The differential diagnosis of abnormal head shapes: separating craniosynostosis from positional deformities and normal variants

The vestibular pathway of the mollusk Hermissenda crassicornis mediates a reflexive, unconditioned response to disorientation, clinging, that has been conserved during evolution even to the emergence of our own species. This response becomes associated with a visual stimulus (mediated by a precisely ordered visual-vestibular synaptic network) according to principles of Pavlovian conditioning that are also followed in human learning. It is not entirely surprising therefore that molecular and biophysical cascades responsible for this associative learning appear to function in both mollusks and mammals. In brief, combinational elevation of (Ca2+)i, diacylglycerol, and arachidonic acid activates protein kinase C to phosphorylate the Ca2+ and guanosine triphosphate-binding protein, cp20 (now called calexcitin (Nelson T, et al. Proc Natl Acad Sci USA 1996;93:13808-13)), which potently inactivates postsynaptic voltage-dependent K+ currents and thereby increases synaptic weight. Longer term changes included rearrangement of synaptic terminals and modified protein synthesis. This cascade has also been implicated in other associative-learning paradigms (e.g., spatial maze, olfactory discrimination) and as a pathophysiologic target in early Alzheimer's disease. Recent molecular biologic experiments also demonstrate the dependence of associative memory (but not long-term potentiation) on voltage-dependent K+ currents. Theoretic learning models based on these findings focus on dendritic spine clusters and yield computer implementations with powerful pattern-recognition capabilities.     

Presynaptic facilitation revisited: state and time dependence

The mechanisms underlying short-term presynaptic facilitation, the enhancement of transmitter release from sensory neurons in Aplysia, induced by serotonin (5-HT), can be divided into two categories: (1) changes in ionic conductances leading to spike broadening and enhancement of Ca2+ influx; and (2) actions on the machinery for transmitter release that are independent of spike broadening and the resulting increases in Ca2+ influx. Spike broadening and the associated enhancement of excitability are induced by the modulation of K+ conductances in the sensory neuron. The cellular mechanisms that contribute to the enhancement of release that is independent of spike broadening are not known and may involve vesicle mobilization or other steps in exocytotic release. These two facilitatory actions of 5-HT are mediated by at least two second-messenger-activated protein kinase systems, protein kinase A (PKA) and protein kinase C (PKC). These two second-messenger cascades overlap in their contributions to synaptic facilitation. However, their relative contributions to enhancement of transmitter release are not simply synergistic but are state- and time-dependent. The state dependence is a reflection of the synapse's previous history of activity. When the synapse is rested (and not depressed), a brief pulse of 5-HT (lasting from 10 sec to 5 min) produces its actions primarily through PKA via both spike broadening-dependent and -independent mechanisms. The broadening primarily involves the modulation of a voltage-dependent K+ current, IKV, with a small contribution by a voltage-independent K+ current, IKS. By contrast, the enhancement of excitability is mediated primarily by the modulation of IKS. As the synapse becomes depressed with repeated activity, the contribution of PKC becomes progressively more important. As is the case with PKA, PKC produces its action both by broadening the spike via modulation of IKV and by a spike broadening-independent mechanism. In addition to being state-dependent, the mechanisms of facilitation are time-dependent. There are differences in the response to 5-HT when it is given briefly to produce short-term facilitation or when the exposure is prolonged. When exposure is brief (< or = 5 min), PKA dominates. When exposure is prolonged (10-20 min), PKC becomes dominant as it is with depressed synapses. Thus, synaptic plasticity appears to be expressed in several overlapping time domains, and the transition between very short-term facilitation and various intermediate duration phases seems to involve interactive processes between the kinases.     

