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In vivo investigation of genome activity and synaptic plasticity of neurons in snails during learning.

The present report describes in vivo investigations of genome activity and its role in the mechanisms forming long-term synaptic plasticity in defensive behavior command neuron LPl1 during the acquisition of nociceptive sensitization by common snails. Transcription processes were recorded using SYTO 16, a specific fluorescent indicator of DNA activity, along with in vivo computer image analysis. Studies in control snails showed that application of nociceptive stimuli to the head led to biphasic changes in the bioelectrical responses of neurons to tactile and chemical stimulation--depression of responses in the short-term stage (during the 1 h after training) and their facilitation during the long-term stage of sensitization (more than 24 h). There were marked increases in fluorescence over the nucleus of the command neuron stained with SYTO 16 at 15-20 min from the start of training, this lasting 4-5 h. Acquisition of sensitization in the presence of the RNA synthesis inhibitor actinomycin D (20 microM) to the neuron led to the complete elimination of changes in fluorescence and synaptic facilitation in the responses of LPl1 to sensory stimulation in the long-term stage of sensitization but had no effect during the short-term stage of sensitization. Actinomycin D given 30 min after the end of acquisition of sensitization (1 h after the start) had no effect on the dynamics of fluorescence or synaptic facilitation. Thus, the acquisition of nociceptive sensitization is accompanied by a rapid (within 15-20 min) activation of the DNA of neuron LPl1 and subsequent (about 1 h) display of long-term synaptic facilitation. Induction of both processes was suppressed by the RNA synthesis inhibitor over a relatively short time period--1 h from the moment at which training started.

Action Potentials↗

Synergy between growth factors and transmitters required for catecholamine differentiation in brain neurons.

The phenotypically plastic neurons of the embryonic mouse striatum were used to explore mechanisms of catecholamine differentiation in culture. De novo transcription and translation of the CA biosynthetic enzyme, tyrosine hydroxylase (TH), was induced in striatal neurons exposed, simultaneously or sequentially, to the growth factor, acidic fibroblast growth factor (aFGF) and a catecholamine. Although dopamine was the most potent aFGF partner (ED50 = 4 microM), a number of substances, including dopamine (D1) receptor agonists, beta-adrenoceptor agonists, and dopamine uptake inhibitors also trigger TH induction when accompanied by aFGF. However, since none of the receptor antagonists nor transport blockers tested could inhibit dopamine's action, the mechanism remains obscure. Structure-activity analysis suggests that effective aFGF partners all contain an amine group separated from a catechol nucleus by two carbons. Thus, TH expression can be novelly induced by the synergistic interaction of aFGF, and to a lesser extent basic FGF, and a variety of CA-containing partner molecules. We speculate that a similar association between growth factor and transmitter may be required in development for the differentiation of a CA phenotype in brain neurons.

Animals↗

Glial protein S100B modulates long-term neuronal synaptic plasticity.

Glial cells are traditionally regarded as elements for structural support and ionic homeostasis, but have recently attracted attention as putative integral elements of the machinery involved in synaptic transmission and plasticity. Here, we demonstrate that calcium-binding protein S100B, which is synthesized in considerable amounts in astrocytes (a major glial cell subtype), modulates long-term synaptic plasticity. Mutant mice devoid of S100B developed normally and had no detectable abnormalities in the cytoarchitecture of the brain. These mutant mice, however, had strengthened synaptic plasticity as identified by enhanced long-term potentiation (LTP) in the hippocampal CA1 region. Perfusion of hippocampal slices with recombinant S100B proteins reversed the levels of LTP in the mutant slices to those of the wild-type slices, indicating that S100B might act extracellularly. In addition to enhanced LTP, mutant mice had enhanced spatial memory in the Morris water maze test and enhanced fear memory in the contextual fear conditioning. The results indicate that S100B is a glial modulator of neuronal synaptic plasticity and strengthen the notion that glial-neuronal interaction is important for information processing in the brain.

