Instituto do Cérebro
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Master Thesis Níveis de hipocretina-1 no líquido cefalorraquidiano de ratos tratados com antidepressivos e em um modelo animal de depressão(Universidade Federal de São Paulo, 2008-01-01) Pontes, Josy Carolina Covan; Tufik, Sergio; Pedrazzoli, MarioDoctoral Thesis Contribuição das proteínas tirosina cinases e da cálciocalmodulina cinase tipo II em modelos animais de epilepsia(Universidade Federal de São Paulo, 2005) Queiroz, Claudio Marcos Teixeira de; Mello, Luiz Eugênio Araújo de Moraes; http://lattes.cnpq.br/3384801391828521; Caraisco, Norberto Garcia; Moraes, Márcio Flávio Dutra; Priel, Margareth Rose; Xavier, Gilberto FernandoTemporal lobe epilepsies are highly refractory to pharmacological treatment. Up to 70% of these patients undergo chirurgical resection of temporal region, procedure with important consequences for the social, economic and psychological spheres. Experimental animal models that mimic temporal lobe epilepsy provide an insightful approach to study the neural basis of epilepsy as well as create opportunities to test promising therapeutic drugs. The present thesis tests the antiepileptogenic activity of two protein tyrosine kinase inhibitors and the relevance of Ca+2/calmodulin kinase type II (CaMKII) mutants. Multiples morphological and physiological alterations take place after a traumatic brain injury (in this thesis, the status epilepticus) leading the animal to an epileptic conditions. During this period, the epileptogenesis process, there is strong tyrsine phosphorylation with the activation of many second messengers. The first two chapters of the thesis describe experiments in which herbimycin A and K-252a, two protein tyrosine kinase inhibitors, were used to attenuate synaptic plasticity and epileptogenesis. The third chapter, the dentate gyrus network was studied after angular bundle stimulation in animals presenting one punctual mutation at the autoinhibitory phosphorylation site of the CaMKII. In the first chapter, we showed that one single herbimycin A injection (348μM, 5μL, icv) was able to attenuate long-term potentiation (LTP) in the commissural CA3 neurons and also, to decrease status epilepticus- (SE-) induced neuronal activation (c-Fos expression) in almost 40%. Although markedly acute effects, the present herbimycin A treatment was not able to diminish spontaneous seizure frequency, cell death or aberrant mossy fiber sprouting observed after the pilocarpine-induced SE. Curiously, herbimycin-treated animals presented decreased neo-Timm staining in the hilus and CA3 region despite the epileptic condition. In the second chapter, we confirmed the ability of protein tyrosine kinase inhibitors to decrease SE-induced neuronal activation. Herbimycin A icv treatment altered the kainic acid-induced epileptiform profile in EEG recordings. Cell death pattern was not altered by any pharmacological treatment. These results suggest that protein tyrosine kinase inhibitiors are able to modify the acute neuronal activation and plasticity (ictogenesis or LTP) but is ineffective in attenuating the epileptogenesis process. In the third chapter, we studied the dentate gyrus excitability and plasticity after angular bundle stimulation in CaMKII mutant animals. Once in its self-sustained mode, this mutation does not allow the reduction of the catalytic activity of the kinase. These animals present normal electrophysiological profiles (similar to wild-type animals) but with reduced amplitude. Shortterm plasticity was clearly altered. Mutant animals presented increased variability in the responses to trains of stimulation at 1 and 2 Hz, and at at 5Hz stronger paired-pulse inhibition. Accordingly to the literature, we also showed that the epileptiform susceptibility depends on the stimulation pattern used in both animals (mutants vs. wild-type). Thus, although the mutation did not altered the behavior and the electrographic kindling evolution, we showed that mutant animals were prone to afterdischarges when stimulate by an intermittent theta-burst stimulation. On the other hand, the same animals needed more bursts to induce afterdischarges when the stimulation was set in the continuos mode. Taken together, the present results contribute to a better understanding of the protein tyrosine kinase and CaMKII function in neuronal plasticity underlying the epileptogenesis process and sum efforts in searching for a clinic antiepileptogenic drug.Doctoral Thesis The genomic response to song and the representation of complex sounds in the auditory system of zebra finches(2008-06) Velho, Tarciso André Ferreira; Mello, Claudio V.The consolidation of long-lasting sensory memories requires the activation of gene expression programs. However, to fully understand the contribution of genomic events necessary for sensory learning, it is necessary to characterize the components involved in this response, their induction kinetics, and the possible functional interactions among individual components. Birdsong represents one of the best natural behaviors to study gene expression induced by auditory stimulation in awake, freely behaving