involves both temporal variability in secretion at single synapses in the network as well as spatial variability in the secretion at different synapses. The role of this stochastic variability in controlling the size of the granule cell output to a level independent of the size of the input and in separating overlapping inputs has been determined analytically as well as by simulation. The regulation of granule-cell output activity to a reasonably constant value for different size inputs does not occur in the absence of an inhibitory interneuron when both spatial and temporal stochastic variability occurs at the remaining synapses; it is still very poor in the presence of such an interneuron but in the absence of stochastic variability. However, quite good regulation is achieved when the inhibitory interneuron is present with spatial and temporal stochastic variability of secretion at synapses in the network. Excellent regulation is achieved if, in addition, allowance is made for the nonlinear behaviour of the input-output characteristics of inhibitory interneurons. The capacity of granule-cell networks to separate overlapping patterns of activity on their inputs is adequate, with spatial variability in the secretion at synapses, but is improved if there is also temporal variability in the stochastic secretion at individual synapses, although this is at the expense of reliability in the network. Other factors which improve pattern separation are control of the output to very low activity levels, and a restriction on the cumulative size of the excitatory input terminals of each granule cell. Application of the theory to the input neural networks of the cerebellum and the hippocampus shows the role of stochastic variability in quantal transmission in determining the capacity of these networks for pattern separation and activity regulation.     

Two Ca(2+)-dependent steps controlling synaptic vesicle fusion and replenishment at the cerebellar basket cell terminal

Cerebellar basket cells inhibit postsynaptic Purkinje cells in a rapid and precise manner. To investigate the mechanisms of transmitter release underlying this rapid inhibition, Ca(2+) uncaging was employed to measure the intracellular Ca(2+) dependence of transmitter release and the kinetics of synaptic vesicle pool transitions in immature basket cell synapses at room temperature. Vesicle release properties distinct from those previously observed at excitatory synapses were seen, including a relatively high intracellular Ca(2+) sensitivity of vesicle fusion, rapid vesicle pool mobilization with few reluctant vesicles, and vesicle replenishment driven by unusually high Ca(2+) levels from both local and residual Ca(2+) sources during action potential trains. These results suggest that inhibitory basket cell synapses are optimized for rapid and precise temporal and spatial Ca(2+) coordination of synaptic vesicle fusion and replenishment, which may contribute to the unique physiology of inhibitory synaptic transmission, including phasic release during action potential trains and tonic release by residual intracellular Ca(2+).     

外周输入依赖的嗅球颗粒细胞的突触结构可塑性

活动依赖的突触结构可塑性是学习和记忆的基础.哺乳动物,尤其是啮齿类动物,具有高度发达的嗅觉系统和惊人的气味学习和记忆能力.本研究以CNGA2敲除而导致外周输入缺失的小鼠为模型,研究嗅球内活动依赖的突触结构可塑性.利用特异性的突触前和突触后标记物,发现外周输入缺失减少了突触标记蛋白突触素(synaptophysin)和抑制性突触标记蛋白桥蛋白(gephyrin)在嗅球外网状层和颗粒细胞层中的表达;兴奋性突触标记蛋白囊泡谷氨酸转运蛋白1(VGluT1)的表达水平只在外网状层中有显著下降,而在颗粒细胞层中没有明显变化.进一步通过活体质粒电转标记嗅球颗粒细胞后发现,CNGA2敲除小鼠颗粒细胞上位于外网状层中的远端树突棘密度显著减小,而位于颗粒细胞层中的近端树突棘密度没有明显变化.这些结果表明颗粒细胞上的树-树突触具有对外周活动依赖的结构可塑性,而轴-树突触则无.     

