Organizing principles across the senses

ABSTRACT This thesis is composed of two main parts. The first addressed the question of whether the auditory and somatosensory systems, like their visual counterpart, comprise parallel functional pathways for processing identity and spatial attributes (so-called `what' and `where' pathways, respectively). The second part examined the independence of control processes mediating task switching across 'what' and `where' pathways in the auditory and visual modalities. Concerning the first part, electrical neuroimaging of event-related potentials identified the spatio-temporal mechanisms subserving auditory (see Appendix, Study n°1) and vibrotactile (see Appendix, Study n°2) processing during two types of blocks of trials. `What' blocks varied stimuli in their frequency independently of their location.. `Where' blocks varied the same stimuli in their location independently of their frequency. Concerning the second part (see Appendix, Study n°3), a psychophysical task-switching paradigm was used to investigate the hypothesis that the efficacy of control processes depends on the extent of overlap between the neural circuitry mediating the different tasks at hand, such that more effective task preparation (and by extension smaller switch costs) is achieved when the anatomical/functional overlap of this circuitry is small. Performance costs associated with switching tasks and/or switching sensory modalities were measured. Tasks required the analysis of either the identity or spatial location of environmental objects (`what' and `where' tasks, respectively) that were presented either visually or acoustically on any given trial. Pretrial cues informed participants of the upcoming task, but not of the sensory modality. - In the audio-visual domain, the results showed that switch costs between tasks were significantly smaller when the sensory modality of the task switched versus when it repeated. In addition, switch costs between the senses were correlated only when the sensory modality of the task repeated across trials and not when it switched. The collective evidence not only supports the independence of control processes mediating task switching and modality switching, but also the hypothesis that switch costs reflect competitive interterence between neural circuits that in turn can be diminished when these neural circuits are distinct. - In the auditory and somatosensory domains, the findings show that a segregation of location vs. recognition information is observed across sensory systems and that these happen around 100ms for both sensory modalities. - Also, our results show that functionally specialized pathways for audition and somatosensation involve largely overlapping brain regions, i.e. posterior superior and middle temporal cortices and inferior parietal areas. Both these properties (synchrony of differential processing and overlapping brain regions) probably optimize the relationships across sensory modalities. - Therefore, these results may be indicative of a computationally advantageous organization for processing spatial anal identity information.

Non-traumatic spinal cord ischaemia in childhood - clinical manifestation, neuroimaging and outcome.

BACKGROUND: Spinal cord ischaemia is rare in childhood and information on clinical presentation and outcome is scarce. METHODS: This is a retrospective analysis of eight patients and 75 additional cases from the literature. Data search included: patient's age, primary manifestation, risk factors, neuroimaging and outcome. RESULTS: Five female and three male patients gave consent to participate. Mean age was 12.5 years (10-15 years). Six patients presented with paraplegia; this was preceded by pain in four. Brown Sequard syndrome and quadriparesis were the two others' presenting condition. Sensation levels were thoracolumbar in seven cases. Bladder dysfunction only or bladder and bowel dysfunction were reported in eight and five patients respectively. Time to maximal symptom manifestation was <12 h in 7/8. Risk factors included surgery, minor trauma, recent infection, and thrombophilia. Mean follow-up was 3.3 years (0.25-6.3 years). Three patients remained wheelchair-dependent and three patients were ambulatory without aid. Bladder function recovered fully in five children. Most affected aspects of quality of life were physical and mental well-being and self-perception. T2-weighted-MR images showed pencil-like hyperintensity (8/8) in sagittal and H-shaped or snake-eyes-like lesion (6/8) in axial views. Analyses of all 83 patients were in congruence with the above results of the study group. CONCLUSION: Spinal cord ischaemia in childhood presenting with pain, paraplegia, and bladder dysfunction has high morbidity concerning motor problems and quality of life. Acute arterial ischaemic event in children seems similar to adult events with respect to clinical presentation and, surprisingly, also in outcome.

Modification de la composition des cigarettes durant te XXe siècle: rôle de l'industrie du tabac et effet sur la dépendance tabagique [Chemicals added to cigarettes and their effects on tobacco dependence]

This paper summarizes data on the factors involved in addiction and dependence to cigarettes. Nicotine has been intensively studied by the tobacco industry, for instance for its addictive effect at the lowest possible rates. The addition of diammonium phosphate and urea produces an alcalinization of the pH of cigarette smoke, and promotes the absorption and the trans-membrane passage of nicotine. The taste, the smell of smoke, and the visual aspect of the pack of cigarettes are also sensory components that promote addiction. Finally, menthol, sugar, cocoa and liquorice added to cigarettes also play a role in dependence and addiction to cigarettes by, for instance, making an anesthetic effect on the airways.

