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Neurobiology of an addiction memory.

The existence of an "addiction memory" (AM) and its importance in relapse occurrence and maintenance of learned addictive behaviour will be explained with neurobiological and clinical arguments. Because the human brain is an open learning system, which reveals its own neuronal connectivity through the experience of the perceived environment with its own state, the personal AM is interpreted as an individual acquired software disturbance in relation to selectively integrating "feedback loops" and "comparator systems" of neuronal information processing. This is in accordance with the experience that the AM and its specific cue reactivity can be activated at any time by relapse-endangering complex internal and/or external situations with cue stimulated craving. The AM becomes part of the personality represented on the molecular level via the neuronal level and the neuropsychological level, especially in the episodic memory. This neurobiological unchangeable imprinted addictive behaviour with "loss of control" and "obsessive-compulsive craving" was also found in a long-term learning model with rats (Wolffgramm). Identical homological phylogenetically old brain structures for learning mechanisms allow the comparison between human and animal behaviour. The AM seems to be a clinical-empirical proved reality. It is compatible with recently discussed results of neurosciences.

Animals↗

Analysis of induced gamma-band activity in EEG during visual perception of Korean, English, Chinese words.

The oscillation of brain activities in the gamma-band is known to be a manifestation of the formation of neuronal assemblies that jointly constitute neural correlates of feature binding and conscious awareness. Visual word perception is a task that demands a considerable amount of cognitive resources and integration of information from multiple functionally connected neuronal circuits at various scales. Thus, it is anticipated that a substantial increase in gamma-band activity (GBA) would be observed during visual word perception. The purpose of this study was to examine whether meaningful increases in GBA occur during visual word perception and to explore similarities and differences in the amount and spatiotemporal GBA patterns while native Korean subjects perceive Korean, English, and Chinese words. We also aimed at identifying relationships between GBA increase and a behavioral measure such as response time. The results of power spectrum and time-frequency analyses showed that the increases in GBA were most significant in the prefrontal, frontal, and temporal sites, which are known to be relevant to visual word perception. The GBAs in the prefrontal and temporal sites were significantly correlated with response time. The differences in spatiotemporal patterns of GBA among languages were not prominent compared to inter-individual differences.

Adult↗

A model study of cellular short-term memory produced by slowly inactivating potassium conductances.

We analyzed the cellular short-term memory effects induced by a slowly inactivating potassium (Ks) conductance using a biophysical model of a neuron. We first described latency-to-first-spike and temporal changes in firing frequency as a function of parameters of the model, injected current and prior history of the neuron (deinactivation level) under current clamp. This provided a complete set of properties describing the Ks conductance in a neuron. We then showed that the action of the Ks conductance is not generally appropriate for controlling latency-to-first-spike under random synaptic stimulation. However, reliable latencies were found when neuronal population computation was used. Ks inactivation was found to control the rate of convergence to steady-state discharge behavior and to allow frequency to increase at variable rates in sets of synaptically connected neurons. These results suggest that inactivation of the Ks conductance can have a reliable influence on the behavior of neuronal populations under real physiological conditions.

Action Potentials↗

Morphology and projections of myenteric neurons to colonic fiber bundles of the cat.

Regulation of colon function depends on the location of nerve cell bodies and the distribution of intrinsic nerve fibers in the myenteric plexus. The morphology and projections of myenteric neurons through colonic fiber bundles in cat colon were determined using in vivo retrograde transport of HRP and Fast blue. Myenteric neurons were found to project from at least 5 to 59 mm orad (mean: 42 mm) or aborad (mean: 54 mm) through colonic fiber bundles. Approximately 73% of labelled cells were in ganglia within 2.8 mm of colonic fiber bundles in the axis of circular muscle fibers; none was beyond 7.7 mm. There were 2 soma morphologies. One type (Dogiel type I) had a mean soma diameter of 40.5 microns and had a rough somal surface. There were few if any short, broad dendrites, but its one long process extended to a branch point of an adjacent colonic fiber bundle. The other type (Dogiel type III) had a mean soma diameter of 26.4 microns, had a smooth somal surface and had few if any fine dendrites. It also projected a single long axon to colonic fiber bundles. There were twice as many Dogiel type III neurons. We conclude that myenteric neurons in the cat colon project both orad and aborad over relatively long distances through colonic fiber bundles where they form another intrinsic neuronal connection for the myenteric plexus.

