Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-07-21T17:25:58Z No. of bitstreams: 1 AndreaLimaDeSa_TESE.pdf: 4573844 bytes, checksum: 9f1a31fbaa0a719d2f0fb7406f6aca31 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-07-22T12:47:11Z (GMT) No. of bitstreams: 1 AndreaLimaDeSa_TESE.pdf: 4573844 bytes, checksum: 9f1a31fbaa0a719d2f0fb7406f6aca31 (MD5) / Made available in DSpace on 2016-07-22T12:47:11Z (GMT). No. of bitstreams: 1 AndreaLimaDeSa_TESE.pdf: 4573844 bytes, checksum: 9f1a31fbaa0a719d2f0fb7406f6aca31 (MD5) Previous issue date: 2014-09-05 / O c?rtex somatosensorial prim?rio (S1), recebe informa??es dos receptores t?teis localizados na periferia sensorial e desempenha um papel crucial na explora??o ambiental. No entanto, essa regi?o do SNC adulto, como v?rias outras, apresenta uma redu??o expressiva no seu potencial pl?stico na fase adulta. Esse fato se deve ? presen?a de estruturas e subst?ncias que impedem a regenera??o dos neuritos ap?s a les?o, como por exemplo os componentes da matriz extracelular (MEC) presentes nas redes perineuronais. O amadurecimento das redes perineuronais (RPNs) coincide com o fechamento do per?odo cr?tico de plasticidade, pois os proteoglicanos da matriz extracelular atuam na estabiliza??o dos contatos sin?pticos. A remo??o dos componentes desta matriz ? uma manobra promissora para o restabelecimento da plasticidade e da recupera??o funcional de ?reas lesionadas do sistema nervoso central de animais adultos. Na presente tese, realizamos a remo??o das PGSCs do meio extracelular do c?rtex cerebral como terapia para restaurar a plasticidade e promover a regenera??o morfofuncional do c?rtex somest?sico prim?ria (SI) ap?s remo??o das vibrissas mistaciais durante o per?odo cr?tico. O tratamento com CABC mostrou-se eficaz para o estabelecimento de plasticidade cerebral com altera??es axonais, celulares e recupera??o funcional. / The primary somatosensory cortex (S1) receives inputs from peripheral tactile receptors and plays a crucial role on many important behaviors. However, the plastic potential of this region is greatly reduced during adulthood, limiting functional recovery after injuries. This fact is due to the presence, in the brain parenchima, of structures and substances that have an inhibitory effect on plasticity, such as chondroitin sulfate proteoglicans (CSP) present in the perineuronal.nets (PNNs) surrounding a subset of neurons. Maturation of PNNs coincide with the closure of critical periods of plasticity in cortical areas, since CSP act to stabilize synaptic contacts. Removal of CSP is proven to be an effective therapeutic approach to restore plasticity and increase the odds of functional recovery after cortical lesion. In the present work, we removed CSP from the sensorimotor cortex of rats to restore plasticity and promote the compensatory morphofunctional regeneration of cortical circuits modified by removal of mystacial vibrissae during the critical period. Treatment with the CSP-digesting enzyme chondroitinase ABC proved efficient to restore plasticity in S1 circuits, as evidenced by morphological rearrangements and functional recovery.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-12-29T19:00:45Z No. of bitstreams: 1 AndersonHenriqueFrancaFigueredoLeao_TESE.pdf: 9217812 bytes, checksum: cac2716089a2fdc3b21b756ad7ac5444 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-01-02T21:43:34Z (GMT) No. of bitstreams: 1 AndersonHenriqueFrancaFigueredoLeao_TESE.pdf: 9217812 bytes, checksum: cac2716089a2fdc3b21b756ad7ac5444 (MD5) / Made available in DSpace on 2017-01-02T21:43:34Z (GMT). No. of bitstreams: 1 AndersonHenriqueFrancaFigueredoLeao_TESE.pdf: 9217812 bytes, checksum: cac2716089a2fdc3b21b756ad7ac5444 (MD5) Previous issue date: 2016-05-06 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / A Doen?a de Parkinson (DP) ? um dist?rbio motor relacionado ao envelhecimento que atualmente acomete de 1-2% da popula??o mundial acima dos 60 anos. No Brasil, estima-se que esta acometa aproximadamente 600 mil indiv?duos, configurando-se como uma enfermidade de import?ncia para pa?ses em processo de incremento da expectativa de vida. A epidemiologia da DP revela fatores de risco intr?nsecos e extr?nsecos ao paciente que definem a chance de desenvolvimento do dist?rbio. Muta??es pontuais e polimorfismos com significado funcional s?o tidos como fatores gen?ticos predisponentes, enquanto a exposi??o a pesticidas e toxinas destacam-se como fatores ambientais. No entanto, poucos estudos em modelos animais focam em investigar a intera??o entre estes fatores. Isto pode ser alcan?ado comparando-se os efeitos de subst?ncias indutoras de parkinsonismo em linhagens de ratos com diferentes contextos gen?ticos. Recentemente, o tratamento repetido com baixas doses de reserpina - um inibidor irrevers?vel do transportador vesicular de monoaminas (VMAT2) - foi proposto como um modelo progressivo para a DP. Sob este regime de tratamento, roedores apresentam, de forma progressiva, comprometimento motor, cognitivo, e altera??es neuroqu?micas compat?veis com a fisiopatologia da DP. Em paralelo, comparados a ratos Wistar, animais da linhagem SHR (Spontaneously Hypertensive Rats) s?o resistentes ? indu??o da discinesia oral pelo tratamento agudo com reserpina. Em vista destes achados, n?s buscamos avaliar se ratos SHR seriam resistentes aos d?ficits motores e altera??es neuroqu?micas quando submetidos ao modelo progressivo para DP induzido por reserpina. Portanto, n?s submetemos ratos Wistar e SHR ao tratamento agudo (1 mg/kg) ou repetido (15 inje??es de 0,1 mg/kg, em dias alternados) com reserpina e investigamos a progress?o dos d?ficits motores nas tarefas de catalepsia em barra, discinesia oral, e atividade espont?nea em campo aberto. Observamos ent?o que, para ambos os regimes de tratamento, animais SHR se mostram resilientes ao preju?zo motor em todas as dimens?es motoras avaliadas. Ainda, estas diferen?as se manifestaram tanto na lat?ncia para o surgimento do comprometimento motor como para a magnitude deste. Estas altera??es foram ainda acompanhadas por decr?scimo na express?o da tirosina hidroxilase (TH) e incremento na express?o de ?