Architectural and Functional Similarities between Trimeric ATP-Gated P2X Receptors and Acid-Sensing Ion Channels

ATP-gated P2X receptors and acid-sensing ion channels are two distinct ligand-gated ion channels that assemble into trimers. They are involved in many important physiological functions such as pain sensation and are recognized as important therapeutic targets. They have unrelated primary structures and respond to different ligands (ATP and protons) and are thus considered as two different ion channels. As a consequence, comparisons of the biophysical properties and underlying mechanisms have only been rarely made between these two channels. However, the recent determination of their molecular structures by X-ray crystallography has revealed unexpected parallels in the architecture of the two pores, providing a basis for possible functional analogies. In this review, we analyze the structural and functional similarities that are shared by these trimeric ion channels, and we outline key unanswered questions that, if addressed experimentally, may help us to elucidate how two unrelated ion channels have adopted a similar fold of the pore.

The costs of crossing paths and switching tasks between audition and vision.

Switching from one functional or cognitive operation to another is thought to rely on executive/control processes. The efficacy of these processes may depend on the extent of overlap between neural circuitry mediating the different tasks; more effective task preparation (and by extension smaller switch costs) is achieved when this overlap is small. We investigated the performance costs associated with switching tasks and/or switching sensory modalities. Participants discriminated either the identity or spatial location of objects that were presented either visually or acoustically. Switch costs between tasks were significantly smaller when the sensory modality of the task switched versus when it repeated. This was the case irrespective of whether the pre-trial cue informed participants only of the upcoming task, but not sensory modality (Experiment 1) or whether the pre-trial cue was informative about both the upcoming task and sensory modality (Experiment 2). In addition, in both experiments switch costs between the senses were positively correlated when the sensory modality of the task repeated across trials and not when it switched. The collective evidence supports the independence of control processes mediating task switching and modality switching and also the hypothesis that switch costs reflect competitive interference between neural circuits.

Fatigue: revue et approche diagnostique [Fatigue: review and systematic approach to potential causes]

Fatigue is defined as a sensation of exhaustion during or after usual activities. As much as one third of patients consulting a primary care physician report this complaint. After investigation, two-thirds of the patients have a somatic or psychiatric diagnosis. This review presents a seven-step approach to the patient who complains of fatigue.

The Sensation of colour

The figurative painter accesses very complex levels of knowledge. To produce a painting requires, first, a deep analysis of the image of the reality and, afterwards, the study of the reconstruction of this reality. This is not about a process of copying, but a process of the comprehension of the concepts that appear in the representation. The drawing guides us in the process of the production of the surface and in the distribution of the colours that, after all, are the data with which the vision mechanism builds the visual reality. Knowing the colour and its behaviour have always been a requirement for the figurative painter. From that knowledge we can draw wider conclusions.

Regulatory roles of the GacS/GacA two-component system in plant-associated and other gram-negative bacteria.

The sensor kinase GacS and the response regulator GacA are members of a two-component system that is present in a wide variety of gram-negative bacteria and has been studied mainly in enteric bacteria and fluorescent pseudomonads. The GacS/GacA system controls the production of secondary metabolites and extracellular enzymes involved in pathogenicity to plants and animals, biocontrol of soilborne plant diseases, ecological fitness, or tolerance to stress. A current model proposes that GacS senses a still-unknown signal and activates, via a phosphorelay mechanism, the GacA transcription regulator, which in turn triggers the expression of target genes. The GacS protein belongs to the unorthodox sensor kinases, characterized by an autophosphorylation, a receiver, and an output domain. The periplasmic loop domain of GacS is poorly conserved in diverse bacteria. Thus, a common signal interacting with this domain would be unexpected. Based on a comparison with the transcriptional regulator NarL, a secondary structure can be predicted for the GacA sensor kinases. Certain genes whose expression is regulated by the GacS/GacA system are regulated in parallel by the small RNA binding protein RsmA (CsrA) at a posttranscriptional level. It is suggested that the GacS/GacA system operates a switch between primary and secondary metabolism, with a major involvement of posttranscriptional control mechanisms.

Free conjunctival autologous graft for bleb repair and bleb reduction after trabeculectomy and nonpenetrating filtering surgery.

