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At least 37 records · Page 2Linked to original sources
PubMed2000

Topographic projection from the optic tectum to the auditory space map in the inferior colliculus of the barn owl.

In the barn owl (Tyto alba), the external nucleus of the inferior colliculus (ICX) contains a map of auditory space that is calibrated by visual experience. The source of the visually based instructive signal to the ICX is unknown. Injections of biotinylated dextran amine and Fluoro-Gold in the ICX retrogradely labelled neurons in layers 8-15 of the ipsilateral optic tectum (OT) that could carry this instructive signal. This projection was point-to-point and in register with the feed-forward, auditory projection from the ICX to the OT. Most labelled neurons were in layers 10-11, and most were bipolar. Tripolar, multipolar, and unipolar neurons were also observed. Multipolar neurons had dendrites that were oriented parallel to the tectal laminae. In contrast, most labelled bipolar and tripolar neurons had dendrites oriented perpendicular to the tectal laminae, extending superficially into the retino-recipient laminae and deep into the auditory recipient laminae. Therefore, these neurons were positioned to receive both visual and auditory information from particular locations in space. Biocytin injected into the superficial layers of the OT labelled bouton-laden axons in the ICX. These axons were generally finer than, but had similar bouton densities as, feed-forward auditory fibers in the ICX, labelled by injections of biocytin into the central nucleus of the inferior colliculus (ICC). These data demonstrate a point-to-point projection from the OT to the ICX that could provide a spatial template for calibrating the auditory space map in the ICX.

Animals↗
PubMed2006

Time is a rubberband: neuronal activity in monkey motor cortex in relation to time estimation.

Anticipation of predictable events is crucial for organizing motor performance. Using instructed delay tasks, it has been shown that even when delay duration is kept constant, reaction time fluctuates from trial to trial. As time estimation is at the core of anticipatory behavior, it is reasonable to speculate whether neuronal delay activity correlates with the subjective estimate of time. As a consequence of the scalar property of time estimation processes, the variability in time estimation increases continuously as time passes during the delay. This scalar property may then be reflected in the increasing variability in neuronal delay activity. We thus studied the influence of temporal prior information on neuronal delay activity in monkey motor cortex in two conceptually different tasks in which two equally probable delay durations were randomly presented. We hypothesized that if one considers the animal's subjective time as the time which elapses between the first (instruction) signal and movement onset, then, by suppressing this temporal variability, across-trial variability in neuronal discharge should decrease. We thus defined a new time scale in each trial such that, after rescaling, the time between the instruction signal and movement onset was identical in all trials. Each spike was then displaced in time accordingly. As expected, the variability in the timing of neuronal peak discharges no longer increased during the trial. This suggests a direct link between the temporal profile of spiking activity and time estimation. The timing of motor cortical activity reflected the 'elasticity' of the animal's subjective time.

Action Potentials↗
PubMed2000

Song selectivity and sensorimotor signals in vocal learning and production.

Bird song, like human speech, is a learned vocal behavior that requires auditory feedback. Both as juveniles, while they learn to sing, and as adults, songbirds use auditory feedback to compare their own vocalizations with an internal model of a target song. Here we describe experiments that explore a role for the songbird anterior forebrain pathway (AFP), a basal ganglia-forebrain circuit, in evaluating song feedback and modifying vocal output. First, neural recordings in anesthetized, juvenile birds show that single AFP neurons are specialized to process the song stimuli that are compared during sensorimotor learning. AFP neurons are tuned to both the bird's own song and the tutor song, even when these stimuli are manipulated to be very different from each other. Second, behavioral experiments in adult birds demonstrate that lesions to the AFP block the deterioration of song that normally follows deafening. This observation suggests that deafening results in an instructive signal, indicating a mismatch between feedback and the internal song model, and that the AFP is involved in generating or transmitting this instructive signal. Finally, neural recordings from behaving birds reveal robust singing-related activity in the AFP. This activity is likely to originate from premotor areas and could be modulated by auditory feedback of the bird's own voice. One possibility is that this activity represents an efference copy, predicting the sensory consequences of motor commands. Overall, these studies illustrate that sensory and motor processes are highly interrelated in this circuit devoted to vocal learning, as is true for brain areas involved in speech.

Animal Communication↗
PubMed1993

Thymocyte development in major histocompatibility complex-deficient mice: evidence for stochastic commitment to the CD4 and CD8 lineages.