The protective role of mild acidic pH shifts on synaptic NMDA current in hippocampal slices

Glutamate is a major neurotransmitter in the CNS. Its release activates NMDA and non-NMDA receptors on the postsynaptic membrane. NMDA receptor activation is shown to be important in physiological and pathological events. The modulatory sites on the NMDA receptor-channel ionophore complex are important in the regulation of the channel's cation conductance. Regulation of the channel by proton concentration may be important in the alkalinization that occurs during the normal release of glutamate or in the acidification that occurs during hypoxia/ischemia. In this study, the selective downregulation of the NMDA channel with slight extracellular pH changes and reversibility of this modulation have been shown in hippocampal slices. It has also been shown that hippocampal slices are more responsive to pH changes than other experimental preparations. The downregulation of the NMDA current may represent a native control mechanism. Direct and indirect modulation caused by extracellular pH changes on the NMDA receptor ionophore complex might be important in the overall response of the neuron under pathophysiological changes.     

Time domains of neuronal Ca2+ signaling and associative memory: steps through a calexcitin, ryanodine receptor, K+ channel cascade

Synaptic changes that underlie associative learning and memory begin with temporally related activity of two or more independent synaptic inputs to common postsynaptic targets. In turn, temporally related molecular events regulate cytosolic Ca2+ during progressively longer-lasting time domains. Associative learning behaviors of living animals have been correlated with changes of neuronal voltage-dependent K+ currents, protein kinase C-mediated phosphorylation and synthesis of the Ca2+ and GTP-binding protein, calexcitin (CE),and increased expression of the Ca2+-releasing ryanodine receptor (type II). These molecular events, some of which have been found to be dysfunctional in Alzheimer's disease, provide means of altering dendritic excitability and thus synaptic efficacy during induction, consolidation and storage of associative memory. Apparently, such stages of behavioral learning correspond to sequential differences of Ca2+ signaling that could occur in spatially segregated dendritic compartments distributed across brain structures, such as the hippocampus.     

Leech photoreceptors project their galectin-containing processes into the optic neuropils where they contact AP cells

We characterized a subset of leech sensory afferents, the photoreceptors, in terms of their molecular composition, anatomical distribution, and candidate postsynaptic partners. For reagents, we used an antiserum generated against purified LL35, a 35 kD leech lactose-binding protein (galectin); monoclonal antibody (mAb) Lan3-2, which is specific for a mannose-containing epitope common to the full set of sensory afferents; and dye injections. Photoreceptors differ from other types of sensory afferents by their abundant expression of galectin. However, photoreceptors share in common with other sensory modalities the mannose-containing epitope recognized by mAb Lan3-2. Photoreceptors from a given segment project their axons directly into the CNS ganglion innervating the same segment. They assemble in a target region, the optic neuropil, which is separate from the target regions of other sensory modalities. They also extend their axons as an optic tract into the connective to innervate optic neuropils of other CNS ganglia, thereby providing extensive intersegmental innervation for the 33 CNS ganglia comprising the leech nerve cord. Because of its intimate contact with the optic neuropil, a central neuron, the AP effector cell, is a strong candidate second order visual neuron. In confocal images, the AP cell projects its primary axon for about 100 microns alongside the optic neuropil. In electron micrographs, spines emanating from the axon of the AP cell make contact with vesicle laden nerve terminals of photoreceptors. Leech photoreceptors and their second order visual neurons represent a simple visual system for studying the mechanisms of axonal targeting.     

Differential effects of 4-aminopyridine, serotonin, and phorbol esters on facilitation of sensorimotor connections in Aplysia

