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Greater than 50% of all spinal cord injuries (SCIs) in humans occur at the cervical level and the biggest desire of quadriplegic patients is recovery of hand and digit function. Several weeks after spinal cord injury, re-organization and re-modeling of spared endogenous pathways occurs and plasticity of both supraspinal and interneuronal networks are believed to mediate functional recovery. Propriospinal interneurons (PNs) are neurons found entirely in the spinal cord with axons projecting to different spinal segments. PNs function by modulating locomotion, integrating supraspinal motor pathways and peripheral sensory afferents. Recent studies have postulated that if PNs are spared following SCI, these neurons can contribute to functional recovery by establishing synaptic connections onto motor neurons. However, to what extent cervical PNs are involved in recovery of reaching behavior is not known. In our first study, we generated a lentiviral vector that permits highly efficient retrograde transport (HiRet) upon uptake at synaptic terminals in order to map supraspinal and interneuronal populations terminating near forelimb motoneurons (MNs) innervating the limb. With this vector, we found neurons labeled within the C3-C4 spinal cord and in the red nucleus, two major populations which are known to modulate forelimb reaching behavior. We also proceeded to use a novel two-viral vector method to specifically label ipsilateral C3-C4 PNs with tetracycline-inducible GFP. Histological analysis showed detailed labeling of somas, dendrites along with axon terminals. Based on this data, we proceeded to determine the contribution of C3-C4 PNs and rubrospinal neurons on forelimb reaching and grasping before and after cervical SCI. In our second study, we have examined a double-infection technique for shutdown of PNs and rubrospinal neurons (RSNs) in adult rats. Adult rats were microinjected with a lentiviral vector expressing tetracycline-inducible inhibitory DREADDs into C6-T1 spinal levels. Adeno-associated viral vectors (AAV2) expressing TetON mixed with GIRK2 were injected into the red nucleus and C3-C4 spinal levels respectively. Rats were tested for deficits in reaching behaviors upon application of doxycycline and clozapine-n-oxide (CNO) administration. No behavioral deficits were observed pre-injury. Rats then received a C5 spinal cord lesion to sever cortical input to forelimb motoneurons and were allowed four weeks to spontaneously recover. Upon re-administration of CNO to activate inhibitory DREADDs, deficits were observed in forelimb reaching. Histological analysis of the C3-C4 spinal cord and red nucleus showed DREADD+ neurons co-expressing GIRK2 in somas and dendrites of PNs and RSNs. PN terminals expressing DREADD were observed near C6-T1 motoneurons and in the brainstem. Control animals did not show substantial deficits with CNO administration. These results indicate both rubro- and propriospinal pathways are necessary for recovery of forelimb reaching. In a separate study, we sought to determine if promoting severed CST sprouting rostral to a C5 lesion near C3-C4 PNs could improve behavioral recovery post SCI. Past studies have examined sprouting and regeneration of corticospinal tract (CST) fibers post-cervical SCI through viral upregulation of key components of the PI3K/Akt/mTOR cascade. We examined the regenerative growth potential of CST fibers that are transduced with AAV2 expressing constituively active Akt3 or STAT3 both separately and in combination (Akt3 + STAT3). We have observed significant increases in CST axonal sprouting and regeneration in Akt3 and Akt3 + STAT3 transduced samples. However, no recovery was observed as animals transduced with viral constitutively active Akt3 displayed an epileptic phenotype. Further, epileptic animals with constitutively active Akt3 were found to have significant cortical neuron cell hypertrophy, activatived astrogliosis, increased dendritic arbors and hemimegencephalitis (HME). These results indicate a new model for examining mechanisms of HME and mTOR hyperactivity-induced epilepsy in adult rodents. / Biomedical Sciences

