Master of Science / Department of Animal Sciences and Industry / John Michael Gonzalez / The objective of this body of work was to examine effects of growth-promoting technologies (GP) on Longissimus lumborum meat tenderness, focusing on alterations of muscle fiber cross-sectional area (CSA) and collagen solubility. Two studies were conducted and analyzed as randomized complete block designs with repeated measures with GP and day of postmortem aging (DOA) as main effects. Treatments consisted of: a control (CON), implant only (IMP), and implant and [beta]-adrenergic agonist (COMBO). The [beta]-adrenergic agonist utilized for the first was zilpaterol hydrochloride, while the second study examined ractopamine hydrochloride. Objective tenderness of strip loin steaks was measured through Warner-Bratzler shear force (WBSF) after 2 (study 2) or 3 (study 1), 7, 14, 21, or 35 d of postmortem aging. Muscle fiber CSA and collagen solubility were analyzed via immunohistochemistry and hydroxyproline content, respectively. For the first study there was a treatment × DOA interaction (P < 0.01) for WBSF. Compared to CON steaks, IMP steaks had greater (P = 0.01) WBSF on d 3, but were similar (P = 0.21) by d 14. The COMBO steaks remained less tender at all-time points (P < 0.04) except d 21 (P = 0.13) when compared to the CON. Growth-promoting treatment increased the CSA of all three muscle fiber types (P < 0.01), but had no effect on collagen solubility measures (P > 0.21). The second study observed no treatment × DOA interaction (P = 0.54) for WBSF, but GP increased (P < 0.01) WBSF across all DOA. Growth-promoting treatment tended to increase the CSA of type I and IIX fibers (P < 0.10), and increased (P < 0.01) type IIA fiber CSA. In agreement with the first study, there was no treatment × DOA interaction or treatment effect on collagen solubility (P > 0.75). The addition of GP to feedlot heifer production increased WBSF of strip loin steaks and fiber CSA, but did not impact collagen characteristics.

O agonista beta-adrenérgico ractopamina (RAC) modifica a composição da carcaça suína por aumentar a massa muscular e reduzir a deposição de gordura. O objetivo neste estudo foi avaliar os efeitos do tempo de fornecimento de RAC sobre o desempenho, concentração de ureia plasmática (CUP), características de carcaça e expressão gênica dos receptores beta- adrenérgicos (beta-AR) e das isoformas da cadeia pesada de miosina (MyHC) em suínos em terminação. Oitenta suínos, machos castrados (PV inicial = 69,42 ± 1,24 kg), foram utilizados em um experimento em blocos completos casualizados com cinco tratamentos, oito repetições por tratamento e dois animais por unidade experimental (baia). Os tratamentos consistiram de rações sem RAC (controle) ou com 10 ppm de RAC fornecidas por 7, 14, 21 ou 28 dias préabate. O PV individual e o consumo de ração por baia foram obtidos para determinar o ganho diário de peso (GDP), o consumo diário de ração (CDR) e a conversão alimentar (CA). Amostras de sangue foram coletadas para determinação da CUP. No final do experimento, os animais (PV final = 102,46 ± 1,44 kg) foram abatidos e amostras de pelos e do músculo Longissimus dorsi coletadas. As carcaças foram avaliadas 24 horas post-mortem. As amostras de pelos foram utilizadas para detecção da mutação no gene do receptor de rianodina do tipo 1 (RYR1). A expressão gênica dos beta-AR (subtipos beta1 e beta2) e das isoformas MyHC (I, IIa, IIx/d e IIb) foi quantificada nas amostras de músculo. As análises estatísticas foram realizadas apenas com os animais homozigotos dominantes para a mutação no gene do RYR1. O aumento no período de fornecimento de RAC não afetou (P > 0,05) o PV final, o GDP e o CDR, porém resultou em melhora linear (P < 0,01) na CA. Melhoras (P < 0,05) nas médias semanais de GDP e CA foram observadas durante os primeiros 