Hebbian mechanisms help explain development of multisensory integration in the superior colliculus: a neural network model.

The superior colliculus (SC) integrates relevant sensory information (visual, auditory, somatosensory) from several cortical and subcortical structures, to program orientation responses to external events. However, this capacity is not present at birth, and it is acquired only through interactions with cross-modal events during maturation. Mathematical models provide a quantitative framework, valuable in helping to clarify the specific neural mechanisms underlying the maturation of the multisensory integration in the SC. We extended a neural network model of the adult SC (Cuppini et al., Front Integr Neurosci 4:1-15, 2010) to describe the development of this phenomenon starting from an immature state, based on known or suspected anatomy and physiology, in which: (1) AES afferents are present but weak, (2) Responses are driven from non-AES afferents, and (3) The visual inputs have a marginal spatial tuning. Sensory experience was modeled by repeatedly presenting modality-specific and cross-modal stimuli. Synapses in the network were modified by simple Hebbian learning rules. As a consequence of this exposure, (1) Receptive fields shrink and come into spatial register, and (2) SC neurons gained the adult characteristic integrative properties: enhancement, depression, and inverse effectiveness. Importantly, the unique architecture of the model guided the development so that integration became dependent on the relationship between the cortical input and the SC. Manipulations of the statistics of the experience during the development changed the integrative profiles of the neurons, and results matched well with the results of physiological studies.

A semantic model to study neural organization of language in bilingualism.

A neural network model of object semantic representation is used to simulate learning of new words from a foreign language. The network consists of feature areas, devoted to description of object properties, and a lexical area, devoted to words representation. Neurons in the feature areas are implemented as Wilson-Cowan oscillators, to allow segmentation of different simultaneous objects via gamma-band synchronization. Excitatory synapses among neurons in the feature and lexical areas are learned, during a training phase, via a Hebbian rule. In this work, we first assume that some words in the first language (L1) and the corresponding object representations are initially learned during a preliminary training phase. Subsequently, second-language (L2) words are learned by simultaneously presenting the new word together with the L1 one. A competitive mechanism between the two words is also implemented by the use of inhibitory interneurons. Simulations show that, after a weak training, the L2 word allows retrieval of the object properties but requires engagement of the first language. Conversely, after a prolonged training, the L2 word becomes able to retrieve object per se. In this case, a conflict between words can occur, requiring a higher-level decision mechanism.

A neural network model of semantic memory linking feature-based object representation and words.

Recent theories in cognitive neuroscience suggest that semantic memory is a distributed process, which involves many cortical areas and is based on a multimodal representation of objects. The aim of this work is to extend a previous model of object representation to realize a semantic memory, in which sensory-motor representations of objects are linked with words. The model assumes that each object is described as a collection of features, coded in different cortical areas via a topological organization. Features in different objects are segmented via gamma-band synchronization of neural oscillators. The feature areas are further connected with a lexical area, devoted to the representation of words. Synapses among the feature areas, and among the lexical area and the feature areas are trained via a time-dependent Hebbian rule, during a period in which individual objects are presented together with the corresponding words. Simulation results demonstrate that, during the retrieval phase, the network can deal with the simultaneous presence of objects (from sensory-motor inputs) and words (from acoustic inputs), can correctly associate objects with words and segment objects even in the presence of incomplete information. Moreover, the network can realize some semantic links among words representing objects with shared features. These results support the idea that semantic memory can be described as an integrated process, whose content is retrieved by the co-activation of different multimodal regions. In perspective, extended versions of this model may be used to test conceptual theories, and to provide a quantitative assessment of existing data (for instance concerning patients with neural deficits).

Object segmentation and reconstruction via an oscillatory neural network: interaction among learning, memory, topological organization and gamma-band synchronization.

Synchronization of neuronal activity in the gamma-band has been shown to play an important role in higher cognitive functions, by grouping together the necessary information in different cortical areas to achieve a coherent perception. In the present work, we used a neural network of Wilson-Cowan oscillators to analyze the problem of binding and segmentation of high-level objects. Binding is achieved by implementing in the network the similarity and prior knowledge Gestalt rules. Similarity law is realized via topological maps within the network. Prior knowledge originates by means of a Hebbian rule of synaptic change; objects are memorized in the network with different strengths. Segmentation is realized via a global inhibitor which allows desynchronisation among multiple objects avoiding interference. Simulation results performed with a 40x40 neural grid, using three simultaneous input objects, show that the network is able to recognize and segment objects in several different conditions (different degrees of incompleteness or distortion of input patterns), exhibiting the higher reconstruction performances the higher the strength of object memory. The presented model represents an integrated approach for investigating the relationships among learning, memory, topological organization and gamma-band synchronization.

