Tenocytes are the principal cells of the human Achilles tendon. In tendinosis, changes in the metabolism and morphology of these cells occur. Neurotrophins are growth factors essential for the development of the nervous system. Tumour necrosis factor alpha (TNF-α) has been found to kill sarcomas but has destructive effects in several major diseases. The two systems have interaction effects and are associated with apoptosis, proliferation, and pain signalling in various diseases. Whether these systems are present in the Achilles tendon and in Achilles tendinosis is unknown. The hypothesis is that the tenocytes produce substances belonging to these systems. In Studies I–III, we show that the potent effects of these substances are also likely to occur in the Achilles tendon. We found tenocyte immunoreactions for the neurotrophins brain-derived neurotrophic factor (BDNF), the nerve growth factor (NGF), the neurotrophin receptor p75, and for TNF-α and both of its receptors, TNFR1 and TNFR2. This occurred in both subjects with painful mid-portion Achilles tendinosis, and in controls. Furthermore, we found mRNA expression for BDNF and TNF-α in tenocytes, which proves that these cells produce these substances. TNFR1 mRNA was also detected for the tenocytes, and TNFR1 immunoreactions were upregulated in tendinosis tendons. This might explain why tenocytes in tendinosis undergo apoptosis more often than in normal tendons. Total physical activity (TPA) level and blood concentration of both soluble TNFR1 and BDNF were measured in Study IV. The results showed that the blood concentration of both factors were similar in subjects with tendinosis and in controls. Nevertheless, the TPA level was related to the blood concentration of sTNFR1 in tendinosis, but not in controls. This relationship should be studied further. The findings of this doctoral thesis show that neurotrophin and TNF-α systems are expressed in the Achilles tendon. We believe that the functions include tissue remodelling, proliferation and apoptosis.

Biological responses to orthodontic forces involve various cell types, these include fibroblasts, endothelial cells, blood vessels and sensory nerves in the periodontal ligament as well as osteoblasts, osteoclasts and cementoblasts in roots and bone surfaces. Neurotrophins are believed to interact with these cells to initiate the process of bone resorption particularly during orthodontic tooth movement. Neuropeptides released from sensory neurons have been shown to modulate the tissue inflammatory responses. In addition, neurotrophins, including nerve growth factor (NGF), play an important role in neural cell differentiation and survival. The exact localization and function of neurotrophins and neurotrophic receptors in the dento-alveolar complex remains unclear. Moreover, the identity and distribution of structures expressing neurotrophins and neurotrophic receptors has yet to be fully determined. It is reasonable to propose that periodontal ligament and alveolar bone remodelling may be influenced by NGF. In addition, anti-NGF may block neurochemical changes and, hence, inhibit orthodontic tooth movement. The aims of this research were to investigate the cells responsible for NGF secretion within the periodontal ligament (PDL), pulp and bone, and the effect that anti-NGF might have on orthodontic tooth movement. 28, 8 week-old, male Sprague-Dawley rats were randomly divided into control and experimental groups. Fourteen experimental animals had anti-NGF injected paradentally. Animals were sacrificed at 7 and 14 days. Sections from an earlier study were examined and stained using TRAP for osteoclast identification and analysed histomorphometrically to enable comparisons between control and experimental groups. The findings of this investigation indicated that injections of anti-NGF did not significantly affect the rate of tooth movement with the use of different tooth movement measurement methods. TRAP staining proved to be a useful and reliable marker of osteoclasts. TRAP-positive osteoclastic cells were detected in both anti-NGF and control groups. However, the TRAP-positive cells were not stained intensely with NGF immunolabelling. On the other hand, cells that were stained intensely with NGF, were TRAP-negative. The results suggested that both sympathetic and nociceptive nerves might function in counter balance to modulate bone resorption, and osteoclasts might not be directly responsible for NGF secretion within the PDL and bone. Further studies to determine the effect of NGF on tooth movement are warranted to more clearly identify the NGF expressing cells within the rat dento-alveolar complex and possible role played by NGF in orthodontic tooth movement. / http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297498 / Thesis (D.Clin.Dent.)-- School of Dentistry, 2007