21 dias de fornecimento de RAC, no entanto, o crescimento animal declinou (P < 0,05) na 4ª semana de tratamento. A CUP apresentou efeito quadrático (P < 0,01) com o aumento na duração do fornecimento de RAC. Houve aumento linear (P <= 0,01) no peso da carcaça quente, na profundidade do músculo Longissimus dorsi, na área de olho de lombo e na relação carne:gordura com o aumento na duração do tratamento com RAC. Não foram detectados efeitos da RAC (P > 0,05) sobre a expressão gênica dos beta1-AR e das isoformas MyHC IIa e MyHC IIx/d, porém o aumento no período de fornecimento de RAC tendeu a reduzir linearmente (P = 0,08) a expressão gênica dos beta2-AR. Embora os níveis de RNAm da isoforma MyHC I tenham sido reduzidos linearmente (P < 0,01), a expressão gênica da isoforma MyHC IIb aumentou linearmente (P < 0,01) com o aumento na duração do tratamento com RAC. Portanto, as melhores respostas de desempenho e carcaça ocorreram quando a RAC foi fornecida por 21 e 28 dias, respectivamente. Além disso, o agonista alterou a expressão gênica das isoformas MyHC, e é possível que a ação da RAC esteja relacionada com a população de beta2-AR. / The beta-adrenergic agonist ractopamine (RAC) modifies the swine carcass composition by increasing muscle mass and decreasing fat deposition. The objective in this study was to evaluate the effects of RAC feeding duration on performance, plasma urea nitrogen (PUN) concentration, carcass traits, and gene expression of beta-adrenergic receptors (beta-AR) and myosin heavy chain (MyHC) isoforms in finishing pigs. Eighty barrows (initial BW = 69.42 ± 1.24 kg) were used in a randomized complete block design experiment with five treatments, eight replicates per treatment, and two animals per experimental unit (pen). The dietary treatments consisted of diets containing no RAC (control) or 10 ppm RAC fed for 7, 14, 21, or 28 days before slaughter. Individual pig BW and pen feed disappearance were obtained to determine average daily gain (ADG), average daily feed intake (ADFI), and feed to gain ratio (F:G). Blood samples were collected for determination of PUN concentrations. At the end of the experiment, pigs (final BW = 102.46 ± 1.44 kg) were slaughtered and hair and Longissimus dorsi muscle samples collected. The carcasses were evaluated 24 hours postmortem. Hair samples were used to detect the mutation of the ryanodine receptor type 1 (RYR1) gene. Gene expression of beta-AR (beta1- and beta2-subtypes) and MyHC isoforms (I, IIa, IIx/d, and IIb) was quantified in the muscle samples. Statistical analyses were performed using only the homozygous dominant pigs for the RYR1 gene mutation. Increasing RAC feeding period did not affect (P > 0.05) final BW, ADG, and ADFI, but resulted in a linear improvement (P < 0.01) in F:G. Average weekly improvements (P < 0.05) in ADG and F:G were observed during the first 21 days of RAC feeding, however, animal growth declined (P < 0.05) in the 4th week of treatment. The PUN concentrations showed a quadratic effect (P < 0.01) as RAC feeding duration increased. There were linear increases (P <= 0.01) in hot carcass weight, Longissimus dorsi muscle depth, loin eye area, and muscle to fat ratio as RAC treatment duration increased. No effects of RAC feeding (P > 0.05) were detected for beta1-AR and for isoforms of MyHC IIa and MyHC IIx/d gene expression, but increasing RAC feeding period tended to linearly decrease (P = 0.08) beta2-AR gene expression. Even though mRNA levels of MyHC I isoform decreased linearly (P < 0.01), gene expression of MyHC IIb isoform increased linearly (P < 0.01) as RAC treatment duration increased. Therefore, greater growth and carcass responses occurred when RAC was fed for 21 and 28 days, respectively. Furthermore, the agonist altered the MyHC gene expression and the RAC action may be related to the beta2-AR population.

