Primary visual cortex is a classic model to study experience-dependent brain plasticity. In early life, if one eye is deprived of normal vision, there can be a dramatic change in the ocular dominance of the striate cortex such that the large majority of neurons lose responsiveness to the deprived eye and, consequently, the ocular dominance distribution shifts in favor of the open eye. Interestingly, the visual experience dependent plasticity following monocular deprivation (MD) occurs during a transient developmental period, which is called the critical period. MD hardly induces ocular dominance plasticity beyond critical period. The mechanisms underlying ocular dominance plasticity during the critical period are not fully understood. It has been proposed that long-term depression (LTD) may underlie the loss of cortical neuronal responsiveness to the deprived eye. However, discordant results have been reported in terms of the role of LTD and LTP in visual plasticity due to the lack of specific blockers. Here we report the prevention of the normally-occurring ocular dominance (OD) shift to the open eye following MD by using a specific long-term depression (LTD) blocking peptide derived from the GluR2 subunit of the a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR). We were able to prevent the shift of OD to the open eye with systemic or local administration of the GluR2 peptide. Both electrophysiological and anatomical approaches were taken to demonstrate the peptide effect. Moreover, enhancing LTD with D-serine, a NMDA receptor co-agonist, brought back the ocular dominance plasticity in adult mice subject to four-day MD and, therefore, reopened the critical period. Our data indicate that LTD plays an essential role in visual plasticity during the critical period and the developmental regulation of LTD may account for the closure of critical period in adult. In an additional study, we have found anisomycin, a protein synthesis inhibitor, produces a time-dependent decline in the magnitude of the field EPSP (fEPSP) in mouse primary visual cortex and that this anisomycin-mediated fEPSP depression occludes NMDA receptor dependent LTD. In contrast, another two protein synthesis inhibitors, emetine and cycloheximide, have no effect either on baseline synaptic transmission and or on LTD. We propose that anisomycin-LTD might be mediated by p38 MAP kinase since anisomycin is also a potent activator of the P38/JNK MAPK pathway. In agreement with notion, the decline of the fEPSP caused by anisomycin can be rescued by the application of the P38 inhibitor SB203580, but not by the JNK inhibitor SP600125. The occlusion of LFS-LTD by anisomycin-induced fEPSP decline suggests that common mechanisms may be shared between the two forms of synaptic depression. Consistent with this view, bath application of the membrane permeant peptide discussed above, which specifically blocks regulated AMPA receptor endocytosis, thereby preventing the expression of LFS-LTD, prior to anisomycin treatment significantly reduced the anisomycin-induced decline of the fEPSP. In conclusion, this study indicates that anisomycin produces long-lasting depression of AMPA receptor-mediated synaptic transmission by activating P38 MAPK-mediated endocytosis of AMPA receptors in neonatal mouse visual cortex.