Submitted by Leticia Schettini (leticia@ufrrj.br) on 2017-04-24T14:23:01Z No. of bitstreams: 1 2016 - Carlos Augusto dos Santos Sousa.pdf: 2340153 bytes, checksum: 5ef373f242c2c4700a9a9e55280bc62c (MD5) / Made available in DSpace on 2017-04-24T14:23:01Z (GMT). No. of bitstreams: 1 2016 - Carlos Augusto dos Santos Sousa.pdf: 2340153 bytes, checksum: 5ef373f242c2c4700a9a9e55280bc62c (MD5) Previous issue date: 2016-02-03 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Morphology studies provide knowledge that allow us to understand how animals interact with the natural environment or in captivity. In this context, the comparative anatomy of the formation of the brachial plexus awakens interest since the nineteenth century and remains one of the most intriguing topics of contemporary anatomy. The aim of this study was to describe the origin and the antimeric distribution of the brachial plexus nerves in Macaca mulatta, as well as the innervated muscles. Ten male rhesus monkeys (Macaca mulatta) were used, from the Non-human Primates? Breeding Department at the Laboratory Animals Breeding Centre (Cecal/Fiocruz), donated to the Animal Anatomy Department of the Rural Federal University of Rio de Janeiro (UFRRJ). The specimens were fixed in formaldehyde solution by infusion of 10% solution. They were subsequently wrapped in a low-density polythene container with 500 liters of formaldehyde 30% solution over a period of 12 months. After this period, they were washed in running water and subjected to X-ray examinations of the neck at the Small Animals Veterinary Hospital of the UFRRJ to characterize the number of cervical vertebrae. Then, they had both antimeres dissected aiming at the exposure of the origins and the nerves arising from the brachial plexus. Data were presented both in absolute frequency and in simple percentage. In 11 (55%) animals the resulting nerves were constituted by the connections between the ventral spinal branches C5, C6, C7, C8 and T1. In 5 (25%) animals, the participants roots were C4, C5, C6, C7, C8, T1 and T2. In 2 (10%) animals C5, C6, C7, C8, T1 and T2. In the other 2 (10%) animals the formation of the plexus was observed from C6, C7, C8, T1 and T2. The ventral branches formed three nerve trunks: cranial, middle and caudal. The suprascapular nerves, subscapular, axillary, musculocutaneous, radial, median, ulnar innervated the intrinsic muscles and the subclavian nerve innervated the thoracodorsal, medial cutaneous arm and forearm, long thoracic, cranial pectoral and caudal pectoral innervate extrinsic muscles. The results obtained in this study contribute to the comparative anatomy of primates and to the information for applied research, serving as basis for clinical and surgical procedures that uses this species as an animal model. / Estudos morfol?gicos fornecem conhecimentos que permitem entender o modo como os animais interagem com o ambiente natural ou em cativeiro. O objetivo desse estudo foi descrever a origem e a distribui??o antim?rica dos nervos do plexo braquial em Macaca mulatta, assim como dos m?sculos inervados. Foram utilizados 10 cad?veres de Macaca mulatta do sexo masculino, oriundos do Servi?o de Cria??o de Primatas N?o Humanos do Centro de Cria??o de Animais de Laborat?rio (Cecal/Fiocruz) doados a ?rea de Anatomia Animal da Universidade Federal Rural do Rio de Janeiro (UFRRJ). Os esp?cimes foram fixados com perfus?o de solu??o de formalde?do a 10%. Posteriormente, foram acondicionados em caixas de polietileno de baixa densidade com capacidade de 500 litros contendo solu??o de formalde?do a 30% por um per?odo de 12 meses. Ap?s este per?odo, foram lavados em ?gua corrente e submetidos a exames radiogr?ficos da regi?o cervical no Hospital Veterin?rio de Pequenos Animais da UFRRJ para a caracteriza??o do n?mero de v?rtebras cervicais. Em seguida, foram dissecados at? a exposi??o das origens e dos nervos oriundos do plexo braquial. Os dados foram representados em frequ?ncia absoluta e percentual simples. Em 11 (55%) os nervos resultantes foram constitu?dos das conex?es entre os ramos espinhais ventrais de C5, C6, C7, C8 e T1. Em 5 (25%) as ra?zes participantes foram C4, C5, C6, C7, C8, T1 e T2. Em 2 (10%) de C5, C6, C7, C8, T1 e T2. Em outros 2 (10%) verificamos a constitui??o do plexo a partir de C6, C7, C8, T1 e T2. Os ramos ventrais formaram tr?s troncos nervosos: cranial, m?dio e caudal. Os nervos supraescapular, subescapulares, axilar, musculocut?neo, radial, mediano, ulnar inervaram a musculatura intr?nseca e os nervos subcl?vios, toracodorsal, tor?cico longo, peitoral cranial e peitoral caudal inervaram a musculatura extr?nseca. Tamb?m foram registrados os nervos cut?neos oriundos do plexo braquial, sendo eles o nervo cut?neo medial do bra?o, nervo cut?neo medial do antebra?o e ramos para a musculatura cut?nea do tronco. Os dados descritos neste estudo contribuem para a anatomia comparada de primatas e fornecem informa??es para a pesquisa aplicada, servindo como base para procedimentos cl?nico-cir?rgicos em que venha a se utilizar esta esp?cie como modelo experimental.