PURPOSE: To describe methods and outcomes of excisional revision of a filtering bleb (bleb revision) using free conjunctival autologous graft either for bleb repair or for bleb reduction after trabeculectomy and deep sclerectomy with an implant. METHODS: Retrospective medical records were reviewed for a consecutive non-comparative case series comprising patients who underwent excisional revision of a filtering bleb between May 1998-January 2001. Excisional revision using free conjunctival autologous graft (bleb revision) was performed either for bleb repair, to treat early and late leaks and hypotony with maculopathy, or for bleb reduction, to improve ocular pain, discomfort, burning, foreign body sensation, tearing, and fluctuations of visual acuity. The revision consisted of bleb excision and free conjunctival autologous graft. The bleb histopathology was analyzed in patients who underwent bleb repair. RESULTS: Sixteen patients were included in the study, consisting of nine patients who had a trabeculectomy and seven patients who had a deep sclerectomy with an implant. Bleb revision was necessary in 14 patients due to leaking filtering bleb (bleb repair), and in 2 patients due to bleb dysesthesia (bleb reduction). After a follow-up of 15.1 +/- 8.4 months, the mean intraocular pressure (IOP) rose from 7.8 +/- 6.3 mm Hg to 14.3 +/- 6.5 mm Hg, and the visual acuity from 0.4 +/- 0.3 to 0.7 +/- 0.3, with a P value of 0.008 and 0.03, respectively. The complete success rate at 32 months, according to the Kaplan-Meier survival curve, was 38.3%, and the qualified success rate was 83.3%. Four patients (25%) required additional suturing for persistent bleb leak. To control IOP, antiglaucoma medical therapy was needed for six patients (37.5%) and repeated glaucoma surgery was needed for one patient. CONCLUSION: Free conjunctival autologous graft is a safe and successful procedure for bleb repair and bleb reduction. However, patients should be aware of the postoperative possibility of requiring medical or surgical intervention for IOP control after revision.

ROLES OF ACID-SENSING ION CHANNELS (ASICS) IN PERIPHERAL NEUROPEPTIDE SECRETION AND PAIN

Acid-sensing ion channels (ASICs) are non-voltage-gated sodium channels activated by an extracellular acidification. They are widely expressed in neurons of the central and peripheral nervous system. ASICs have a role in learning, the expression of fear, in neuronal death after cerebral ischemia, and in pain sensation. Tissue damage leads to the release of inflammatory mediators. There is a subpopulation of sensory neurons which are able to release the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). Neurogenic inflammation refers to the process whereby peripheral release of the neuropeptides CGRP and SP induces vasodilation and extravasation of plasma proteins, respectively. Our laboratory has previously shown that calcium-permeable homomeric ASIC1a channels are present in a majority of CGRP- or SP-expressing small diameter sensory neurons. In the first part of my thesis, we tested the hypothesis that a local acidification can produce an ASIC-mediated calcium-dependant neuropeptide secretion. We have first verified the co-expression of ASICs and CGRP/SP using immunochemistry and in-situ hybridization on dissociated rat dorsal root ganglion (DRG) neurons. We found that most CGRP/SP-positive neurons also expressed ASIC1a and ASIC3 subunits. Calcium imaging experiments with Fura-2 dye showed that an extracellular acidification can induce an increase of intracellular Ca2+ concentration, which is essential for secretion. This increase of intracellular Ca2+ concentration is, at least in some cells, ASIC-dependent, as it can be prevented by amiloride, an ASIC antagonist, and by Psalmotoxin (PcTx1), a specific ASIC1a antagonist. We identified a sub-population of neurons whose acid-induced Ca2+ entry was completely abolished by amiloride, an amiloride-resistant population which does not express ASICs, but rather another acid-sensing channel, possibly transient receptor potential vanilloïde 1 (TRPV1), and a population expressing both H+-gated channel types. Voltage-gated calcium channels (Cavs) may also mediate Ca2+ entry. Co-application of the Cavs inhibitors (ω-conotoxin MVIIC, Mibefradil and Nifedipine) reduced the Ca2+ increase in neurons expressing ASICs during an acidification to pH 6. This indicates that ASICs can depolarise the neuron and activate Cavs. Homomeric ASIC1a are Ca2+-permeable and allow a direct entry of Ca2+ into the cell; other ASICs mediate an indirect entry of Ca2+ by inducing a membrane depolarisation that activates Cavs. We showed with a secretion assay that CGRP secretion can be induced by extracellular acidification in cultured rat DRG neurons. Amiloride and PcTx1 were not able to inhibit the secretion at acidic pH, but BCTC, a TRPV1 inhibitor was able to decrease the secretion induced by an extracellular acidification in our in vitro secretion assay. In conclusion, these results show that in DRG neurons a mild extracellular acidification can induce a calcium-dependent neuropeptide secretion. Even if our data show that ASICs can mediate an increase of intracellular Ca2+ concentration, this appears not to be sufficient to trigger neuropeptide secretion. TRPV1, a calcium channel whose activation induces a sustained current - in contrary of ASICs - played in our experimental conditions a predominant role in neurosecretion. In the second part of my thesis, we focused on the role of ASICs in neuropathic pain. We used the spared nerve injury (SNI) model which consists in a nerve injury that induces symptoms of neuropathic pain such as mechanical allodynia. We have previously shown that the SNI model modifies ASIC currents in dissociated rat DRG neurons. We hypothesized that ASICs could play a role in the development of mechanical allodynia. The SNI model was performed on ASIC1a, -2, and -3 knock-out mice and wild type littermates. We measured mechanical allodynia on these mice with calibrated von Frey filaments. There were no differences between the wild-type and the ASIC1, or ASIC2 knockout mice. ASIC3 null mice were less sensitive than wild type mice at 21 day after SNI, indicating a role for ASIC3. Finally, to investigate other possible roles of ASICs in the perception of the environment, we measured the baseline heat responses. We used two different models; the tail flick model and the hot plate model. ASIC1a null mice showed increased thermal allodynia behaviour in the hot plate test at three different temperatures (49, 52, 55°C) compared to their wild type littermates. On the contrary, ASIC2 null mice showed reduced thermal allodynia behaviour in the hot plate test compared to their wild type littermates at the three same temperatures. We conclude that ASIC1a and ASIC2 in mice can play a role in temperature sensing. It is currently not understood how ASICs are involved in temperature sensing and what the reason for the opposed effects in the two knockout models is.