Animals↗

Changes in protein kinase C and its presynaptic substrate B-50/GAP-43 after intrauterine exposure to methylazoxy-methanol, a treatment inducing cortical and hippocampal damage and cognitive deficit in rats.

The involvement of protein kinase C (PKC)-dependent processes in adaptive and plastic changes underlying neuronal plasticity was tested in an in vivo animal model characterized by targeted cellular ablation of cortical and hippocampal neurons, cognitive impairment and lack of induction of long-term potentiation. [3H]Phorbol ester binding performed on brain slices revealed a 67.4 and 35.0% increase in membrane-bound protein kinase C in the cortex and hippocampus respectively of rats treated with methylazoxy-methanol acetate compared with saline-treated control rats, and there was no modification in the expression of mRNAs of different protein kinase C isozymes. In situ phosphorylation experiments performed with 32Pi-labelled synaptosomes from the affected areas demonstrated that the phosphorylation of the nervous tissue-specific presynaptic membrane-associated protein kinase C substrate B-50/GAP-43 was increased by 51.4 and 44.8% in cortex and hippocampus respectively. Western blot analysis of protein kinase C in synaptosomal cytosol and membrane fractions prepared from cortex and hippocampus showed an increased proportion of protein kinase C in the membrane compartment in treated animals, but no change in the total synaptosomal protein kinase C activity. Our data are consistent with increased activity of presynaptic protein kinase C and predict a sustained increase in glutamate release in methylazoxy-methanol-treated rats.

Animals↗

[Correlation between different forms of trace phenomena in the activity of rabbit visual cortex neurons].

Plastic changes in the components of the unit responses in the rabbit visual cortex (VC) in the course of electrical stimulation (with different parameters) of the lateral geniculate body (LGB) were compared with the capacity of the same units for trace driving to the LGB preceding stimulation. Potentiation of inhibition (inhibitory pauses) in reponse to electrical LGB stimulation is the main plastic phenomenon in the activity of VC units. Trace driving is characteristic predominantly of units with enhanced plasticity of the excitatory sign, a tendency toward epileptiform activity after LGB tetanization. In most cases inhibitory reaction is expressed in weakening of the periodic component of neuronal activity corresponding to the frequency of stimulation. The level of trace suppression of periodicity positively correlates with potentiation of the inhibitory pause during prolonged LGB stimulation.

Animals↗

Plasticity of neuronal connections in developing brains of mammals.

Although mature nervous systems show substantial malleability following various surgical or environmental manipulations, developing brains show far more prominent plasticity, particularly in terms of morphological features. Neuronal circuits, for example, can be dramatically rewired following neonatal but not adult brain lesions. It remains unknown why neuronal circuits in developing brains show such remarkable plasticity. A number of anatomical and physiological studies suggest that there are transient projections in developing brains and they are eliminated by cell death and/or collateral elimination as development proceeds. This raises a possibility that aberrant projections observed following various surgical or environmental manipulations such as partial denervation, results from retention or stabilization of transient projections. However, evidence suggests that cell death does not play an important role in developmental fine-tuning of neuronal projections. Furthermore, although the elimination of axon collaterals takes place, individual neurons appear to elaborate axonal arbors in appropriate target areas, resulting in a net increase in the size of axonal arbor emerging from individual neurons. In accord with these observations, the number of synapses appear to increase during the period when axonal elimination proceeds. Taken together, reinforcement of appropriate projections rather than elimination of excessive connections plays a major role in developmental specification of neuronal connections. Appearance of aberrant projections after partial denervation may not be a consequence of disordered axonal growth, since they form topographic maps which precisely mirrors those for normal projections. They may be induced due to reinforcement of pre-existing neuronal connections rather than to construction of novel pathways. Observations of axonal morphology in denervated areas indicate that lesion-induced enlargement of projections is due to transformation of axonal morphology, from simple and poorly branched to multiply branched. Perhaps such simple and poorly branched axons in inappropriate target areas may represent ones in the course of elimination but they may serve as a source of sprouting when denervated. In other words, after total elimination of axons any surgical or environmental manipulation cannot induce enlargement of projections. The mechanisms underlying such modifiability of neuronal connections remains unclarified but possible participation of an activity-dependent competitive mechanism is discussed.