-sinucle?na na via nigro-estriatal de ambas linhagens submetidas ao tratamento com reserpina. Estas altera??es neuroqu?micas resultantes do tratamento com reserpina tamb?m se refletiram nos n?veis de monoaminas - dopamina e serotonina - na via nigro-estriatal destes animais. De modo geral, como no comportamento motor, animais SHR apresentaram atraso para a deple??o de monoaminas e menor magnitude deste efeito. Em conclus?o, os resultados aqui apresentados claramente corroboram a resili?ncia de ratos SHR ao modelo progressivo da DP. Estes achados exp?em novos alvos potenciais para as diferen?as neuroqu?micas, moleculares e gen?ticas na linhagem SHR relevantes para o estudo da susceptibilidade ? DP. / Parkinson?s disease (PD) is an aging-related progressive neurodegenerative disorder characterized by motor and non-motor symptoms, which affects 1-2% of the world population above 60 years old. In Brazil, this approximately 600 thousand people live with this disorder. Thus, PD is an important burden to countries with increasing life expectancy. The epidemiology of PD highlight intrinsic and extrinsic risk factors that are stochastic to the development of the disorder. Predisposing genetic factors comprise punctual mutations and polymorphisms with functional significance, while exposition to toxins is emphasizedas environmental factors. Nevertheless, few animal studies focus on the investigation of the interaction between these factors. Such may be accomplished by comparing the effects of substances that cause parkinsonism on rat strains with different genetic backgrounds. Recently, the repeated treatment with a low-dose of reserpine ? an irreversible inhibitor of the vesicular monoamine transporter (VMAT2) ? was suggested as a progressive model of PD. Rats under this treatment regimen show progressive catalepsy behavior, oral dyskinesia and spontaneous motor activity decrement. In parallel, compared to Wistar rats, SHR (Spontaneously Hypertensive Rat) are resistant to acute reserpine-induced oral dyskinesia. In view of these findings, we aimed to assess whether SHR would be resistant to repeated reserpine-induced motor and neurochemical deficits when submitted to the progressive model of PD. Thus, we submitted Wistar and SHR rats to the acute (1 mg/kg) or repeated (0,1 mg/kg, 15x, every other day) treatment with reserpine and investigated the progression of motor deficits in the catalepsy bar, oral dyskinesia, and spontaneous activity on the open field. Our results revealed that, for both treatment regimens, SHR rats were resistant to the motor impairment for all motor parameters assessed. Moreover, these differences were detected for both the latency to instauration and the magnitude of the impairment. The alterations were concomitant to a decrement in the optical density of tyrosine hydroxylase and an increment in ?-synuclein immunostaining by immunohistochemistryin the nigro-striatal pathway of both strains submitted to reserpine treatment. These neurochemical alterations resulted from reserpine treatment also reflected in the levels of monoamines ? dopamine and serotonin ? in the nigro-striatal pathway of these animals. Altogether, similarly to the motor behavior, SHR rats displayed lower magnitude and a delay to monoamine depletion. In conclusion, the current results clearly evidence the resilience of SHR to the repeated low-dose reserpine protocol. These findings uncover new potential underlying neurochemical, molecular and genetic differences in the SHR strain relevant to the study of susceptibility to PD.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-11-03T20:50:56Z No. of bitstreams: 1 JessicaDeAndradePessoa_DISSERT.pdf: 10020769 bytes, checksum: daeec5fd94bc7d6846a49b3d22ead059 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-11-17T19:54:39Z (GMT) No. of bitstreams: 1 JessicaDeAndradePessoa_DISSERT.pdf: 10020769 bytes, checksum: daeec5fd94bc7d6846a49b3d22ead059 (MD5) / Made available in DSpace on 2017-11-17T19:54:39Z (GMT). No. of bitstreams: 1 JessicaDeAndradePessoa_DISSERT.pdf: 10020769 bytes, checksum: daeec5fd94bc7d6846a49b3d22ead059 (MD5) Previous issue date: 2017-07-27 / A ayahuasca ? uma bebida com propriedades psicod?licas amplamente utilizada por popula??es ind?genas da regi?o amaz?nica. Esse preparo cont?m a triptamina psicod?lica N,N-dimetiltriptamina (DMT), e inibidores da monoamina oxidase (iMAO), como harmina e harmalina. A ayahuasca ? considerada um psicod?lico seroton?rgico, e que pode levar a um estado alterado de consci?ncia com semelhan?as a uma experi?ncia on?rica, com intensas altera??es na percep??o, pensamentos, humor, emo??o, e experi?ncias tidas como m?sticas. Correlatos neurais dos efeitos agudos da ayahuasca t?m sido investigados por diferentes t?cnicas de neuroimagem funcional, incluindo a eletroencefalografia (EEG). Neste trabalho exploramos mudan?as espectrais de EEG em 50 volunt?rios saud?veis, utilizando desenho randomizado duplo-cego placebo-controlado. Metade recebeu uma sess?o com a ayahuasca, a outra metade com placebo. Ap?s a administra??o da subst?ncia, os volunt?rios foram monitorados durante 4 horas por um equipamento de EEG. A fim de melhorar a qualidade dos dados, os volunt?rios foram solicitados a realizar 2 tarefas simples em tr?s instantes espec?ficos: antes da ingest?o, 2h e 4 horas ap?s a ingest?o. Na primeira tarefa, deveriam tentar permanecer acordados, e intercalar per?odos de 20 segundos de olhos abertos, e 40 segundos de olhos fechados, durante 5 minutos. Na segunda tarefa, eles deveriam permanecer de olhos fechados, tentando se manter acordados, por outros 5 minutos. A an?lise espectral (2h) revelou que a pot?ncia de alfa ? significativamente menor no grupo ayahuasca que no placebo nas regi?es occipital e temporoparietal ? direita. Encontramos, ainda, aumento significativo em 2h na pot?ncia de teta na regi?o temporoparietal ? direita. A an?lise de correla??o revelou correspond?ncias entre a pot?ncia de alfa (2h) e a pontua??o obtida em duas escalas sens?veis aos efeitos de psicod?licos - a Hallucinogen Rating Scale (HRS) e o Mystical Experience Questionnaire (MEQ). Apresentamos, ainda, achados de tra?ados curiosos, encontrados na inspe??o visual dos tra?ados de EEG. De modo geral, nossos resultados sugerem que a inibi??o das oscila??es alfa em regi?es posteriores do c?rebro desempenha papel importante na experi?ncia psicod?lica, talvez compartilhando mecanismos presentes durante a experi?ncia on?rica. / Ayahuasca is a brew with psychedelic properties largely used by indigenous populations from the Amazon basin. It contains the psychedelic tryptamine N,N-dimethyltriptamine (DMT), and monoamine oxidase inhibitors (iMAO), such as harmine and harmaline. Ayahuasca is consid-ered to be a serotonergic psychedelic, capable of inducing an altered state of consciousness with similarities to an oneiric experience, with intense alterations in perception, though, humor, emo-tion, and mystical-type experiences. The neural correlates of its acute effects have been inves-tigated by different neuroimaging techniques, including electroencephalography (EEG). In this study, we explored EEG spectral changes in 48 healthy volunteers using a randomized double-blind placebo-controlled trial. Half of the volunteers received ayahuasca, half received placebo. We used an EEG system to monitor all volunteers throughout the dosing session, which lasted approximately 4-hours. Aiming to improve data quality, the volunteers were asked to perform two controlled tasks at three specific moments: before intake, 2h and 4h after intake. For the first task, they alternated moments of eyes open (20 seconds) with eyes closed (40 seconds) for 5 minutes, avoiding falling asleep. During the second task they should keep their eyes closed for another 5 minutes, again avoiding falling asleep. Spectral analysis at 2h after intake shows reduced alpha power, and increased theta and beta in the ayahuasca group with respect to the placebo, mainly in occipital and right temporoparietal regions. Correlation analysis revealed correspondences between the alpha power (2h) and individual scores on two scales used to measure psychedelic effects ? the Hallucinogen Rating Scale (HRS) and the Mystical Experi-ence Questionnaire (MEQ). Additionally, we also present EEG traces with electrophysiological events that might be of importance for the representation of the psychedelic experience. Over-all, our results suggest that the inhibition of alpha oscillations, increased theta and beta in right posterior brain regions play an important role on the psychedelic experience, maybe sharing mechanisms present during the oneiric experience.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2018-01-16T18:01:47Z No. of bitstreams: 1 KatiaSimoneDeAraujoNobregaRocha_DISSERT.pdf: 15764760 bytes, checksum: 8bfb9a0320607958c4f488fa38d6706c (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2018-01-22T11:31:34Z (GMT) No. of bitstreams: 1 KatiaSimoneDeAraujoNobregaRocha_DISSERT.pdf: 15764760 bytes, checksum: 8bfb9a0320607958c4f488fa38d6706c (MD5) / Made available in DSpace on 2018-01-22T11:31:34Z (GMT). No. of bitstreams: 1 KatiaSimoneDeAraujoNobregaRocha_DISSERT.pdf: 15764760 bytes, checksum: 8bfb9a0320607958c4f488fa38d6706c (MD5) Previous issue date: 2017-08-31 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / Cortical gamma oscillations (30 - 90 Hz) have been implicated in various cognitive processes, such as perceptual binding and attention. So far, most evidence in support of this hypothesis is based on studies that used artificial and simplified stimuli, such as moving gratings and bars. Recently, experimental work using natural images led to conflicting conclusions. In a paradigm that required human subjects to maintain fixation, electrocorticogram signals (ECoG) showed gamma for grating stimuli but not for static images or pink noise (Hermes et al., 2015). On the contrary, analysis of ECoG in the early visual cortex of macaque monkeys revealed strong gamma components for free viewing of natural scenes (Brunet et al., 2015). Here, we aim to clarify these discrepancies using a paradigm that allowed direct comparisons between fixation vs. free viewing conditions, for both simplified stimuli (moving and static gratings) and natural scenes (static and moving images). Recordings of spiking activity and local field potentials (LFPs) were obtained from the central and the peripheral representations of V1. Our results show that in capuchins (N= 3 monkeys), as previously described in macaques and humans, gamma is characteristically strong when stimulus parameters, such as size, orientation, and speed are set at to optimal values. Comparisons between fixation vs. free viewing conditions and gratings vs. natural stimuli revealed that gamma is always high for optimal grating stimuli, regardless of viewing condition (N= 93 recording sites, 2 monkeys). However, gamma is surprisingly absent during free viewing of natural images and movies. Similar negative findings were also obtained when the monkeys were exposed to real-world scenes, such as objects and other animals in the laboratory. The present results suggest that strong, narrow-band, gamma responses in V1 are primarily associated with the selective activation of cell populations sharing similar response properties. Therefore, gamma may be seen as a resonance phenomenon of the underlying cortical connectivity. Overall, our results belittle the importance of gamma as a critical cortical mechanism for vision. / As oscila??es corticais gama (30 - 90 Hz) t?m sido implicadas em