Parkinson's disease is the second commonest neurodegenerative disease currently treated symptomatically. It is a multifactorial disease involving mechanisms ranging from protein aggregation to mitochondrial dysfunction, oxidative stress and dopamine dysregulation. The levels of α-synuclein have been causatively linked to the development and progression of Parkinson's disease. Therefore α-synuclein lowering strategies are valid approaches in Parkinson's disease. Neuropathologically, Lewy Bodies in the vulnerable substantia nigra of Parkinson's disease patients are less ubiquitinated and specifically less K-63 ubiquitinated than Lewy bodies in the cortex, suggesting differential activation or regulation of ubiquitin interactors. A targeted screen for such interactors revealed that the Deubiquitinating enzyme Usp8 is upregulated in the substantia nigra of Parkinson's disease brains and is inversely correlated with the degree of total and K-63 ubiquitination. Using genetic knockdown and overexpression techniques, Usp8 was found to colocalize and directly interact with α-synuclein. It was found to de-ubiquitinate α-synuclein and increase its half-life. Its knockdown increased the total and K-63 α-synuclein ubiquitination and decreased its levels by 35% at least partly by increasing its degradation via the lysosome. In vivo in the Drosophila melanogaster, Usp8 knockdown demonstrated protection against α-synuclein toxicity. It rescued in a specific manner the rough eye phenotype, the age-dependent locomotive defect and the loss of dopaminergic neurons caused by the expression of α-synuclein. Specific and effective pharmacological Usp8 inhibition also has the potential to lower α-synuclein levels. Collectively, the evidence produced in my thesis suggests that Usp8 could be a potential target for the future disease-modifying therapies in Parkinson's disease.

Orientador: Paola Castro Moraes / Coorientador: Luiza da Silva Lopes / Banca: Artur Gouveia Rocha / Banca: Annelise Carla Camplesi dos Santos / Banca: Gustavo Garkalns de Souza Oliveira / Banca: Andrigo Barboza dDe Nardi / Resumo: A lesão medular não é um evento incomum na medicina humana e veterinária e resulta em disfunções neurológicas de graus variados. Apesar dos esforços no tratamento, lesões medulares frequentemente causam sequelas permanentes, desde déficit proprioceptivo isolado até paralisia completa de membros. A membrana confeccionada à base de látex natural extraído da seringueira Hevea brasiliensis tem sido utilizada com sucesso para regeneração de tecidos, e seu potencial regenerador foi reconhecido como sendo de uma fração proteica conhecida como proteína P1. Este novo biomaterial foi eficaz em vários testes de regeneração em animais de experimentação e humanos, e, ainda que tenha mostrado potencial regenerador em teste de lesão de nervo periférico, a proteína ainda não foi testada em Sistema Nervoso Central. Objetivou-se avaliar o potencial regenerador da fração proteica extraída do látex natural (P1) na hemissecção da medula espinhal em ratos. Foram utilizados 18 ratos machos adultos submetidos à hemissecção medular no segmento medular T13 subdivididos em dois grupos: GHP (tratados com proteína P1 em gel de ácido hialurônico) e GHSP (tratado somente com ácido hialurônico). Foram realizadas análises neuroclínicas, bem como avaliação funcional da marcha em plataforma de acrílico. Após oito semanas os animais foram submetidos à eutanásia e os segmentos medulares envolvidos foram avaliados por histoquímica pela coloração Tricrômico de Masson e Luxol Fast Blue, além de avaliação da reação ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Spinal cord injury is not an uncommon event in human and veterinary medicine and results in neurological dysfunctions of varying degrees. Despite efforts in treatment, spinal cord injuries often cause permanent sequelae, ranging from isolated proprioceptive deficit to complete limb paralysis. The membrane made from natural latex extracted from the rubber tree Hevea brasiliensis has been successfully used for tissue regeneration and its regenerative potential has been recognized as being of a protein fraction known as P1 protein. This new biomaterial has been effective in several regeneration tests in experimental animals and humans, and although it has shown a potential regenerator in a peripheral nerve injury test, the protein has not yet been tested in the Central Nervous System. The objective of this study was to evaluate the regenerative potential of the protein fraction extracted from natural latex (P1) in the hemisection of the spinal cord in rats. Eighteen adult male rats submitted to medullary hemisection in the T13 medullary segment were subdivided into two groups: GHP (treated with protein P1 in hyaluronic acid gel) and GHSP (treated with hyaluronic acid only). Neuroclinical analyzes were performed as well as functional evaluation of gait on acrylic platform. After eight weeks the animals were submitted to euthanasia and the involved spinal segments were evaluated by histochemistry by Masson and Luxol Fast Blue Trichrome staining, as well as evaluation of the astrog... (Complete abstract click electronic access below) / Doutor