Neuroscience robotics to investigate multisensory integration and bodily awareness.

Humans experience the self as localized within their body. This aspect of bodily self-consciousness can be experimentally manipulated by exposing individuals to conflicting multisensory input, or can be abnormal following focal brain injury. Recent technological developments helped to unravel some of the mechanisms underlying multisensory integration and self-location, but the neural underpinnings are still under investigation, and the manual application of stimuli resulted in large variability difficult to control. This paper presents the development and evaluation of an MR-compatible stroking device capable of presenting moving tactile stimuli to both legs and the back of participants lying on a scanner bed while acquiring functional neuroimaging data. The platform consists of four independent stroking devices with a travel of 16-20 cm and a maximum stroking velocity of 15 cm/s, actuated over non-magnetic ultrasonic motors. Complemented with virtual reality, this setup provides a unique research platform allowing to investigate multisensory integration and its effects on self-location under well-controlled experimental conditions. The MR-compatibility of the system was evaluated in both a 3 and a 7 Tesla scanner and showed negligible interference with brain imaging. In a preliminary study using a prototype device with only one tactile stimulator, fMRI data acquired on 12 healthy participants showed visuo-tactile synchrony-related and body-specific modulations of the brain activity in bilateral temporoparietal cortex.

International union of basic and clinical pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel.

The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.

Color sensation in figurative painting

The figurative painter accesses very complex levels of knowledge. To produce a painting requires, first, a deep analysis of the image of the reality and, afterwards, the study of the reconstruction of this reality. This is not about a process of copying, but a process of the comprehension of the concepts that appear in the representation. The drawing guides us in the process of the production of the surface and in the distribution of the colours that, after all, are the data with which the vision mechanism builds the visual reality. Knowing the colour and its behaviour have always been a requirement for the figurative painter. From that knowledge we can draw wider conclusions.

A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a.

Acid-sensing ion channels (ASICs) are key receptors for extracellular protons. These neuronal nonvoltage-gated Na(+) channels are involved in learning, the expression of fear, neurodegeneration after ischemia, and pain sensation. We have applied a systematic approach to identify potential pH sensors in ASIC1a and to elucidate the mechanisms by which pH variations govern ASIC gating. We first calculated the pK(a) value of all extracellular His, Glu, and Asp residues using a Poisson-Boltzmann continuum approach, based on the ASIC three-dimensional structure, to identify candidate pH-sensing residues. The role of these residues was then assessed by site-directed mutagenesis and chemical modification, combined with functional analysis. The localization of putative pH-sensing residues suggests that pH changes control ASIC gating by protonation/deprotonation of many residues per subunit in different channel domains. Analysis of the function of residues in the palm domain close to the central vertical axis of the channel allowed for prediction of conformational changes of this region during gating. Our study provides a basis for the intrinsic ASIC pH dependence and describes an approach that can also be applied to the investigation of the mechanisms of the pH dependence of other proteins.