The mechanism resulting in commitment of precursor cells in the thymus to either the CD4 or CD8 lineage remains poorly understood. In principle, this may reflect a stochastic process or may reflect instructional signals from host major histocompatibility complex (MHC) molecules. We have examined the role of MHC products in subset commitment by using mice deficient in class I or class II MHC products. Normal numbers of committed CD4 intermediates (CD4+ CD8lo) develop in the thymus in the absence of class II molecules. Similarly, CD8 transitional cells (CD4loCD8+) are present in the thymus of mice lacking class I products. These findings suggest that commitment of CD4+8+ precursor cells to either lineage is a stochastic process that does not depend on instructive signals from MHC molecules (i.e., expression of alternative differentiative options by uncommitted precursor cells is independent of this environmental signal). These studies also suggest that an interaction between the T-cell antigen receptor (TCR) and MHC molecules that is independent of CD4/CD8 coreceptor engagement enhances stochastic coreceptor downregulation substantially and leads to upregulation of TCR expression as a prelude to selective events that require joint coreceptor/TCR engagement. We suggest that this initial interaction molds the TCR repertoire of stochastically generated T-cell subsets toward recognition of self-MHC products.

Animals↗
PubMed1993

A role for wingless in the segmental gradient of Drosophila?

The wild-type functions of the Wnt family of genes are still little understood (for review see Nusse and Varmus, Cell 69, 1073-1087, 1992). In Drosophila, the wingless (D-Wnt-1) protein is expressed in segmental stripes: its absence leads to a complete failure of segmentation, loss of engrailed expression and lack of pattern in the cuticle. A predominating hypothesis is that the spatial distribution of wingless is crucial to pattern; it might carry an instructive signal from cells that secrete the protein to cells nearby, or it might form a concentration gradient which acts as a morphogen. We tested these hypotheses by expressing wingless ubiquitously in wingless- embryos. The distribution of wingless protein in these embryos is uniform. Despite this, engrailed expression persists, is confined to the most anterior third of the parasegment, and delineates the parasegment border. The cuticle shows a segmentally reiterated pattern and, dorsally, the denticles are normally distributed and oriented. Because all these position-specific features cannot have been placed by a local source or a differential distribution of wingless protein, we conclude that, in the early embryo, the role of wingless is neither to act as a local instructive signal, nor as a morphogen. We propose an alternative hypothesis that the wild-type function of the wingless protein is to maintain and 'seal' the parasegment borders; in its absence the borders fail to isolate abutting segmental gradients.

Animals↗
PubMed1992

Human ameloblastoma tumors express the amelogenin gene.

Instructive signals are responsible for the regulation of the expression of gene products characteristic of many cell lineages during normal development and potentially during neoplasia. The odontogenic origin of ameloblastomas is based largely on the similarity in histologic appearance between the tumor and the developing tooth organ. A pathognomonic pattern for odontogenic tissue-specific gene expression in ameloblastomas has not been previously shown. In these studies, the gene expression parameters for human ameloblastomas have been characterized with the techniques of messenger RNA phenotyping in combination with Northern and in situ hybridization analysis of messenger RNA. The results of these studies confirm that amelogenin, a gene transcribed solely by differentiated ameloblasts, was expressed by epithelial cells from human ameloblastomas. This observation suggests that the instructive signals required for ameloblast differentiation are shared during normal development and tumorigenesis of odontogenic epithelium.

Ameloblastoma↗
PubMed2005

High-level activation of cyclic AMP signaling attenuates bone morphogenetic protein 2-induced sympathoadrenal lineage development and promotes melanogenesis in neural crest cultures.

The intensity of cyclic AMP (cAMP) signaling is a differential instructive signal in neural crest (NC) cell specification. By an unknown mechanism, sympathoadrenal lineage specification is suppressed by high-level activation of cAMP signaling. In NC cultures, high-level activation of cAMP signaling mediates protein kinase A (PKA)-dependent Rap1-B-Raf-ERK1/2 activation, leading to cytoplasmic accumulation of phospho-Smad1, thus terminating bone morphogenetic protein 2 (BMP2)-induced sympathoadrenal cell development. Concurrently, cAMP signaling induces transcription of the melanocyte-determining transcription factor Mitf and melanogenesis. dnACREB and E1A inhibit Mitf expression and melanogenesis, supporting the notion that CREB activation is necessary for melanogenesis. However, constitutively active CREB(DIEDML) without PKA activation is insufficient for Mitf expression and melanogenesis, indicating PKA regulates additional aspects of Mitf transcription. Thus, high-level activation of cAMP signaling plays a dual role in NC cell differentiation: attenuation of BMP2-induced sympathoadrenal cell development and induction of melanogenesis. We conclude the intensity of activation of signal transduction cascades determines cell lineage segregation mechanisms.

