Methimazole in treatment-resistant depression.
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Adult↗
Biomedical subjects
W Singer
Publications and source records attributed to W Singer.
Agonists of cholinergic and noradrenergic receptors facilitate synergistically the induction of long-term potentiation in slices of rat visual cortex.
Acetylcholine (ACh) and noradrenaline (NA) have been shown to facilitate experience-dependent modifications of synaptic connectivity during postnatal development of the kitten visual cortex. To further investigate the mechanisms of this facilitation we studied the effects of these neuromodulators in an in vitro model of use-dependent synaptic plasticity. We have chosen long-term potentiation (LTP) in rat visual cortex slices because it shares several features with the in vivo model. In both cases induction of synaptic modifications requires that postsynaptic activation reaches a critical threshold and in both cases changes are induced more easily in young animals and when N-methyl-D-aspartate (NMDA) receptor-gated conductances are activated. Intracellular recordings were obtained from regular spiking cells in supragranular layers of rat visual cortex and LTP was induced by tetanic stimulation of the underlying white matter. Both cholinergic and noradrenergic agonists raised the probability that tetanic stimuli induced LTP and as in vivo they acted synergistically. These effects were mediated by agonists of muscarinic and beta-receptors, respectively. The agonists of both receptor systems enhanced the depolarizing response to the tetanus and increased NMDA receptor-gated conductances during this response. We suggest that this mode of action also accounts for the facilitatory effects which ACh and NA have on use-dependent synaptic plasticity in the developing visual cortex.
Acetylcholine↗
Selection of intrinsic horizontal connections in the visual cortex by correlated neuronal activity.
In the visual cortex of the brain, long-ranging tangentially oriented axon collaterals interconnect regularly spaced clusters of cells. These connections develop after birth and attain their specificity by pruning. To test whether there is selective stabilization of connections between those cells that exhibit correlated activity, kittens were raised with artificially induced strabismus (eye deviation) to eliminate the correlation between signals from the two eyes. In area 17, cell clusters were driven almost exclusively from either the right or the left eye and tangential intracortical fibers preferentially connected cell groups activated by the same eye. Thus, circuit selection depends on visual experience, and the selection criterion is the correlation of activity.
Aging↗
Intracellular injection of Ca2+ chelators blocks induction of long-term depression in rat visual cortex.
In a variety of brain structures repetitive activation of synaptic connections can lead to long-term potentiation (LTP) or long-term depression (LTD) of synaptic transmission, and these modifications are held responsible for memory formation. Here we examine the role of postsynaptic Ca2+ concentration in the induction of LTD in the neocortex. In layer III cells of the rat visual cortex, LTD can be induced by tetanic stimulation of afferent fibers ascending from the white matter. We show that LTD induction is reliably blocked by intracellular injection of either EGTA or BAPTA [bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate], two different Ca2+ chelators. This confirms that the processes underlying the induction of LTD in neocortex are located postsynaptically and indicates that they depend on intracellular Ca2+ concentration. Thus, both LTP and LTD induction appear to involve calcium-mediated processes in the postsynaptic neuron. We propose that LTD is caused by a surge of calcium either through voltage-gated Ca2+ conductances and/or by transmitter-induced release of calcium from intracellular stores.
Animals↗
Otto Detlev Creutzfeldt, 1927-1992.
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Germany↗
Temporal coding in the visual cortex: new vistas on integration in the nervous system.
Although our knowledge of the cellular components of the cortex is accumulating rapidly, we are still largely ignorant about how distributed neuronal activity can be integrated to contribute to unified perception and behaviour. In the visual system, it is still unresolved how responses of feature-detecting neurons can be bound into representations of perceptual objects. Recent crosscorrelation studies show that visual cortical neurons synchronize their responses depending on how coherent features are in the visual field. These results support the hypothesis that temporal correlation of neuronal discharges may serve to bind distributed neuronal activity into unique representations. Furthermore, these studies indicate that neuronal responses with an oscillatory temporal structure may be particularly advantageous as carrier signals for such a temporal coding mechanism. Based on these recent findings, it is suggested here that binding of neuronal activity by a temporal code may provide a solution to the problem of integration in distributed neuronal networks.
Animals↗
Synchronization of oscillatory neuronal responses in cat striate cortex: temporal properties.