SPECIALIZED MEMBRANE JUNCTIONS BETWEEN NEURONS IN THE VERTEBRATE CEREBELLAR CORTEX

"Gap" junctions, the morphological correlate for low-resistance junctions, are demonstrated between some mossy fiber terminals and granule cell dendrites in some lower vertebrate cerebella (gymnotid and frog). Most of the gap junctions (GJs) seen in the gymnotid-fish cerebellum exhibit an asymmetrical configuration, the electron-opaque cytoplasmic material underlying the junction being more extensive in the dendritic than in the axonal side. In the frog cerebellum, the GJs have a symmetrical distribution of such electron-opaque material. In both species the GJs are encountered at the same synaptic interface as the conventional synaptic zone (CSZ), constituting "mixed synapses" in a morphological sense. The axonal surface covered by CSZs is larger than that covered by GJs. In mammalian cerebellum, GJs are observed only in the molecular layer, between perikarya, dendrites, or perikarya and dendrites of the inhibitory interneurons. These GJs are intermixed with attachment plates and intermediary junctions interpreted as simply adhesive. In the mammalian cerebellum, a new type of junction which resembles the septate junctions (SJs) of invertebrate epithelia is observed between axonal branches forming the tip of the brush of basket fibers around the initial segment of the Purkinje cell axon. It is suggested that such junctions may be modified forms of septate junctions. The physiological implications of the possible existence of high-resistance cross-bridges between basket cell terminals, which may compartmentalize the extracellular space and thus regulate extracellular current flow, must be considered.     

Loss of synapses in the dentate gyrus of the senescent rat.

Synapses were counted in electron micrographs of the middle third of the molecular layer of the dentate gyrus of Fischer 344 rats, 3 months and 25 months of age. A 27% decrease in the number of synapses was found in senescent animals compared with young adults. This loss of synapses could not be correlated with changes in synaptic size. tissue volume or number of postsynaptic granule cells.     

Observation and Investigation of “Reverse Breakdown” in a Discharge Tube

A discharge operating in a 80-cm-long discharge tube with an inner diameter of 15 mm, filled with a 3 : 1 neon–argon mixture at a pressure of 1 Torr, was investigated experimentally. Square voltage pulses with a period of 1 s were supplied to one of the tube electrodes, the second electrode being ungrounded. The initial stage of breakdown—the primary breakdown between the high-voltage (active) electrode and the tube wall, accompanied by the propagation of the prebreakdown ionization wave—was the same as in the conventional scheme with a grounded low-voltage electrode. Since the discharge gap was not closed, the discharge was not ignited. An essentially new effect was observed after the end of the voltage pulse. After a certain time interval, voltage spikes of opposite polarity, the amplitude and shape of which were close to those observed during the primary breakdown, appeared in the voltage and current waveforms of the active electrode. Simultaneously, a radiation pulse from the region adjacent to the active electrode was observed and an ionization wave began to propagate toward the second electrode. This work is dedicated to investigating this effect (which was named “reverse breakdown”) and analyzing its mechanism. A conclusion is made on the similarity of this phenomenon to the processes occurring in atmospheric-pressure dielectric barrier discharges.     

Immunocytochemistry of glycine in small neurons of the granule cell areas of the guinea pig dorsal cochlear nucleus: a post-embedding ultrastructural study

The axon terminals of the acoustic nerve contact different part of the cochlear nucleus including granule cell areas. Little is known of the cell composition and neural circuits of granule cell areas present in the fusiform and upper polymorphic layers of the dorsal cochlear nucleus in the guinea pig. The present ultrastructural immunocytochemical study exploits the technique of post-embedding immunogold and silver intensification to reveal the characteristics of small neurons in granule cell areas. Few neurons (Golgi-stellate cells) use glycine as inhibitory neurotransmitter which is present in symmetric synaptic boutons with pleomorphic and flat vesicles. In contrast, most neurons (granule and unipolar brush cells) are not glycine-positive, and presumably not excitatory. Most of the large axons (mossy fibres) in granule areas are probably excitatory (glycine-negative and storing round synaptic vesicles) and contact unipolar brush cells forming large synapses or granule cell dendrites by small synapses. A few large glycinergic boutons (inhibitory) also contact unipolar brush cells. The excitatory circuit of mossy fibre-unipolar brush and granule cells may be inhibited by the glycinergic terminals from the few glycinergic cells (Golgi-stellate neurons) present within the granule cell areas. The latter are not contacted by large mossy-like glycine terminals.