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PubMed2006

Learning and memory: traditional and systems approaches.

The aims of the present work were to consider the characteristics of learning and memory from the point of view of a systems approach and to compare this view with the traditional approach. Neuron activity is regarded not as a response to the synaptic influx resulting in excitation but as a means of altering the cell's relationship with its environment, whose "action" is to eliminate discordance between the cell's "needs" and its microenvironment. The neuronal mechanisms of learning and consolidation of memory are regarded not as formation of a stable increase in the efficiency of synaptic transmission in circuits of connected neurons, but as a system genesis event which confers new system specializations on neurons which do not have to be directly connected synaptically. The roles of the processes of selection, reconsolidatory modification of previously formed memories, gene activation, neurogenesis, and apoptosis in systems genesis occurring both in normal and pathological conditions are discussed. Individual development is regarded as a sequence of system genesis events. The systems approach is applied to the phenomenon of long-term potentiation. In conclusion, a scheme including different types and stages of memory formation is presented.

Animals↗
PubMed1995

Activity-dependent remodeling of connections in the mammalian visual system.

The development of precise connections in the mammalian central nervous system requires neural activity. Synchronous patterns of afferent activity, and coincident afferent and target activity are required for specifying the neuronal connectivity that characterizes the adult visual pathway in mammals. During development, postsynaptic target neurons communicate with presynaptic afferents. Recent evidence suggests that the mechanisms that underlie activity-dependent development of connections in the visual system may share significant similarities with the mechanisms responsible for synaptic plasticity in the adult brain.

Afferent Pathways↗
PubMed2005

Endogenous brain-derived neurotrophic factor protects dopaminergic nigral neurons against transneuronal degeneration induced by striatal excitotoxic injury.

Injury to the central nervous system causes atrophy or death of connecting neurons and can modify the expression of neurotrophic factors. We observed transneuronal upregulation of brain-derived neurotrophic factor (BDNF) expression in the rat ipsilateral substantia nigra pars compacta after a striatal lesion induced by kainate. This effect is developmentally regulated because the enhancement of nigral BDNF expression was only observed when striatal lesion was performed on postnatal day (P) 15 and in adulthood, but not at P7. Interestingly, the lack of regulation of BDNF was coincident with the transynaptic degeneration of nigral neurons after striatal excitotoxic injury. Hence, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta decreased when the lesion was performed at P7, but not at P15 or at P30. The analysis of the functional significance of this BDNF upregulation was done using trkB-IgG fusion proteins. After striatal injury, blockade of endogenous BDNF by trkB fusion proteins induced an atrophy of the dopaminergic neurons of the pars compacta. The injection of trkB-IgG fusion proteins did not modify the effects of kainate in the substantia nigra pars reticulata. Thus, our results show that BDNF exerts an autocrine/paracrine protective effect selectively on dopaminergic neurons against the loss of trophic support from the target striatum.

Age Factors↗
PubMed2003

Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline.

Neuronal connectivity is established by the axo-dendritic polarity, correct guidance and targeting of neurons. Unlike for axons, the mechanisms responsible for directed outgrowth of dendrites are not well understood. Using single-cell labeling, we describe specific guidance defects in dendrites of identified neurons in frazzled, robo, netrin and commissureless mutant embryos of Drosophila melanogaster. We found that the cell-surface molecules Frazzled and Robo work as guidance molecules not only for axons but also for dendrites as they navigate within the CNS. Furthermore, we report that each neuron showed a cell-autonomous and independent use of guidance molecules.

Animals↗
PubMed2000

Caspase requirement for neuronal apoptosis and neurodegeneration.

The execution of the apoptotic programme involves a relatively few pathways that converge on activation of the caspase family of proteases. However, increasing evidence indicates that apoptotic-like features can be found also when cells are treated with inhibitors of caspases. This has posed questions as to whether death with apoptotic features can still occur in a caspase-independent way, and whether caspase inhibitors may then be used to prevent excess apoptosis in disease. Metabolic defects, loss of neuronal connectivity and cell loss characterise several neurodegenerative diseases. Targeting excessive cell demise may be one therapeutic strategy. However, loss of connectivity and neurite regression may not be part of the apoptotic programme, and degenerating neurons might use multiple execution pathways. In addition, metabolic defects leading to ATP depletion can preclude caspase activation and consequently switch execution of cell death towards necrosis. The possibility of inhibiting apoptosis as strategy to treat neurodegenerative disease is discussed in this review.

Animals↗
PubMed2003

Role of the corpus callosum in functional connectivity.