Evolution and functional characterisation of the IR chemosensory receptors in the Drosophila larval gustatory system

Chemosensory receptor gene families encode divergent proteins capable of detecting a huge diversity of environmental stimuli that are constantly changing over evolutionary time as organisms adapt to distinct ecological niches. While olfaction is dedicated to the detection of volatile compounds, taste is key to assess food quality for nutritional value and presence of toxic substances. The sense of taste also provides initial signals to mediate endocrine regulation of appetite and food metabolism and plays a role in kin recognition. The fruit fly Drosophila melanogaster is a very good model for studying smell and taste because these senses are very important in insects and because a broad variety of genetic tools are available in Drosophila. Recently, a family of 66 chemosensory receptors, the Ionotropic Receptors (IRs) was described in fruit flies. IRs are distantly related to ionotropic glutamate receptors (iGluRs), but their evolutionary origin from these synaptic receptors is unclear. While 16 IRs are expressed in the olfactory system, nothing is known about the other members of this repertoire. In this thesis, I describe bioinformatic, expression and functional analyses of the IRs aimed at understanding how these receptors have evolved, and at characterising the role of the non-olfactory IRs. I show that these have emerged at the basis of the protostome lineage and probably have acquired their sensory function very early. Moreover, although several IRs are conserved across insects, there are rapid and dramatic changes in the size and divergence of IR repertoires across species. I then performed a comprehensive analysis of IR expression in the larva of Drosophila melanogaster, which is a good model to study taste and feeding mechanisms as it spends most of its time eating or foraging. I found that most of the divergent members of the IR repertoire are expressed in both peripheral and internal gustatory neurons, suggesting that these are involved in taste perception. Finally, through the establishment of a new neurophysiological assay in larvae, I identified for the first time subsets of IR neurons that preferentially detect sugars and amino acids, indicating that IRs might be involved in sensing these compounds. Together, my results indicate that IRs are an evolutionarily dynamic and functionally versatile family of receptors. In contrast to the olfactory IRs that are well-conserved, gustatory IRs are rapidly evolving species-specific receptors that are likely to be involved in detecting a wide variety of tastants. - La plupart des animaux possèdent de grandes familles de récepteurs chimiosensoriels dont la fonction est de détecter l'immense diversité de composés chimiques présents dans l'environnement. Ces récepteurs évoluent en même temps que les organismes s'adaptent à leur écosystème. Il existe deux manières de percevoir ces signaux chimiques : l'olfaction et le goût. Alors que le système olfactif perçoit les composés volatiles, le sens du goût permet d'évaluer, par contact, la qualité de la nourriture, de détecter des substances toxiques et de réguler l'appétit et le métabolisme. L'un des organismes modèles les plus pertinents pour étudier le sens du goût est le stade larvaire de la mouche du vinaigre Drosophila melanogaster. En effet, la principale fonction du stade larvaire est de trouver de la nourriture et de manger. De plus, il est possible d'utiliser tous les outils génétiques développés chez la drosophile. Récemment, une nouvelle famille de 66 récepteurs chimiosensoriels appelés Récepteurs Ionotropiques (IRs) a été découverte chez la drosophile. Bien que leur orogine soit peu claire, ces récepteurs sont similaires aux récepteurs ionotropiques glutamatergiques impliqués dans la transmission synaptique. 16 IRs sont exprimés dans le système olfactif de la mouche adulte, mais pour l'instant on ne connaît rien des autres membres de cette famille. Durant ma thèse, j'ai effectué des recherches sur l'évolution de ces récepteurs ainsi que sur l'expression et la fonction des IRs non olfactifs. Je démontre que les IRs sont apparus chez l'ancêtre commun des protostomiens et ont probablement acquis leur fonction sensorielle très rapidement. De plus, bien qu'un certain nombre d'IRs olfactifs soient conservés chez les insectes, d'importantes variations dans la taille et la divergence des répertoires d'IRs entre les espèces ont été constatées. J'ai également découvert qu'un grand nombre d'IRs non olfactifs sont exprimés dans différents organes gustatifs, ce qui leur confère probablement une fonction dans la perception des goûts. Finalement, pour la première fois, des neurones exprimant des IRs ont été identifiés pour leur fonction dans la perception de sucres et d'acides aminés chez la larve. Mes résultats présentent les IRs comme une famille très dynamique, aux fonctions très variées, qui joue un rôle tant dans l'odorat que dans le goût, et dont la fonction est restée importante tout au long de l'évolution. De plus, l'identification de neurones spécialisés dans la perception de certains composés permettra l'étude des circuits neuronaux impliqués dans le traitement de ces informations.