O transtorno bipolar (TB) é uma doença crônica, altamente incapacitante e sua fisiopatologia não esta bem esclarecida. Apresenta altas taxas de comorbidades clínicas e risco de suicídio trazendo prejuízos e custos significativos para o indivíduo com a doença e para a sociedade. Existem evidências que relacionam o TB à alterações no fator de crescimento semelhante à insulina tipo 1 (IGF- 1) e nos sistemas endócrino e imune. O objetivo deste estudo foi avaliar os níveis séricos de IGF-1 em pacientes bipolares comparados com indivíduos controle e sua relação com a inflamação. Foram selecionados 31 pacientes com TB e 33 controles saudáveis. Foram avaliadas as concentrações séricas de IGF-1, hormônio do crescimento (GH), insulina e fator de necrose tumoral α (TNF-α). Como resultado deste estudo, observamos que os níveis séricos de IGF-1 estavam aumentados em pacientes com TB em relação aos controles (p = 0,001). Não foram observadas diferenças estatisticamente significativas entre os grupos nas dosagens de insulina, GH e TNF- α. Este estudo sugere uma associação entre IGF-1 na fisiopatologia do transtorno bipolar. É possível que este aumento periférico esteja relacionado com um aumento da resistência do IGF- 1 no SNC, reduzindo assim a sua ação neuroprotetora. / Bipolar disorder (BD) is a chronic, highly debilitating and its pathophysiology is not well understood. It offers high rates of clinical comorbidities and suicide risk causing losses and significant costs to the individual with the disease and society. There is evidence that relates to changes in TB-like growth factor type 1 insulin (IGF-1) and the endocrine and immune systems. The aim of this study was to evaluate serum levels of IGF-1 in bipolar patients compared with control subjects and their relationship to inflammation. We selected 31 patients with TB and 33 healthy controls. Serum concentrations of IGF-1, growth hormone, were evaluated (GH), insulin and tumor necrosis factor α (TNF-α). As a result of this study, we observed that serum levels of IGF-1 were increased in TB patients compared to controls (p = 0.001). No statistically significant differences were found between groups in insulin dosages, GH, and TNF-α. This study suggests an association between IGF-1 in the pathophysiology of bipolar disorder. It is possible that this increase is associated with peripheral increased IGF-1 resistance in the CNS, thus reducing its neuroprotective action.

O transtorno bipolar (TB) é uma doença crônica, altamente incapacitante e sua fisiopatologia não esta bem esclarecida. Apresenta altas taxas de comorbidades clínicas e risco de suicídio trazendo prejuízos e custos significativos para o indivíduo com a doença e para a sociedade. Existem evidências que relacionam o TB à alterações no fator de crescimento semelhante à insulina tipo 1 (IGF- 1) e nos sistemas endócrino e imune. O objetivo deste estudo foi avaliar os níveis séricos de IGF-1 em pacientes bipolares comparados com indivíduos controle e sua relação com a inflamação. Foram selecionados 31 pacientes com TB e 33 controles saudáveis. Foram avaliadas as concentrações séricas de IGF-1, hormônio do crescimento (GH), insulina e fator de necrose tumoral α (TNF-α). Como resultado deste estudo, observamos que os níveis séricos de IGF-1 estavam aumentados em pacientes com TB em relação aos controles (p = 0,001). Não foram observadas diferenças estatisticamente significativas entre os grupos nas dosagens de insulina, GH e TNF- α. Este estudo sugere uma associação entre IGF-1 na fisiopatologia do transtorno bipolar. É possível que este aumento periférico esteja relacionado com um aumento da resistência do IGF- 1 no SNC, reduzindo assim a sua ação neuroprotetora. / Bipolar disorder (BD) is a chronic, highly debilitating and its pathophysiology is not well understood. It offers high rates of clinical comorbidities and suicide risk causing losses and significant costs to the individual with the disease and society. There is evidence that relates to changes in TB-like growth factor type 1 insulin (IGF-1) and the endocrine and immune systems. The aim of this study was to evaluate serum levels of IGF-1 in bipolar patients compared with control subjects and their relationship to inflammation. We selected 31 patients with TB and 33 healthy controls. Serum concentrations of IGF-1, growth hormone, were evaluated (GH), insulin and tumor necrosis factor α (TNF-α). As a result of this study, we observed that serum levels of IGF-1 were increased in TB patients compared to controls (p = 0.001). No statistically significant differences were found between groups in insulin dosages, GH, and TNF-α. This study suggests an association between IGF-1 in the pathophysiology of bipolar disorder. It is possible that this increase is associated with peripheral increased IGF-1 resistance in the CNS, thus reducing its neuroprotective action.