Afferent Pathways↗

Effects of postural changes of the upper limb on reflex transmission in the lower limb. Cervicolumbar reflex interactions in man.

The influence of passive changes in upper limb position on the excitability of three myotatic arc reflexes (soleus, quadriceps, and biceps femoris) of the lower limb has been explored on 42 volunteers. The results indicate that the excitability of the three myotatic arcs can be influenced at a distance by postural modifications of the upper limb. When the ipsilateral upper limb is forwards or the contralateral backwards, a facilitation of both soleus and quadriceps tendon reflexes is observed while the biceps femoris reflexes are reduced. This pattern of facilitation and inhibition is reversed when the ipsilateral upper limb is backwards or the contralateral forwards. The facilitations as well as inhibitions of proximal myotatic arc reflexes are quantitatively more marked than that of the soleus reflex. Facilitation and inhibition are not linearly related to the angle of the arm with the trunk. Effects begin at a considerable angle, become maximal at 45 degrees, and progressively disappear for greater values. It is suggested that the distinct pattern of facilitation and inhibition which is exerted in reciprocal fashion on extensor and flexor motor nuclei might depend on the long propriospinal neurones connecting cervical and lumbar enlargements.

Achilles Tendon↗

Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons.

Axon outgrowth is the first step in the formation of neuronal connections, but the pathways that regulate axon extension are still poorly understood. We find that mice deficient in calcineurin-NFAT signaling have dramatic defects in axonal outgrowth, yet have little or no defect in neuronal differentiation or survival. In vitro, sensory and commissural neurons lacking calcineurin function or NFATc2, c3, and c4 are unable to respond to neurotrophins or netrin-1 with efficient axonal outgrowth. Neurotrophins and netrins stimulate calcineurin-dependent nuclear localization of NFATc4 and activation of NFAT-mediated gene transcription in cultured primary neurons. These data indicate that the ability of these embryonic axons to respond to growth factors with rapid outgrowth requires activation of calcineurin/NFAT signaling by these factors. The precise parsing of signals for elongation turning and survival could allow independent control of these processes during development.

Active Transport, Cell Nucleus↗

Adenovirus-mediated WGA gene delivery for transsynaptic labeling of mouse olfactory pathways.

Detailed knowledge of neuronal connectivity patterns is indispensable for studies of various aspects of brain functions. We previously established a genetic strategy for visualization of multisynaptic neural pathways by expressing wheat germ agglutinin (WGA) transgene under the control of neuron type-specific promoter elements in transgenic mice and Drosophila. In this paper, we have developed a WGA-expressing recombinant adenoviral vector system and applied it for analysis of the olfactory system. When the WGA-expressing adenovirus was infused into a mouse nostril, various types of cells throughout the olfactory epithelium were infected and expressed WGA protein robustly. WGA transgene products in the olfactory sensory neurons were anterogradely transported along their axons to the olfactory bulb and transsynaptically transferred in glomeruli to dendrites of the second-order neurons, mitral and tufted cells. WGA protein was further conveyed via the lateral olfactory tract to the olfactory cortical areas including the anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral entorhinal cortex. In addition, transsynaptic retrograde labeling was observed in cholinergic neurons in the horizontal limb of diagonal band, serotonergic neurons in the median raphe nucleus, and noradrenergic neurons in the locus coeruleus, all of which project centrifugal fibers to the olfactory bulb. Thus, the WGA-expressing adenovirus is a useful and powerful tool for tracing neural pathways and could be used in animals that are not amenable to the transgenic technology.

Adenoviridae↗

Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 neurones.

