Cholinergic enhancement of perceptual learning : behavioral, physiological, and neuro-pharmacological study in the rat primary visual cortex

Les cortices sensoriels sont des régions cérébrales essentielles pour la perception. En particulier, le cortex visuel traite l’information visuelle en provenance de la rétine qui transite par le thalamus. Les neurones sont les unités fonctionnelles qui transforment l'information sensorielle en signaux électriques, la transfèrent vers le cortex et l'intègrent. Les neurones du cortex visuel sont spécialisés et analysent différents aspects des stimuli visuels. La force des connections entre les neurones peut être modulée par la persistance de l'activité pré-synaptique et induit une augmentation ou une diminution du signal post-synaptique à long terme. Ces modifications de la connectivité synaptique peuvent induire la réorganisation de la carte corticale, c’est à dire la représentation de ce stimulus et la puissance de son traitement cortical. Cette réorganisation est connue sous le nom de plasticité corticale. Elle est particulièrement active durant la période de développement, mais elle s’observe aussi chez l’adulte, par exemple durant l’apprentissage. Le neurotransmetteur acétylcholine (ACh) est impliqué dans de nombreuses fonctions cognitives telles que l’apprentissage ou l’attention et il est important pour la plasticité corticale. En particulier, les récepteurs nicotiniques et muscariniques du sous-type M1 et M2 sont les récepteurs cholinergiques impliqués dans l’induction de la plasticité corticale. L’objectif principal de la présente thèse est de déterminer les mécanismes de plasticité corticale induits par la stimulation du système cholinergique au niveau du télencéphale basal et de définir les effets sur l’amélioration de la perception sensorielle. Afin d’induire la plasticité corticale, j’ai jumelé des stimulations visuelles à des injections intracorticales d’agoniste cholinergique (carbachol) ou à une stimulation du télencéphale basal (neurones cholinergiques qui innervent le cortex visuel primaire). J'ai analysé les potentiels évoqués visuels (PEVs) dans le cortex visuel primaire des rats pendant 4 à 8 heures après le couplage. Afin de préciser l’action de l’ACh sur l’activité des PEVs dans V1, j’ai injecté individuellement l’antagoniste des récepteurs muscariniques, nicotiniques, α7 ou NMDA avant l’infusion de carbachol. La stimulation du système cholinergique jumelée avec une stimulation visuelle augmente l’amplitude des PEVs durant plus de 8h. Le blocage des récepteurs muscarinique, nicotinique et NMDA abolit complètement cette amélioration, tandis que l’inhibition des récepteurs α7 a induit une augmentation instantanée des PEVs. Ces résultats suggèrent que l'ACh facilite à long terme la réponse aux stimuli visuels et que cette facilitation implique les récepteurs nicotiniques, muscariniques et une interaction avec les récepteur NMDA dans le cortex visuel. Ces mécanismes sont semblables à la potentiation à long-terme, évènement physiologique lié à l’apprentissage. L’étape suivante était d’évaluer si l’effet de l’amplification cholinergique de l’entrée de l’information visuelle résultait non seulement en une modification de l’activité corticale mais aussi de la perception visuelle. J’ai donc mesuré l’amélioration de l’acuité visuelle de rats adultes éveillés exposés durant 10 minutes par jour pendant deux semaines à un stimulus visuel de type «réseau sinusoïdal» couplé à une stimulation électrique du télencéphale basal. L’acuité visuelle a été mesurée avant et après le couplage des stimulations visuelle et cholinergique à l’aide d’une tâche de discrimination visuelle. L’acuité visuelle du rat pour le stimulus d’entrainement a été augmentée après la période d’entrainement. L’augmentation de l’acuité visuelle n’a pas été observée lorsque la stimulation visuelle seule ou celle du télencéphale basal seul, ni lorsque les fibres cholinergiques ont été lésées avant la stimulation visuelle. Une augmentation à long terme de la réactivité corticale du cortex visuel primaire des neurones pyramidaux et des interneurones GABAergiques a été montrée par l’immunoréactivité au c-Fos. Ainsi, lorsque couplé à un entrainement visuel, le système cholinergique améliore les performances visuelles pour l’orientation et ce probablement par l’optimisation du processus d’attention et de plasticité corticale dans l’aire V1. Afin d’étudier les mécanismes pharmacologiques impliqués dans l’amélioration de la perception visuelle, j’ai comparé les PEVs avant