abstract: Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia. / Dissertation/Thesis / Ph.D. Psychology 2013

abstract: Stroke remains the leading cause of adult disability in developed countries. Most survivors live with residual motor impairments that severely diminish independence and quality of life. After stroke, the only accepted treatment for these patients is motor rehabilitation. However, the amount and kind of rehabilitation required to induce clinically significant improvements in motor function is rarely given due to the constraints of our current health care system. Research reported in this dissertation contributes towards developing adjuvant therapies that may augment the impact of motor rehabilitation and improve functional outcome. These studies have demonstrated reorganization of maps within motor cortex as a function of experience in both healthy and brain-injured animals by using intracortical microstimulation technique. Furthermore, synaptic plasticity has been identified as a key neural mechanism in directing motor map plasticity, evidenced by restoration of movement representations within the spared cortical tissue accompanied by increase in synapse number translating into motor improvement after stroke. There is increasing evidence that brain-derived neurotrophic factor (BDNF) modulates synaptic and morphological plasticity in the developing and mature nervous system. Unfortunately, BDNF itself is a poor candidate because of its short half-life, low penetration through the blood brain barrier, and activating multiple receptor units, p75 and TrkB on the neuronal membrane. In order to circumvent this problem efficacy of two recently developed novel TrkB agonists, LM22A-4 and 7,8-dihydroxyflavone, that actively penetrate the blood brain barrier and enhance functional recovery. Findings from these dissertation studies indicate that administration of these pharmacological compounds, accompanied by motor rehabilitation provide a powerful therapeutic tool for stroke recovery. / Dissertation/Thesis / Ph.D. Neuroscience 2013

No description available.

O objetivo desta pesquisa foi avaliar os efeitos do período de administração de cloridrato de zilpaterol (CZ) e do tempo de confinamento no desempenho, características de carcaça, rendimento de cortes cárneos comerciais e na qualidade de carne de bovinos Nelore. Foram utilizados 96 bovinos machos não castrados da raça Nelore, com peso vivo inicial de 377 ± 25,1 kg. O delineamento utilizado foi o de blocos completos casualizados em esquema fatorial 4 × 2, sendo quatro períodos de administração com CZ (0, 20, 30 ou 40 dias) e dois tempos de confinamento (90 ou 117 dias). O período de suplementação com CZ (8,33 mg/kg de matéria seca total) iniciou-se 23, 33 e 43 dias antes do abate. Nos últimos três dias que antecederam o abate todos os animais foram alimentados com a dieta sem CZ, respeitando o período de carência do produto. O contrafilé (músculo Longissimus thoracis et lumborum) de todas as meias-carcaças esquerdas foi amostrado para as análises de qualidade de carne. Com exceção da área do olho de lombo obtida por ultrassom (P = 0,02) e área do olho de lombo medida na carcaça resfriada (P = 0,05), não houve interação entre período de administração de CZ e tempo de confinamento (P > 0,10). O aumento do período de suplementação com CZ proporcionou aumento linear da eficiência alimentar (P < 0,01), peso de carcaça quente (P < 0,01), rendimento de carcaça quente (P < 0,01) e rendimento de carne desossada (P < 0,01). Os bifes de contrafilé de animais suplementados com CZ apresentaram maior conteúdo percentual de proteína (P < 0,01), enquanto que a espessura de gordura subcutânea (P = 0,04) e o conteúdo percentual de lipídios intramusculares (P < 0,01) diminuíram com administração de CZ. O valor percentual de ácidos graxos poliinsaturados totais aumentou (P = 0,01) com a administração de CZ, sendo atribuído principalmente ao aumento percentual do ácido linoleico (18:2 cis-9, cis-12; P = 0,01) e ácido araquidônico (20:4 n-6; P < 0,01). A força de cisalhamento