Adrenal Glands↗
PubMed1999

Sensory-motor transformation and motor planning in the primate frontal cortex.

To examine the role of the frontal cortex in sensory-motor processing, we trained a Rhesus monkey to perform a behavioral task with alternations between localization (LOC) and non-localization (NL) paradigms. In the LOC block, the monkey had to remember the modality and location of two sequential cues. Two different GO signals instructed the monkey to touch the memorized location of either auditory or visual spatial cues (GO-AUD or GO-VIS, respectively). In the NL paradigm the monkey received the same stimuli, but was instructed to touch a fixed target, disregarding the location and modality of the spatial and GO signals. Reaction time was significantly longer after GO-AUD signals in the LOC mode compared to the reaction time following GO-VIS signals, or in the NL mode. We examined 961 neurons in the frontal cortex and 427 parietal neurons. A group of frontal task-related neurons (72/430; 16.7%) showed evoked activity both after the visual and the GO-AUD stimuli in the LOC mode. The units did not respond to the GO-VIS signal that instructed the monkey to move to the same location, or to the identical stimuli in the NL mode. No such neurons were found in the sampled areas of the parietal cortex. Our findings suggest that the monkey initially planned a default response towards the location of the visual stimulus and immediately updated his motor plans when instructed to touch the memorized location of the auditory stimulus. We suggest that frontal activity may also be related to such modifications of sensory-motor associations.

Animals↗
PubMed2003

Inhibitory control of eye movements during oculomotor countermanding in adults with attention-deficit hyperactivity disorder.

Children with attention-deficit hyperactivity disorder (ADHD) are impulsive, and that impulsiveness can be measured using a countermanding task. Although the overt behaviors of ADHD attenuate with age, it is not clear how well impulsiveness is controlled in adults with ADHD. We tested ADHD adults with an oculomotor countermanding task. The task included two conditions: on 75% of the trials, participants viewed a central fixation marker and then looked to an eccentric target that appeared simultaneous with the disappearance of the fixation marker; on 25% of the trials, a signal was presented at variable delays after target appearance. The signal instructed subjects to stop, or countermand, an eye movement to the target. A correct movement in this case would be to hold gaze at the central fixation location. We expected ADHD participants to be impulsive in their countermanding performance. Additionally, we expected that a visual stop signal at the central fixation location would assist oculomotor countermanding because the signal is presented in the "stop" location, at fixation. To test whether a central stop signal positively biased countermanding, we used a three types of stop signal to instruct the stop: a central visual marker, a peripheral visual signal, and a non-localized sound. All subjects performed best with the central visual stop signal. Subjects with ADHD were less able to countermand eye movements and were influenced more negatively by the non-central signals. Oculomotor countermanding may be useful for quantifying impulsive dysfunction in adults with ADHD especially if a non-central stop signal is applied.

Acoustic Stimulation↗
PubMed1994

Neuronal activity in the primate supplementary, pre-supplementary and premotor cortex during externally and internally instructed sequential movements.

This study recorded the activity of neurons in the (i) supplementary motor area (SMA), (ii) pre-SMA (the motor area immediately rostral to the SMA), (iii) premotor cortex (PMC) and (iv) primary motor cortex (MI), while the monkey performed a conditional sequential motor task that ensures sequencing of multiple movements to the same manipulandum. This paradigm was chosen in order to prevent the participation of spatial cues in prompting the correct motor sequence. Three different movements (turn-push-pull) were performed under two task conditions: (i) internally determined (I): the monkey had to generate a pre-determined sequence from memory and without visual guidance; (ii) externally triggered (E): the correct sequence of movements was performed by following lights illuminated one after the other. Neuronal activity during the following periods were analyzed: instruction (300 ms following the onset of the auditory instruction signal); delay (interval between the end of the instruction period or the termination of the previous movement and the movement trigger); premovement (interval between the trigger signal and the movement onset); movement (interval between the mechanically-sensed movement onset and the completion of the movement) and reward (500 ms period centered at the time of reward delivery). Pre-SMA neurons were generally more active during the delay and premovement as compared to the movement, instruction and reward periods. Activity in the pre-SMA was more related to E during the pre-movement period, but exhibited a preferential relationship to I in the movement period. SMA neurons were more active when the sequential motor task was internally generated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Tyrosine kinase signal specificity: lessons from the HGF receptor.