The refinement and plasticity of neuronal connections require synaptic activity and neurotrophin signalling; their specific contributions and interplay are, however, poorly understood. We show here that brain-derived neurotrophic factor (BDNF) increased spine density in apical dendrites of CA1 pyramidal neurones in organotypic slice cultures prepared from postnatal rat hippocampal slices. This effect was observed also in the absence of action potentials, and even when miniature synaptic transmission was inhibited with botulinum neurotoxin C (BoNT/C). There were, however, marked differences in the morphology of individual spines induced by BDNF across these different levels of spontaneous ongoing synaptic activity. During both normal synaptic transmission, and when action potentials were blocked with TTX, BDNF increased the proportion of stubby, type-I spines. However, when SNARE-dependent vesicular release was inhibited with BoNT/C, BDNF increased the proportion of thin, type-III spines. Our results indicate that BDNF increases spine density irrespective of the levels of synaptic transmission. In addition, miniature synaptic transmission provides sufficient activity for the functional translation of BDNF-triggered spinogenesis into clearly defined morphological spine types, favouring those spines potentially responsible for coordinated Ca2+ transients thought to mediate synaptic plasticity. We propose that BDNF/TrkB signalling represents a mechanism of expression of both morphological and physiological homeostatic plasticity in the hippocampus, leading to a more efficient synaptic information transfer across widespread levels of synaptic activity.

Action Potentials↗

Dendritic anomalies in a freezing model of microgyria: a parametric study.

Despite easier recognition of focal developmental cortical anomalies with modern morphological and functional imaging techniques, mechanisms leading to refractory epilepsy are still poorly understood. Recent experimental studies have shown that not only the lesioned cortex, but also the apparently normal adjacent cortex undergoes morphological changes and alterations of its neuronal connections. To further investigate the modifications of the cortex surrounding a focal maldevelopmental lesion, we applied a freezing insult to newborn rat cortex, resulting in a focal cortical malformation similar to human microgyria. Corticocortical associative neurons were retrogradely labeled in a Golgi-like fashion using biotinylated dextran amine combined with NMDA. In addition to previously reported alterations, a considerable spine loss was observed in the basal dendrites of neurons located in the eulaminated cortex adjacent to the lesion. These data demonstrate profound maldevelopmental alterations which are not limited to the macroscopically abnormal lesion, but extend at a cellular level to the surrounding cortex. The observed alterations may contribute to the increased excitability of the cortex harboring a microgyric lesion as well as the frequently associated cognitive impairment.

Animals↗

Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN.

Axonal growth is fundamental to the establishment of neuronal connectivity in the brain. However, the cell-intrinsic mechanisms that govern axonal morphogenesis remain to be elucidated. The ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC) suppresses the growth of axons in postmitotic neurons. Here, we report that Cdh1-APC operates in the nucleus to inhibit axonal growth. We also identify the transcriptional corepressor SnoN as a key target of neuronal Cdh1-APC that promotes axonal growth. Cdh1 forms a physical complex with SnoN and stimulates the ubiquitin-dependent proteasomal degradation of SnoN in neurons. Knockdown of SnoN in neurons significantly reduces axonal growth and suppresses Cdh1 RNAi enhancement of axonal growth. In addition, SnoN knockdown in vivo suggests an essential function for SnoN in the development of granule neuron parallel fibers in the cerebellar cortex. These findings define Cdh1-APC and SnoN as components of a cell-intrinsic pathway that orchestrates axonal morphogenesis in a transcription-dependent manner in the mammalian brain.

Anaphase-Promoting Complex-Cyclosome↗

Transplanted CNS stem cells form functional synapses in vivo.

An understanding of developmental mechanisms and new cell therapies can be achieved by transplantation into the nervous system. Multipotential stem cells have been isolated from the foetal and adult central nervous system (CNS). Immortalized and primary precursor cells integrate into the developing brain generating both neurons and glia as defined by immunological and morphological criteria. Here we show for the first time that in vitro-expanded CNS precursors, upon transplantation into the brains of rats, form electrically active and functionally connected neurons. These neurons exhibit spontaneous and evoked postsynaptic events and respond to focal glutamate application. Donor cells were grafted into the foetal hippocampus, and the amplitude and frequency of spontaneous synaptic events were monitored in the grafted cells in area CA1 for the first month of postnatal life. The formation of synapses onto grafted neurons indicates that grafted CNS stem cells can be used to study synaptic development in vivo and has important implications for clinical cell replacement therapies.