BACKGROUND AND PURPOSE: Regional cerebral blood flow fluctuates synchronously in corresponding brain regions between the hemispheres. This synchrony implies neuronal connections between brain regions. The synchrony of blood flow changes is defined operationally as functional connectivity. Our purpose was to measure functional connectivity in patients with corpus callosal agenesis, in whom the interhemispheric connectivity is hypothetically diminished. METHODS: In three patients with agenesis of the corpus callosum, functional MR imaging was performed while patients performed text-listening and finger-tapping tasks. Functional images were also acquired while the patients performed no specific task (resting state). Regions of activation temporally correlated with the performance of the tasks were identified by cross-correlating the task data with a reference function. Voxel clusters (seed voxels) that corresponded to regions of activation in the task-activation data set were selected in the resting data set. All the voxels in the resting 3D data set that had a correlation coefficient exceeding 0.4 were identified. The number of these voxels in the ipsilateral and contralateral hemispheres was tabulated. RESULTS: In all patients, technically adequate functional MR and functional connectivity MR maps were obtained. For both tasks, activation was found in both hemispheres. For all of the seed voxels, significantly more functionally connected voxels were found in the ipsilateral hemisphere than in the contralateral hemisphere. For most seed voxels, no functionally connected voxels were found in the contralateral hemisphere. CONCLUSION: Interhemispheric functional connectivity in the motor and auditory cortices is diminished in patients with agenesis of the corpus callosum compared with that of healthy subjects.

Adult↗
PubMed1998

The variable discharge of cortical neurons: implications for connectivity, computation, and information coding.

Cortical neurons exhibit tremendous variability in the number and temporal distribution of spikes in their discharge patterns. Furthermore, this variability appears to be conserved over large regions of the cerebral cortex, suggesting that it is neither reduced nor expanded from stage to stage within a processing pathway. To investigate the principles underlying such statistical homogeneity, we have analyzed a model of synaptic integration incorporating a highly simplified integrate and fire mechanism with decay. We analyzed a "high-input regime" in which neurons receive hundreds of excitatory synaptic inputs during each interspike interval. To produce a graded response in this regime, the neuron must balance excitation with inhibition. We find that a simple integrate and fire mechanism with balanced excitation and inhibition produces a highly variable interspike interval, consistent with experimental data. Detailed information about the temporal pattern of synaptic inputs cannot be recovered from the pattern of output spikes, and we infer that cortical neurons are unlikely to transmit information in the temporal pattern of spike discharge. Rather, we suggest that quantities are represented as rate codes in ensembles of 50-100 neurons. These column-like ensembles tolerate large fractions of common synaptic input and yet covary only weakly in their spike discharge. We find that an ensemble of 100 neurons provides a reliable estimate of rate in just one interspike interval (10-50 msec). Finally, we derived an expression for the variance of the neural spike count that leads to a stable propagation of signal and noise in networks of neurons-that is, conditions that do not impose an accumulation or diminution of noise. The solution implies that single neurons perform simple algebra resembling averaging, and that more sophisticated computations arise by virtue of the anatomical convergence of novel combinations of inputs to the cortical column from external sources.

Action Potentials↗
PubMed2006

Long-term neuroretinal full-thickness transplants in a large animal model of severe retinitis pigmentosa.

BACKGROUND: The purpose of this study was to explore neuroretinal transplantation in a large animal model of severe retinitis pigmentosa and to establish graft development, long-term survival, graft-host integration, and effects on the host retina. METHODS: Rhodopsin transgenic pigs, aged 6 months, received in one eye a fetal full-thickness neuroretinal sheet in the subretinal space by means of vitrectomy and retinotomy. Six months postoperatively, eyes were studied in the light microscope and with immunohistochemical markers. Full-field electroretinography (ERG) was performed at 4 and 6 months. RESULTS: Laminated grafts with well-organized photoreceptors, rod bipolar cells, and Müller cells were found in five of six eyes. Neuronal connections between graft and host retina were not seen. In the five eyes containing a graft, the number of surviving rods in the host retina was significantly higher compared with unoperated eyes. The ERG did not reveal any significant difference in b-wave amplitude between operated and control eyes, but the cone-derived response in operated eyes increased significantly from 4 to 6 months while the rod response in control eyes decreased significantly. CONCLUSIONS: Fetal full-thickness neuroretina can be transplanted safely to an eye with severe retinal degeneration. In their major part, the transplants develop a normal laminated morphology and survive for at least 6 months. Graft and host retinal neurons do not form connections. Retinal function in the host is reduced initially by the surgical trauma, but the presence of a well-laminated graft counteracts this effect and rescues rods from degeneration.