et après le couplage de la stimulation visuelle/cholinergique en présence d’agonistes/antagonistes sélectifs. Les injections intracorticales des différents agents pharmacologiques pendant le couplage ont montré que les récepteurs nicotiniques et M1 muscariniques amplifient la réponse corticale tandis que les récepteurs M2 muscariniques inhibent les neurones GABAergiques induisant un effet excitateur. L’infusion d’antagoniste du GABA corrobore l’hypothèse que le système inhibiteur est essentiel pour induire la plasticité corticale. Ces résultats démontrent que l’entrainement visuel jumelé avec la stimulation cholinergique améliore la plasticité corticale et qu’elle est contrôlée par les récepteurs nicotinique et muscariniques M1 et M2. Mes résultats suggèrent que le système cholinergique est un système neuromodulateur qui peut améliorer la perception sensorielle lors d’un apprentissage perceptuel. Les mécanismes d’amélioration perceptuelle induits par l’acétylcholine sont liés aux processus d’attention, de potentialisation à long-terme et de modulation de la balance d’influx excitateur/inhibiteur. En particulier, le couplage de l’activité cholinergique avec une stimulation visuelle augmente le ratio de signal / bruit et ainsi la détection de cibles. L’augmentation de la concentration cholinergique corticale potentialise l’afférence thalamocorticale, ce qui facilite le traitement d’un nouveau stimulus et diminue la signalisation cortico-corticale minimisant ainsi la modulation latérale. Ceci est contrôlé par différents sous-types de récepteurs cholinergiques situés sur les neurones GABAergiques ou glutamatergiques des différentes couches corticales. La présente thèse montre qu’une stimulation électrique dans le télencéphale basal a un effet similaire à l’infusion d’agoniste cholinergique et qu’un couplage de stimulations visuelle et cholinergique induit la plasticité corticale. Ce jumelage répété de stimulations visuelle/cholinergique augmente la capacité de discrimination visuelle et améliore la perception. Cette amélioration est corrélée à une amplification de l’activité neuronale démontrée par immunocytochimie du c-Fos. L’immunocytochimie montre aussi une différence entre l’activité des neurones glutamatergiques et GABAergiques dans les différentes couches corticales. L’injection pharmacologique pendant la stimulation visuelle/cholinergique suggère que les récepteurs nicotiniques, muscariniques M1 peuvent amplifier la réponse excitatrice tandis que les récepteurs M2 contrôlent l’activation GABAergique. Ainsi, le système cholinergique activé au cours du processus visuel induit des mécanismes de plasticité corticale et peut ainsi améliorer la capacité perceptive. De meilleures connaissances sur ces actions ouvrent la possibilité d’accélérer la restauration des fonctions visuelles lors d’un déficit ou d’amplifier la fonction cognitive.Sensory cortex is an essential area where sensory perception occurs. Especially visual cortex processes visual information transmitted from the retina through the thalamus. By different neuronal activation the information is segregated and sent to diverse visual area for interpretation. Neurons are the basic unit that transform sensory information into electrophysiological signal, transfer to the cortex and integrate it. Connection between neurons can be modulated depending on the persistent presynaptic activity inducing either a long-term increase or decrease of the post-synaptic activity. Modification in synaptic strength can affect large area and induce reorganization of cortical map (i.e. cortical plasticity) which changes the representation of the visual stimulus and its weight in visual processing. Cortical plasticity can occur during juvenile while forming developmental connection or in adult while acquiring novel information (i.e. learning). The neurotransmitter ACh is involved in many cognitive functions, such as learning or attention and it was demonstrated that lesioning or blocking cholinergic system diminishes cortical plasticity. It was shown that nicotinic, M1 subtype and M2 subtype muscarinic receptors are the major cholinergic receptors abundant in the cortex and implicated during cortical plasticity induction. In a first part, I analyzed visual evoked potentials (VEPs) in V1 of rats during a 4-8h period after coupling visual stimulation to an intracortical injection of ACh agonist carbachol or stimulation of basal forebrain. To clarify the action of ACh on VEP activity in V1, we individually injected muscarinic, nicotinic, α7, and