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-24T17:09:38Z No. of bitstreams: 1 Cabo, Carolina Serra Jogaib [Dissertação, 2014].pdf: 1585469 bytes, checksum: c26025e0cb73856aeb3ee836ea718d62 (MD5) / Made available in DSpace on 2017-03-24T17:09:38Z (GMT). No. of bitstreams: 1 Cabo, Carolina Serra Jogaib [Dissertação, 2014].pdf: 1585469 bytes, checksum: c26025e0cb73856aeb3ee836ea718d62 (MD5) / Estudos sobre os efeitos do extrato aquoso da Eugenia punicifolia (EP) demonstram sua ação na neurotransmissão da junção neuromuscular. Entretanto, apesar de saber que o aumento da neurotransmissão colinérgica pode apresentar atividade neuroprotetora e atuar na plasticidade neuronal, não existem estudos sobre o efeito do extrato de EP em células do Sistema Nervoso Central. O objetivo deste trabalho foi estudar o efeito do extrato diclorometano de EP sobre células da retina de ratos neonatos in vitro no que tange à proliferação celular, modulação do fenótipo colinérgico e aos níveis de fator de crescimento do nervo (NGF), fator neurotrófico derivado do cérebro (BDNF) e da interleucina IL-4. Foram realizadas culturas primárias de células da retina de ratos neonatos da linhagem Lister Hooded de ambos os sexos, dia pós-natal 0-2. As culturas foram plaqueadas em placas de Petri pré-tratadas com poli-L-ornitina, na densidade de 1,0x105 cel/cm2, receberam meio 199 ou 1μg/mL do extrato diclorometano de Eugenia punicifolia (EP 1μg/mL) e foram mantidas por 48 horas a 37°C, em atmosfera de 95% de ar e 5% de CO2. O método bioquímico utilizado para análise da proliferação celular foi a incorporação de [3H]-timidina. Os níveis dos receptores muscarínicos, de neurotrofinas e citocinas foram determinados por Western Blot. Todos os dados são apresentados em relação à porcentagem do controle (100%). Os procedimentos experimentais foram aprovados pelo Comitê de Ética no Uso de Animais da UFF (Projeto nº 186/2012). Os resultados mostram que o tratamento das culturas com diferentes concentrações do extrato diclorometano de EP por 48h induziu aumento dependente da concentração na proliferação celular, sendo o aumento mais significativo observado na concentração de 1μg/mL, concentração que foi utilizada em todos os experimentos. Foi observada a redução nos níveis dos receptores muscarínicos M1 e M4, e nos níveis de transportador de acetilcolina associado à vesícula, aumento na expressão do receptor M3 e nenhuma alteração nos níveis do receptor M5. Observou-se, também, que o extrato diclorometano de EP aumenta os níveis de NGF e da interleucina-4, e diminui dos níveis de BDNF. Os resultados sugerem que o extrato diclorometano de EP exerce efeito proliferativo e de diferenciação através da alteração do fenótipo colinérgico da retina e da participação de fatores neurotróficos / Studies on the effects of the Eugenia punicifolia (EP) aqueous extract demonstrate its action on neurotransmission in the neuromuscular junction. However, despite knowing that increased cholinergic neurotransmission may have neuroprotective activity and act in neuronal plasticity, there are no studies on the effect of the extract of EP in cells of the Central Nervous System. The aim of this work was to study the effect of the dichloromethane extract of EP on retinal cells of neonatal rats in vitro with respect to cell proliferation, modulation of the cholinergic phenotype and levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and interleukin IL-4. Primary cell cultures of neonatal rat retina from Hooded Lister strain of both sexes, postnatal day 0-2 were performed. Cultures were plated on pre-treated Petri plates with poly-L- ornithine at a density of 1.0 x105 cel/cm2 received medium 199 or 1μg/mL of dichloromethane extract of E. punicifolia (EP 1μg/mL) and kept for 48 hours at 37°C in an atmosphere of 95% air and 5% CO2. The method used for biochemical analysis of cellular proliferation was the incorporation of [3H]-thymidine. The levels of muscarinic receptors, neurotrophins and cytokines were determined by Western blot. All data are presented in relation to the percentage of control (100%). The experimental procedures were approved by the Ethics Committee on Animal Use of UFF (Project nº 186/2012). The results show that treatment of cultures with different concentrations of the dichloromethane extract of EP for 48h induces an increase in cell proliferation, with the most significant increase observed with the concentration of 1μg/mL, concentration, which was used in all experiments. A reduction in levels of muscarinic receptors M1 and M4, and VAChT was observed, an increase in expression of the M3 receptor and no change in the levels of the M5 receptor were observed. Also was observed that the dichloromethane extract of EP increased NGF levels and interleukin-4, and decreases levels of BDNF. The results suggest that the dichloromethane extract of EP exerts a proliferative effect and differentiation by altering the cholinergic phenotype of the retina and the involvement of neurotrophic factors