Previously, we have demonstrated that a subpopulation of visual cortical neurons exhibit oscillatory responses to their preferred stimuli at a frequency near 50 Hz (Gray & Singer, 1989). These responses can selectively synchronize over large distances of cortex in a stimulus-specific manner (Gray et al., 1989; Engel et al., 1990 alpha). Here we report the results of a new analysis which reveals the fine temporal structure inherent in these interactions. We utilized pairs of recordings of the local field potential (LFP) activity from area 17 in the anesthetized cat which met two criteria. The LFP was correlated with the underlying unit activity at each site and the recording sites were at least 5 mm apart in cortex. A moving-window technique was applied to compute cross correlograms on 100-ms epochs of data repeated at intervals of 30 ms for a period of 3 s during each direction of stimulus movement. A statistical test was devised to determine the significance of detected correlations. In this way we were able to determine the magnitude, phase difference, frequency, and duration of correlated oscillations as a function of time. The results demonstrate that (1) the duration of synchrony is variable and lasts from 100-900 ms; (2) the phase differences between and the frequencies of synchronized responses are also variable within and between events and range from +3 to -3 ms and 40-60 Hz, respectively; and (3) multiple correlation events often occur within a single stimulus period. These results demonstrate a high degree of dynamic variability and a rapid onset and offset of synchrony among interacting populations of neurons which is consistent with the requirements of a mechanism for feature integration.
Animals↗
Thyroid hormone use to enhance the effects of drugs.
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Antidepressive Agents↗
Human pituitary null cell adenomas and oncocytomas in vitro: effects of adenohypophysiotropic hormones and gonadal steroids on hormone secretion and tumor cell morphology.
Human pituitary null cell adenomas and oncocytomas are not associated with evidence of excess hormone secretion in vivo; their cellular derivation has not been clarified by morphologic investigation. In this study we examined 41 null cell adenomas and 58 oncocytomas in vitro to determine hormone release and its response to several adenohypophysiotropic hormones and gonadal steroids. In vitro, 96/99 tumors released LH, FSH, and/or alpha-subunit of glycoprotein hormones. TSH was released by 11 tumors. GH, PRL, and ACTH were found in small quantities in 11, 8, and 5 tumors, respectively. Only 3 tumors released no detectable hormones. Incubations with test substances were examined at 2- and 24-h periods for up to 72 h. All but 3 of 53 tumors showed marked and persistent increases in the release of LH, FSH, and/or alpha-subunit in response to GnRH in short and long duration experiments. Secretion of LH, FSH, or alpha-subunit was stimulated to more than 150% of control by TRH in 37/48 tumors, by CRH in 10/20, by GRH in 7/20. Estradiol, progesterone, and testosterone increased release of FSH, LH, and/or alpha-subunit in 23/32, 3/12, and 3/12 tumors, respectively, and reduced their release in 6/32, 5/12, and 7/12, respectively. In tumors which showed no response to gonadal steroids, GnRH in combination with estradiol, progesterone, or testosterone yielded the same result as GnRH alone; in tumors inhibited by gonadal steroids, GnRH in combination with one of those substances reduced the response to GnRH. No secretion of GH, PRL, ACTH, or TSH was detected after incubation with GRH, estradiol, CRH, or TRH except in the tumors which initially released GH, PRL, or TSH. Ultrastructural examination of cultured cells from 15 cases revealed morphologic alterations that correlated with changes in hormone release and could be quantified by morphometry. This study represents the largest analysis of hormone production and release in vitro and morphologic correlation of clinically nonfunctioning pituitary adenomas. The responsiveness of gonadotropin secretion by null cell adenomas and oncocytomas to GnRH and gonadal steroids resembles that of gonadotroph adenomas. However, the unexpected increases in gonadotropin release attributable to several other adenohypophysiotropic hormones and the release of multiple hormones suggests that null cell adenomas and oncocytomas may represent neoplasms derived from uncommitted or committed precursor cells that can undergo differentiation towards several cell lines.
Adenoma↗
Hormone secretion in vitro by plurihormonal pituitary adenomas of the acidophil cell line.
