Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Montana, 2007. / Title from title screen Description based on contents viewed Oct. 12, 2007. Includes bibliographical references (p. 151-177).

Dans cette thèse, nous avons étudié le codage prédictif and sa relation avec la perception et les oscillations. Nous avons, dans l'introduction, fait une revue des connaissances sur les neurones et le néocortex et un état de l'art du codage prédictif. Dans les chapitres principaux, nous avons tout d'abord, proposé l'idée, au travers d'une étude théorique, que la temporalité de la décharge crée une inhibition sélective dans les réseaux excitateurs non-sélectifs rétroactifs. Ensuite, nous avons montré les effets perceptuels du codage prédictif: la perception de la forme améliore la perception du contraste. Enfin, nous avons montré que le codage prédictif peut utiliser des oscillations dans différentes bandes de fréquences pour transmettre les informations en avant et en rétroaction. Cette thèse a fourni un mécanisme neuronal viable et innovant pour le codage prédictif soutenu par des données empiriques démontrant des prédictions rétroactives excitatrices et une relation forte entre codage prédictif et oscillations. / In this thesis, we investigated predictive coding and its relationship with perception and oscillations. We first reviewed my current understanding about facts of neuron and neocortex and state-of-the-arts of predictive coding in the introduction. In the main chapters, firstly, we proposed the idea that correlated spike times create selective inhibition in a nonselective excitatory feedback network in a theoretical study. Then, we showed the perceptual effect of predictive coding: shape perception enhances perceived contrast. At last, we showed that predictive coding can use oscillations with different frequencies for feedforward and feedback. This thesis provided an innovative and viable neuronal mechanism for predictive coding and empirical evidence for excitatory predictive feedback and the close relationship between the predictive coding and oscillations.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23104号 / 医博第4731号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 林 康紀, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The amino acid, 6-hydroxydopa (6-OHDOPA), found at the active site of amine oxidases, exists as a keto-enol. Exogenously administered 6-OHDOPA is an excitotoxin like β-N-oxalylamino-L-alanine (BOAA) and β-N-methylamino-L-alanine (BMAA), acting at the non-N-methyl-D-aspartate (non-NMDA) α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. BMAA and BOAA are causal factors of neurolathyrism in humans. Much exogenously administered 6-OHDOPA is biotransformed by aminoacid decarboxylase (AADC) to the highly potent and catecholamine-(CA) selective neurotoxin, 6-hydroxydopamine (6-OHDA). 6-OHDOPA destroys locus coeruleus noradrenergic perikarya and produces associated denervation of brain by norepinephrine-(NE) containing fibers. Opiopeptides and opioids enhance neurotoxic effects of 6-OHDOPA on noradrenergic nerves, by a naloxone-reversible process. An understanding of mechanisms underlying neurotoxic effects of 6-OHDOPA can be helpful in defining actions of known and newfound amino acids and for investigating their potential neurotoxic properties.

The brain network is a multiscale hierarchical organization from neurons and local circuits to macroscopic brain areas. The precise synaptic transmission at each synapse is therefore crucial for neural communication and the generation of orchestrated behaviors. Activation of presynaptic voltage-gated calcium channels (CaV2) initiates synaptic vesicle release and plays a key role in neurotransmission. In this dissertation, I have aimed to uncover how CaV2 activity affects synaptic transmission, circuit function and behavioral outcomes using Caenorhabditis elegans as a model. The C. elegans genome encodes an ensemble of highly conserved neurotransmission machinery, providing an opportunity to study the molecular mechanisms of synaptic function in a powerful genetic system. I identified a novel gain of function CaV2α1 mutation that causes CaV2 channels to activate at a lower membrane potential and slow the inactivation. Cell-specific expression of these gain-of-function CaV2 channels is sufficient to hyper-activate neurons of interest, offering a way to study their roles in a given circuit. CaV2(gf) mutants display behavioral hyperactivity and an excitation-dominant synaptic transmission. Imbalanced excitation and inhibition of the nervous system have been associated with several neurological disorders, including Familial Hemiplegic Migraine type 1 (FHM1) which is caused by gain- of-function mutations in the human CaV2.1α1 gene. I showed that animals carrying C. elegans CaV2α1 transgenes with corresponding human FHM1 mutations recapitulate the hyperactive behavioral phenotype exhibited by CaV2(gf) mutants, strongly suggesting the molecular function of CaV2 channels is highly conserved from C. elegans to human. Through performing a genome-wide forward genetic screen looking for CaV2α(gf) suppressors, we isolated new alleles of genes that required for CaV2 trafficking, localization and function. These regulators include subunits of CaV2 channel complex, components of synaptic and dense core vesicle release machinery as well as predicted extracellular proteins. Taken together, this work advances the understanding of CaV2 malfunction at both cellular and circuit levels, and provides a genetically amenable model for neurological disorders associated with excitation-inhibition imbalance. Additionally, through identifying regulators of CaV2, this research provides new avenues for understanding the CaV2 channel mediated neurotransmission and potential pharmacological targets for the treatments of calcium channelopathies.

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