Serotonergic modulation of sensory neurons in Aplysia and their synaptic connections with follower cells has been used extensively as a model system with which to study mechanisms underlying neuronal plasticity. Serotonin (5-HT)-induced facilitation of sensorimotor connections is due to at least two processes: a process related to the broadening of presynaptic action potentials and a spike-duration-independent (SDI) process that may involve mobilization of transmitter. We have examined the relationship between spike broadening and synaptic facilitation of relatively nondepressed sensorimotor connections in the intact pleural-pedal ganglia. Previously, 5-HT-induced spike broadening in the sensory neuron was shown to be primarily due to the modulation of a voltage-dependent K+ current (Ik.v). Low concentrations (20-30 microM) of 4-aminopyridine (4-AP) were used to rather selectively block Ik.v. 4-AP increased spike duration in the sensory neuron and the excitatory postsynaptic potential (EPSP) in the motor neuron. The temporal development of 4-AP-induced spike broadening closely parallel that of synaptic facilitation. Thus spike broadening via the reduction of Ik.v can directly contribute to synaptic facilitation. The relationship between spike broadening induced by 5-HT (10 microM) and enhancement of the EPSP was also analyzed. We found that components of 5-HT-induced synaptic facilitation preceded the development of 5-HT-induced spike broadening. The comparison between the results of 4-AP and 5-HT revealed that the SDI processes made an important contribution to the rapid development of 5-HT-induced synaptic facilitation and that spike broadening made an important contribution to its maintenance. The SDI process and a slowly developing component of 5-HT-induced spike broadening are mediated, at least in part, by the activation of protein kinase C (PKC). Application of phorbol 12,13-diacetate (PDAc), an activator of PKC, partially mimicked the effects of 5-HT on spike duration and the EPSP. PDAc-induced enhancement of the EPSP preceded the slower development of PDAc-induced spike broadening. Like 5-HT, PDAc enhanced the EPSP via both spike broadening and the SDI processes. In addition, a 15-min exposure to PDAc occluded 5-HT-induced enhancement of the EPSP, suggesting that PKC and 5-HT engage similar or overlapping mechanisms. On the basis of these results and others, we propose a time-dependent hypothesis for the 5-HT-induced synaptic facilitation of nondepressed synapses, in which multiple second-messenger/protein kinase systems mediate the actions of 5-HT via both spike-duration-dependent and SDI processes.     

Relaxation and muscular tension: A biobehavioristic explanation.

Relaxation and muscular tension are commonly ascribed to cohere to metaphorical principles of stimulus-response (S-R) that presumably are isomorphic with neurally based reflexive mechanisms that are not modifiable by learning. However, purely S-R principles have been progressively replaced in modern learning theory with expectancy or discrepancy models of learning that do not recognize separate neural processes that subserve operant (R-S) and respondent (S-R) conditioning. An alternative explanation for the relaxation response and muscular tension is provided that is derived from principles of modern learning theory. It is demonstrated theoretically and through practical procedure that muscular relaxation is a homeostatic resting state and muscular tension is a function of simple biopsychologic processes of incentive motivation or learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Animal learning comes of age.

The current status of the field of animal learning is described in historical context. Three themes that have provided major impetus for the study of animal learning are identified: comparative cognition, animal models of human behavior, and functional neurology. The historical roots of these themes are described, followed by examples of contemporary research relevant to each theme. Important recent changes in conceptualization of basic conditioning phenomena are also described. The review suggests that the field of animal learning continues to contribute in unique and important ways to the understanding of behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Developmental changes of potassium currents of embryonic leech ganglion cells in primary culture

The expression of calcium-activated potassium currents (IK(Ca)), delayed outward rectifier potassium currents (IK(slow)), and transient outward currents (IA) was studied during the development of the nervous system of the leech using the whole-cell patch-clamp recording technique. Dissociated cells were isolated from leech embryos between stage E7 and E16 and maintained in primary culture. K+ currents were recorded at E7, when only few anterior ganglia had formed beneath the primordial mouth. IK(slow) was present in all cells tested, while IK(Ca) was expressed in only 67% of the cells studied. Even as early as E7, different types of IK(Ca) have been found. Neither frequency of occurrence nor the charge density of IK(Ca) showed significant changes between E7 and E16. The density of IK(slow), however, increased by a factor of two between E7 and E8, which resulted in a significant increase in the total K+ current of these cells. This rise in potassium outward current developed in parallel with the appearance of Na+ and Ca2+ inward currents (Schirrmacher and Deitmer: J Exp Biol 155:435-453, 1991) during early development, shaping the electrical excitability in embryonic leech neurones. I(A) could be separated by its voltage-dependence and pharmacological properties. The current was detected at stage E9, when all 32 ganglia are formed in the embryo. The frequency of occurrence of I(A) increased from 16% at E9 to 70% at E15. The channel density, steady state inactivation, and kinetics showed no significant changes during development.     

