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The understanding of parallel processing and of the mechanisms underlying neural networks in the brain is certainly one of the most challenging problems of contemporary science. During the last decades significant progress has been made by the combination of different techniques, which have elucidated properties at a cellular and molecular level. However, in order to make significant progress in this field, it is necessary to gather more direct experimental data on the parallel processing occurring in the nervous system. Indeed the nervous system overcomes the limitations of its elementary components by employing a massive degree of parallelism, through the extremely rich set of synaptic interconnections between neurons. This book gathers a selection of the contributions presented during the NATO ASI School "Neuronal Circuits and Networks" held at the Ettore Majorana Center in Erice, Sicily, from June 15 to 27, 1997. The purpose of the School was to present an overview of recent results on single cell properties, the dynamics of neuronal networks and modelling of the nervous system. The School and the present book propose an interdisciplinary approach of experimental and theoretical aspects of brain functions combining different techniques and methodologies.



Single Neuron Properties


Modal gating of sodium channels and possible physiological lmplications on hereditary myopathies

Three human genetic syndromes hyperkalemic periodic paralysis, paramyotonia congenita and potassium aggravated myotonia, have been associated in recent years with mutations of the gene SCN4A located in chromosome 17q (23.1 to 25.2) which encodes the α-subunit of the voltage-gated sodium channel of the adult skeletal muscle Barchi 1995; Cannon 1996; George 1995; Hoffman et al. 1995; Lehmann-Horn and Rüidel 1996). The 17 single-point mutations identified to date in SCN4A are spread over both cytoplasmic and extracellular regions of the polypeptide, some near the voltage sensors others near the putative inactivation domain, and do not show any obvious clustering pattern associated with distinctive clinical features. A leading pattern is missing also in the correlation of clinical syndromes and electrophysiological properties of thel0 mutations studied so far in situ (Cannon et al. 1991; Lerche et al. 1993) or in heterologous expression (Cannon and Strittmatter 1993; Hoffman et al. 1995; Ji et al. 1996; Mitrovic et al. 1995; Mitrovic et al. 1994; Mitrovic et al. 1993). The most obvious abnormalities (notably a slightly slower and incomplete inactivation) can account for muscle hyperexcitability and repetitive firing instead of normal action potentials (Cannon et al., 1993b), and are consistent with the realatively mild and episodic character of the disorders.
Oscar Moran, Mario Nizzari, Franco Conti

c-Fos Protein and NADPH-Diaphorase Detection in Rat Midbrain and Spinal Cord After Contusion Injury

Spinal cord injury appears to involve neuroplastic remodeling or cell death that is the result of intense neuronal cells response to lesion. The damage may occur near the site of lesion, as well as in proximal brain areas. Thus, neurons located in brain centers and functionally connected to the damaged areas may present constitutive changes after spinal cord damage. Experimental studies and clinical observations show that spinal cord trauma may be amplified by secondary neuronal damage. However, little is known about the molecular mechanism that initiates and maintains this neuronal reaction. We have started an investigation of neural changes induced by acute spinal cord injury. We assessed the degree of functional neurologic impairment that follows spinal cord injury by behavioral tests and histological methods. In lesioned areas and throughout the central nervous system expression of the transcription factor protein c-Fos was investigated by immunocytochemistry. The localization of c-Fos may indicate, in addition to neuronal activation spatial and temporal patterns related to the type of stimulus and to the long-term variation in neuronal physiology. In parallel to identify spinal neurons that synthesize Nitric Oxide cells and fibers histochemically stained for NADPH diaphorase (a nitric oxide synthase) were studied. Fos expression was detected in NADPH-diaphorase positive cells at intermedio lateral column central canal dorsal horn including nucleus trigeminalis caudalis two hours after contusion by weight drop. It was found that NADPH-diaphorase is induced in spinal motoneurons neurons that are normally NADPH-diaphorase negative; however no Fos protein expression was detected in these cells. The results suggest that central nervous system areas close or proximal to the lesion site are activated after contusion by weight drop. In addition they show that Fos protein expression and changes on NADPH-diaphorase activity after spinal cord contusion are not necessarily dependent on each other.
E. A. Del Bel, H. L. A. Defino

Fourier analysis applied to the study of the electrical activity of midbrain dopaminergic neurons