Pituitary tumors producing GH and PRL are morphologically classified as monomorphous bihormonal acidophil stem cell adenomas (ASCAs) which cause hyperprolactinemia and two tumor types which are usually associated with acromegaly, the monomorphous plurihormonal mammosomatotroph adenomas (MSAs) and bimorphous mixed somatotroph-lactotroph adenomas. We studied 12 MSAs, 2 ASCAs, and 10 mixed adenomas in vitro to assess the secretory behavior of these tumors diagnosed by immunohistochemistry and electron microscopy. GH release by MSAs and all but one mixed tumor was greater than that of PRL; the opposite was true of the ASCAs. One mixed tumor which caused impotence and hyperprolactinemia contained predominantly lactotrophs and released greater amounts of PRL than of GH in vitro. All 12 MSAs and 6 of 10 mixed tumors released alpha-subunit of glycoprotein hormones. Incubation with GHRH increased release of GH and PRL by all tumors and of alpha-subunit when present; the responses of all hormones were parallel among MSAs whereas among mixed adenomas, GH and alpha-subunit had greater responses than PRL. TRH stimulated GH, PRL, and alpha-subunit release by MSAs in parallel; among mixed adenomas, PRL response was generally greater than that of GH or alpha-subunit. SRIH markedly reduced GH release by all MSAs; it inhibited GH and alpha-subunit release by mixed tumors more than it affected PRL. Bromocriptine inhibited GH, PRL, and alpha-subunit release by most MSAs and mixed tumors but did not inhibit GH or PRL release by ASCAs. This study demonstrates release of GH, PRL, and alpha-subunit by these morphologically classified plurihormonal tumors in vitro. Variable quantities of GH and PRL released by the different tumor types correlate with immunohistochemical and clinical data. The dynamic studies indicate that regulation of GH, PRL, and alpha-subunit release can be affected by GHRH, TRH, SRIH, and bromocriptine in these adenomas and suggest differences in receptor status. Our data strengthen the view that these three plurihormonal adenomas of the acidophil cell line are not only morphologically but also functionally different and warrant separation.
Adenoma, Acidophil↗
Antidepressants and thyroid hormone levels.
We assessed the effect of treatment with the tricyclic antidepressant, desipramine, on peripheral thyroid hormone levels in 28 severely depressed patients. Only those whose depression responded showed a decrease in their thyroxine levels without alteration of other thyroid function tests. In a second study involving 38 depressed patients, we observed an increased response to antidepressant treatment with the addition of triiodothyronine but not equivalent doses of thyroxine (T4). The finding is consistent with the decreases in plasma T4 levels which accompany an antidepressant response to desipramine.
Depressive Disorder↗
Direct physiological evidence for scene segmentation by temporal coding.
Theoretical studies have suggested that scene segmentation may be accomplished by a temporal coding mechanism using synchronization of neuronal responses. Here we report a direct experimental test of this hypothesis. Neuronal responses were recorded simultaneously from two to four sites with overlapping receptive fields in cat visual cortex. Correlation analysis revealed that all cells synchronized their responses irrespective of their orientation preference when they were activated by a single light bar. However, when stimulated with two superimposed light bars of different orientations, the same cells segregated into distinct assemblies according to their orientation preferences. Within each of these assemblies responses were synchronized, but correlation was absent between the two assemblies. These results are compatible with the hypothesis that responses to individual objects in a scene are distinguished by synchrony, whereas responses to different objects show no temporal correlation, thus allowing for the segmentation of superimposed stimuli. We conclude that stimulus-specific synchronization of spatially distributed neuronal responses may provide a physiological mechanism for scene segmentation.
Animals↗
Synchronization of oscillatory neuronal responses between striate and extrastriate visual cortical areas of the cat.
Recent studies have shown that neurons in area 17 of cat visual cortex display oscillatory responses which can synchronize across spatially separate orientation columns. Here, we demonstrate that unit responses recorded from the posteromedial lateral suprasylvian area, a visual association area specialized for the analysis of motion, also exhibit an oscillatory temporal structure. Cross-correlation analysis of unit responses reveals that cells in area 17 and the posteromedial lateral suprasylvian area can oscillate synchronously. Moreover, we find that the interareal synchronization is sensitive to features of the visual stimuli, such as spatial continuity and coherence of motion. These results support the hypothesis that synchronous neuronal oscillations may serve to establish relationships between features processed in different areas of visual cortex.
Animals↗
Interhemispheric synchronization of oscillatory neuronal responses in cat visual cortex.
Neurons in area 17 of cat visual cortex display oscillatory responses that can synchronize across spatially separate columns in a stimulus-specific way. Response synchronization has now been shown to occur also between neurons in area 17 of the right and left cerebral hemispheres. This synchronization was abolished by section of the corpus callosum. Thus, the response synchronization is mediated by corticocortical connections. These data are compatible with the hypothesis that temporal synchrony of neuronal discharges serves to bind features within and between the visual hemifields.
Animals↗
Developmental changes in the susceptibility to long-term potentiation of neurones in rat visual cortex slices.