processos cognitivos como a liga??o perceptual e a aten??o. At? agora, a maioria das evid?ncias que servem de suporte para esta hip?tese ? baseada em e s t u d o s a p a r t i r do uso de e s t ? m u l o s s i m p l e s e artificiais, como grades e barras luminosas. Recentemente, no entanto, estudos experimentais utilizando imagens naturais levaram a conclus?es conflitantes. Em um paradigma em humanos que requeria fixa??o mantida, sinais eletrocorticogr?ficos (ECoG) mostraram gama para grades, mas n?o p a r a imagens e s t ? t i c a s ou r u ? d o r o s a (Hermes e t a l . , 2 0 1 5 ) . Contrariamente, a an?lise dos sinais ECoG no c?rtex visual de macacosreso revelou fortes componentes gama para a livre observa??o de cenas naturais (Brunet et al., 2015). Neste estudo, temos por objetivo esclarecer essas discrep?ncias utilizando-se de um paradigma que permitiu compara??es diretas entre uma condi??o de fixa??o vs. uma condi??o de observa??o livre, tanto para est?mulos simplificados (grades m?veis e e s t ? t i c a s ) q u a n t o p a r a c e n a s n a t u r a i s ( i m a g e n s e s t ? t i c a s e em movimento). Registros de potenciais de a??o e de potenciais de campo locais (LFPs) foram obtidos para a representa??o central e perif?rica de V1. Nossos resultados demonstram que em macacos-capuchinhos (N = 3), como descrito anteriormente para macacos-reso e humanos, a gama ? caracteristicamente forte, sempre que os par?metros do est?mulo, como tamanho, orienta??o e velocidade, s?o definidos para a ativa??o ?tima das c?lulas. Compara??es entre condi??es de fixa??o e de livre observa??o e grades vs. est?mulos naturais revelaram que a gama ? sempre forte para grades de orienta??o ?tima, independentemente da condi??o de visualiza??o (N = 93 s?tios de registro, 2 macacos). No entanto, a gama est? surpreendentemente ausente durante a livre visualiza??o de imagens e filmes naturais. Achados negativos semelhantes tamb?m foram obtidos quando os macacos foram expostos a cenas do mundo real, como objetos e outros animais no laborat?rio. Os presentes resultados sugerem que, no c?rtex visual prim?rio, a atividade gama ? principalmente associada ? ativa??o seletiva de popula??es neuronais que compartilham propriedades de resposta similares. Portanto, a gama pode ser vista como um fen?meno de resson?ncia da conectividade cortical subjacente. Em geral, nossos resultados minimizam a import?ncia da gama como um mecanismo cortical chave para a vis?o.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-08-16T23:02:45Z No. of bitstreams: 1 AnaMariaAraujoSoares_DISSERT.pdf: 3132164 bytes, checksum: 1d26fedd574b389db008072f0a9d4fcb (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-08-24T00:27:46Z (GMT) No. of bitstreams: 1 AnaMariaAraujoSoares_DISSERT.pdf: 3132164 bytes, checksum: 1d26fedd574b389db008072f0a9d4fcb (MD5) / Made available in DSpace on 2016-08-24T00:27:46Z (GMT). No. of bitstreams: 1 AnaMariaAraujoSoares_DISSERT.pdf: 3132164 bytes, checksum: 1d26fedd574b389db008072f0a9d4fcb (MD5) Previous issue date: 2015-10-30 / O autismo ? um transtorno do desenvolvimento que se manifesta nos primeiros anos de vida e apresenta semiologia heterog?nea. Esta patologia afeta a matura??o do enc?falo e produz altera??es sensoriais, de linguagem e de intera??o social no in?cio na inf?ncia. O modelo experimental de autismo utilizando ?cido valproico (VPA) durante o per?odo gestacional tem sido demonstrado ter alta validade de face e permitir estudos tanto das bases neuropatol?gicas quanto neuro-funcionais durante o desenvolvimento. A despeito do recente interesse por este modelo como instrumento de compreens?o dos aspectos b?sicos da fisiopatologia do autismo, a maioria dos estudos experimentais t?m se concentrado nos aspectos comportamentais, histol?gicos e celulares. Neste trabalho, foram propostas estrat?gias experimentais de avalia??o comportamental associadas a eletrofisiologia \textit{in vivo}, uma t?cnica que nunca fora utilizada para avalia??o desse modelo. Animais controles e experimentais, submetidos previamente a um procedimento cir?rgico para implante de eletrodos cr?nicos, participaram de experimentos de livre explora??o, intera??o social e condicionamento ao medo. / O autismo ? um transtorno do desenvolvimento que se manifesta nos primeiros anos de vida e apresenta semiologia heterog?nea. Esta patologia afeta a matura??o do enc?falo e produz altera??es sensoriais, de linguagem e de intera??o social no in?cio na inf?ncia. O modelo experimental de autismo utilizando ?cido valproico (VPA) durante o per?odo gestacional tem sido demonstrado ter alta validade de face e permitir estudos tanto das bases neuropatol?gicas quanto neuro-funcionais durante o desenvolvimento. A despeito do recente interesse por este modelo como instrumento de compreens?o dos aspectos b?sicos da fisiopatologia do autismo, a maioria dos estudos experimentais t?m se concentrado nos aspectos comportamentais, histol?gicos e celulares. Neste trabalho, foram propostas estrat?gias experimentais de avalia??o comportamental associadas a eletrofisiologia \textit{in vivo}, uma t?cnica que nunca fora utilizada para avalia??o desse modelo. Animais controles e experimentais, submetidos previamente a um procedimento cir?rgico para implante de eletrodos cr?nicos, participaram de experimentos de livre explora??o, intera??o social e condicionamento ao medo.