Primary visual cortex is a classic model to study experience-dependent brain plasticity. In early life, if one eye is deprived of normal vision, there can be a dramatic change in the ocular dominance of the striate cortex such that the large majority of neurons lose responsiveness to the deprived eye and, consequently, the ocular dominance distribution shifts in favor of the open eye. Interestingly, the visual experience dependent plasticity following monocular deprivation (MD) occurs during a transient developmental period, which is called the critical period. MD hardly induces ocular dominance plasticity beyond critical period. The mechanisms underlying ocular dominance plasticity during the critical period are not fully understood. It has been proposed that long-term depression (LTD) may underlie the loss of cortical neuronal responsiveness to the deprived eye. However, discordant results have been reported in terms of the role of LTD and LTP in visual plasticity due to the lack of specific blockers. Here we report the prevention of the normally-occurring ocular dominance (OD) shift to the open eye following MD by using a specific long-term depression (LTD) blocking peptide derived from the GluR2 subunit of the a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR). We were able to prevent the shift of OD to the open eye with systemic or local administration of the GluR2 peptide. Both electrophysiological and anatomical approaches were taken to demonstrate the peptide effect. Moreover, enhancing LTD with D-serine, a NMDA receptor co-agonist, brought back the ocular dominance plasticity in adult mice subject to four-day MD and, therefore, reopened the critical period. Our data indicate that LTD plays an essential role in visual plasticity during the critical period and the developmental regulation of LTD may account for the closure of critical period in adult. In an additional study, we have found anisomycin, a protein synthesis inhibitor, produces a time-dependent decline in the magnitude of the field EPSP (fEPSP) in mouse primary visual cortex and that this anisomycin-mediated fEPSP depression occludes NMDA receptor dependent LTD. In contrast, another two protein synthesis inhibitors, emetine and cycloheximide, have no effect either on baseline synaptic transmission and or on LTD. We propose that anisomycin-LTD might be mediated by p38 MAP kinase since anisomycin is also a potent activator of the P38/JNK MAPK pathway. In agreement with notion, the decline of the fEPSP caused by anisomycin can be rescued by the application of the P38 inhibitor SB203580, but not by the JNK inhibitor SP600125. The occlusion of LFS-LTD by anisomycin-induced fEPSP decline suggests that common mechanisms may be shared between the two forms of synaptic depression. Consistent with this view, bath application of the membrane permeant peptide discussed above, which specifically blocks regulated AMPA receptor endocytosis, thereby preventing the expression of LFS-LTD, prior to anisomycin treatment significantly reduced the anisomycin-induced decline of the fEPSP. In conclusion, this study indicates that anisomycin produces long-lasting depression of AMPA receptor-mediated synaptic transmission by activating P38 MAPK-mediated endocytosis of AMPA receptors in neonatal mouse visual cortex.

Primary visual cortex is a classic model to study experience-dependent brain plasticity. In early life, if one eye is deprived of normal vision, there can be a dramatic change in the ocular dominance of the striate cortex such that the large majority of neurons lose responsiveness to the deprived eye and, consequently, the ocular dominance distribution shifts in favor of the open eye. Interestingly, the visual experience dependent plasticity following monocular deprivation (MD) occurs during a transient developmental period, which is called the critical period. MD hardly induces ocular dominance plasticity beyond critical period. The mechanisms underlying ocular dominance plasticity during the critical period are not fully understood. It has been proposed that long-term depression (LTD) may underlie the loss of cortical neuronal responsiveness to the deprived eye. However, discordant results have been reported in terms of the role of LTD and LTP in visual plasticity due to the lack of specific blockers. Here we report the prevention of the normally-occurring ocular dominance (OD) shift to the open eye following MD by using a specific long-term depression (LTD) blocking peptide derived from the GluR2 subunit of the a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR). We were able to prevent the shift of OD to the open eye with systemic or local administration of the GluR2 peptide. Both electrophysiological and anatomical approaches were taken to demonstrate the peptide effect. Moreover, enhancing LTD with D-serine, a NMDA receptor co-agonist, brought back the ocular dominance plasticity in adult mice subject to four-day MD and, therefore, reopened the critical period. Our data indicate that LTD plays an essential role in visual plasticity during the critical period and the developmental regulation of LTD may account for the closure of critical