NMDA receptor antagonists just before carbachol infusion. Stimulation of the cholinergic system paired with visual stimulation significantly increased VEP amplitude for long-term. Pre-inhibition of muscarinic, nicotinic and NMDA receptor completely abolished this long-term enhancement, while α7 inhibition induced an instant increase of VEP amplitude. This suggests a role of ACh in facilitating visual stimuli responsiveness which involves nicotinic and muscarinic receptors with an interaction of NMDA transmission in the visual cortex. These mechanisms were similar to long-term potentiation, a neurobiological mechanism of learning. In a second step, I evaluate whether cholinergic modulation of visual neurons results in cortical activity and visual perception changes. Awake adult rats were exposed repetitively for two weeks to an orientation-specific grating with coupling visual stimulation to an electrical stimulation of the basal forebrain. The visual acuity, as measured using a visual water maze before and after coupling visual/cholinergic stimulation was increased. The increase in visual acuity was not observed when visual or basal forebrain stimulation was performed separately nor when cholinergic fibers were selectively lesioned prior to the visual stimulation. There was a long-lasting increase in cortical reactivity of the primary visual cortex shown by c-Fos immunoreactivity of both pyramidal and GABAergic interneuron. These findings demonstrate that when coupled with visual training, the cholinergic system improves visual performance for the trained orientation probably through enhancement of attentional processes and cortical plasticity in V1 related to the ratio of excitatory/inhibitory inputs. Finally, I also investigated the different pharmacological mechanisms involved in the visual enhancement. Pre- and post-pairing visual/cholinergic stimulation VEP were compared with selective administered agonist/antagonist during the pairing. Awaken adult rats were exposed during 10 minutes per day for 1 week to an orientation specific grating with an electrical stimulation of the basal forebrain. Intracortical injection of different pharmacological agents during pairing demonstrated that nicotinic and M1 muscarinic receptors are used to amplify cortical response while M2 muscarinic receptor suppresses GABAergic neurons to disinhibit excitatory neurons. Infusion of GABAergic antagonist supported that inhibitory system is crucial to induce cortical plasticity. These findings demonstrate that visual training coupled with the cholinergic stimulation enhances the cortical plasticity mediated by nicotinic, M1 and M2 muscarinic receptors, which the latter induces a disinhibition by suppressing GABAergic neuron. The cholinergic system is a potent neuromodulatory system. Boosting this system during perceptual learning robustly enhances the sensory perception. Especially, pairing a cholinergic activation with a visual stimulation increases the signal-to-noise ratio, cue detection ability in the primary visual cortex. This cholinergic enhancement increases the strength of thalamocortical afferent to facilitate the treatment of a novel stimulus while decreasing the cortico-cortical signaling to minimize recurrent or top-down modulation. This is mediated by different cholinergic receptor subtypes located in both glutamatergic and GABAergic neurons of the different cortical layers. The mechanisms of cholinergic enhancement are closely linked to attentional processes, long-term potentiation and modulation of the excitatory/inhibitory balance. The present thesis shows that electrical stimulation of the basal forebrain has similar effect with cholinergic agonist release and pairing visual/cholinergic stimulation induces cortical plasticity. Repetitive pairing of visual/cholinergic increases visual discrimination capacity and enhances perceptual ability. This enhancement is followed by an augmentation of neuronal activity demonstrated by c-Fos immunohistochemistry. Immunoreactivity also shows difference in glutamatergic and GABAergic neurons activities between layers. Pharmacological injection during visual/cholinergic pairing suggests that nicotinic and M1 muscarinic receptor can amplify excitatory response while M2 receptor controls GABAergic activation. Altogether cholinergic system activated during visual process induces cortical plasticity and can enhance perceptual ability. Further understanding of this training has the potential to accelerate visual recovery or boost cognitive function