In this study, electrophysiological techniques and computational methods were used to investigate the effect of the selective serotonin reuptake inhibitors fluvoxamine paroxetine sertraline and citalopram on the basal activity of dopamine (DA) neurons in the ventral tegmental area. Acute injection of fluvoxamine paroxetine sertraline and citalopram (20-1280 µg/kg i.v) caused a dose-dependent inhibition of some ventral tegmental area DA neurons but it did not affect the basal firing rate of other DA cells. A Fast-Fourier-Transformation based analysis of the basal activity of 45 ventral tegmental area DA neurons showed a positive correlation between the value of a functional operator (Ψ) equivalent to the density-power­spectrum of the signals and the degree of selective serotonin reuptake inhibitors-induced inhibition of ventral tegmental area DA cells. All ventral tegmental area DA neurons sampled were subdivided into two subclasses: (A) neurons with no changes in their basal firing rate and (B) neurons showing an approximately linear inhibitory effect in response to selective serotonin reuptake inhibitors. The neurons belonging to the subclass A showed a more regular behavior of the interspike interval functions corresponding to lower values detected by the functional operator Ψ whereas the neurons belonging to the subclass B showed a less regular behavior of interspike interval functions corresponding to higher Ψ values detected by the same functional operator. SSRIs also caused a dose-dependent increase of the percentage of spikes occurring in bursts in neurons belonging to subclass A (low values of Ψ) whereas the mean basal firing rate of these cells was not affected. Moreover administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.25-80 µg/kg i.v) increased the firing rate of midbrain DA neurons with higher ‘P values. It is suggested that this difference in density-power-spectrum could reflect the asymmetry of serotonergic input to the ventral tegmental area DA neurons and the differential effects of selective serotonin reuptake inhibitors and of 8-OH-DPAT on these neurons might depend on the characteristics of their basal firing mode.
Michele Di Mascio, Giuseppe Di Giovanni, Ennio Esposito

Regulation by Intracellular Calcium of the Activity of GABAA Receptors in Two Different Types of Neurons

The levels of intracellular free calcium in nerve cells are critical for the activity of many enzymes and for several cell functions such as, for example exocytosis [2] and its regulation [7]. Free calcium levels are regulated by buffering systems compartmentation and extrusion from the cell. Calcium entry into nerve cells is also of importance in the regulation of gene expression. In particular in hippocampal cells it has been demonstrated that according to the route of calcium entry different genes are activated [1].
Aroldo Cupello, Holger Hydén, Maria V. Rapallino, Mauro Robello

Dynamics of Transmitter Release at CA3 Hippocampal Excitatory Synapses

Release of neurotransmitter is a stochastic process that can be studied by analysing whole cell postsynaptic currents evoked by repetitive activations of presynaptic fibres. In the case of the hippocampus, the stimulation of the Stratum Lucidum-Radiatum with a pipette filled with extracellular solution evokes excitatory postsynaptic currents (EPSCs) in CM3 pyramidal neurones. In the presence of GABAA receptors antagonists in experiments in which 4 pulses at 50 ms intervals are delivered several times synaptic responses show different behaviours (EPSC patterns). EPSC patterns can be classified in terms of potentiation or depression of the mean amplitudes of the second third and fourth EPSC with respect to the first one. EPSC patterns in which the second and the third EPSCs are potentiated with respect to the first one are characteristic of synapses with a low release probability. In these synapses the residual calcium increases the release probability. In contrast in synapses with a high initial release probability vesicle depletion generates patterns in which all EPSC are depressed. A stochastic model that takes into account both changes in release probability and modifications in the number of synaptic vesicles available for exocytosis can account for the different synaptic behaviours that can be generated. This approach is a generalisation of the quantal analysis theory that can be used to investigate different features of synaptic function and plasticity.
Marco Canepari, Enrico Cherubini

Responses of Isolated Olfactory Sensory Neurons to Odorants

The detection of odorant molecules begins in the nasal epithelium where olfactory sensory neurons interact with odorant stimuli from the external world and produce electrical signals that are transmitted to the brain. Olfactory sensory neurons are small bipolar neurons with several fine cilia. The binding of odorant molecules to odorant receptor proteins in the cilia triggers an enzymatic cascade that leads to the onset of an inward ionic current, depolarization of the membrane and generation of action potentials that are conducted along the neuron’s axon to the olfactory bulb, where further processing of odorant information occurs (for reviews see Refs. [1,11,14,15]).
Cristiana Picco, Paola Gavazzo, Stuart Firestein, Anna Menini

Neuronal Networks


Long-Term Changes (LTC) of Evoked Field Potentials in the Amygdala: A Model of Emotional Memory