Animals↗
PubMed1984

Monosynaptic inhibition of phrenic motoneurons: a long descending projection from Bötzinger neurons.

Synaptic connections between medullary expiratory neurons and phrenic motoneurons were studied in anesthetized cats using spike-triggered averaging of synaptic noise in phrenic motoneurons. Monosynaptic inhibition of phrenic motoneurons originating from the rostral medullary expiratory neurons of the Bötzinger complex was revealed. Neither mono- nor disynaptic inhibition from expiratory neurons of the nucleus retroambigualis was found. It was concluded that Bötzinger complex expiratory neurons make long descending inhibitory connections with phrenic motoneurons: the expiratory neurons of the nucleus retroambigualis do not appear to make synaptic connections with phrenic motoneurons.

Animals↗
PubMed2006

Saccade-related spread of activity across superior colliculus may arise from asymmetry of internal connections.

The superior colliculus (SC) receives a retinotopic projection of the contralateral visual field in which the representation of the central field is expanded with respect to the peripheral field. The visual projection forms a nonlinear, approximately logarithmic, map on the SC. Models of the SC commonly assume that the function defining the strength of neuronal connections within this map (the kernel) depends only on the distance between two neurons, and is thus isotropic and homogeneous. However, if the connection strength is based on the distance between two stimuli in sensory space, the kernel will be asymmetric because of the nonlinear projection onto the brain map. We show, using a model of the SC, that one consequence of these asymmetric intrinsic connections is that activity initiated at one point spreads across the map. We compare this simulated spread with the spread observed experimentally around the time of saccadic eye movements with respect to direction of spread, differing effects of local and global inhibition, and the consequences of localized inactivation on the SC map. Early studies suggested that the SC spread was caused by feedback of eye displacement during a saccade, but subsequent studies were inconsistent with this feedback hypothesis. In our new model, the spread is autonomous, resulting from intrinsic connections within the SC, and thus does not depend on eye movement feedback. Other sensory maps in the brain (e.g., visual cortex) are also nonlinear and our analysis suggests that the consequences of asymmetric connections in those areas should be considered.

Algorithms↗
PubMed1997

Mutation in the phosphorylation sites of MAP kinase blocks learning-related internalization of apCAM in Aplysia sensory neurons.

The synaptic growth that accompanies 5-HT-induced long-term facilitation of the sensory to motor neuron connection in Aplysia is associated with the internalization of apCAM at the surface membrane of the sensory neuron. We have now used epitope tags to examine the fate of each of the two apCAM isoforms (membrane bound and GPI-linked) and find that only the transmembrane form is internalized. This internalization can be blocked by overexpression of transmembrane constructs with a single point mutation in the two MAPK consensus sites, as well as by injection of a specific MAPK antagonist into sensory neurons. These data suggest MAPK phosphorylation at the membrane is important for the internalization of apCAMs and, thus, may represent an early regulatory step in the growth of new synaptic connections that accompanies long-term facilitation.

Animals↗
PubMed1995

Anatomy of neurons crossing the tritocerebral commissures of the cockroach Periplaneta americana (Blattaria).

The neuronal connections of the tritocerebral commissures of Periplaneta americana were studied in the brain-suboesophageal ganglion complex and the stomatogastric nervous system by means of heavy metal iontophoresis through cut nerve ends followed by silver intensification. The tritocerebral commissure 1 (Tc1) contains mainly the processes of the subpharyngeal nerve (Spn) whose neurons are located in both tritocerebral lobes and in the frontal ganglion. Some neurons of the frontal ganglion project through the Tc1 to the contralateral tritocerebrum. A few fibers in this commissure were observed projecting to the protocerebrum and the suboesophageal ganglion. There are tritocerebral neurons which pass through the Tc1 or the tritocerebral commissure 2 (Tc2) and extend on into the stomatogastric nervous system. One axon of a descending giant neuron appears in the Tc2. This neuron lies in the tritocerebrum and connects the brain to the contralateral side of the ventral nerve cord. In addition, sensory fibers of the labral nerve (Ln) traverse both commissures to the opposite tritocerebrum. The anatomical and physiological relevance of the identified neuronal pathways is discussed.

Animals↗
PubMed2003

Herpes simplex virus type 1 glycoprotein B sorting in hippocampal neurons.

Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that spreads in the nervous system in functionally connected neurons. Determining how HSV-1 components are sorted in neurons is critical to elucidate the mechanisms of virus neuroinvasion. By using recombinant viruses expressing glycoprotein B (gB) tagged with green fluorescent protein (GFP), the subcellular localization of this envelope protein was visualized in infected hippocampal neurons in culture. Results obtained using a fully infectious recombinant virus containing GFP inserted into the ectodomain of gB support the view that capsids and gB are transported separately in neuron processes. Moreover, they show that during infection gB is sorted to the dendritic tree and the axons of polarized hippocampal neurons. However, GFP insertion into the cytoplasmic tail of gB impaired the maturation of the resulting fusion protein and caused its retention in the endoplasmic reticulum. The defective protein did not gain access to axons of infected neurons. These results suggest that the cytoplasmic tail of gB plays a role in maturation and transport and subsequently in axonal sorting in differentiated hippocampal neurons.

Animals↗
PubMed2003

Asynchronous states and the emergence of synchrony in large networks of interacting excitatory and inhibitory neurons.

We investigate theoretically the conditions for the emergence of synchronous activity in large networks, consisting of two populations of extensively connected neurons, one excitatory and one inhibitory. The neurons are modeled with quadratic integrate-and-fire dynamics, which provide a very good approximation for the subthreshold behavior of a large class of neurons. In addition to their synaptic recurrent inputs, the neurons receive a tonic external input that varies from neuron to neuron. Because of its relative simplicity, this model can be studied analytically. We investigate the stability of the asynchronous state (AS) of the network with given average firing rates of the two populations. First, we show that the AS can remain stable even if the synaptic couplings are strong. Then we investigate the conditions under which this state can be destabilized. We show that this can happen in four generic ways. The first is a saddle-node bifurcation, which leads to another state with different average firing rates. This bifurcation, which occurs for strong enough recurrent excitation, does not correspond to the emergence of synchrony. In contrast, in the three other instability mechanisms, Hopf bifurcations, which correspond to the emergence of oscillatory synchronous activity, occur. We show that these mechanisms can be differentiated by the firing patterns they generate and their dependence on the mutual interactions of the inhibitory neurons and cross talk between the two populations. We also show that besides these codimension 1 bifurcations, the system can display several codimension 2 bifurcations: Takens-Bogdanov, Gavrielov-Guckenheimer, and double Hopf bifurcations.

Excitatory Postsynaptic Potentials↗
PubMed1978

[Distribution of association fibers impinging upon the middle suprasylvian sulcus area (MSs area) in the cat (author's transl)].

Following lesions of various cortical areas of altogether 13 adult cats, the distribution of degenerating fibers in the cortical area surrounding the middle suprasylvian sulcus (MSs area) has been studied with the method of Fink and Heimer. Association fibers from the visual cortex mostly end in the vicinity of fundus of the medial wall of the MSs area and a fair number of fibers do in the fundus area of the posterior portion of its lateral wall. Most of the fibers terminate in layers III-V. Fibers from the auditory cortex terminante in the lip of the lateral wall, while few fibers end in the fundus and the medial wall. The fibers from the somatosensory cortex chiefly end in the vicinity of the fundus terminate in layers III-V. The "association cortex" sends a good amount of fibers to the lip region and the upper area of the media wall and lesser amount to the posterior part of the lateral wall of the MSs. The fibers terminant in layer III. From the present and the previous findings, it has become evident that inputs of different kinds of sensory modalities converge upon th elayers III-IV of the MSs area from the various cortical functional areas, and that the MSs area also sends fibers back to the sensory cortical areas. In addition, it has reciprocal connections with some thalamic nuclear groups, e.g., the "pulvinar posterior" system. Based upon the findings of neuronal connections, it can be suggested that the MSs area may play an important role with regard to the "integration of sensory inputs" in the cat cerebral cortex.

Animals↗
PubMed1989

Synaptic connections between motor neurons and interneurons in the fourth thoracic ganglion of the crayfish, Procambarus clarkii.

1. A new preparation of the thoracic nervous system of the crayfish, Procambarus clarkii, has been developed, in which it is possible to work with identified members of motor neuronal pools. 2. In such a preparation, it is possible to dissect all specific proximal motor nerves (protractor, retractor, anterior elevator, posterior elevator, and depressor). Motor neurons innervating the four proximal muscles of the fourth walking leg have been identified both physiologically and anatomically by staining the recorded motor neuron with Lucifer yellow through the microelectrode. 3. By the use of cobalt chloride, we have mapped the distribution of somata of all motor neurons within the fourth thoracic ganglion that innervate the different groups of muscles controlling the movement of the fourth walking leg. 4. Most motor neurons innervating the same muscle seem to be electrically coupled, except some depressor motor neurons. 5. Motor neurons innervating antagonist muscles are linked by inhibitory connections. These connections are reciprocal for protractor and retractor motor neurons but usually not reciprocal between elevator and depressor motor neurons. 6. Walking interneurons were identified as neurons without axons in any motor nerve, which modified the motor neuronal activity. Some of them have been injected with Lucifer yellow. 7. Some interneurons make synaptic connections only with antagonist motor neurons that control the movement of one joint. Probably their functional role is to reinforce or to limit the antagonism between each pair of antagonist motor neurons. 8. Other interneurons make synaptic connections with motor neurons innervating muscles controlling different leg joints. These interneurons may play a role in generating the motor patterns that underlie forward and backward walking.