Animals↗

fMRI models of dendritic and astrocytic networks.

In order to elucidate the relationships between hierarchical structures within the neocortical neuropil and the information carried by an ensemble of neurons encompassing a single voxel, it is essential to predict through volume conductor modeling LFPs representing average extracellular potentials, which are expressed in terms of interstitial potentials of individual cells in networks of gap-junctionally connected astrocytes and synaptically connected neurons. These relationships have been provided and can then be used to investigate how the underlying neuronal population activity can be inferred from the measurement of the BOLD signal through electrovascular coupling mechanisms across the blood-brain barrier. The importance of both synaptic and extrasynaptic transmission as the basis of electrophysiological indices triggering vascular responses between dendritic and astrocytic networks, and sequential configurations of firing patterns in composite neural networks is emphasized. The purpose of this review is to show how fMRI data may be used to draw conclusions about the information transmitted by individual neurons in populations generating the BOLD signal.

Animals↗

Giant depolarizing potentials: the septal pole of the hippocampus paces the activity of the developing intact septohippocampal complex in vitro.

In neonatal hippocampal slices, recurrent spontaneous giant depolarizing potentials (GDPs) provide neuronal synchronized firing and Ca2+ oscillations. To investigate the possible role of GDPs in the synchronization of neuronal activity in intact neonatal limbic structures, we used multiple simultaneous electrophysiological recordings in the recently described preparation of intact neonatal septohippocampal complex in vitro. Combined whole-cell (in single or pairs of cells) and extracellular field recordings (one to five simultaneous recording sites) from the CA3 hippocampal region and various parts of the septum indicated that spontaneous GDPs, which can be initiated anywhere along the longitudinal hippocampal axis, are most often initiated in the septal poles of hippocampus and propagate to medial septum and temporal poles of both hippocampi simultaneously. GDPs were abolished in the medial septum but not in the hippocampus after surgical separation of both structures, suggesting hippocampal origin of GDPs. The preferential septotemporal orientation of GDP propagation observed in the intact hippocampus was associated with a corresponding gradient of GDP frequency in isolated portions of hippocampus. Accordingly, most GDPs propagated in the septotemporal direction in both septal and temporal hippocampal isolated halves, and whereas GDP frequency remained similar in the septal part of hippocampus after its surgical isolation, it progressively decreased in more temporally isolated portions of the hippocampus. Because GDPs provide most of the synaptic drive of neonatal neurons, they may modulate the development of neuronal connections in the immature limbic system.

Animals↗

[Connection of efferent neurons and afferent vestibular nuclei in rat].

OBJECTIVE: To study the connection between the efferent and afferent vestibular neurons in the center neural system. METHODS: In the present study, a retrograde neuron tracer horseradish peroxidase (HRP) was injected into the surrounding of efferent vestibular neurons located in the inner side of the facial genu of the rat and after following 48 hours for the retrograde axonal transport of this tracer, then its presence in neurons of the brain stem was demonstrated histochemically. RESULTS: Neurons labeled with HRP were found bilaterally in both Medial vestibular nuclei (MVe) and lateral vestibular nuclei (LVe). Approximately 80% of the neurons in each were located in the MVe on the side ipsilateral to the injection. CONCLUSIONS: There is a direct connection between the efferent and afferent vestibular neurons. These findings suggest that there is an afferent-efferent feedback regulatory mechanism in the vestibular system.

Animals↗

Molecular analysis of axonal target specificity and synapse formation.

The development of neuronal connectivity requires the growth of axons to their target region and the formation of dendritic trees that extend into specific layers. Within the target region growth cones, the tips of extending axons are guided to finer target fields including specific subcellular compartments where they form synapses. In this article we highlight recent progress on molecular aspects of axonal subcellular target selection such as the axon initial segment or specific sublaminae of the vertebrate retina. We then discuss the very recent progress on the molecular analysis of synapse formation in the central nervous system, including the direction of differentiation into an inhibitory or excitatory synapse. Apparently, initial synaptic contacts are structurally and functionally modulated by neuronal activity, raising the question how neuronal activity can modify synaptic circuits. We therefore also focus on neural proteins that are up-regulated, secreted or converted by synaptic activity and, thus, might represent molecular candidates for experience-driven refinement or remodeling of synaptic connections.