Modulation cholinergique à long terme des potentiels évoqués visuels dans le cortex visuel chez le rat

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Cholinergic Pairing with Visual Activation Results in Long-Term Enhancement of Visual Evoked Potentials

Acetylcholine (ACh) contributes to learning processes by modulating cortical plasticity in terms of intensity of neuronal activity and selectivity properties of cortical neurons. However, it is not known if ACh induces long term effects within the primary visual cortex (V1) that could sustain visual learning mechanisms. In the present study we analyzed visual evoked potentials (VEPs) in V1 of rats during a 4–8 h period after coupling visual stimulation to an intracortical injection of ACh analog carbachol or stimulation of basal forebrain. To clarify the action of ACh on VEP activity in V1, we individually pre-injected muscarinic (scopolamine), nicotinic (mecamylamine), α7 (methyllycaconitine), and NMDA (CPP) receptor antagonists before carbachol infusion. Stimulation of the cholinergic system paired with visual stimulation significantly increased VEP amplitude (56%) during a 6 h period. Pre-treatment with scopolamine, mecamylamine and CPP completely abolished this long-term enhancement, while α7 inhibition induced an instant increase of VEP amplitude. This suggests a role of ACh in facilitating visual stimuli responsiveness through mechanisms comparable to LTP which involve nicotinic and muscarinic receptors with an interaction of NMDA transmission in the visual cortex

Temperature-dependent evolutions of excitonic superfluid plasma frequency in a srong excitonic insulator candidate, Ta2_2NiSe5_5

We investigate an interesting anisotropic van der Waals material, Ta$_{2}$NiSe$_{5}$, using optical spectroscopy. Ta$_{2}$NiSe$_{5}$ has been known as one of the few excitonic insulators proposed over 50 years ago. Ta$_{2}$NiSe$_{5}$ has quasi-one dimensional chains along the $a$-axis. We have obtained anisotropic optical properties of a single crystal Ta$_{2}$NiSe$_{5}$ along the $a$- and $c$-axes. The measured $a$- and $c$-axis optical conductivities exhibit large anisotropic electronic and phononic properties. With regard to the $a$-axis optical conductivity, a sharp peak near 3050 cm$^{-1}$ at 9 K, with a well-defined optical gap ($\Delta^{EI} \simeq$ 1800 cm$^{-1}$) and a strong temperature-dependence, is observed. With an increase in temperature, this peak broadens and the optical energy gap closes around $\sim$325 K($T_c^{EI}$). The spectral weight redistribution with respect to the frequency and temperature indicates that the normalized optical energy gap ($\Delta^{EI}(T)/\Delta^{EI}(0)$) is $1-(T/T_c^{EI})^2$. The temperature-dependent superfluid plasma frequency of the excitonic condensation in Ta$_{2}$NiSe$_{5}$ has been determined from measured optical data. Our findings may be useful for future research on excitonic insulators.Comment: 17 pages, 5 figure