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-08-25T20:54:16Z No. of bitstreams: 1 MalekChouchane_TESE.pdf: 3043835 bytes, checksum: b90ef34a2d4072ef5abda48d216aebb4 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-08-26T21:40:31Z (GMT) No. of bitstreams: 1 MalekChouchane_TESE.pdf: 3043835 bytes, checksum: b90ef34a2d4072ef5abda48d216aebb4 (MD5) / Made available in DSpace on 2016-08-26T21:40:31Z (GMT). No. of bitstreams: 1 MalekChouchane_TESE.pdf: 3043835 bytes, checksum: b90ef34a2d4072ef5abda48d216aebb4 (MD5) Previous issue date: 2016-02-29 / Recently, the field of cellular reprogramming has been revolutionized by works showing the potential to directly lineage-reprogram somatic cells into neurons upon overexpression of specific transcription factors. This technique offers a promising strategy to study the molecular mechanisms of neuronal specification, identify potential therapeutic targets for neurological diseases and eventually repair the central nervous system damaged by neurological conditions. Notably, studies with cortical astroglia revealed the high potential of these cells to reprogram into neurons using a single neuronal transcription factor. However, it remains unknown whether astroglia isolated from different regions of the central nervous system have the same neurogenic potential and generate induced neurons (iN) with similar phenotypes. Similarly, little is known about the fate that iNs could adopt after transplantation in the brain of host animals. In this study we compare the potential to reprogram astroglial cells isolated from the postnatal cerebral cortex and cerebellum into iNs both in vitro and in vivo using the proneural transcription factors Neurogenin-2 (Neurog2) and Achaete scute homolog-1 (Ascl1). Our results indicate cerebellar astroglia can be reprogrammed into induced neurons (iNs) with similar efficiencies to cerebral cortex astroglia. Notably however, while iNs in vitro adopt fates reminiscent of cortical or cerebellar neurons depending on the astroglial population used for reprogramming, in situ, after transplantation in the postnatal and adult mouse brain, iNs adopt fates compatible with the region of integration. Thus, our data suggest that the origin of the astroglial population used for lineage-reprogramming affects the fate of iNs in vitro, but this imprinting can be overridden by environmental cues after grafting.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-04-01T19:13:13Z No. of bitstreams: 1 JoseHenriqueTarginoDiasGois_DISSERT.pdf: 8111349 bytes, checksum: df4a2a7f9ab95c60e4e75a96288b99f9 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-04-06T00:26:58Z (GMT) No. of bitstreams: 1 JoseHenriqueTarginoDiasGois_DISSERT.pdf: 8111349 bytes, checksum: df4a2a7f9ab95c60e4e75a96288b99f9 (MD5) / Made available in DSpace on 2016-04-06T00:26:58Z (GMT). No. of bitstreams: 1 JoseHenriqueTarginoDiasGois_DISSERT.pdf: 8111349 bytes, checksum: df4a2a7f9ab95c60e4e75a96288b99f9 (MD5) Previous issue date: 2015-02-24 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq / A administra??o de nicotina em seres humanos e roedores ? pensada como um melhorador de mem?ria e aten??o, tamb?m pelo seu efeito positivo na Doen?a de Alzheimer. O complexo do Septo Medial / Banda Diagonal de Broca (MS/DBB) ? um dos principais sistemas colin?rgicos ? massivamente projetado para o hipocampo atrav?s da F?mbria-F?rnix, via esta chamada de via septo-hipocampal. Foi demonstrado que o MS/DBB afeta diretamente o potencial de campo local (LFP) e a organiza??o r?tmica do hipocampo, especialmente na gera??o do ritmo teta - um LFP r?tmico intrinsecamente relacionado com a fun??o mnem?nica do hipocampo. Experimentos in vitro deram evid?ncias de que a nicotina aplicada no MS/DBB pode gerar um ritmo teta na rede local do MS/DBB. Assim, o presente estudo se prop?e a elucidar a fun??o da nicotina no MS/DBB sobre a via septo-hipocampal. Experimentos in vivo, comparando o efeito de microinfus?es no MS/DBB de solu??o salina (n = 5) ou nicotina (n = 8) em camundongos anestesiados por ketamina/xilazina mostraram um aumento na densidade de pot?ncia no espectro banda de gama (35 a 55 Hz) em ambas as estruturas (teste de Wilcoxon Rank-Sum, p = 0,038), mas sem alterar a coer?ncia entre as estruturas na mesma banda (teste de Wilcoxon Rank-Sum, p = 0,60). Houve tamb?m uma diminui??o na densidade pot?ncia na banda delta (1-3 Hz) ? oscila??o induzida pela ketamina. Realizamos tamb?m experimentos in vitro sobre o efeito da nicotina na voltagem de membrana e no potencial de a??o de neur?nios do MS/DBB. Registramos neur?nios (n=22) em current-clamp antes e depois da presen?a de nicotina no meio extracellular; 12 neur?nios responderam ? nicotina, metade aumentou a taxa de potenciais de a??o; outros seis diminu?ram, diferindo significativamente no limiar do potencial de a??o (- 47,3 ? 0,9 mV vs. -41 ? 1,9 mV, respectivamente, p = 0,007) e na largura do disparo (1,6 ? 0,08 vs. 2 ms ? 0,12 ms, respectivamente, p = 0,01). Al?m disso, realizamos outro conjunto de experimentos in vitro, relativo ? conectividade das tr?s grandes popula??es neuronais de MS / DBB que usam a acetilcolina, GABA ou glutamato como neurotransmissores. O registro pareado de patch-clamp mostrou que neur?nios glutamat?rgicos e GABA?rgicos realizam contatos intra-septais capazes de produzir correntes sin?pticas em neur?nios p?s-sin?pticos do MS/DBB. A probabilidade da conectividade entre diferentes popula??es neuronais foi implementada em um modelo realista que corrobora que a rede ? altamente sens?vel ? gera??o de ritmo gama. Juntamente com os dados dispon?veis, o conjunto completo de experi?ncias corrobora que a nicotina pode atuar como potenciador cognitivo, e um substrato eletrofisiol?gico prov?vel ? atrav?s da indu??o de oscila??o gama no circuito local do MS/DBB. / Nicotine administration in humans and rodents enhances memory and attention, and also has a positive effect in Alzheimer's Disease. The Medial Septum / Diagonal Band of Broca complex (MS/DBB) ? a main cholinergic system ? massively projects to the hippocampus through the fimbria-fornix, and this pathway is called the septohippocampal pathway. It has been demonstrated that the MS/DBB acts directly on the local field potential (LFP) rhythmic organization of the hippocampus, especially in the rhythmogenesis of Theta (4-8Hz) ? an oscillation intrinsically linked to hippocampus mnemonic function. In vitro experiments gave evidence that nicotine