Spatial learning affects immature granule cell survival in adult rat dentate gyrus.

Neurogenesis occurs throughout life in mammalian dentate gyrus. The effect of learning on newborn cell survival was studied in rat. Rats were trained on a hippocampus-dependent spatial learning task by using Morris water maze. Neurogenesis was evaluated by 5-bromo-2'deoxyuridine administered before learning. Several newborn cells expressed the immature neuron marker TOAD-64. The main findings were as follows: (1) the survival of newborn cells was enhanced by learning at early stage of differentiation; (2) the newborn cells saved by learning were mainly located in the rostral part of external blade of granule cell layer and (3) there was a correlation between the actual individual learning and newborn cell survival.

Neurogenesis in the adult rat dentate gyrus is enhanced by vitamin E deficiency.

Neurogenesis occurs throughout adult life in rat dentate gyrus. Factors and mechanisms of adult neurogenesis regulation are not well known. Vitamin E deficiency has been found to deliver a neurogenetic potential in rat dorsal root ganglia. To determine whether the role of tocopherols in adult neurogenesis may be generalized to the central nervous system, changes in adult rat dentate gyrus neurogenesis were investigated in vitamin E deficiency. Neurogenesis was quantitatively studied by determination of the density of 5-bromo-2'-deoxyuridine (BrdU)-labeled cells and by determination of the total number of cells in the granule cell layer. The BrdU-labeled cells were immunocytochemically characterized by demonstration of neuronal marker calbindin D28K. The following results were found: (1) the volume of the granule layer increased in controls from 1 to 5 months of age, mainly due to cell density decrease; (2) the volume increased by a similar amount in vitamin E-deficient rats, mainly because of an increase in cell number; (3) BrdU-positive cells were more numerous in vitamin E-deficient rats in comparison to age-matched controls; (4) the increase in proliferated cells was located in the hilus and in the plexiform layer. This study confirms that neurogenesis occurs within adult dentate gyrus and demonstrates that this process is enhanced in vitamin E deficiency. This finding indicates that vitamin E may be an exogenous factor regulating adult neurogenesis.

Glucose-6-phosphate dehydrogenase and glutathione reductase support antioxidant enzymes in nerves and muscles of rats during nerve regeneration.

The effects of the rat sciatic nerve crush on the activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT) were examined in regenerating nerve and in two reinnervating muscles: the slow twitch soleus and the fast twitch extensor digitorum longus (edl). The enzyme activities in the crushed side, were compared with the contralateral homologue tissues and basal values, determined in uncrushed animals. In the crushed side, the activity of G6PD, GR, GPX and CAT of the sciatic nerve and both muscles markedly increased in comparison with the uncrushed side. In the nerve and in both muscles, SOD activity decreased at 13 days, then rose to values higher than normal, but the pattern of the crushed side was not significantly different from that of the uncrushed. In the uncrushed side, we observed a significant increase of nerve G6PD, GPX and CAT activities compared to basal values, while in both muscles, values fluctuated around the normal without any significant variation. The mechanism of these enzymatic changes is unknown, however our work suggests that: (i) during nerve regeneration, an oxidative stress occurs in nerve and muscle, which causes adaptive responses in antioxidant enzymes; (ii) the maximum antioxidant power is expressed during the period of synaptic retraction; (iii) G6PD and GR activities are synergistically modulated with GPX and CAT, while SOD activity appears independently regulated.

Motor nerve sprouting induction by a nerve explant in normal and vitamin E-deficient rats.

Sprouting induction by a peripheral degenerating nerve has been evaluated in normal and vitamin E-deficient rats. A piece of sural nerve was grafted close to the peroneal nerve of the same animal: at one and two months after grafting thin unmyelinated axons were visible in the graft and they were sometimes functionally active; when nerve explant was frozen before grafting, sprouting induction did not take place either in controls or in vitamin E-deficient animals. No difference was noted in sprouting induction between the two groups, while degeneration showed a different time course. Some hypotheses of possible stimuli of sprouting induction are discussed.