[pt] Na presente dissertação elaboramos um mapa dos debates sobre a possibilidade de se articular Psicanálise e Neurociência, em que identificamos três grupos principais, cada um com seus próprios pressupostos, em função dos quais lhes atribuímos diferentes designações: hibridação, isolamento e interlocução. Posicionamo-nos a favor do terceiro grupo - interlocução - e contrariamente aos demais, deixando explícito, ao longo da dissertação, o motivo do nosso posicionamento. Na medida em que os debates sobre Psicanálise e Neurociência tendem a abarcar a questão da (a)cientificidade da Psicanálise, decidimos, a fim de oferecer consistência ao nosso trabalho, investigar esta questão. Deve-se notar que o início da nossa investigação apresenta a transição do Freud neurologista para o Freud psicanalista no intuito de mostrar que ele seria o principal representante do grupo, cujos pressupostos e propostas pretendemos defender. Defendemos, em última análise, uma interlocução entre Psicanálise e Neurociência desde que se respeitem os limites epistemológicos de cada campo. / [en] In this dissertation we develop a map of the debates about whether we can articulate Psychoanalysis and Neuroscience, in which we identify three main groups, each with its own assumptions, which we designate as: hybridisation, isolation, and interlocution. We favour the position of the third group - interlocution - and oppose the others, setting out during the dissertation the reasons for our position. To the extent that the debates about Psychoanalysis and Neuroscience cover the question of the scientific nature of psychoanalysis, we decide to explore this topic with the aim of providing consistency. It should be noted that we start our investigation with the transition from Freud the neurologist to Freud the psychoanalyst, to show that he is the leading member of the group whose assumptions and theories we intend to support. We argue, in the last analysis, in favour of an interlocution between Psychoanalysis and Neuroscience as long as the epistemological limits of each camp are respected.

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Made available in DSpace on 2014-06-11T19:23:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-27Bitstream added on 2014-06-13T20:30:35Z : No. of bitstreams: 1 albernaz_rm_me_jabo.pdf: 606225 bytes, checksum: fc8139f6f3b1c020259e97b3cecff7e3 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A modalidade de rodeio denominada Prova do Laço de Bezerro tem sido questionada sobre a ocorrência de possíveis lesões nas vértebras cervicais ocasionadas pela tração da corda no pescoço dos bezerros. Neste trabalho avaliou-se 15 bezerros mestiços, machos ou fêmeas, entre cinco e seis meses de idade experimentalmente submetidos a prova do laço. Os animais foram laçados três vezes por semana, em dias alternados, durante cinco semanas, somando o total geral de 225 laçadas. A prova experimental foi realizada de forma semelhante à prova oficial, pelo mesmo cavaleiro profissional da modalidade. Os bezerros foram avaliados mediante exame clínico geral e neurológico ao início da primeira, durante a terceira e ao término da quinta semana experimental. Radiografias simples e contrastadas das vértebras cervicais foram efetuadas ao início da primeira e ao término da quinta semana de experimento. Os métodos de laçadas foram acompanhados e classificados qualitativamente em fortes ou fracos. Não foram encontradas alterações clínicas e radiográficas nos animais durante o experimento. O rigor da laçada foi considerado forte em 77% dos casos. O fato de não terem sido encontradas alterações clínicas e radiográficas indicam que a ocorrência de lesões cervicais em bezerros submetidos a prova de laço não é tão alta como o propalado, entretanto, trata-se de procedimento rude e agressivo. Número mais expressivo de experimentos semelhantes a este deverá ser conduzido tanto sob condições controladas como em provas reais para confirmar os dados da presente pesquisa. / The modality of roundup Calf Roping has been questioned on the occurrence of possible injuries in the cervical vertebrae caused by the rope tension in calfs neck. In this work 15 calves, male or female, ages varying from five and six months experimentally submitted to calf roping were evaluated. The procedure was carried through three times per week, in alternated days, during five weeks, adding the total of 225 lassoed. The experimental test was carried through of similar form to the official test, for the same professional knight of the modality. The calves had been evaluated by means of general and neurological clinical examination to the beginning of the first one, during third and to the ending of the fifth experimental week. Simple and contrasted x-rays of the cervical vertebrae had been made to the beginning of the first one and the ending of the fifth week of experiment. The lassoed methods had been observed and classified qualitatively in weak or strong. Clinical and radiographic alterations in the animais during the experiment had not been found. The severity of the lassoed was considered strong in 77% of the cases. The fact not to have been found clinical and radiographic abnormalities indicates that the occurrence of cervical injuries in calves submitted to calf roping is not as high as divulged, however, is about aggressive and rude procedure. Similar experiments must be made in such a way to be lead under controlled conditions as in real tests to confirm the data of the present research.