Le cancer colorectal (CCR) est le premier cancer digestif dans les pays occidentaux. Malgré les progrès thérapeutiques réalisés au cours des deux dernières décennies, la survie relative à 5 ans ne dépasse pas 56%, et s’abaisse à 11,3% pour les patients métastatiques. Le pronostic est lié au stade de développement de la maladie au moment du diagnostic. Les décès sont en rapport avec une résistance primaire de la masse tumorale aux thérapies, ou la survenue de récidive, en rapport avec une maladie microscopique résiduelle, non contrôlée par les thérapies systémiques adjuvantes. Le travail réalisé au sein de notre laboratoire portant sur deux voies de signalisation met en leurs rôles dans le CCR : les neurotrophines (NTs, facteurs de croissance impliqués dans la survie des cellules cancéreuses) et l’autophagie (processus de recyclage cellulaire impliqué dans la résistance au stress). Le but de cette étude a été d’analyser la part de ces deux voies dans la survie des cellules du cancer colo-rectal et l’impact de leur inhibition sur le devenir cellulaire et l’évolution tumorale. L’étude a été menée sur deux lignées cellulaires provenant du même patient : SW480 (tumeur primaire) et SW620 (invasion ganglionnaire), aussi utilisées pour la réalisation de greffes sous cutanées sur le modèle murin Nude. De plus, la présence de principales protéines des NTs (TrkB) et de l’autophagie (LC3) a été analysée dans les tissus de patients. Des travaux précédents menés sur des cultures de CCR ont montré que la surexpression de TrkB était associée à la survie cellulaire. Nous avons donc choisi d’inhiber la voie des NTs avec le K252a (100nM). Sur culture cellulaire de CCR, in vitro, l’inactivation de la voie PI3K / AKT, induit une activation de l’autophagie. A l’opposé, le blocage du flux autophagique par une approche pharmacologique (avec la chloroquine, CQ ; 25µM) ou par une approche transcriptomique (siRNA anti-ATG5) induit une suractivation de la signalisation des NTs, via le couple TrkB/BDNF. Ainsi, les deux voies de survie se compensent mutuellement et la double inhibition permet l’amélioration de l’effet des simples traitements. L’utilisation des deux inhibiteurs in vivo induit une réduction spectaculaire du volume tumoral (voire même la disparition dans certains cas). Finalement, la présence de la forme active du TrkB (phospho TrkB) et de la forme active de la LC3 (LC3II), démontrant l’activation de ces deux voies dans les tissus de patients, a été observée. L’ensemble de ces résultats montre que l’activation des voies des NTs et de l’autophagie contribue à la survie des cellules de CCR. L’approche qui consiste à la double inhibition des NTs et de l’autophagie pourrait être un point majeur pour le développement de nouvelles thérapies dans le CCR. / Colorectal cancer (CRC) is the first digestive cancer in occidental countries. Despite effective therapies, cases of resistance and/or recurrence exist. Our laboratory works on two signaling pathways regulating balance between survival and cell death: neurotrophins (NTs, growth factors involved in cancer cells survival) and autophagy (cellular recycling involved in stress resistance). The aim of this study was to investigate relationship between these two pathways and the impact of their inhibition on cell fate and tumor evolution.Studies were performed on two CRC cell lines derived from the same patient: SW480 (primary tumor) and SW620 (node invasion), also used for subcutaneous xenografts on Nude mouse model. In addition, presence of major proteins of NTs (TrkB) and autophagy (LC3) were assessed in patient’s tissues.Previous work showed that TrkB overexpression is associated with pro-survival signaling in CRC cell. So, we choose to inhibit NTs pathway with K252a (100 nM). As expected, inactivation of the PI3K / AKT pathway was observed and CRC cells were able to activate autophagy. At the opposite, blocking autophagic flux by pharmacologic approach (chloroquine; CQ; 25µM) or by transcriptomic approach (siRNA against ATG5) induced over-activation of the NTs pathway, via TrkB/BDNF. Thus, both survival pathways compensate each other. Moreover, dual inhibition allowed improving the effect of single treatment through a significant reduction of metabolic activity. The using of both inhibitors in vivo induces a spectacular reduction of tumor volume (or even disappearance in some cases). Presence of active form of TrkB (phospho TrkB) and active form of LC3 (LC3-II) demonstrating activation of these two pathways, in patient’s tissues have been observed. Taken together, our results showed that activation of NTs and autophagy contribute to CRC cell survival. The approach consisting of dual inhibition of NTs and autophagy could be a major point for new CRC therapies development.