We investigated with intracellular recordings from rat visual cortex slices whether the susceptibility to undergo long-term potentiation (LTP) is age-dependent and whether it is correlated with the expression of synaptic responses mediated by N-methyl-D-aspartate (NMDA) receptors. Test and tetanic stimuli were applied to the white matter and post-tetanic modifications of the amplitude of postsynaptic potentials (PSPs) were assessed in regular spiking cells of supragranular layers. At 2 weeks of age, the amplitudes of early (8-10 ms post-stimulus) and late (20 ms post-stimulus) PSP-components increased after tetanic stimulation to 137.1 +/- 13.4% and 141.3 +/- 12.1% of the pretetanic controls, respectively. At 3 weeks, potentiation of both PSP-components was less pronounced but still significant, the late component being on average more potentiated than the early one. At 4 weeks, PSPs were no longer potentiated. Bath application of 25 microM DL-2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, blocked LTP induction both at 2 and at 3 weeks. We also studied developmental changes of two synaptic responses known to influence the susceptibility of cortical neurones to LTP, the NMDA receptor-mediated excitatory PSP (EPSP) and the initial inhibitory PSP (iIPSP). The amplitude of the APV-sensitive EPSP decreased with age and reached adult values in 4-week-old animals. The iIPSPs were pronounced already at 2 weeks and showed no marked change during further development. The results suggest a close correlation between the susceptibility to undergo LTP and the extent to which NMDA receptor-gated conductances contribute to the synaptic response.(ABSTRACT TRUNCATED AT 250 WORDS)
2-Amino-5-phosphonovalerate↗
Developmental changes of calcium currents in the visual cortex of the cat.
During a critical period of postnatal development the visual cortex of kittens is susceptible to experience-dependent modifications of neuronal response properties. Evidence is accumulating that these modifications are triggered by a transient neuronal calcium (Ca) influx. To further investigate this issue we measured extracellular Ca concentrations with ion-sensitive microelectrodes and compared the magnitude and the distribution of stimulus-evoked Ca fluxes in slices of the visual cortex of 4- to 5-week-old kittens and of 6-month-old adult cats. Stimulation of the white matter at 15 Hz for 8 s caused transient decreases of the extracellular Ca concentration (delta Cao) in slices of both age groups and in all cortical layers. However, there were developmental changes in the laminar distribution of the delta Cao: in kittens, they were maximal in layer IV whereas in adult cats they were most pronounced in the supragranular layers. The ratios between the amplitudes of delta Cao in layer IV and the supragranular layers were 1.65 +/- 0.26 in kittens and 0.43 +/- 0.2 in adult cats. These changes in laminar distribution resemble the laminar specific decay of neuronal malleability and parallel the developmental redistribution of 1,4-Dihydropyridine-sensitive Ca channels. Because of these correlations we interpret our findings as support for the hypothesis that experience-dependent modifications are triggered by Ca influx.
Aging↗
The effect of short periods of monocular deprivation on excitatory transmission in the striate cortex of kittens: a current source density analysis.
The goal of this study was to assess changes in synaptic activity in the visual cortex of kittens following brief periods of monocular deprivation. Field potentials evoked by electrical stimulation of both optic nerves were registered in vertical penetrations through areas 17 and 18 of 4-5 week-old kittens which had been monocularly deprived for 2-7 days. In order to assess the laminar distribution of synaptic currents these field potentials were subjected to a current source density analysis. Current source density profiles elicited from the deprived eye differed from those induced from the normal eye in several respects: 1) The amplitudes of the responses showed considerable variation at different recording sites across the tangential dimension of cortex. 2) On the average, sinks and sources were markedly reduced, and this reduction was relatively more pronounced in non-granular than in granular layers. 3) However, in 30% of the tracks the layer IV sink showed no attenuation. It was reduced in 48% of the tracks and completely suppressed in 22% of the tracks. These results indicate that a substantial fraction of the deprived thalamocortical synapses remained functional, but that many of these synaptic events remained subthreshold. The significance of these findings is discussed in the context of recovery processes following reverse suture.
Animals↗
Neuroscience in the former GDR.
Until 1945, when Germany was subdivided into four occupied territories, scientific traditions and science policy were the same throughout Germany. Then came 45 years of increasing separation and diverging development. Now, the East and West are again formally united and their inhabitants are experiencing, with an intensity that was not anticipated, just how different their countries have become.
Academies and Institutes↗