The identification of the amygdala as an essential neural substrate for fear conditioning has permitted neurophysiological examinations of synaptic processes in the amygdala that may mediate fear conditioning. We examined synaptic plasticity in the thalamo­amygdala pathway known to mediate acoustic fear conditioning and the hippocampal-amygdala pathway, involved in contextual fear conditioning. Results indicate that theta burst high frequency stimulation can induce either LTP or LTD in both pathways. The mechanisms responsible for long-term changes (LTC) in the amygdala are to a great extent elusive and further work is planned to elucidate them.
Dan Yaniv, Gal Richter-Levin

Role of Nitric Oxide on Emotional and Motor Behaviour

Nitric Oxide (NO) has been proposed as a new neurotransmitter/neuromodulator in the Central Nervous System (CNS). Microinjections of inhibitors of NO synthase (NOS) the enzyme responsible for NO formation into the dorsal central grey induce anxiolytic effects in rats. On the other hand SIN-1 a NO donor microinjected into these regions induces flight reactions. However although systemic injections of low doses of NOS inhibitors induce anxiolytic effects in the elevated plus maze higher doses decrease maze exploration. This may involve motor effects of this compounds since we showed that they can induce catalepsy in a dose dependent manner in rodents either after systemic or Intra-striatal injections. These results suggest that NO may be related to the control of motor and emotional behaviour.
E. A. Del Bel, R. M. W. de Oliveira, F. S. Guimarães

Multi-Site Recording of Neural Activity using Planar Electrode Arrays

Since the first proposal for an Ion-Sensitive FET in 1970 [4] micro-fabrication technology has become one of the key-techniques for building sensor devices for biological measurements. With technical innovation in the field of electronic engineering sensors for neurophysiological recording have also been investigated extensively. The most promising advantage of this type of sensor is the capability for integrating multiple electrodes on a single device. This has allowed us to visualize spatially propagating activity at a fine time resolution.
Y. Jimbo, A. Kawana

Optical Insights Into Cerebellar Circuitry

It is commonly accepted that a deeper understanding of how neural networks function will depend on the ability to monitor brain activity with high temporal and spatial resolution. The need for such monitoring systems led in the early seventies to the development of optical imaging techniques using voltage-sensitive dyes (Ross et al. 1974). The technique is based on the detection of light emitted from special dye molecules that bind to membranes and fluoresce proportionally to the membrane potential. In its current state the method is particularly suitable for monitoring synchronized activity in large neuron populations as demonstrated here in the cerebellar cortex.
Dana Cohen, Yosef Yarom

Activity-dependent regulation of neuronal network excitability

Electric activity plays a major role in the fine-tuning of neuronal connections during development. Since alterations in connectivity will in turn affect network activity it is clear that neuronal network formation is the result of reciprocal interactions between the activity and the structure of the network. To investigate the role of electric activity in neuronal network development we use primary cultures of dissociated fetal rat cerebral cortex. Following prolonged suppression of spontaneous electric activity in culture neuronal firing showed a strong increase in stereotyped burst firing at the expense of variable non-burst firing. This mode of firing could be mimicked by blocking GABAergic inhibition indicating that chronic suppression of electric activity induced a shift in the balance between excitation and inhibition resulting in overexcitation. Chronic silencing induced a disproportionate decrease in GABA content while the release of glutamate and aspartate was facilitated in early cultures. As a result the ratio of stimulated release of excitatory versus inhibitory neurotransmitter was increased in line with our hypothesis. Conversely prolonged depolarization increased GABAergic staining intensity without affecting the density of GABAergic neurons. These data suggest that during brain development compensatory mechanisms may operate which serve to keep the level and/or pattern of electric activity within physiological limits. We propose a negative feed-back loop whereby electric activity stimulates the synthesis and release of BDNF which through trkB receptors on GABAergic neurons stimulates GABAergic network activity restraining overall network activity.
G. J. A. Ramakers, F. Kloosterman, P. van Hulten, J. van Pelt, M. A. Corner