Le brain-derived neurotrophic factor (BDNF) est une protéine de la famille des neurotrophines ayant été initialement découverte au système nerveux central, où elle est impliquée dans la mémoire et l‘apprentissage par la régulation de la croissance et de la survie neuronale. Les effets du BDNF sont médiés par le tropomyosin receptor kinase B (TrkB) et le récepteur pan-neurotrophique de 75 kDa (p75NTR). Le BDNF est le résultat du clivage d’une protéine précurseur, le proBDNF, laquelle a plutôt des effets pro-apoptotiques sur les neurones. Malgré sa découverte au cerveau, le BDNF est retrouvé en concentrations beaucoup plus importantes dans la circulation sanguine, où il est majoritairement contenu dans les plaquettes. Il est rapporté que ces cellules peuvent contenir des concentrations de BDNF allant de 100 à 1000 fois celles retrouvées au cerveau et que celles-ci peuvent être altérées par certaines maladies neurologiques. Malgré les importantes concentrations de BDNF qu’elles contiennent, très peu d’études ont investigué la présence du proBDNF ainsi que des récepteurs TrkB et p75NTR dans les plaquettes. Dans ces études, l’identification de ces protéines au niveau plaquettaire ne représentait pas un objectif primaire et les résultats obtenus ne sont souvent pas présentés. Jusqu’à présent, le proBDNF et les récepteurs TrkB et p75NTR n’ont pas été répertoriés dans les plaquettes. L’objectif principal de ce mémoire était d’investiguer la présence du proBDNF ainsi que des récepteurs TrkB et p75NTR dans les plaquettes de volontaires sains humains et de caractériser ces protéines dans le cas où elles seraient présentes. Les résultats obtenus suggèrent que les plaquettes expriment chacune de ces trois protéines, mais que les isoformes retrouvées au niveau plaquettaire diffèrent de celles retrouvées au cerveau. Les résultats proposent également que ces différences ne résident pas dans le profil de N-glycosylation des protéines. L’identité exacte des protéines étudiées n’a pas pu être confirmée par séquençage et leur nature demeure donc à confirmer. La présence plaquettaire du proBDNF et des récepteurs TrkB et p75NTR pourrait s’avérer intéressante au niveau des biomarqueurs périphériques de certaines maladies neuronales et psychiatriques. Leur présence pourrait aussi permettre la progression des connaissances dans le domaine de la biologie plaquettaire. / The brain-derived neurotrophic factor (BDNF) is a protein that was initially identified in the central nervous system, where it is involved in learning and memory by promoting neuronal growth and survival. These effects of BDNF are mediated through its binding to the tropomyosin receptor kinase B (TrkB) and the 75 kDa pan-neurotrophic receptor (p75NTR). Mature BDNF results from the cleavage of its precursor protein proBDNF, which rather has a proapoptotic effect on neurons. While discovered in the brain, BDNF is found in much higher abundance in the blood circulation, where it is mostly contained within platelets. It has been shown that BDNF concentration in platelets can reach up to 1000 times those of the brain, and that peripheral BDNF levels are altered in certain neurological and psychiatric diseases. Despite these important BDNF concentrations in platelets, very few studies assessed the presence of proBDNF, TrkB and p75NTR in these cells. Furthermore, identification of these proteins in platelets was not a main objective of the studies that did assess that question. Consequently, methodology is not always described, and the results are mostly reported as data not shown. Until now, proBDNF, TrkB and p75NTR have not been reported in platelets. The main objective of this master’s thesis was to investigate the presence of proBDNF as well as receptors TrkB and p75NTR in healthy human platelets, and to characterize them if they were found in these cells. The results suggest that platelets express all three proteins, but that the isoforms found in platelets differ from the ones found in the brain. Also, the results show that these differences are not explained by differential N-glycosylation patterns. The identity of the proteins of interest could not be verified by protein sequencing, and their exact nature is yet to be confirmed. The presence of proBDNF as well as the TrkB and p75NTR receptors in platelets could be of interest in the search of peripheral biomarkers for neurological diseases. In addition, presence of these proteins at the platelet level could pave the way for further studies investigating their functions in platelets, and possibly result in advances in our knowledge of platelet biology.