applied to the MS/DBB generates a local network Theta rhythm within the MS/DBB. Thus, the present study proposes to elucidate the function of nicotine in the MS/DBB on the septo-hippocampal pathway. In vivo experiments compared the effect of MS/DBB microinfusion of saline (n=5) and nicotine (n=8) on Ketamine/Xylazine anaesthetized mice. We observed power spectrum density in the Gamma range (35 to 55 Hz) increasing in both structures (Wilcoxon Rank-Sum test, p=0.038) but with no change in coherence between these structures in the same range (Wilcoxon Rank-Sum test, p=0.60). There was also a decrease in power of the ketamineinduced Delta oscillation (1 to 3 Hz). We also performed in vitro experiments on the effect of nicotine on membrane voltage and action potential. We patch-clamped 22 neurons in current-clamp mode; 12 neurons were responsive to nicotine, half of them increased firing rate and other 6 decreased, and they significantly differed in action potential threshold (-47.3?0.9 mV vs. -41?1.9 mV, respectively, p=0.007) and halfwidth time (1.6?0.08 ms vs. 2?0.12 ms, respectively, p=0.01). Furthermore, we performed another set of in vitro experiments concerning the connectivity of the three major neuronal populations of MS/DBB that use acetylcholine, GABA or glutamate as neurotransmitter. Paired patch-clamp recordings found that glutamatergic and GABAergic neurons realize intra-septal connections that produce sizable currents in MS/DBB postsynaptic neurons. The probability of connectivity between different neuronal populations gave rise to a MS/DBB topology that was implemented in a realistic model, which corroborates that the network is highly sensitive to the generation of Gamma rhythm. Together, the data available in the full set of experiments suggests that nicotine may act as a cognitive enhancer, by inducing gamma oscillation in the local circuitry of the MS/DBB.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-04-26T20:08:35Z No. of bitstreams: 1 ThawannMalfattiBorges_DISSERT.pdf: 27333324 bytes, checksum: 7928d876effa4fd0184f0b246ecd1c34 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-04-29T20:35:41Z (GMT) No. of bitstreams: 1 ThawannMalfattiBorges_DISSERT.pdf: 27333324 bytes, checksum: 7928d876effa4fd0184f0b246ecd1c34 (MD5) / Made available in DSpace on 2016-04-29T20:35:41Z (GMT). No. of bitstreams: 1 ThawannMalfattiBorges_DISSERT.pdf: 27333324 bytes, checksum: 7928d876effa4fd0184f0b246ecd1c34 (MD5) Previous issue date: 2015-06-26 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Tinnitus is the perception of a sound in the absence of a corresponding physical stimulus. It is not clear yet what mechanisms are involved in tinnitus and how it starts and/or becomes chronic. Due to the relationship between tinnitus and somatosensory trauma/stimuli, the dorsal cochlear nucleus (DCN), a region known to integrate somatosensory and auditory pathways, has been identified as a potential key structure in the generation of phantom sound perception. Here, we target specific neuronal populations in the DCN to allow further investigation on how this region may contribute to the generation of tinnitus signals that spread to other auditory areas. We examined the expression of optogenetic proteins (Channelrhodopsin 2 - ChR2; and enhanced Archaerhodopsin 3.0 - eArch3.0), targeting neurons expressing Calmoduline Kinase II alpha (CaMKIIa) promoter in wild-type C57/Bl6 mice and neurons expressing nicotinic acetylcholine receptor subunit alpha-2 promoter (ChRNA2) in ChRNA2- Cre transgenic C57/Bl6 mice, using local virus injection, verified by fluorescence microscopy. Unit responses were differentiated based on their electrophysiological response to sound. We then investigated if firing of neurons expressing optogenetic tools can be controlled in vivo and if the same neurons also fire action potentials in response to precisely timed sound stimulation. Both in vivo and preliminary in vitro data shows that neurons expressing ChR2 do respond to sound, and that they furthermore also can respond to light stimulation with a stable and similar waveform. Moreover, in vivo data shows that neurons expressing eArch3.0, responding to sound, will decrease their firing rate when exposed to green light. Thereby showing that optogenetic tools can be used functionally in the DCN, it is possible to further test tinnitus theories by, for example, producing an increased firing rate in the DCN, trying to mimic tinnitus; or inhibiting increased spontaneous firing rate in the DCN of animals with noise-induced or salycilate-induced tinnitus.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2018-01-24T12:39:09Z No. of bitstreams: 1 MarkusMichaelHilscher_TESE.pdf: 11039544 bytes, checksum: 9754abf5e62f785551c64a4ba1a727d0 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2018-01-29T12:29:16Z (GMT) No. of bitstreams: 1 MarkusMichaelHilscher_TESE.pdf: 11039544 bytes, checksum: 9754abf5e62f785551c64a4ba1a727d0 (MD5) / Made available in DSpace on 2018-01-29T12:29:16Z (GMT). No. of bitstreams: 1 MarkusMichaelHilscher_TESE.pdf: 11039544 bytes, checksum: 9754abf5e62f785551c64a4ba1a727d0 (MD5) Previous issue date: 2016-12-01 / A sincroniza??o neuronal surge de uma intera??o cooperativa de v?rios tipos celulares atrav?s de excita??o e inibi??o. Os mecanismos por tr?s desse tipo de coordena??o neuronal s?o, provavelmente, os mais din?micos entre as fun??es cerebrais, dificultando sua compreens?o. Entre os fatores que dificultam o estudo da sincronia, pode-se citar: o vasto n?mero de tipos de celulares, a diversidade de processos sin?pticos, a contribui??o de uma multiplicidade de canais e correntes i?nicas, entre outros. Essa tese tem como objetivo entender o papel de interneur?nios que especificamente inervam o dom?nio distal dos dendritos de c?lulas piramidais do hipocampo e neoc?rtex, na sincroniza??o de neur?nios em suas respectivas redes. A distribui??o de