A rat model was used to determine whether prenatal cocaine exposure results in long-term changes in hippocampal-dependent contextual fear conditioning. Pregnant dams received either 40 mg/kg cocaine HCl SC (COC), an equal volume of 0.9% saline (SAL), or received no injections (UT) from gestational day 8 through 20. SAL animals were also pair-fed to COC subjects. Experiment 1 tested one-trial contextual fear conditioning in adult male offspring. Freezing and defecation were measures of fear. Prenatal cocaine exposure did not affect context conditioning, but there was an overall increase in SAL and COC defecation, indicating an increased generalized fear in these subjects. To better mimic binge cocaine use, COC dams in Experiment 2 and 3 received 20 mg/kg cocaine HCl SC, b.i.d. A preliminary open field task revealed that SAL offspring were more exploratory than UT controls and that females were more active than males. In Experiment 2, adult male and female offspring received 4 days of context conditioning and 3 days of no-shock extinction. During extinction, access to an adjacent chamber enabled the observation of four additional measures of fear: side crossing, latency, nose crossing, and side-differential. Experiment 2 repeated previous reports of gender-specific contextual fear. Males showed a greater level of freezing and defecation, higher latencies and side-differentials, and a lower level of side crossings and nose crossings than females. Prenatal cocaine exposure resulted in exaggerated gender-specific fear conditioning as measured by nose-crossing and side differential during extinction. Experiment 3 tested the effects of prenatal cocaine exposure on latent inhibition (LI) of contextual fear in year-old females. Vertical nose crossing (VNC), freezing, and defecation were measures of fear. LI was evidenced as an attenuation of freezing and VNC in pre-exposed (PE) animals compared to non-pre-exposed subjects. Prenatal cocaine exposure resulted in an enhanced LI effect. COC females showed a low level of baseline VNC, but COC-PE subjects showed a greater level of VNC than controls following the first shock during conditioning. The results of these experiments suggest that the effects of prenatal cocaine exposure on hippocampal-dependent learning are subtle, selective, and gender specific.

These studies examined the pharmacokinetics of cocaine following its chronic subcutaneous (s.c.) administration to pregnant rats and the effects of this treatment on neurotensin/neuromedin (NT/N) mRNA expression in the brains of their offspring. First, I examined the distribution of cocaine and its metabolites benzoylecgonine (BE) and norcocaine in pregnant rats following twice-daily s.c. injections of 20 mg/kg cocaine from gestational day (GD) 8–GD 21. Following a single injection on GD 21, maternal and fetal trunk blood, fetal brains, and amniotic fluid (AF) were collected at 8 separate time points from 5 min to 12 h. Cocaine peaked in maternal plasma at 1 h and at 2 h in fetal plasma, fetal brain and AF. Peak BE levels were detected at 4 h in maternal plasma, fetal plasma, and fetal brain, and at 8 h in the AF. An additional group of dams given both injections on GD 21 and sacrificed 2 h later showed increased concentrations of BE in both fetal compartments and in the AF. Previously undetectable, norcocaine was now measurable in the AF. Chronic cocaine administration increases NT/N mRNA in the nucleus accumbens. To further understand the mechanisms involved, I conducted a dose response study evaluating the role of the D3 receptor on the expression of NT/N mRNA in the nucleus accumbens shell using in situ hybridization. Animals were sacrificed 3 h following an acute challenge with either the D3 agonist PD 128904 or the antagonist nafadotride. As neither compound significantly altered NT/N mRNA levels, no further work was performed with these drugs. To examine the effects of prenatal cocaine exposure on neurotensin expression, adult male offspring from either cocaine (40 mg/kg daily, GD 8–21) or saline-injected dams were treated with a single daily i.p. injection of cocaine or saline for 10 days and sacrificed 1 h after the last injection. This treatment resulted in increased NT/N mRNA in the nucleus accumbens, fundus, striati, and dorsomedial striatum regardless of prenatal treatment, and significantly greater NT/N mRNA expression within the medial preoptic nucleus (MPN) of offspring from pair-fed saline dams. Thus, prenatal cocaine exposure alters the NT/N response in the MPN to postnatal cocaine challenge.