There are two major lines of thinking concerning the mechanisms responsible for specificity in receptor tyrosine kinase signalling. On one hand, receptors might provide instructive signals that dictate cell-fate decisions and, on the other, they might generate permissive signals unleashing responses that are inherently defined in the protein repertoire of target cells. Recent data indicate that the signalling activity of the Met receptor for hepatocyte growth factor is affected by association with cell-specific surface molecules, namely the alpha6beta4 integrin, Plexin B1 and CD44. This suggests that integration of cell-restricted expression of receptor partners that modulate kinase outputs with the intrinsic signalling features of receptors is required for specification of biological responses.

Animals↗
PubMed1997

Bone morphogenetic proteins in the nervous system.

Bone morphogenetic proteins (BMPs) are a rapidly expanding subclass of the transforming growth factor superfamily. BMP ligands and receptor subunits are present throughout neural development within discrete regions of the embryonic brain and within neural crest-derived pre- and post-migratory zones. BMPs initially inhibit the formation of neuroectoderm during gastrulation while, within the neural tube, they act as gradient morphogens to promote the differentiation of dorsal cell types and intermediate cell types throughout co-operative signaling. In the peripheral nervous system, BMPs act as instructive signals for neuronal lineage commitment and promote graded stages of neuronal differentiation. By contrast, within the CNS, these same factors promote astroglial lineage elaboration from embryonic subventricular zone progenitor cells, with concurrent suppression of the neuronal or oligodendroglial lineages, or both. In addition, BMPs act on more lineage-restricted embryonic CNS progenitor cells to promote regional neuronal survival and cellular differentiation. Furthermore, these versatile cytokines induce selective apoptosis of discrete rhombencephalic neural crest-associated cellular populations. These observations suggest that the BMPs exhibit a broad range of cellular and context-specific effects during multiple stages of neural development.

Animals↗
PubMed2005

Restricted response of mesencephalic neural crest to sympathetic differentiation signals in the trunk.

Lineage diversification in the vertebrate neural crest may occur via instructive signals acting on pluripotent cells, and/or via early specification of subpopulations towards particular lineages. Mesencephalic neural crest cells normally form cholinergic parasympathetic neurons in the ciliary ganglion, while trunk neural crest cells normally form both catecholaminergic and cholinergic neurons in sympathetic ganglia. In contrast to trunk neural crest cells, mesencephalic neural crest cells apparently fail to express the catecholaminergic transcription factor dHAND in response to BMPs in the head environment. Here, we show that migrating quail mesencephalic neural crest cells grafted into the trunk of host chick embryos colonise the sympathetic ganglia. While many express dHAND and form tyrosine hydroxylase (TH)-positive catecholaminergic neurons, the proportion that expresses either dHAND or TH is significantly smaller than that of quail trunk neural crest cells under the same conditions. Furthermore, the proportion of quail mesencephalic neural crest cells that is TH+ in the sympathetic ganglia decreases with time, while the proportion of TH+ quail trunk neural crest-derived cells increases. Thus, a subset of mesencephalic neural crest cells fails to express dHAND or TH in the sympathetic ganglia, while a further subset initiates but fails to maintain TH expression. Taken together, our results suggest that a subpopulation of migrating mesencephalic neural crest cells is refractory to catecholaminergic differentiation signals in the trunk. We suggest that this heterogeneity, together with local signals that repress catecholaminergic differentiation, may ensure that most ciliary neurons adopt a cholinergic fate.

Animals↗
PubMed2005

The importance of being agranular: a comparative account of visual and motor cortex.

The agranular cortex is an important landmark-anatomically, as the architectural flag of mammalian motor cortex, and historically, as a spur to the development of theories of localization of function. But why, exactly, do agranularity and motor function go together? To address this question, it should be noted that not only does motor cortex lack granular layer four, it also has a relatively thinner layer three. Therefore, it is the two layers which principally constitute the ascending pathways through the sensory (granular) cortex that have regressed in motor cortex: simply stated, motor cortex does not engage in serial reprocessing of incoming sensory data. But why should a granular architecture not be demanded by the downstream relay of motor instructions through the motor cortex? The scant anatomical evidence available regarding laminar patterns suggests that the pathways from frontal and premotor areas to the primary motor cortex actually bear a greater resemblance to the descending, or feedback connections of sensory cortex that avoid the granular layer. The action of feedback connections is generally described as "modulatory" at a cellular level, or "selective" in terms of systems analysis. By contrast, ascending connections may be labelled "driving" or "instructive". Where the motor cortex uses driving inputs, they are most readily identified as sensory signals instructing the visual location of targets and the kinaesthetic state of the body. Visual signals may activate motor concepts, e.g. "mirror neurons", and the motor plan must select the appropriate muscles and forces to put the plan into action, if the decision to move is taken. This, perhaps, is why "driving" motor signals might be inappropriate-the optimal selection and its execution are conditional upon both kinaesthetic and motivational factors. The argument, summarized above, is constructed in honour of Korbinian Brodmann's centenary, and follows two of the fundamental principles of his school of thought: that uniformities in cortical structure, and development imply global conservation of some aspects of function, whereas regional variations in architecture can be used to chart the "organs" of the cortex, and perhaps to understand their functional differences.