[Muscle reinnervation in rats treated with vitamin E]. / La reinnervazione del muscolo nel ratto trattato con vitamina E.

During muscle reinnervation, a transitory phase of polyinnervation occurs. In reinnervated muscles of vitamin E deficient rats, sprouting and polyinnervation are increased with respect to reinnervated controls. In this work, polyinnervation was observed in reinnervated extensor digitorum longus (edl) muscle of rats treated with pharmacological doses of vitamin E. Sciatic nerve was crushed and edl muscle was examined electrophysiologically at 30, 40 and 60 days after denervation. The percentage of polyinnervated cells in controls peaked at 30 days and thus it decreased. In muscles of vitamin E treated rats, the time course of percentage of polyinnervated muscle cells was qualitatively the same, but it was decreased at all times.

Glucose-6-phosphate dehydrogenase activity in dorsal root ganglia of vitamin E-deficient rats.

The effect of dietary vitamin E on the activity of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) was studied in the dorsal root ganglia of rat. One-month-old male Sprague-Dawley rats were randomly assigned to two dietary treatment groups for 2 months. The first received a standard diet supplemented with vitamin E, the second was fed a basal vitamin E-deficient diet. The activity of G6PD was markedly decreased in ganglia of the deficient animals with respect to the controls. On the other hand, the activity of the 6PGD was not significantly altered in the deficient animals. In the red cells the two enzyme activities presented a similar situation and the level of the reduced glutathione in the red cells was not significantly altered by the status of dietary vitamin E. Kinetic analysis with crude extracts of ganglia or partially purified G6PD demonstrated that there was no direct modulatory effect of the vitamin on the enzyme activity. Moreover, nondenaturing gel electrophoresis performed in this study revealed that none of the three G6PD activity bands which appeared on the acrylamide gel were significantly altered in the deficient animals. At present, the mechanism linking the G6PD activity with the status of dietary vitamin E remains unknown. Our results suggest, however, that a reduced NADPH generation produced by a decay of G6PD activity may limit the glutathione peroxidase, a very active enzyme in detoxifying peroxides, and may predispose the nervous tissue to oxidant injury.

Time course of sprouting during muscle reinnervation in vitamin E-deficient rats.

A typical aspect of motoneuron plasticity is the sprouting which occurs during muscle reinnervation, resulting in a transitory multiple innervation of the muscle cells. In order to verify the effect of a decreased protection from free radical attack on the sprouting, the multiple innervation in the extensor digitorum longus muscle, following sciatic nerve crush and regeneration, was studied in vitamin E-deficient rats. Thus, the innervated end-plates and the end-plates with multiple innervation were studied with histochemical and electrophysiological techniques. The percentage of innervated end-plates was similar in both groups at 30 as well as at 60 days after nerve crush. Nevertheless, multiple innervation was found in a larger part of the muscle and it lasted longer in the deficient rats. This finding is discussed in relation to some of the major hypotheses of sprouting; it may be relevant in the treatment of some lesions of peripheral nerve.

Maturation of the spontaneous transmitter release by regenerated nerve endings in vitamin E-deficient rats.

In order to verify the importance of the protection against lipid peroxidation in presynaptic differentiation and maturation, the reappearance and maturation of the spontaneous transmitter release during the extensor digitorum longus muscle reinnervation following a lesion of the sciatic nerve were studied in normal and vitamin E-deficient rats. The study was carried out by intracellular recordings in order to observe the miniature end plate potentials in the reinnervated end plates. In control and vitamin E-deficient rats the first signs of muscle innervation reappeared simultaneously, but in the latter the spontaneous transmitter release mechanism matured more slowly; furthermore, in the long-term, very low mepp frequencies continued to occur. The data suggest a slowing of the transmitter release mechanism maturation and a protracted rearrangement of innervation in the deficient rats.

Effect of ethanol on the spontaneous transmitter release by nerve endings in the process of maturation.

Ethanol stimulates the spontaneous transmitter release from motor nerve endings, as shown by the increase of miniature end plate potential (m.e.p.p.) frequency at the neuro-muscular junction. The stimulation of acetylcholine spontaneous quantal release by ethanol is greater in regenerating than in mature nerve endings. The different effects of ethanol on regenerating nerve endings may be related to changes of chemical-physical membrane properties.