NMDA and D2-like receptors modulate cognitive flexibility in a color discrimination reversal task in pigeons.

Reversal and extinction learning represent forms of cognitive flexibility that refer to the ability of an animal to alter behavior in response to unanticipated changes on environmental demands. A role for dopamine and glutamate in modulating this behavior has been implicated. Here, we determined the effects of intracerebroventricular injections in pigeons' forebrain of the D2-like receptor agonist quinpirole, the D2-like receptor antagonist sulpiride and the N-methyl-d-aspartate receptor antagonist AP-5 on initial acquisition and reversal of a color discrimination task. On day one, pigeons had to learn to discriminate two color keys. On day two, pigeons first performed a retention test, which was followed by a reversal of the reward contingencies of the two color keys. None of the drugs altered performance in the initial acquisition of color discrimination or affected the retention of the learned color key. In contrast, all drugs impaired reversal learning by increasing trials and incorrect responses in the reversal session. Our data support the hypothesis that D2-like receptor mechanisms, like N-methyl-d-aspartate receptor modulations, are involved in cognitive flexibility and relearning processes, but not in initial learning of stimulus-reward association. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

等径弯角挤压工艺(ECAEP)研究现状

等径弯角挤压是制备块状细晶材料的一种大塑性变形工艺，目前得到国内外高度重视．本文简要介绍了等径弯角挤压工艺的基本原理和变形特点，从理论上对其变形方式和机理进行了分析，并详细介绍了该工艺的应用领域。     

Placental glutathione S-transferase (GST-P) induction as a potential mechanism for the anti-carcinogenic effect of the coffee-specific components cafestol and kahweol

The coffee specific diterpenes cafestol and kahweol (C + K) have been reported to be anti-carcinogenic in several animal models. It has been postulated that this activity may be related to their ability to induce glutathione S-transferases (GSTs). We investigated the influence of a mixture of C + K, incorporated at various levels in the diet of Sprague-Dawley rats, on the expression of different hepatic GST iso-enzymes. Liver samples were examined using isoform-specific GST substrates and antibodies, and highly selective oligomers were employed to determine effects at the RNA level. A dose-dependent increase in general GST activity was observed in male and female animals following 28 or 90 days of treatment. A time-course study demonstrated that the maximal effect was observed within 5 days of treatment. Little or no effect was found on the activity of GST alpha and mu iso-enzymes. The most striking observation was a dose-dependent induction of placental glutathione S-transferase (GST-P) which could be demonstrated at the mRNA, protein and enzymatic levels. This effect was observed in both male and female rats. The maximal induction was attained within 5 days of treatment with C + K, remained elevated with continued treatment, but was reversible on withdrawal of treatment. Immunohistochemical examination of liver slices revealed a strong even distribution of GST-P expression throughout the acinus at the highest dose of C + K, while at lower doses the induction of GST-P occurred predominantly in periportal hepatocytes. There was no indication of the presence of preneoplastic foci and, furthermore, the effect of C + K on the GST-P was completely reversible. These findings indicate that the anticarcinogenic mechanism of C + K may involve a specific induction of GST-P and suggest a potential role for GST-P in detoxifying carcinogenic compounds.     