animals. The present work addresses the properties and functional consequences of the genomic response to birdsong in zebra finches (Taeniopygia guttata), with a specific focus on the caudomedial nidopallium (NCM), a cortical-like auditory area involved in song auditory processing and memorization. We found that song induces a wellorchestrated cascade of gene expression that includes early and late genes. Early genes are co-expressed by NCM neurons and their induction is regulated by the mitogen-activated protein (MAP) kinase pathway. In addition, we also found that the induction of early genes is locally modulated by norepinephrine. We have also identified two late genes, syn2 and syn3, whose induction is repressed by early song-induced proteins genes in NCM. Functionally, we show that blockade of this response by α-adrenergic antagonists disrupts the long-term maintenance of long-lasting neuronal changes triggered by song. Finally, we show that the pattern of early song-induce gene expression in NCM is stimulus dependent. These patterns also indicate the existence of functional subdomains of more or less selectivity towards conspecific songs. Overall, these results help us understand the functional significance of the genomic response to song and the functional organization of sound representation in a higher order auditory area of the songbird brain.Master Thesis Aplicações de processos estocásticos à Biomedicina(2005-11-27) Tort, Adriano Bretanha Lopes; Lopes, Artur O.Doctoral Thesis Novos progenitores na zona marginal do córtex cerebral em desenvolvimento(2006) Costa, Marcos Romualdo; Pereira, Cecília HedinDuring development, telencephalic neuroepithelial cells proliferate and give rise to progenitors, which are responsible for the sequential generation of different types of neurons, astrocytes and oligodendrocytes in the cerebral cortex. To date, telencephalic progenitors would be located in the ventricular (VZ) and subventricular (SVZ) zones. Their position along the rostro-caudal and dorsoventral axis is related to gene expression territories and the generation of specific cell types, such that dorsal telencephalic VZ/ZVZ generates glutamatergic neurons and ventral VZ/ZVZ GABAergic neurons. In this work we investigated the in vivo and in vitro proliferative potential of the marginal zone (MZ) described to harbor migrating and differentiating neurons during corticogenesis. We determined the phenotype of MZ proliferative cells and by clonal analysis with infection by GFP (green fluorescent protein) containing retroviruses we followed the lineages derived from the progenitors in vitro. Proliferative cells in vivo were labeled by BrdU (bromodeoxyuridine, S phase cell cycle marker) combined to immunohistochemistry for the identification of BrdU antigen and the phosphorylated form of H3 –histone (expressed at the end of G2 and during M phase of the cell cycle). We identified proliferative cells in mice MZ from embryonic day (E)14 (just after preplate division when MZ becomes distinguishable) and through all corticogenesis with a three fold increase in E18. Proliferative cells in the MZ do not express Pax6 or Tbr2, transcriptional factors typical of VZ and SVZ precursors respectively. During corticogenesis, this precursor population displays a latero-medial gradient of expression of Olig2, such that perinatally, all proliferative cells in the MZ express Olig2. Clonal lineage analysis from these precursors revealed a high gliogenic potential (~70% pure glial clones) when compared to VZ/SVZ (2,3%). Furthermore, MZ displays neurogenic potential since 30% of all clones contained neurons identified by class III β-tubulin immunolabeling. Here we show that pure glial clones in the MZ are significantly larger than those generated by VZ. Concluding, the dorsal MZ is a neurogenic and gliogenic niche in the developing cerebral cortex containing proliferative cells with distinct phenotypic characteristics from the VZ and SVZ. By clonal lineage analysis in vitro, we demonstrated different proliferative behaviors and neuro-gliogenic potential from cells isolated from the MZ and VZ/SVZ indicating a novel type of progenitor in the cerebral cortex.Doctoral Thesis Expressão de GABA e plasticidade do fenótipo neuroquímico e morfológico de células da Zona Subventricular pós-natal(2008) Sequerra, Eduardo Bouth; Pereira, Cecília HedinThe subventricular zone (SVZ) is proliferative epithelium that continuously gives rise to new neurons in postnatal and adult mammals. The neurons generated in the SVZ migrate through the rostral migratory stream (RMS) where they differentiate in GABAergic interneurons. A characteristic of these neuron precursors is that they start to express GABA while they are still in the SVZ. This fact can lead to the conclusion that at this time they are already commited to the GABAergic phenotype. However, to affirm this one has to show that the origin of GABA in these cells is the same as in mature neurons. One of the most important steps to define GABAergic commitment in neurons is to demonstrate the expression of glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA in mature neurons. Here we show that SVZ cells display low levels of GAD immunocytochemistry and enzyme activity as compared with the olfactory bulb. We also show that these cells are able to synthesize GABA using an alternative source, the putrescine pathway. To test the importance of putrescine made GABA in vivo, we pharmacolgically inhibited putrescine synthesis through DFMO administration. We observed that this treatment lead to an increase of GAD expression in the SVZ and RMS. We also show here that SVZ cells can display phenotypic plasticity. Co-culturing SVZ explants and dorsal telencephalic slices, a spot of glutamatergic neurogenesis, we observed that a subpopulation of SVZ derived neurons differentiated into GABAergic neurons and another into glutamatergic pyramidal neurons. Our working hypothesis is that the putrescine pathway is a mechanism to synthesize GABA without commitment to the GABAergic phenotype. The release of putrescine derived GABA inhibits GAD expression leaving these neuroblasts in an undifferentiated state. The inhibition of putrescine synthesis caused an upregulation of GAD expression which would lead to GABAergic commitment. If we present these neuroblasts with different signals, as those present in the embryonic dorsal telencephalon, they would show plasticity in their phenotypic fate and differentiate into other neurochemical and morphological phenotypes, one of which is the glutamatergic pyramidal neuron.Doctoral Thesis Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas(Universidade Federal do Rio Grande do Sul, 2005-12) Tort, Adriano Bretanha Lopes; Souza, Diogo Onofre Gomes de; Lara, Diogo Rizzato; http://lattes.cnpq.br/0468757957130419; http://lattes.cnpq.br/9534019126486839; http://lattes.cnpq.br/3181888189086405The aims of this work were the search for new atypical antipsychotics presenting low cost and the understanding of the mechanism of action leading to atypical antipsychotic profile. The results obtained are presented in two distinct parts based on their nature, namely, experimental (first part) or theoretical (second part). For the development of the first part, a webcam based software to measure locomotion of rodents was programmed. After that, it was investigated the effect of guanosine, flunarizine and cinnarizine on animal models of psychosis, as well as in other behavioral tasks. Guanosine was chosen because it has been shown to interact with the glutamatergic system – which is known to be involved in the pathophysiology of schizophrenia – by promoting astrocytic glutamate reuptake. Flunarizine and cinnarizine, two calcium channel blockers commonly used in many countries to treat vertigo and migraine, were chosen because they were shown to induce extrapyramidal signs in elder patients, which was later related to moderate antagonist properties at dopamine D2 receptors. Guanosine was able to reduce a NMDA antagonist (MK-801) induced hyperlocomotion, whereas it had no effect on the hyperlocomotion induced by amphetamine, and it is discussed that its utility as antipsychotic drug should be further evaluated. Both cinnarizine and flunarizine were able to reduce the hyperlocomotion induced by MK-801 and amphetamine at doses that presented no significant cataleptic behavior. It was therefore concluded that these compounds have a potential atypical antipsychotic profile, with the advantage of already approved for commercial use, presenting well tolerability and very low cost when compared to current commercially available atypical antipsychotics. The second part of this thesis presents some theoretical mathematical results that can be derived from the law of mass action theory applied to receptor binding linked with known PET experimental data. These results present insights to the understanding of the differences between typical and atypical profile of antipsychotics regarding the generation of extrapyramidal syndrome. It is argued that cultural and commercial aspects related to the nowadays employed posology of typical antipsychotics can be responsible for the difference seen in profile, once some typical antipsychotics are prescribed in proportionally higher doses in relation to their affinities, leading therefore to higher dopaminergic blockade. A short plasmatic half-life is also pointed as a possible important factor leading to an atipical profile. Moreover, the second part of this thesis also points to some misconception currently being used in the scientific literature regarding the time-course of dopaminergic occupation, such as the concept of receptor occupation half-life. As a last theoretical based result, it is proposed an algorithm for antipsychotic dose reduction in patients presenting extrapyramidal signs and symptoms.Article Role of neuronal reverberation during slow wave sleep in the consolidation of recently acquired memory traces(2009-10-19) Cota, V.R.; Pereira, C.; Souza, A. C.; Nicolelis, M. A. L.; Ribeiro, Sidarta Tollendal GomesConference Experience-dependent reactivation of the calcium signal transduction pathway in the rat hippocampus during sleep(2009-10-20) Pereira, C. M.; Cota, V. R.; Santos, S.; Dias, G.; Souza, A. C.; Ribeiro, Sidarta Tollendal Gomes; Nicolelis, M. A. L.