period in adult. In an additional study, we have found anisomycin, a protein synthesis inhibitor, produces a time-dependent decline in the magnitude of the field EPSP (fEPSP) in mouse primary visual cortex and that this anisomycin-mediated fEPSP depression occludes NMDA receptor dependent LTD. In contrast, another two protein synthesis inhibitors, emetine and cycloheximide, have no effect either on baseline synaptic transmission and or on LTD. We propose that anisomycin-LTD might be mediated by p38 MAP kinase since anisomycin is also a potent activator of the P38/JNK MAPK pathway. In agreement with notion, the decline of the fEPSP caused by anisomycin can be rescued by the application of the P38 inhibitor SB203580, but not by the JNK inhibitor SP600125. The occlusion of LFS-LTD by anisomycin-induced fEPSP decline suggests that common mechanisms may be shared between the two forms of synaptic depression. Consistent with this view, bath application of the membrane permeant peptide discussed above, which specifically blocks regulated AMPA receptor endocytosis, thereby preventing the expression of LFS-LTD, prior to anisomycin treatment significantly reduced the anisomycin-induced decline of the fEPSP. In conclusion, this study indicates that anisomycin produces long-lasting depression of AMPA receptor-mediated synaptic transmission by activating P38 MAPK-mediated endocytosis of AMPA receptors in neonatal mouse visual cortex. / Medicine, Faculty of / Graduate

Deafferented cortical visual areas exhibit topographical plasticity such that their constituent neural populations adapt to the loss of sensory input through the expansion and eventual remapping of receptive fields to new regions of space. Such representational plasticity is most compelling in the long-term (months or years) but begins within seconds of retinal deafferentation (short-term plasticity). The neural mechanism proposed to underlie topographical plasticity is one of disinhibition whereby long-range horizontal inputs are "unmasked" by a reduction in local inhibitory drive. In this dissertation, four experiments investigated the neural mechanisms of short-term visual plasticity and disinhibition in humans using a combination of psychophysics and event-related potentials (ERPs). Short-term visual plasticity was induced using a stimulus-induced analog of retinal deafferentation known as an artifical scotoma. Artificial scotomas provide a useful paradigm for the study of short-term plasticity as they induce disinhibition but are temporary and reversible. Experiment 1 measured contrast response functions from within the boundaries of an artificial scotoma and evaluated them relative to a sham control condition. Changes in the contrast response function suggest that disinhibition can be conceived of in terms of two dependent but separable processes: receptive field expansion and unrestricted neural gain. A two-process model of disinhibition is proposed. A complementary ERP study (Experiment 2) recorded visual evoked potentials elicited by probes appearing within the boundaries of an artificial scotoma. Results revealed a neural correlate of disinhibition consistent with origins in striate and extrastriate visual areas. Experiment 3 and 4 were exploratory examinations of the representation of space surrounding an artificial scotoma and revealed a neural correlate of invading activity from normal cortex. Together, the results of these four studies strengthen the understanding of the neural mechanisms that underlie short-term plasticity and provide a conceptual framework for their evaluation.

La construction de la représentation de soi est basée sur l'intégration des informations que l'on reçoit des différentes modalités sensorielles telles que les informations visuelles, auditives, tactiles ou proprioceptives. L'interaction entre les actions et les mouvements, et plus récemment les interactions sociales et l'espace ont été étudiées essentiellement au niveau comportemental, moins au niveau fonctionnel et beaucoup reste encore à élucider. En particulier, il est important et essentiel de comprendre exactement quels processus sont impliqués dans la construction d'une représentation spatiale et comment ces processus sont mis en oeuvre, non seulement au niveau local par l'activité de neurones spécifiques, dans une zone corticale spécifique, mais aussi à l'échelle du réseau dans son ensemble ainsi qu'à l'échelle du cerveau entier. Le premier axe de ma thèse s'intéresse à l'espace peripersonnel, qui est l'espace le plus proche de nous et qui représente l'un des sous-espaces fonctionnels de la représentation spatiale. Nous faisons l'hypothèse que ce sont les mêmes régions qui contribuent à la convergence multisensorielle, à la prédiction des conséquences sur le traitement tactile d'une stimulation visuelle approchant le corps et à la construction de l'espace peripersonnel. Pour tester cette hypothèse, nous avons étudié l'effet des aspects prédictifs temporels et spatiaux d'un stimulus visuel dynamique sur la détection du stimulus tactile chez l'Homme (étude comportementale) et le primate non humain (étude en IRM fonctionnelle) ainsi que les bases neuronales de la