At the moment, in the daily health care for horses there is a lack of technical aids for private use. As a horse owner you need to physically palpate the horse’s limbs to detect signs of injury and lameness. It is difficult and the signs are usually vague and hard to distinguish. Technology and interaction design could be the solution to this problem. The related research this paper builds on are: clinical complementary diagnostic methods for lameness diagnosis, wearable health monitor systems for humans and smart textiles on horses. The question this paper tries to answer is: How to develop and design a prototype of a product that is an aid for horse owners to document and better understand changes in surface temperature of the horse’s fetlock? To answer this question a user-centered design process was used. A survey, expert domain interview, design and development of a prototype, two different user testings’ and a design workshop. The result is a prototype of a palpating aid called EquumTemp. It is used by the horse owner as a second opinion on the status of their horse fetlock temperature. EquumTemp measures, stores and documents surface temperature of the fetlock. The prototype was tested by the author for 2 weeks and by three different potential users. The knowledge gained from the project resulted in defined product requirements. / Just nu, i den dagliga vården för hästar finns det en brist på tekniska hjälpmedel för privat bruk. Som hästägare måste du fysiskt palpera hästens ben för att upptäcka tecken på skador och hälta. Det är svårt och tecknen är oftast vaga och svåra att urskilja. Teknik och interaktionsdesign kan vara lösningen på detta problem. Relaterad forskning som denna rapport bygger på är: kliniska diagnostiska metoder för att diagnostisera hälta, monitorsystem för att övervaka människors hälsa och smarta textilier på hästar. Frågan denna rapport försöker besvara är: Hur man utvecklar och designar en prototyp av en produkt som är ett hjälpmedel för hästägare att dokumentera och bättre förstå förändringar i yttemperatur av hästens kotled? För att besvara denna fråga användes en användarcentrerad designprocess. En användarundersökning, expert domän intervju, design och utveckling av en prototyp, två olika användartestningar och en designworkshop. Resultatet är en prototyp av ett palperingshjälpmedel som kallas EquumTemp. Den används av hästägaren för att mäta hästens hud temperatur runt kotan. EquumTemp mäter, lagrar och dokument yttemperaturen runt kotan. Prototypen testades av författaren i 2 veckor och av tre olika potentiella användare. Kunskapen från projektet resulterade i definierade produktkrav.