Spatial and Temporal Regulation of BDNF Action in Synaptic Plasticity

Molecules involved in synaptic plasticity need to be targeted to the appropriate subcellular domains and to be expressed at the right time during modulation of the synaptic activity. We show that the mRNAs for BDNF and TrkB have a dendritic localisation in cultured hippocampal neurons. Exposure of cells to high potassium for different times, differentially increases both the dendritic extension of BDNF and TrkB mRNAs and their protein levels in the distal portion of dendrites. The activity dependent modulation of mRNA targeting and protein accumulation in the dendrites may provide a mechanism for achieving local regulation of the activity of neurotrophins and their receptors with a time course compatible with their involvement in synaptic potentiation. Further, we put the hypothesis forward that the enhanced mRNA dendritic content for BDNF and TrkB might be involved in the synaptic tagging of a subset of dendritic branches.
Enrico Tongiorgi, Massimo Righi, Mauro Benedetti, Antonino Cattaneo

Map projection rewiring in the adult cerebellum after lesions

Functional recovery following a lesion in the brain depends on the ability of the injured neurones to regrow their axons up to the target and to restore the original projection map. In this review we show that these two important processes occur in the rat olivocerebellar pathway both during the developmental stage and in the mature brain. Axotomised olivocerebellar neurones regenerated t into a graft of freshly dissociated Schwann cells and some of them reached previously deafferented Purkinje cells. To study the specificity of the newly formed connections we have adopted three experimental protocols aimed at seeing the specificity of reinnervation into sagittally oriented Purkinje cell bands identified by zebrin II antibodies. First, during postnatal development, following unilateral pedunculotomy, fibres from the uninjured pathway cross the cerebellar midline to reinnervate symmetrical Purkinje cell bands. Second, by grafting embryonic Purkinje cells in the mature cerebellum, olivocerebellar fibres reached the specific neurochemically defined Purkinje cell compartments into the graft. Third, in the mature cerebellum, following a subtotal inferior olive lesion, collateral sprouting of the surviving climbing fibres was confined into the proper cortical compartment. These results show that olivocerebellar fibres have a strong intrinsic capability to regrow their axons and that this growth is not randomly oriented, but it is regulated by selective interactions between distinct subsets of inferior olive axons and target neurones.
P. Strata, M. Zagrebelsky, M. Bravin, F. Rossi

Models and Theoretical Approaches


Regulatory effects of long term biochemical processes in integrate-and-fire model neurons

The understanding of the dynamics of networks of biological neurons, by means of mathematical descriptions, computer simulations (20) and artificial emulations of their electrophysiological properties (7, 8, 15, 16), is a central issue in computational neuroscience research. Many models have been proposed and a broad class of them shares the same qualitative features (1, 5).
Marco Bove, Michele Giugliano, Massimo Grattarola

A Formal Approach to the Translation of Cortical Maps

We introduce a formal method and its mathematical description for the translation of cortical maps. This method is based on three new classifications for cortical areas and projections between them and can easily be converted into algorithms for connectivity databases. As this approach works on logical, non-metric relations between parcellation schemes, in a minority of cases the translation leads to ambiguous results. However, we present several methods by which possible ambiguity can be minimized. Generally, this approach provides a framework for the translation of connectivity data in an objective and reproducible way and thus helps to overcome methodological difficulties of previous neuroanatomical databases.
Klaas E. Stephan, Rolf Kötter

From Self-Organized Fluid Machines to Living Liquid Crystals

The self-organization of amoeboid cells is discussed. The ordered state of amoeboid cells is produced out of a uniform state by an instability of the intracellular signal chain. The temporal pattern makes the the machine cycle while the spatial pattern produces the spatial spread machine: (i) an inactivated cellular state is predicted for low pumping; (ii) an isotropic mode for higher pumping (cell adhesion but no migration); (iii) a polar mode for even higher pumping (adhesion and directed migration); (iv) a bipolar activated cellular mode for even higher pumping (cell elongation and orientation); The machine characteristics of the different activated modes are discussed. An automatic controller (= controller with feedback) is responsible for the angle of migration and for angle of orientation. Migrating and interacting cells can form condensed states: A polar nematic liquid crystal is found for cells in the polar mode and an apolar nematic liquid crystal for cells in the bipolar mode.
Hans Gruler

The Metric Content of Spatial Views as Represented in the Primate Hippocampus

Coexisting memory representations of the same information may differ in the amount of structure they embody, i.e. in the metric of relationships among individual memory items. Such an amount of structure may be quantified by the metric content index. We extract the metric content of the representation of spatial views in the monkey hippocampus and parahippocampal cortical areas, and find indications of quantitative differences that might be associated with the connectivity pattern in different neural substrates.
Alessandro Treves, Pierre Georges-Francois, Stefano Panzeri, Robert G Robertson, Edmund T Rolls


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