Animals↗

Possible mechanisms of plastic reorganizations of neuronal activity during different schedules of intracellular electrostimulation according to the data of systems analysis.

The influence of rhythmic, random, and associative intracellular electrostimulation has been studied in individual identified and nonidentified neurons of the isolated CNS of the pond snail under the conditions of a controllable experiment. Using the methods of cluster, correlation, and factor analyses, an assessment is given and a comparison made of the changes in the character of the spontaneous spike activity induced by these modes of influence. It has been shown that the associations of the principal frequency-temporal characteristics of the endogenous rhythmicity of the neurons with the parameters of the external influences are identified only during stimulation associated with specific components of the endogenous rhythmicity, and are practically absent in the case of rhythmic and random electrostimulation. Three factors determining the formation of the structure of the spike impulse activity during the application of suprathreshold stimulations were distinguished. With respect to the composition of the variables included in them, they can be interpreted as: 1) the factor of intensity of the spontaneous activity; 2) the factor of the variability of the interimpulse intervals; and 3) the reinforcing factor. The possible endoneuronal mechanisms of the formation of adaptive reorganizations of the spontaneous activity under the conditions of associative influences are discussed.

Animals↗

Effects of nicotine on neurogenesis and plasticity of hippocampal neurons.

To study nicotine's effects on neurogenesis in the dentate gyrus of the hippocampus, nicotine was injected intraperitoneally into adult rats. After sacrificing, the hippocampal formation was processed for immunohistochemical staining of PSA-NCAM, NeuN and GFAP. Nicotine decreased numbers of PSA-NCAM(+) and NeuN(+) cells dose-dependently.

Animals↗

Immunohistochemical demonstration of plasticity in GABA neurons of the adult rat dentate gyrus.

The distribution of GABA fibers within the dentate gyrus was immunohistochemically examined following lesions of the entorhinal cortex in the adult rat. A major change in the pattern of the GAD immunoreactive fibers within the molecular layer, characterized by a marked increase in the density of fibers in the outer molecular layer, was observed. This change in the lamination of the dentate GABA fibers following entorhinal lesions appeared very similar to the changes which occur in acetylcholinesterase staining following entorhinal denervation of the dentate. These results provide morphological support for the sprouting of GABA fibers in the dentate gyrus in response to perforant path destruction.

Acetylcholinesterase↗

RGS2 determines short-term synaptic plasticity in hippocampal neurons by regulating Gi/o-mediated inhibition of presynaptic Ca2+ channels.

RGS2, one of the small members of the regulator of G protein signaling (RGS) family, is highly expressed in brain and regulates G(i/o) as well as G(q)-coupled receptor pathways. RGS2 modulates anxiety, aggression, and blood pressure in mice, suggesting that RGS2 regulates synaptic circuits underlying animal physiology and behavior. How RGS2 in brain influences synaptic activity is unknown. We therefore analyzed the synaptic function of RGS2 in hippocampal neurons by comparing electrophysiological recordings from RGS2 knockout and wild-type mice. Our study provides a general mechanism of the action of the RGS family containing RGS2 by demonstrating that RGS2 increases synaptic vesicle release by downregulating the G(i/o)-mediated presynaptic Ca(2+) channel inhibition and therefore provides an explanation of how regulation of RGS2 expression can modulate the function of neuronal circuits underlying behavior.

Animals↗

Morphological plasticity of postsynaptic neurones in reactive synaptogenesis.