This dissertation investigated the allocation of visuo-spatial attention during dynamic viewing. The hypothesis of an attentional focus that is initially centered at fixation and then shifts to the location of a forthcoming eye fixation prior to the overt eye movement was tested. Participants performed three different dual tasks while their eye movements and manual responses were recorded. The primary tasks all required sequential left-to-right eye movements; they were silent reading (Experiment 1), oculomotor scanning of text without vowels (Experiment 2), and visual search for a target letter (Experiment 3). A speeded manual response was made to an asterisk that appeared early or late after the onset of a critical fixation (25 or 170 ms probe delay), and either to the left of, or directly above, or to the right of the currently fixated character ($-$10, $-$5, 0, +5, or +10 characters probe eccentricity). It was predicted that early probes should be detected equally fast in the left and right hemifield, while responses to late probes should be faster when they appeared in the right than in the left visual hemifield. Selective facilitation of manual probe detection latencies near the location of the forthcoming eye fixation was found in the visual search task, but not during reading or scanning. Fixation times increased and saccade lengths decreased as a consequence of probing in all three tasks. Fixation durations were less prolonged when the probe appeared in the right than in the left hemifield; the critical saccades were largest when the probe appeared at +10 characters and smallest when it appeared at +5 characters eccentricity. In summary, detection latencies in the search task supported the attentional predictions, and the eye movement data provided consistent indirect support for the notion of attention shifts prior to eye movements. Task-specific processing demands may have diluted further evidence in the probe detection times from reading and scanning. Individual reaction times further revealed considerable intra- and interindividual differences. It is concluded that the present dual task combination with its dual motor response requirements may not be adequate to assess visuo-spatial attention allocation during sequential eye movement tasks.

Bakgrund: Stroke är ett globalt folkhälsoproblem. De som drabbas av stroke kan få komplikationer som kräver långtidsrehabilitering. Rehabiliteringen börjar på sjukhuset och fortsätter därefter i hemmiljön, sjuksköterskor har till uppgift är att värna om patientens egenansvar. Egenansvaret gynnas av patientens delaktighet i rehabiliteringen och främjas genom en personcentrerad vård. Genom att beskriva patienters erfarenheter av egenansvar synliggörs en ökad förståelse för deras situation. Förståelsen kan också möjliggöra för vårdpersonal att bli ett stöd för patienten i egenansvaret. Syfte: Syftet var att beskriva patienters erfarenheter av egenansvar under rehabiliteringen efter stroke. Metod: En allmän litteraturöversikt som utgick från kvalitativa artiklar. Artiklarna söktes i två olika databaser och granskades därefter med Högskolan Kristianstads granskningsmall. Analysen utgick från Fribergs (2017a) trestegsanalys. Resultat: Patienters erfarenheter efter en stroke visade på problematiken i att ta egenansvar i rehabiliteringen. Ur analysen framkom två huvudkategorier samt fem subkategorier. Huvudkategorierna är: Behov av stöd för att kunna ta egenansvar under rehabiliteringen samt Egenansvarets betydelse när behovet av stöd i rehabiliteringen avtar. I den första huvudkategorin framkom patienters erfarenheter angående det bristande bemötandet som försvårade för patienter att ta egenansvar. I den andra huvudkategorin belystes den fortsatta utmaningen med det komplexa egenansvaret under rehabiliteringen. Diskussion: Metoddiskussionen utgick ifrån Shentons (2004) trovärdighetsbegrepp. Resultatdiskussionen tar upp tre nyckelfynd vilka innefattar: patienternas behov av stöd, kommunikationens betydelse samt självständighetens betydelse för att kunna ta egenansvar. Dessa diskuteras utifrån Ekmans personcentrerade vårdmodell, ur ett samhällsperspektiv samt etiska aspekter.

Immunocytochemistry was used to study the distribution of gamma-aminobutyric acid (GABA) throughout the central visual nuclei and retina in Rana pipiens. In the diencephalon, intensely-labeled GABA immunoreactive neurons and nerve fibers were observed within the neuropil of Bellonci (nB) and corpus geniculatum (CG), while only immunoreactive puncta were found in the rostral visual nucleus (RVN). In the pretectal region, the posterior thalamic nucleus (nPT) contained the most intensely-labeled GABA immunoreactive perikarya and nerve fibers in the entire brain. Lightly immunoreactive perikarya were also found in the large-celled nucleus lentiformis mesencephali (nLM), as well as in the pretectal gray which contains neurons postsynaptic to the retinal terminal zones within nLM. In the optic tectum (OT), both immunoreactive perikarya and fibers were found within superficial layers 8 and 9; whereas only densely-packed immunoreactive perikarya were evident in the deep tectal layers (i.e. 2, 4, 6). The nucleus of the basal optic root (nBOR) contained a small number of lightly-labeled GABA immunoreactive perikarya mostly located in the dorsal half of the nucleus. A large number of perikarya within the nucleus isthmi (NI) were also lightly immunostained. In the retina, GABA immunoreactivity (both somata and fibers) was observed in all layers except the outer nuclear layer (ONL). Besides GABAergic putative horizontal and amacrine cells in the inner nuclear layer (INL), about 30% of total neurons within ganglion cell layer (GCL) expressed GABA immunoreactivity. Double-labeling studies indicated that about half of the GABA-containing perikarya in the GCL were retinal ganglion cells (RGCs). In addition, three GABAergic projection pathways existing in the visual system of Rana pipiens were demonstrated: (1) from RGCs to the contralateral OT; (2) from nBOR to the pretectal nLM; and (3) bilaterally from the NI to the OT. These results indicate that GABA is an important neurotransmitter in the frog visual system.