Synaptic plasticity in epileptogenesis: cellular mechanisms underlying long-lasting synaptic modifications that require new gene expression.
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Animals↗
Biomedical subjects
C S Wallace
Publications and source records attributed to C S Wallace.
Differential intracellular sorting of immediate early gene mRNAs depends on signals in the mRNA sequence.
This study characterizes the differential targeting of recently synthesized immediate early gene (IEG) mRNAs to neuronal cell bodies versus dendrites and tests the hypothesis that this targeting is based on signals in the encoded proteins. A single electroconvulsive seizure induces the expression of a number of IEG mRNAs in granule cells of the dentate gyrus. Most of these IEG mRNAs remain in the cell body, including two that are characterized in the present study (the mRNAs for NGFI-A and COX-2). In contrast, the mRNA for Arc moved rapidly into dendrites at an apparent rate of approximately 300 micron/hr. Inhibiting protein synthesis with cycloheximide did not disrupt the differential mRNA sorting, demonstrating that the differential targeting of mRNAs is not dependent on translation.
Animals↗
Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites.
Polyribosomal complexes beneath postsynaptic sites on dendrites provide a substrate for local translation of particular mRNAs, but the signals that target mRNAs to synapses remain to be defined. Here, we report that high frequency activation of the perforant path projections to the dentate gyrus causes newly synthesized mRNA for the immediate-early gene (IEG) Arc to localize selectively in activated dendritic segments. Newly synthesized Arc protein also accumulates in the portion of the dendrite that had been synaptically activated. The targeting of Arc mRNA was not disrupted by locally inhibiting protein synthesis, indicating that the signals for mRNA localization reside in the mRNA itself. This novel mechanism through which newly synthesized mRNA is precisely targeted to activated synapses is well suited to play a role in the enduring forms of activity-dependent synaptic modification that require protein synthesis.
Afferent Pathways↗
The Melbourne Family Grief Study, I: Perceptions of family functioning in bereavement.
OBJECTIVE: The aim of this study was to identify patterns of family functioning in adult families after the death of a parent. METHOD: One hundred fifteen families completed measures of family functioning, grief, psychological state, and social adjustment 6 weeks (time 1), 6 months (time 2), and 13 months (time 3) after the death of a parent (a total of 670 individual responses). Cluster analytic methods were applied to develop a typology of perceptions of family functioning during bereavement. RESULTS: Five types of families emerged from dimensions of cohesiveness, conflict, and expressiveness on the Family Environment Scale. Thirty-six percent of the families were considered supportive because of their high cohesiveness, and another 23% resolved conflict effectively. Two types were dysfunctional: hostile families, distinguished by high conflict, low cohesiveness, and poor expressiveness, and sullen families, who had more moderate limitations in these three areas; they declined in frequency from 30% at time 1 to 15% at time 3. The remaining type (26%), termed intermediate, exhibited midrange cohesiveness, low control, and low achievement orientation. The typology at time 1 predicted typologies at time 2 and time 3. There were no age or gender differences among the family types, but offspring, as compared with spouses, were overrepresented in the hostile families. CONCLUSIONS: Family types can be identified, allowing at-risk families to be helped to prevent complications of grief. Screening with the family relationship index of the Family Environment Scale would facilitate such a family-centered approach.
Adaptation, Psychological↗
Circular clustering of protein dihedral angles by Minimum Message Length.
Early work on proteins identified the existence of helices and extended sheets in protein secondary structures, a high-level classification which remains popular today. Using the Snob program for information-theoretic Minimum Message Length (MML) classification, we are able to take the protein dihedral angles as determined by X-ray crystallography, and cluster sets of dihedral angles into groups. Previous work by Hunter and States has applied a similar Bayesian classification method, AutoClass, to protein data with site position represented by 3 Cartesian co-ordinates for each of the alpha-Carbon, beta-Carbon and Nitrogen, totalling 9 co-ordinates. By using the von Mises circular distribution in the Snob program, we are instead able to represent local site properties by the two dihedral angles, phi and psi. Since each site can be modelled as having 2 degrees of freedom, this orientation-invariant dihedral angle representation of the data is more compact than that of nine highly-correlated Cartesian co-ordinates. Using the information-theoretic message length concepts discussed in the paper, such a more concise model is more likely to represent the underlying generating process from which the data came. We report on the results of our classification, plotting the classes in (phi, psi) space; and introducing a symmetric information-theoretic distance measure to build a minimum spanning tree between the classes. We also give a transition matrix between the classes and note the existence of three classes in the region phi approximately -1.09 rad and psi approximately -0.75 rad which are close on the spanning tree and have high inter-transition probabilities. This gives rise to a tight, abundant and self-perpetuating structure.
Computational Biology↗
mRNA distribution within dendrites: relationship to afferent innervation.