représentation de l'espace proche et de la représentation de l'espace lointain, chez le primate non humain (étude en IRM fonctionnelle). Nous mettons en évidence l'implication d'un réseau parieto-frontal, essentiellement composé par l'aire intrapariétale ventrale VIP et l'aire prémotrice F4 qui sont activées par ces trois mécanismes différents. Nous proposons que ce réseau traite non seulement la trajectoire de l'objet approchant vis-à-vis du corps, mais qu'il anticipe également ses conséquences sur le corps et prépare des actions de protection en réponse à ce stimulus approchant. Le deuxième axe de ma thèse porte sur la caractérisation de l'étendue de la plasticité dans la représentation visuelle dans le cerveau adulte (par opposition aux premiers stades de plasticité observées autour des périodes critiques du développement) et en particulier, sur des développements méthodologiques permettant de mesurer les changements fins dans le cortex visuel induits par une telle plasticité. Plus précisément, nous avons développé un ensemble de méthodes d'IRM à haute résolution : imagerie fonctionnelle (cartographie visuelle à haute résolution, IRM au repos), pharmacologique (imagerie spectroscopique du GABA) et structurelle (IRM anatomique, DTI basée sur la diffusion des molécules d'eau), afin de définir des mesures de référence pour évaluer les changements induits par la plasticité à différents moments après son induction, à travers une étude longitudinale réalisée chez les mêmes animaux. Certaines de ces méthodes nécessitent encore quelques raffinements et ajustements mais, dans l'ensemble, elles montrent leur potentiel prometteur pour étudier la plasticité chez les primates non humains. Dans l'ensemble, ce travail de thèse a permis de créer un lien fonctionnel entre les études d'IRMf effectuées chez l'Homme et les études d'enregistrement d'électrophysiologies chez le primate non humain. De plus, il entraine de nouvelles stratégies et pistes d'explorations à étudier dans le domaine de la représentation spatiale, à la fois chez l'Homme et le primate non humain / The construction of the representation of self is based on the integration of information received by our different sensory modalities such as visual, auditory, tactile or proprioceptive information. The interaction between actions and movements and more recently social interactions and space are being explored at the behavioral level, but less so at the functional level and much more remains to be elucidated. In particular, it is important and fundamental to understand exactly which processes are involved in space representation and how, not only from a partial view focusing on specific cortical areas and single neuron processes but at the scale of the whole brain and the functional networks. The first axis of my thesis focuses on peripersonal space, that is the space that is closest to us, and represents one of the functional subspaces of spatial representation. We assume that it is the same regions that contribute to multisensory convergence, to the prediction of the consequences of a looming visual stimulus onto tactile processing and to the construction of peripersonal space. To test this hypothesis, we investigated the effect of the temporal and spatial predictive aspects of a dynamical looming visual stimulus onto tactile stimulus detection in humans (behavioral study) and non-human primates (fMRI study); the neural bases of near space and far space representations, in non-human primate (fMRI study). We highlight the involvement of a parieto-frontal network, essentially composed by the ventral intraparietal area VIP, the premotor area F4 as well as striate and extra-striate cortical regions, which are activated by these three different mechanisms. We propose that this network not only processes the trajectory of the looming object with respect to the body, but also anticipates its consequences onto the body and prepares protective actions in response to the looming stimulus. The second axis of my thesis focuses on characterizing the extent of plasticity in the visual representation of the adult brain (as opposed to the early stages around the critical developmental periods) and in particular, how the associated fine-grained changes in the visual cortex can be precisely quantified along multiple dimensions (anatomical, functional, pharmacological). Specifically, we have developed a set of high-resolution MRI methods to assess functional (high-resolution visual mapping fMRI, rs-MRI), pharmacological (GABA spectroscopy imaging) and structural (anatomical MRI, DTI) imaging to define reference measures against which to evaluate the changes induced by plasticity at different times after its induction, through a longitudinal study performed in the same animals. Some of these methods need to be more refined but they show that they are really promising to study plasticity in nonhuman primate. On the whole, this present doctoral research allows to make a functional link between human fMRI studies and monkey single cell recording studies and provides new strategies and explorations to perform on the spatial representation field both in humans and non-human primates