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Au cours des dernières années, des méthodes non-invasives de stimulations permettant de moduler l’excitabilité des neurones suivant des lésions du système nerveux central ont été développées. Ces méthodes sont maintenant couramment utilisées pour étudier l’effet de l’inhibition du cortex contralésionnel sur la récupération motrice à la suite d’un accident vasculocérébral (AVC). Bien que plusieurs de ces études rapportent des résultats prometteurs, les paramètres permettant une récupération optimale demeurent encore inconnus. Chez les patients victimes d'un AVC, il est difficile de débuter les traitements rapidement et d'initier l’inhibition dans les heures suivant la lésion. L'impact de ce délai est toujours inconnu. De plus, aucune étude n’a jusqu’à maintenant évalué l’effet de la durée de l’inhibition sur la récupération du membre parétique. Dans le laboratoire du Dr Numa Dancause, nous avons utilisé un modèle bien établi de lésion ischémique chez le rat pour explorer ces questions. Nos objectifs étaient d’évaluer 1) si une inactivation de l’hémisphère contralésionnel initiée dans les heures qui suivent la lésion peut favoriser la récupération et 2) l’effet de la durée de l’inactivation sur la récupération du membre parétique. Suite à une lésion dans le cortex moteur induite par injections d’un vasoconstricteur, nous avons inactivé l’hémisphère contralésionnel à l’aide d’une pompe osmotique assurant l’infusion continue d’un agoniste du GABA (Muscimol). Dans différents groupes expérimentaux, nous avons inactivé l’hémisphère contralésionnel pour une durée de 3, 7 et 14 jours suivant la lésion. Dans un autre groupe, le Muscimol a été infusé pour 14 jours mais à un débit moindre de façon à pouvoir étudier le lien entre la fonction du membre non-parétique et la récupération du membre parétique. Les données comportementales de ces groupes ont été comparées à celles d’animaux ayant récupéré de façon spontanée d'une lésion similaire. Nos résultats indiquent que l’augmentation de la durée de l’inactivation (de 3 à 14 jours) accélère la récupération du membre parétique. De plus, les deux groupes ayant reçu une inactivation d'une durée de 14 jours ont montré une plus grande récupération fonctionnelle que le groupe n’ayant pas reçu d’inactivation de l’hémisphère contralésionnel, le groupe contrôle. Nos résultats suggèrent donc que l’inactivation de l’hémisphère contralésionnel initiée dans les heures suivant la lésion favorise la récupération du membre parétique. La durée d’inhibition la plus efficace (14 jours) dans notre modèle animal est beaucoup plus longues que celles utilisées jusqu’à maintenant chez l’homme. Bien qu’il soit difficile d’extrapoler la durée idéale à utiliser chez les patients à partir de nos données, nos résultats suggèrent que des traitements de plus longue durée pourraient être bénéfiques. Finalement, un message clair ressort de nos études sur la récupération fonctionnelle après un AVC: dans le développement de traitements basés sur l’inhibition de l’hémisphère contralésionnel, la durée de l’inactivation est un facteur clef à considérer. / With the introduction of non-invasive brain stimulation methods aimed at modulating the excitability of cortical areas after stroke, many groups are intensively investigating the effects of inhibition of the contralesional hemisphere on functional recovery. Although the reported results of these studies are very promising, limitations of enrolling acute stroke patients as well as technical difficult of establishing continuous inhibition protocols have left several open ended questions regarding the treatment parameters and patient selection. For example, the efficacy of inhibition treatment in acute setting after stroke and the effect of treatment duration are two questions that are virtually unexplored. Therefore, in the laboratory of Prof. Numa Dancause, we took advantage of a well established rodent model of cortical ischemic lesion to gain direct and objective insight about the importance of contralesional inactivation on motor recovery of the paretic limb. Using an Endothelin-1 rodent model of ischemic cortical lesion, we pharmacologically inactivated the contralesional hemisphere with a GABA agonist (Muscimol). By doing so we were interested in the effect of early treatment when contralesional inactivation is initiated rapidly after the lesion. Early after induction of cortical ischemic lesion, the contralesional hemisphere was inactivated with continuous infusion of the Muscimol for 3, 7 or 14 days in three different groups of animals. In a fourth group, Muscimol was infused at slower rate for 14 days to provide additional insights on the relation between the effects of inactivation on the non-paretic forelimb behavior and the recovery of the paretic forelimb. We included a group of animals with spontaneous recovery that received no inactivation after lesion. Our results indicated that increasing inactivation duration (from 3 to 14 days) accelerated the recovery of grasping function. Both groups with 14 days of inactivation had similar recovery profiles and performed better than animals that spontaneously recovered. In fact, the duration of inactivation, not the intensity, correlated with the better functional outcomes. Our results support early contralesional inactivation to improve recovery of the paretic forelimb after cortical lesion. Moreover, based on our results, the duration of inactivation is the most important factor to correlate with the functional outcomes. Therefore, by providing precise temporal and behavioral evidence, our results provide a window of opportunity for the researchers in which the current gap in our understanding of the clinical efficacy of contralesional inhibition in acute phase after stroke can be approached with more confidence.

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