Animals↗

Three-dimensional structure of bidirectional, excitatory chemical synapses in the jellyfish Cyanea capillata.

Neurons in the ectoderm of the perirhopalial tissue of the jellyfish Cyanea capillata were exposed and fixed for electron microscopy under conditions designed to minimize exocytosis of synaptic vesicles. The structure of the bidirectional chemical synapses that connect neurons was examined and the three-dimensional organization of these synapses was determined from reconstructions of serial sections. Synapses were characterized by the accumulation of a relatively few, large synaptic vesicles. These lie in a single layer against the terminal membrane of each terminal. The cytoplasmic side of the vesicles in any one terminal was covered by a single, large, perforated cisternal sheet. In addition, there were numerous smaller, bulbous cisternae that intermingled with the vesicles in the terminal. The structure of any one terminal was mirrored by that of the opposite terminal of the pair. The organization of these synapses is discussed from the viewpoint of cnidarian synapses in general.

Animals↗

Morphological classifications of enteric neurons--100 years after Dogiel.

The first differentiation of enteric neurons into three morphological types was done by the russian histologist A. S. Dogiel on the basis of the different shapes and lengths of their dendrites. Although a number of authors considered his results during the following decades, only a division into two types withstood time: type I neurons had one long and several short processes, whereas type II neurons were characterized by several long processes. Some further structural features were discussed but substantial progress was not made until the late 1970s. This stagnation was due to some inaccuracies in Dogiel's descriptions, to the fact that most histologists in this field followed the reticular concept of the nervous system, to the idea that enteric neurons represent no more than a vegetative, postganglionic relay station between the central nervous system and the periphery, and to methodological difficulties. With the application of modern neuroanatomical techniques it was realized that the enteric nervous system contains a considerable number of neuronal subpopulations. The search for morphological correlates of the chemical diversity of enteric neurons was done mainly in the pig and the guinea-pig. In the pig, additional structural features such as axonal projection, distribution of neurons within ganglia, within different plexuses and along the length of the gut, blood supply etc. were included as criteria for further refining neuronal classification. Most of our knowledge about functional features of enteric neurons, e.g. chemical coding, neuronal connectivity, electrophysiological behaviour, was derived from studies in the guinea-pig small intestine. In light of interspecies differences, comparison of findings from different species is mandatory. The search for morphological and functional peculiarities of human enteric neuronal circuitry has to consider all methodological and conceptual advances made within the past 100 years since the pioneering work of Dogiel.

Anatomy↗

Physiological and pathophysiological roles of excitatory amino acids during central nervous system development.

Recent studies suggest that excitatory amino acids (EAAs) have a wide variety of physiological and pathophysiological roles during central nervous system (CNS) development. In addition to participating in neuronal signal transduction, EAAs also exert trophic influences affecting neuronal survival, growth and differentiation during restricted developmental periods. EAAs also participate in the development and maintenance of neuronal circuitry and regulate several forms of activity-dependent synaptic plasticity such as LTP and segregation of converging retinal inputs to tectum and visual cortex. Pre- and post-synaptic markers of EAA pathways in brain undergo marked ontogenic changes. These markers are commonly overexpressed during development; periods of overproduction often coincide with times when synaptic plasticity is great and when appropriate neuronal connections are consolidated. The electrophysiological and biochemical properties of EAA receptors also undergo marked ontogenic changes. In addition to these physiological roles of EAAs, overactivation of EAA receptors may initiate a cascade of cellular events which produce neuronal injury and death. There is a unique developmental profile of susceptibility of the brain to excitotoxic injury mediated by activation of each of the EAA receptor subtypes. Overactivation of EAA receptors is implicated in the pathophysiology of brain injury in several clinical disorders to which the developing brain is susceptible, including hypoxia-ischemia, epilepsy, physical trauma and some rare genetic abnormalities of amino acid metabolism. Potential therapeutic approaches may be rationally devised based on recent information about the developmental regulation of EAA receptors and their involvement in the pathogenesis of these disorders.

Amino Acids↗