Action Potentials↗
PubMed1992

Neurons in the cockroach nervous system reacting with antisera to the neuropeptide leucokinin I.

Antisera were raised against the myotropic neuropeptide leucokinin I, originally isolated from head extracts of the cockroach Leucophaea maderae. Processes of leucokinin I immunoreactive (LKIR) neurons were distributed throughout the nervous system, but immunoreactive cell bodies were not found in all neuromeres. In the brain, about 160 LKIR cell bodies were distributed in the protocerebrum and optic lobes (no LKIR cell bodies were found in the deuto- and tritocerebrum). In the ventral ganglia, LKIR cell bodies were seen distributed as follows: eight (weakly immunoreactive) in the subesophageal ganglion; about six larger and bilateral clusters of 5 smaller in each of the three thoracic ganglia, and in each of the abdominal ganglia, two pairs of strongly immunoreactive cell bodies were resolved. Many of the LKIR neurons could be described in detail. In the optic lobes, immunoreactive neurons innervate the medulla and accessory medulla. In the brain, three pairs of bilateral LKIR neurons supply branches to distinct sets of nonglomerular neuropil, and two pairs of descending neurons connect the posterior protocerebrum to the antennal lobes and all the ventral ganglia. Other brain neurons innervate the central body, tritocerebrum, and nonglomerular neuropil in protocerebrum. LKIR neurons of the median and lateral neurosecretory cell groups send axons to the corpora cardiaca, frontal ganglion, and tritocerebrum. In the muscle layer of the foregut (crop), bi- and multipolar LKIR neurons with axons running to the retrocerebral complex were resolved. The LKIR neurons in the abdominal ganglia form efferent axons supplying the lateral cardiac nerves, spiracles, and the segmental perivisceral organs. The distribution of immunoreactivity indicates roles for leucokinins as neuromodulators or neurotransmitters in central interneurons arborizing in different portions of the brain, visual system, and ventral ganglia. Also, a function in circuits regulating feeding can be presumed. Furthermore, a role in regulation of heart and possibly respiration can be suggested, and probably leucokinins are released from corpora cardiaca as neurohormones. Leucokinins were isolated by their myotropic action on the Leucophaea hindgut, but no innervation of this portion of the gut could be demonstrated. The distribution of leucokinin immunoreactivity was compared to immunolabeling with antisera against vertebrate tachykinins and lysine vasopressin.

Animals↗
PubMed2003

Merlin links to the cAMP neuronal signaling pathway by anchoring the RIbeta subunit of protein kinase A.

The cAMP-protein kinase A (PKA) pathway, important in neuronal signaling, is regulated by molecules that bind and target PKA regulatory subunits. Of four regulatory subunits, RIbeta is most abundantly expressed in brain. The RIbeta knockout mouse has defects in hippocampal synaptic plasticity, suggesting a role for RIbeta in learning and memory-related functions. Molecules that interact with or regulate RIbeta are still unknown. We identified the neurofibromatosis 2 tumor suppressor protein merlin (schwannomin), a molecule related to the ezrin-radixin-moesin family of membrane-cytoskeleton linker proteins, as a binding partner for RIbeta. Merlin and RIbeta demonstrated a similar expression pattern in central nervous system neurons and an overlapping subcellular localization in cultured hippocampal neurons and transfected cells. The proteins were coprecipitated from brain lysates by cAMP-agarose and coimmunoprecipited from cellular lysates with specific antibodies. In vitro binding studies verified that the interaction is direct. The interaction appeared to be under conformational regulation and was mediated via the alpha-helical region of merlin. Sequence comparison between merlin and known PKA anchoring proteins identified a conserved alpha-helical PKA anchoring protein motif in merlin. These results identify merlin as the first neuronal binding partner for PKA-RIbeta and suggest a novel function for merlin in connecting neuronal cytoskeleton to PKA signaling.

Amino Acid Sequence↗