The majority of neuronal mRNAs are confined to cell bodies, but a few mRNAs are present at high levels in dendrites. Here we report an initial analysis of the relationship between afferent innervation and the distribution of mRNA within dendritic fields. In situ hybridization techniques were used to compare the subcellular distribution of dendritic mRNAs in principal neurons of the hippocampal formation in vivo. The mRNA encoding the alpha subunit of calcium/calmodulin dependent protein kinase II (CAMII kinase) was present at high levels throughout the layers that contain the dendrites of hippocampal pyramidal cells and dentate granule cells. In contrast, the mRNA encoding the high molecular weight microtubule-associated protein MAP2 had a more limited distribution. In the dentate gyrus, labeling for MAP2 was present in a discrete band in the lamina containing proximal dendrites and decreased to low levels in laminae containing distal dendrites. This laminar pattern resembles the distinct terminations of the commissural/associational projection (high MAP2 labeling) and the entorhinal projection (lower MAP2 labeling) upon dendrites of granule cells. To determine if the differential distribution of dendritic mRNAs was regulated by either the presence or activity of afferents, we evaluated mRNA distribution in the dentate molecular layer following (1) removal of the entorhinal input by lesions of the entorhinal cortex or (2) prolonged delivery of potentiating stimulation to entorhinal afferents. Denervation led to modest decreases in the levels of mRNAs for both CAMII and MAP2 but did not lead to detectable alterations in mRNA distribution. Also, prolonged stimulation did not lead to detectable alterations in MAP2 or CAMII mRNA distribution although such stimulation clearly elevated the expression of mRNA for glial fibrillary acidic protein (GFAP).
Afferent Pathways↗
Correspondence between sites of NGFI-A induction and sites of morphological plasticity following exposure to environmental complexity.
To determine if gene regulation may play a role in behaviorally-induced morphological plasticity in the brain, we used in situ hybridization to measure levels of mRNA for the immediate early gene transcription factor NGFI-A (also known as ZENK, zif/268, egr-1 and Krox 24). Brains of periadolescent male rats exposed to 2-4 days of the following behavioral treatments were compared: (1) group housing in a complex environment (EC); (2) individual housing with daily handling (HIC); and (3) individual handling (IC). Quantitative analysis of the autoradiograms revealed that EC rats had significantly higher levels of NGFI-A than IC rats in regions of cortex previously shown to exhibit morphological plasticity (most pronounced in visual cortex), but not in frontal cortex where no dendritic changes have been detected. HIC rats were intermediate between the two groups. These data support an association between structural plasticity and altered patterns of immediate early gene expression.
Animals↗
The posterior probability distribution of alignments and its application to parameter estimation of evolutionary trees and to optimization of multiple alignments.
How to sample alignments from their posterior probability distribution given two strings is shown. This is extended to sampling alignments of more than two strings. The result is first applied to the estimation of the edges of a given evolutionary tree over several strings. Second, when used in conjunction with simulated annealing, it gives a stochastic search method for an optimal multiple alignment.
Algorithms↗
Pharmacologic management of cystic fibrosis.
Standard pharmacologic management of cystic fibrosis is discussed and the role of new agents in the treatment of this disease is explored. Cystic fibrosis is a recessive, fatal genetic disease involving multiple organ systems, in which patients develop pancreatic insufficiency, malabsorption, and repeated pulmonary infections. Pharmacotherapy to date has included broad-spectrum antimicrobials and aggressive nutritional management with microencapsulated pancreatic enzymes. Acute pulmonary exacerbations, caused by Pseudomonas aeruginosa, require combination i.v. antimicrobial therapy for 14 to 21 days. With the recent discovery of the genetic defect responsible for cystic fibrosis, as well as the cellular mechanism, new pharmacologic approaches are being explored to improve treatment. Aerosolized amiloride is being tested to modify the basic defect in the chloride channel. Dornase, a new mucolytic, is used to decrease sputum viscosity and increase mucociliary clearance. Leukoprotease inhibitors are currently being evaluated for decreasing the acute inflammatory reaction in the lung. Gene therapy has been promising, but its role in the management of cystic fibrosis is many years away. Drug therapy for cystic fibrosis has been primarily directed at treating infections with antibiotics and supplementing digestive enzymes and vitamins. New agents and gene therapy may substantially change the morbidity and mortality of this disease.
Adolescent↗
Constructing a minimal diagnostic decision tree.
Classification trees and discriminant function analysis were employed in order to ascertain whether a small number of diagnostic decision rules could be extracted from a large inventory of items. Several models, involving up to 17 symptoms, that led to a broad psychiatric diagnosis were then tested on a small validation sample of 53 patients. All methods, with the exception of CART used without any pruning, generated identical trees involving four items. Almost 90% of the validation sample was able to be correctly classified by all methods although poor classification performance was noted in the case of one particular diagnosis, Schizoaffective Psychosis. In contrast, stepwise linear discriminant analysis originally selected 17 items, although three out of the first four items selected were identical to those chosen by the tree-building methods. Although more research is required, there are indications that the latter methods may be usefully employed in constructing parsimonious decision trees.
Algorithms↗
Finite-state models in the alignment of macromolecules.