Partial deafferentation of certain brain regions (septal nuclei, hippocampus, etc.) in adult animals results (1) in the disappearance of degenerating axon terminals and (2) in the short-term persistence of vacant postsynaptic sites. These postsynaptic sites have been shown to be re-supplied by sprouted axon terminals of intact axons. This paper will demonstrate that, in brain regions (e.g. cerebellar cortex, lateral geniculate nucleus) where axonal sprouting of local elements or of persisting afferent axons is negligible or absent, synaptic reorganization involves the active participation of postsynaptic dendritic and somatic elements of surviving local nerve cells. Synaptic regeneration can be demonstrated by morphological means both in developing and in adult central nervous system. The dendrites may show two types of response to deafferentation: (1) the formation of presynaptic specializations along their otherwise 'classical' postsynaptic membrane (the axonization of dendrites) resulting in the formation of new, dendrodendritic synapses, and (2) the 'adaptive' (structural) reduction in size ('atrophy') of the denervated nerve cell dendritic arborization, leading to a relative increase in density of the surviving (though non-sprouting) afferent axon terminals. In both cases a partial functional recovery can be demonstrated.

Animals↗

Electrophysiological studies on plasticity of cerebellothalamic neurons in rats following neonatal hemicerebellectomy.

Changes in the cerebello-thalamo-cerebral projection following hemicerebellectomy were investigated in 16 rats by laminar field potential analysis of cerebello-cerebral responses in the cerebral cortex and by unitary recording of antidromic responses of cerebellar nuclear neurons to stimulation of the thalamus. In contrast to the occurrence of an exclusively contralateral cerebello-cerebral response in intact rats, a significant bilateral cerebello-cerebral response could be evoked in all 8 rats hemicerebellectomized before 6 days of age (early hemicerebellectomy). On the other hand, in all 5 rats operated on at 8 to 15 days of age (late hemicerebellectomy) and in the 3 rats operated on in adulthood, the cerebello-cerebral response was evoked only contralaterally just as in intact rats. Unitary recordings of antidromic responses of cerebellar nuclear neurons revealed that bilateral or ipsilateral cerebellothalamic projection neurons were remarkably more numerous in early hemicerebellectomized rats than in controls (P less than 0.001). Such neurons were less frequently found in late hemicerebellectomized rats, but they were still more numerous than in controls (P less than 0.005). Absence of the ipsilateral cerebello-cerebral response in late hemicerebellectomized rats indicates that even though bilateral or ipsilateral cerebellothalamic projection neurons may exist in these rats more numerously than in intact rats, they may not be sufficient in number or in efficiency to mediate a detectably response.

Animals↗

Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.

Animals↗

Acute ultrastructural effects of MPTP on the nigrostriatal pathway of the C57BL/6 adult mouse: evidence of compensatory plasticity in nigrostriatal neurons.

Acute doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicited degenerative and apparently compensatory changes in the nigrostriatum of injected animals within 1 day of treatment. In the substantia nigra pars compacta (SNc), low-dose (20 mg/kg) administration elicited early degeneration of mitochondria in the absence of other effects. In the striatum, a low MPTP dose resulted in myelin unwinding, demyelination, cytoplasmic shrinkage, and disturbance of synaptic communication, as evinced by a profound reduction in synaptic vesicle production. High-dose (40 mg/kg) administration generated more drastic axonal degeneration leading to cell elimination in the striatum. At neither dose was mitochondrial disturbance evident in the striatum. Evidence is presented that darkened synaptic boutons, visible at this level of MPTP administration, were part of healthy enlarged axons with an elevated number of synaptic contacts. These spared neuronal processes, therefore, were hypothesized to compensate for the MPTP-induced death of dopaminergic neurons by adaptive structural modifications that would serve to enhance their functional capability.

Animals↗

[Rapid functional plasticity of the neurons in the inferior colliculus and dorsal cochlear nucleus after brief exposure to intense pure tone].

The changes of response properties were observed from the single neuron in inferior colliculus (IC) and dorsal cochlear nucleus (DCN) located in the area bordering the lesion created by intense pure tone. The frequencies of traumatizing tone were chosen higher than the characteristic frequency (CF) of the neurons and beyond their excitatory response area so that the traumatizing tone would not influence the excitatory input to the neurons under study. Different types of disinhibition effects were found in more than half of the neurons after the traumatizing tone. The results indicated a subcortical origination of cortical functional reorganization and the involvement of lateral inhibition in the formation of inhibitory neural networks in both IC and DCN.

Acoustic Stimulation↗