Requirement for tyrosine phosphatase during serotonergic neuromodulation by protein kinase C

Tyrosine kinases and phosphatases are abundant in the nervous system, where they signal cellular differentiation, mediate the responses to growth factors, and direct neurite outgrowth during development. Tyrosine phosphorylation can also alter ion channel activity, but its physiological significance remains unclear. In an identified leech mechanosensory neuron, the ubiquitous neuromodulator serotonin increases the activity of a cation channel by activating protein kinase C (PKC), resulting in membrane depolarization and modulation of the receptive field properties. We observed that the effects on isolated neurons and channels were blocked by inhibiting tyrosine phosphatases. Serotonergic stimulation of PKC thus activates a tyrosine phosphatase activity associated with the channels, which reverses their constitutive inhibition by tyrosine phosphorylation, representing a novel form of neuromodulation.     

L-type Ca2+ channel is involved in the regulation of spontaneous transmitter release at developing neuromuscular synapses

Involvement of an L-type Ca2+ channel in the regulation of spontaneous transmitter release was studied in Xenopus nerve-muscle cultures. The frequency of spontaneous synaptic currents, which reflects impulse-independent acetylcholine release from the nerve terminals, showed a marked increase in high-K+ medium or after treatment with a phorbol ester, 12-O-tetradecanoyl-phorbol 13-acetate, a drug that activates protein kinase C and depolarizes the presynaptic neuron. The potentiation effect of high K+ and 12-O-tetradecanoyl-phorbol 13-acetate requires Ca2+ influx through the L-type Ca2+ channel in the plasma membrane, since it was significantly reduced by the presence of nifedipine, verapamil or diltiazem and enhanced by Bay K 8644, an L-type Ca2+ channel agonist. It was shown recently that adenosine 5'-triphosphate markedly potentiates the spontaneous acetylcholine release at these synapses through the binding of P2-purinoceptors and the activation of protein kinase C. We found in the present study that potentiation effects of adenosine 5'-triphosphate are inhibited by L-type Ca2+ channel blockers, suggesting that the L-type Ca2+ channel is responsible for the positive regulation of spontaneous acetylcholine secretion by adenosine 5'-triphosphate at the developing neuromuscular synapses. Our data suggest that modulation of the L-type Ca2+ channel in embryonic motor nerve terminals is important for the regulation of spontaneous transmitter release.     

Evidence that galanin is a parasympathetic, rather than a sympathetic, neurotransmitter in the baboon pancreas

Various cortical dysplasias, such as agyria-lissencephalia, pachygyria, micropolygyria, neuronal heterotopia and so on, have become relatively common neuropathological findings among the children with intactable epilepsy and mental and/or physical handicap. Together with various environmental factors, gene abnormalities are recently increasing as a cause in various cortical dysplasias. However, details of the pathogenesis still remain unknown. Experimental studies using animal models indicated that inhibition of neuron production, disorders of neuron-glia and neuron-neuron contact, and plastic and unbalanced synaptogenesis subsequent to abnormal neuron production play an important role either separately or in combination in the pathogenesis of various cortical dysplasias.     

Nitric oxide inhibits the dopamine-induced K+ current via guanylate cyclase in Aplysia neurons

Nitric oxide (NO) is produced by the enzyme nitric oxide synthase (NOS) and has been implicated in inter- and intracellular communication in the nervous system. The present study was undertaken to assess the effects of sodium nitroprusside (SNP) and hydroxylamine (HOA), NO donors, on a dopamine (DA)-induced K+ current in identified Aplysia neurons using voltage-clamp and pressure ejection techniques. Bath-applied SNP (10-25 microM) reduced the DA-induced K+ current without affecting the resting membrane conductance and holding current. The DA-induced K+ current also was inhibited by the focal application of 200 microM HOA to the neuron somata. The DA-induced K+ current suppressing effects of SNP and HOA are completely reversible. Pretreatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microM), a specific inhibitor of NO-stimulated guanylate cyclase, and hemoglobin (50 microM), a nitric oxide scavenger, decreased the SNP-induced inhibition of the DA-induced current. In contrast, intracellular injection of 1 mM guanosine 3',5'-cyclic monophosphate (cGMP) or bath-applied 3-isobutyl-1-methylxanthine (IBMX; 50 microM), a non-specific phosphodiesterase inhibitor, inhibited the DA-induced current, mimicking the effect of the NO donors. These results demonstrate that SNP and HOA inhibit the DA-induced K+ current and that the mechanism of NO inhibition of the DA-induced current involves cGMP-dependent protein kinase.     