Antidiabetic Effect of Fresh Nopal ( Opuntia ficus-indica

The objective of the present study was to evaluate α-glucosidase inhibitory and antidiabetic effects of Nopal water extract (NPWE) and Nopal dry power (NADP) in low-dose streptozotocin- (STZ-) induced diabetic rats fed a high-fat diet (HFD). The type 2 diabetic rat model was induced by HFD and low-dose STZ. The rats were divided into four groups as follows: (1) nondiabetic rats fed a regular diet (RD-Control); (2) low-dose STZ-induced diabetic rats fed HFD (HF-STZ-Control); (3) low-dose STZ-induced diabetic rats fed HFD and supplemented with NPWE (100 mg/kg body weight, HF-STZ-NPWE); and (4) low-dose STZ-induced diabetic rats fed HFD and supplemented with comparison medication (rosiglitazone, 10 mg/kg, body weight, HF-STZ-Rosiglitazone). In results, NPWE and NADP had IC50 values of 67.33 and 86.68 μg/mL, both of which exhibit inhibitory activities but lower than that of acarbose (38.05 μg/mL) while NPWE group significantly decreased blood glucose levels compared to control and NPDP group on glucose tolerance in the high-fat diet fed rats model (P<0.05). Also, the blood glucose levels of HR-STZ-NPWE group were significantly lower (P<0.05) than HR-STZ-Control group on low-dose STZ-induced diabetic rats fed HFD. Based on these findings, we suggested that NPWE could be considered for the prevention and/or treatment of blood glucose and a potential use as a dietary supplement

Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM

The Practice of Korean Medicine: An Overview of Clinical Trials in Acupuncture

Acupuncture, one of the Oriental medical therapeutic techniques that can be traced back at least 2500 years, is growing in popularity all over the world. Korea has continued to develop its own unique tradition of medicine throughout its long history, and has formed different types of acupuncture methods. The purpose of this review is to summarize clinical case studies in acupuncture and related therapies, such as acupressure, electric acupuncture, auricular acupuncture and moxibustion in Korea. A survey of Korean journals revealed that a total of 124 studies were published from 1983 to 2001. Results obtained from the survey showed that most clinical studies using acupuncture, electric acupuncture, moxibustion and other traditional therapies could alleviate a relatively broad range of medical problems. However, it should be emphasized that almost all clinical case studies published in various local journals did not follow the ‘good clinical practice’ with respect to regulatory aspects. Since they were not conducted using the randomized double-blinded controls with a large sample size, all the results should be considered as therapeutic indications. This review is an attempt to show the scope of acupuncture in our country and the kind of diseases, after many years of clinical experience, that were deemed valid targets for clinical trials

A Study on the Comparative Analysis of the FLO-2D Model According to Debris Flow Sediment Amount

It is very important to predict the extent of the damage in order to reduce or prevent damage by the debris flow. In the Republic of Korea, various methods are used to understand the characteristics and to estimate the occurrence of the debris flow in an undamaged area, such as simulating disasters using the estimation of debris flow sediment amount based on field survey data. In this study, the runout distance of debris flow was analyzed by using different methods for estimating the debris flow sediment amount, at Wondeok-eup, Samcheok-si, Gangwon-do, where debris flow occurred due to Typhoon Mitak in 2019. The simulation results of the damage area were compared with the actual damage area. The result showed that the simulations generally corresponded to the actual area of damage caused by the sedimentation of debris flow. However, the estimation of damage area varied according to the used method of calculating the debris flow sediment amount

Numerical Simulation Reflecting Buildings in Area Damaged by Debris flow

More than 80% of average annual precipitation in South Korea occurs between June and September owing to heavy rainfall and typhoons in summer, and its land is vulnerable to mountain disasters (landslides and debris flow) as 63% of it is mountainous areas. In this study, an area damaged by debris flow in Wondeok-eup, Samcheok-si, Gangwon-do, Korea under the influence of Typhoon Mitag in 2019 was surveyed and numerical modeling was performed. Topographic data were created using the 5m grid DEM derived through the field survey data and GIS technique as well as the building data of the damaged area, and debris flow modeling was performed using the Hyper KANAKO model. A comparison with the inundation trace map showed that the simulation results based on topographic data that reflected buildings exhibited similar flow patterns and characteristics to the actual damage