canais i?nicos e receptors sin?pticos em dendritos de c?lulas piramidais ? extremamente anisotr?pica. Assim, interneur?nios que inervam dom?nios proximais e distais dos dendritos causam efeitos distintos na c?lula alvo quando ativados. Por exemplo, por??es distais dos dendritos cont?m em abund?ncia um dos principais canais marcapassos em neur?nios: o canal regulado por nucleot?deo c?clico ativado por hiperpolariza??o. Esses canais produzem uma corrente cati?nica despolarizante (Ih) e tem um papel importante na regula??o da excitabilidade neuronal alterando dramaticamente as propriedades de disparo de neur?nios. Usando modelagem computacional, essa tese mostra como a amplitude de Ih em certos tipos celulares muda a taxa de disparo de um neur?nio, sua sincronia al?m da energia espectral e frequ?ncia de oscila??es. Al?m disso, como a express?o de Ih difere entre regi?es cerebrais, localiza??o e tipos celulares, essa tese, fazendo o uso de patch clamp, explora como Ih difere ao longo do eixo dorsoventral do hipocampo em c?lulas oriens-lacunosum moleculare (OLM), que s?o os principais interneur?nios que inervam dendritos distais dessa regi?o. Ademais, estudou-se aqui as c?lulas Martinotti, interneur?nios que inervam os dendritos distais do neoc?rtex. Nesse estudo, mostrou-se como uma popula??o definida de interneur?nios pode ser manipulada com o objetivo de controlar e coordenar o disparo de c?lulas piramidais. Ao fornecer inibi??o com energia e frequ?ncia adequada, as c?lulas Martinotti afetam especificamente um ?nico tipo de c?lula piramidal. Usando optogen?tica para ativar/desativar popula??es de c?lulas Martinotti, ? poss?vel gerar potenciais de a??o rebote em c?lulas piramidais quando alinhadas temporalmente. Os potenciais de a??o rebote, por sua vez, s?o resultado de uma forte inibi??o produzida pelas c?lulas Martinotti, o que faz com que esses esses interneur?nios possam resetar o disparo de c?lulas piramidais. De forma geral, c?lulas Martinotti e c?lulas OLM mostram similaridades surpreendentes em propriedades morfol?gicas, neuroqu?micas e eletrofisiol?gicas. Especialmente, suas longas proje??es axonais para camadas superiores assim como seus modos de disparo lentos, com baixos limiares e acomodativos tornam esses neur?nios singulares em suas capacidades de sincronizar os circuitos nos quais est?o inseridos. / Synchronization among neurons arises from the cooperative interaction of various cell types through excitation and inhibition. The mechanisms behind this type of neuronal orchestration are as versatile as almost no other coordination task in the brain, making its comprehension heavily challenging. Among many others, the high number of involved cell types, the diversity of synaptic processes as well as the contribution of a multitude of ion channels and currents span the plurality of neuronal synchronization mechanisms in our brains. Focusing on two brain areas, the hippocampus and the neocortex, this thesis aims to understand the role of distal dendritetargeting interneurons in shaping pyramidal cell activity and the timing of their action potentials. The distribution of ion channels and synaptic receptors in pyramidal cell dendrites is extremely anisotropic. Thus, interneurons innervating the proximal or distal areas of the dendrites cause different effects in the target cell when activated. For example, the distal portions of the pyramidal cell dendrites contain one of the most prominent pacemaker channels: the hyperpolarizationactivated cyclic nucleotide-gated channels. These channels produce a cationic depolarizing current (Ih) and play an essential role in the regulation of neuronal excitability. Using computational modeling, this thesis shows how the amount of Ih in certain cell types determines their spike rate, synchrony as well as power and frequency of ongoing network oscillations. Moreover, since Ih differs between brain regions as well as cell types and location, this thesis electrophysiologically explores how Ih differs along the dorsoventral axis of hippocampus in oriens-lacunosum moleculare (OLM) cells, the main distal dendrite-targeting interneurons of that region. Utilizing the main distal dendrite-targeting interneuron of the neocortex, the Martinotti cell, this thesis also shows how a defined population of interneurons can be manipulated in order to control and align pyramidal cell firing. By providing the right amount and frequency of inhibition, Martinotti cells are able to synchronize trains of subtype-specific pyramidal cells. Using optogenetic approaches to activate/inactivate populations of Martinotti cells, these dendrite-targeting interneurons are shown to trigger rebound action potentials in pyramidal cells when temporally aligned. The rebound action potentials in turn are the result of strong inhibition by Martinotti cells, giving these distal dendrite-targeting interneurons the power to reset pyramidal cell firing. Overall, Martinotti cells and OLM cells show quite striking similarities in morphological, neurochemical and electrophysiological properties. Especially, their long axonal projections to upper layers as well as their low-threshold, slow spiking fashion and the accommodating firing make these distal dendrite-targeting interneurons so special for neuronal synchronization.