Prefrontal cortex involvement in selective letter generation: a functional magnetic resonance imaging study

Leech neurons exposed to salines containing inorganic Ca(2+)-channel blockers generate rhythmic bursts of impulses. According to an earlier model, these blockers unmask persistent Na+ currents that generate plateau-like depolarizations, each triggering a burst of impulses. The resulting increase in intracellular Na+ activates an outward Na+/K+ pump current that contributes to burst termination. We tested this model by examining systematically the effects of six transition metal ions (Co2+, Ni2+, Mn2+, Cd2+, La3+, and Zn2+) on the electrical activity of neurons in isolated leech ganglia. Each ion induced bursting activity, but the amplitude, form, and persistence of bursting differed with the ion used and its concentration relative to Ca2+. All ions tested suppressed chemical synaptic transmission between identified motor neurons, consistent with block of voltage-dependent Ca2+ currents in these cells. In addition, a strong correlation between suppression of synaptic transmission and burst amplitudes was obtained. Finally, burst duration was increased and the rate of repolarization decreased in reduced K+ saline, as expected for pump-dependent repolarization. These results provide further support for the hypothesis that a novel form of oscillatory electrical activity driven by persistent Na+ currents and the Na+/K+ pump occurs in leech ganglia exposed to Ca(2+)-channel blockers.     

Networks with lateral connectivity. III. Plasticity and reorganization of somatosensory cortex

1. Mechanisms underlying cortical reorganizations were studied using a three-layered neural network model with neuronal groups already formed in the cortical layer. 2. Dynamic changes induced in cortex by behavioral training or intracortical microstimulation (ICMS) were simulated. Both manipulations resulted in reassembly of neuronal groups and formation of stimulus-dependent assemblies. Receptive fields of neurons and cortical representation of inputs also changed. Many neurons that had been weakly responsive or silent became active. 3. Several types of learning models were examined in simulating behavioral training, ICMS-induced dynamic changes, deafferentation, or cortical lesion. Each learning model most accurately reproduced features of experimental data from different manipulations, suggesting that more than one plasticity mechanism might be able to induce dynamic changes in cortex. 4. After skin or cortical stimulation ceased, as spontaneous activity continued, the stimulus-dependent assemblies gradually reverted into structure-dependent neuronal groups. However, relationships among individual neurons and identities of many neurons did not return to their original states. Thus a different set of neurons would be recruited by the same training stimulus sequence on its next presentation. 5. We also reproduced several typical long-term reorganizations caused by pathological manipulations such as cortical lesions, input loss, and digit fusion. 6. In summary, with Hebbian plasticity rules on lateral connections, the network model is capable of reproducing most characteristics of experiments on cortical reorganization. We propose that an important mechanism underlying cortical plastic changes is formation of temporary assemblies that are related to receipt of strongly synchronized localized input. Such stimulus-dependent assemblies can be dissolved by spontaneous activity after removal of the stimuli.     

Amyotrophic lateral sclerosis and viruses

Amyotrophic lateral sclerosis (ALS) is a disease of unknown etiology. A number of theories have been pursued to explain the cause of ALS, including viral infection. This review examines the evidence implicating viruses in the pathogenesis of ALS, as well as current studies of naturally occurring and experimental models of virus-induced motor neuron disease (MND). The association of viruses and ALS remains to be established. The study of animal models of virus-induced MND may shed light on processes relevant to the etiology of ALS.