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No description available.

Delivery of neurotrophins to the injury site via cellular transplants or viral vectors administration has previously been shown to promote recovery of locomotor behavior in the absence of locomotor training in adult spinalized animals. Viral vectors still pose clinical concerns associated to recombinant genetics and the lack of understanding of how they react with the human immune system. Delivery via graft of autologous fibroblast engineered to produce brain derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3) has been shown as a valuable method; however, the need for multiple invasive surgeries, along with the impossibility of delivering a controlled and constant dosage of protein are serious obstacles to obtaining approval by the FDA. The present study was aimed at evaluating the efficacy of BDNF delivered to the lumbar locomotor centers using a clinically translational delivery method at restoring stepping abilities in a large animal model of spinal cord injury. We wanted to evaluate if intrathecal delivery of BDNF to the lumbar spinal cord would promote a locomotor recovery as effective as delivery to the injury site, even at doses low enough not to trigger the side effects observed at high doses. A programmable and implantable mini-pump was used to intrathecally deliver a 50 ng/day dose of BDNF to the lumbar spinal cord for 35 days after spinal thoracic transection. Kinematic evaluation was conducted before, 3 and 5 weeks after injury/pump implant. Ground reaction forces (GRFs) analysis was performed 5 weeks after injury to evaluate the animals’ ability to weight support during locomotion and standing trials. Results showed that treated cats were capable of executing weight-bearing plantar stepping at all velocities tested (0.3-0.8 m/s). Control cats did not recover stepping ability, especially at higher velocities, and dragged their hind paws on the treadmill. We were also interested in measuring the extent of BDNF diffusion within the lumbar area of the spinal cord and the potential damage to the cord caused by catheter insertion. Immunohistological evaluation showed higher BDNF expression in the dorsal root ganglions, with BDNF Immuno-Histo Chemistry (IHC) extending from L3 to L7 in all treated cats. BDNF was also found within multiple cells of the grey matter, although the levels were not significantly higher than background density. Glial fibrillary acidic protein (GFAP) stain was used to measure the immunohistological reaction of the spinal cord to the implanted catheter, and to establish the safety of the delivery method. Gross examination of the spinal cord post-mortem revealed no damage to the cord or the roots with minimal encapsulation of the catheter/pump. Minimal tissue inflammation was revealed by the GFAP stain, underlying the safety of our method. We also wanted to investigate and characterize changes in the locomotor circuitry induced by BDNF delivery. Comparison of multiunit activity in the lumbar area between BDNF treated and non-treated cats allows a better understanding of the mechanism of action of BDNF on the spinal interneurons. This was accomplished by extracellularly recording lumbar interneuronal firing during air-stepping in a 5 weeks post-injury terminal experiment. The cord was exposed at the lumbar level between the L3 and L7 spinal segments. In-vivo recordings of spinal extracellular signals were conducted using two 64 channels microelectrode arrays inserted at the dorsal root entry zone to depths of ~3000µm and ~1500µm. The ability to record simultaneous activity of multiple single neurons made it possible to study the extent to which spiking activity in a given neuron is related to concurrent ensemble spiking activity. A point process generalized linear model (PP-GLM) approach was used to assess the strength of the connections between spike trains. Interneurons activity was assessed in terms of average firing rate, signal-to-noise ratio (SNR), and number of active units per trial. Although BDNF infusion in the lumbar segments did not show significant effect on strengthening synaptic connections, we did find greater multiunit activity in the treated animals, sign of a potential BDNF-induced increase in interneuronal activation, which could be likely involved in recovery of stepping ability after SCI. Together, findings from these aims demonstrated the therapeutic potential of intrathecal lumbar BDNF delivery in spinalized animals. Constant infusion of BDNF to the locomotor centers promotes locomotor recovery similar to training or delivery to the injury site via cellular transplants after complete SCI. Intrathecal delivery by an implantable/programmable pump is a safe and effective method for delivery of a controlled BDNF dosage; it poses minimal risks to the cord and is clinically usable. Lastly, this study confirmed the major involvement of BDNF in increasing the activity of the interneurons in the locomotor circuitry, opening the door to further investigating the mechanism through which neurotrophins induce recovery of locomotion. / Bioengineering