Brain Mapping↗
PubMed1999

Hypothesis: genes which function in a stochastic lineage commitment process are subject to monoallelic expression.

The collection of genes which are now known to be monoallelically expressed in mammals is a diverse set. In the case of the genes which encode transducing receptors, such as immunoglobulins or odoront receptors, monoallelic expression ensures that cell activity is related to encountering a unique ligand. However, some monoallelically expressed genes do not encode receptors, and in these cases the physiological purpose of monoallelic expression is uncertain. Even more puzzling are the cases of imprinted genes, where only the maternal or only the paternal allele is expressed. In this article we consider the hypothesis that some of these cases of monoallelic expression reflect the unusual instances in development in which lineage commitment results from a selective rather than an instructive mechanism. These mechanisms are distinguished by their reliance on either external signals (instructive) or internal, cell autonomous events (selective) to cause the changes in gene expression which correspond to lineage commitment. While the instructive mechanism predicts that lineage commitment genes will be expressed or silenced biallelically, the selective mechanism predicts that commitment genes will be subject to monoallelic expression. Specifically, for the cases in which lineage commitment results from activating gene expression, the selective mechanism predicts that commitment genes will be monoallelically expressed following commitment, such as observed recently for some cytokine and transcription factor genes. For the cases in which extinction of gene expression causes commitment, the selective mechanism predicts that the commitment genes will be monoallelically expressed prior to commitment, as for X-linked and imprinted genes.

Alleles↗
PubMed2005

Hedgehog signaling controls Soma-Germen interactions during Drosophila ovarian morphogenesis.

The genetic analysis of Drosophila adult oogenesis has provided insights into the molecular mechanisms that control cell proliferation, differentiation, migration, and intercellular signaling. However, little is known about the larval and pupal cellular events leading to the formation of the highly organized adult ovary, which is composed of ovarioles each containing germline cells enveloped by specialized somatic cells. We describe here the presence of ovarioles devoid of any germ cells in adult females mutant for fused, which encodes a Hedgehog signal transducing serine/threonine kinase. We show that this phenotype corresponds to a requirement for fused function for the organization of germ cells with respect to ovarian somatic cells during ovariole formation specifically during pupal stages and provide some evidence by means of clonal analysis suggesting that fused function may be necessary in the germline. hedgehog is expressed specifically in somatic terminal filament cells in pupal ovaries, and females bearing hedgehog strong loss-of-function mutations also exhibit aberrant germ cell distribution and formation of agametic ovarioles. These results indicate a positive role for Fused in the transduction of somatic Hedgehog signaling instructing ovariole morphogenesis. We also provide evidence for the use of noncanonical Hedgehog signal transducer(s) within germline cells.

Alleles↗
PubMed2001

Evidence that gammadelta versus alphabeta T cell fate determination is initiated independently of T cell receptor signaling.

Two types of T cells, alphabeta and gammadelta, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of alphabeta lineage T cells requires the surrogate alpha chain (pTalpha), which associates with the T cell receptor (TCR) beta chain to form the pre-TCR. gammadelta lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR gamma and delta genes. It has been proposed that the quality of signals transmitted by the pre-TCR and gammadelta TCR are distinct and that these "instructive" signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25(+)CD44(+)c-kit(+)CD3(-)CD4(-)CD8(-) thymocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into gammadelta versus alphabeta lineage (CD4+CD8+ cells) in the thymus. Upon intrathymic injection, IL-7R(neg-lo) pro-T cells generated a 13-fold higher ratio of alphabeta lineage to gammadelta lineage cells than did IL-7R(+) pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R(+) pro-T cells to develop into TCR-gammadelta T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-gamma gene rearrangement/expression in IL-7R(+) pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.

Animals↗