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2018-01-24T12:39:10Z No. of bitstreams: 1 NataliaBezerraMota_TESE.pdf: 30567436 bytes, checksum: 8f6938a228ec97da35c61175cbbae8b9 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2018-01-29T13:16:13Z (GMT) No. of bitstreams: 1 NataliaBezerraMota_TESE.pdf: 30567436 bytes, checksum: 8f6938a228ec97da35c61175cbbae8b9 (MD5) / Made available in DSpace on 2018-01-29T13:16:13Z (GMT). No. of bitstreams: 1 NataliaBezerraMota_TESE.pdf: 30567436 bytes, checksum: 8f6938a228ec97da35c61175cbbae8b9 (MD5) Previous issue date: 2017-07-11 / Entender comportamentos humanos complexos como a linguagem e suas varia??es em diferentes situa??es ? um importante objetivo de pesquisa h? muitos anos. Uma abordagem natural?stica e quantitativa para medir precisamente varia??es de linguagem do ponto de vista estrutural e sem?ntico apontam para um avan?o nessa ?rea, possibilitando medir varia??es manifestadas em discurso livre que refletem decl?nio cognitivo em situa??es patol?gicas, como nas psicoses, ou no desenvolvimento cognitivo em crian?as durante alfabetiza??o, e at? mesmo durante o processamento de mem?rias em estados fisiol?gicos alterados de consci?ncia, como o que ocorre durante os sonhos. Nesse trabalho iniciaremos discutindo 1) a elabora??o de ferramentas para an?lise de estrutura da fala inspiradas nas descri??es psicopatol?gicas de doen?as mentais, 2) sua aplica??o para diagn?stico diferencial de psicose e dem?ncias, 3) assim como a aplica??o de ferramentas sem?nticas para predi??o de epis?dios psic?ticos. Pela an?lise da estrutura do discurso usando grafos para estudar a trajet?ria de palavras usadas pelos sujeitos ao relatar um sonho, foi poss?vel, por exemplo, verificar que sujeitos portadores do diagn?stico de Esquizofrenia falavam de forma menos conectada que sujeitos com diagn?stico de Transtorno Bipolar do Humor ou sujeitos livres de sintomas psic?ticos. Da mesa forma verificamos que havia uma maior dist?ncia sem?ntica entre frases consecutivas em entrevistas psiqui?tricas de sujeitos em fase prodr?mica de psicose que em seguimento de 2 anos e meio fizeram um epis?dio psic?tico pleno. Seguiremos ampliando esse olhar para al?m do patol?gico, observando 4) como variam essas medidas de estrutura da linguagem com o desenvolvimento cognitivo saud?vel e 5) sua rela??o com a educa??o. Observamos correla??es entre conectividade do relato e performance em testes de intelig?ncia fluida, teoria da mente e performance em leitura. Tamb?m investigamos em uma popula??o ampla com grande varia??o de idades 6) como se d? o desenvolvimento dessas medidas ao longo do desenvolvimento educacional, 7) avaliando o impacto dos anos de educa??o nessa popula??o e 8) seus correlatos com o desenvolvimento hist?rico da literatura em aproximadamente 5.000 anos. De maneira geral, encontramos que padr?es de conectividade cresceram e estabilizaram ao final da idade do bronze, logo antes da era axial, na literatura, e que quanto mais tempo de educa??o tem o sujeito, maiores componentes conectados fazem ao relatar suas mem?rias, valores que se estabilizam apenas ao final do ensino m?dio (desenvolvimento que n?o se observa em popula??o com sintomas de psicose). Finalizaremos aplicando ferramentas de similaridade sem?ntica para 9) medir reverbera??o de mem?rias durante os sonhos e seus correlatos eletrofisiol?gicos em um experimento de transi??o entre vig?lia e sono. Podemos concluir a partir dos resultados que ferramentas estruturais e sem?nticas apresentam grande potencial para melhorar a precis?o de comportamentos humanos complexos expressos na fala, de maneira natural?stica, possibilitando investiga??es reveladoras sobre cogni??o e a consci?ncia humana. / The understanding of complex human behaviors such as language and its variations in different conditions and contexts has been an important research aim for many decades. Naturalistic and quantitative approaches to precisely measure language variations from the structural and semantic points of view have recently emerged, allowing the measurement of variations manifested in free speech that reflect atypical cognitive decline in pathological situations such as psychoses, or typical cognitive development in healthy children during alphabetization, and even the processing of memories in different states of consciousness, such as waking and dreaming. In this work we will start discussing 1) the construction of tools for the analysis of speech structure inspired by the psychopathological descriptions of mental illnesses. 2) their application to the differential diagnosis of psychosis and dementias, and 3) the application of semantic tools to predict psychotic episodes. In the structural level it was possible to observe that subjects with Schizophrenia diagnosis report their dreams with word trajectories represented as graphs less connected than subjects without psychosis or with Bipolar Disorder diagnosis. In the semantic level it was observed a higher semantic distance between consecutive sentences on psychiatric interviews of patients during prodromal psychotic phase 2 years and a half before converting to a psychotic episode. We will proceed by widening this view away from pathology, so as to determine 4) how graph-theoretical measures of language structure vary across healthy cognitive development, and 5) how they relate to indices of academic achievement. We verified a correlation between graph connectedness and cognitive (such as fluid intelligence and theory of mind abilities), as well as academic performances (of reading). Next we will investigate 6) how speech structure varies within a large sample of healthy and psychotic subjects with large age and educational variation, to 7) evaluate the impact of years of education and 8) compare with the development of literature across approximately 5,000 years. In summary, connectedness increases after the Bronze Age (just before start the Axial Age) and the longer time of education the subject had, higher the connected components of his memory reports, values stabilized during high school period, and a developmental trajectory not found in the psychotic population. We will conclude by applying tools to calculate semantic similarity to 9) measure memory reverberation during dreams and their electrophysiological correlates in a sleep transition experiment. The results indicate that the structural and semantic tools used in this work can greatly improve the precision of naturalistic measurements of the complex behaviors expressed in speech.