Minimum message length encoding is a technique of inductive inference with theoretical and practical advantages. It allows the posterior odds-ratio of two theories or hypotheses to be calculated. Here it is applied to problems of aligning or relating two strings, in particular two biological macromolecules. We compare the r-theory, that the strings are related, with the null-theory, that they are not related. If they are related, the probabilities of the various alignments can be calculated. This is done for one-, three-, and five-state models of relation or mutation. These correspond to linear and piecewise linear cost functions on runs of insertions and deletions. We describe how to estimate parameters of a model. The validity of a model is itself an hypothesis and can be objectively tested. This is done on real DNA strings and on artificial data. The tests on artificial data indicate limits on what can be inferred in various situations. The tests on real DNA support either the three- or five-state models over the one-state model. Finally, a fast, approximate minimum message length string comparison algorithm is described.
Algorithms↗
Increases in dendritic length in occipital cortex after 4 days of differential housing in weanling rats.
To assess the capacity for experience to induce rapid alterations in the dendritic fields of cortical neurons, male Long-Evans hooded rats aged 30-31 days were housed in either a complex environment (EC) or an individual cage (IC) for 4 days. The basilar dendrites of layer III pyramidal cells in area 17 of visual cortex were measured in Golgi-stained sections. EC rats exhibited significant increases in total dendritic length and total number of branches. This finding demonstrates that the structural modifications previously reported after 30 days in the complex environment are well underway after only 4 days.
Animals↗
A flexible perforated microelectrode array for extended neural recordings.
A flexible and perforated 32-element planar microelectrode array has been fabricated and used to measure evoked potentials in brain slices. Electrodes are spaced 200 microns apart in a 4 x 8 array and are sandwiched between layers of insulating polyimide. The polyimide sandwich is lifted off its substrate, making it flexible so that it could shape to contoured tissues. Prior to lift off, holes are etched to expose recording sites 15 microns in diameter and to create perforations which allow increased circulation of artificial cerebrospinal fluid to the recording surface of the tissue and, hence, increased viability. Comparisons of evoked potentials measured over time showed an average increase of 10 h to the viability of the slice while using the perforated versus nonperforated arrays.
Animals↗
Lovastatin-induced rhabdomyolysis in the absence of concomitant drugs.
OBJECTIVE: Presentation of a case of lovastatin-induced rhabdomyolysis in the absence of other medications known to potentiate this adverse effect. METHODOLOGY: Case report. RESULTS: A 60-year-old black man developed rhabdomyolysis after receiving lovastatin for 14 months. Rhabdomyolysis developed in the absence of other medications previously reported to cause this adverse effect when administered concomitantly with lovastatin. Adverse drug reaction causality algorithms categorized this reaction as either possible or probable. CONCLUSIONS: Rhabdomyolysis is an uncommon adverse effect associated with lovastatin therapy. Although reported cases of lovastatin-induced rhabdomyolysis were associated with the coadministration of cyclosporine, erythromycin, gemfibrozil, or nicotinic acid, this adverse effect may occur in the absence of these agents.
Humans↗
A case of attempted division of the eighth nerve within the skull for the relief of tinnitus. 1904.
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History, 20th Century↗
Effects of complex experience on somatic growth and organ development in rats.
Rats kept in complex environments (EC) show an array of brain changes relative to animals housed individually (IC). These effects have been explained as due to (a) information storage, (b) chronic stress that causes brain damage, or (c) neuroendocrine effects on brain maturation. Complex experience also affects somatic growth and organ development, and these may be related to the EC/IC brain differences. We have compared somatic growth and internal organs of 315 weanling and adult rats with various histories. (a) Young EC rats showed slower skeletal and visceral growth, while many brain components expand. (b) Although thymus and spleen were lighter in young ECs, immunocompetence was nonsignificantly (p less than .07) higher than in ICs. (c) Somatic growth of adult rats was slow and not very responsive to experience, whereas studies have shown EC/IC brain effects similar to those in young rats. (d) Males had slightly greater EC/IC somatic and visceral differences. (e) The stress index, adrenal weight, varied across age and experience, so chronic stress can not explain EC/IC brain differences. Training paradigms show brain changes similar to those from complex experience, occurring specifically with learning and in brain regions using the information. Learning and memory, therefore remain the best explanation of the EC brain effects.
Adrenal Glands↗
Experience and brain development.
This article considers how experience can influence the developing and mature brain and proposes a new categorization scheme based upon the type of information stored and the brain mechanisms that appear to be involved in storing it. In this scheme, experience-expectant information storage refers to incorporation of environmental information that is ubiquitous in the environment and common to all species members, such as the basic elements of pattern perception. Experience-expectant processes appear to have evolved as a neural preparation for incorporating specific information: in many sensory systems, synaptic connections between nerve cells are overproduced, and a subsequent selection process occurs in which aspects of sensory experience determine the pattern of connections that remains. Experience-dependent information storage refers to incorporation of environmental information that is idiosyncratic, or unique to the individual, such as learning about one's specific physical environment or vocabulary. The neural basis of experience-dependent processes appears to involve active formation of new synaptic connections in response to the events providing the information to be stored. Although these processes probably do not occur entirely independently of one another in development, the categories offer a new view more in accord with neural mechanisms than were terms like "critical" or "sensitive period."
Brain↗
Analysis of nasal support.
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Biomechanical Phenomena↗