das amostras de contrafilé aumentou (P < 0,01) com a inclusão de CZ na dieta, sendo esse resultado independente do tempo de maturação (7, 14, 21 ou 28 dias post-mortem). Observou-se interação entre período de administração de CZ e tempo de maturação (14 ou 28 dias post-mortem) para escore de maciez inicial (P = 0,03) e escore de tecido conjuntivo (P < 0,01), onde o processo de maturação melhorou mais a carne de animais controle do que a carne de animais suplementados com CZ. Mesmo com a diminuição da maciez, os bifes de animais suplementados com CZ foram considerados macios pelos provadores do painel sensorial. O CZ melhora a eficiência de produção de carne de bovinos Nelore, proporcionando aumento na massa muscular dos animais tratados sem alterar o consumo de matéria seca. Por outro lado, o tratamento dos animais com CZ reduz a maciez e a velocidade do processo de amaciamento do contrafilé. / The objective of this research was to evaluate the effects of zilpaterol hydrochloride (ZH) feeding time and feedlot days on performance, carcass characteristics, yield commercial cuts and meat quality of Nellore bulls. Ninety six Nellore bulls with initial body weight of 377 ± 25.1 kg were used in a randomized complete block in 4 × 2 factorial design, with four periods of ZH feeding (0, 20, 30 or 40 d) and 90 or 117 d in the feedlot. The supplementation period with ZH (8.33 mg/kg of dietary dry matter basis) started 23, 33 or 43 d before slaughter. In the last three days prior to slaughter all the animals were fed the diet without ZH, respecting the product grace period. Strip loin (m. Longissimus thoracis et lumborum) of all left-carcases were sampled for meat quality analysis. With the exception of LM area obtained both by ultrasound (P = 0.02) and by refrigerated carcasses (P = 0.05), there was no interaction between periods ZH feeding and days in the feedlot (P > 0.10). The increase of the supplementation period with ZH linearly increased feed efficiency (P < 0.01), hot carcass weight (P < 0.01), hot carcass yield (P < 0.01) and boning yield (P < 0.01). Beef strip loin steaks from animals supplemented with ZH presented a higher percentage of protein content (P < 0.01), while the 12th-rib fat (P = 0.04) and the percentage content of intramuscular fat (P < 0.01) decreased with ZH feeding. The percentage of polyunsaturated fatty acids increased (P = 0.01) with the ZH feeding and was mainly attributed to the increase of linoleic acid (18:2 cis-9, cis-12; P = 0.01) and arachidonic acid (20:4 n-6, P < 0.01). The Warner-Bratzler shear force (P < 0.01) from the strip loin samples increased with the inclusion of dietary ZH and this result was independent of the aging time (7, 14, 21 or 28 d postmortem). There was interaction between ZH feeding period and maturation time (14 or 28 d postmortem) to initial tenderness score (P = 0.03) and connective tissue score (P < 0.01), showing that the maturation process improved meat tenderness of control animals rather than ZH animals. Despite the initial meat tenderness decrease, strip loin steaks of animals supplemented with ZH were still considered tender by trained evaluators. ZH improves Nellore bulls meat production efficiency, providing an increase in muscle mass of the treated animals with no change in dry matter intake. However, treatment of animals with ZH reduces the tenderness and the speed of the strip loin maturation process.

Le récepteur membranaire TGR5 (Takeda G Protein-coupled Receptor 5), est un récepteur ubiquitaire sensible aux acides biliaires. Il est exprimé dans de nombreux tissus et organes dont l’intestin (dans les cellules entéroendocrines L), la vésicule biliaire, les muscles lisses et squelettiques, le tissu adipeux brun et dans certaines cellules immunitaires. Des études menées in vitro et in vivo chez l’animal ont montré des effets bénéfiques de l’activation de TGR5 sur l’homéostasie énergétique et glucidique. Il est maintenant communément admis que les effets bénéfiques de TGR5 sur l'homéostasie du glucose sont, au moins en partie, médiés par sa capacité à promouvoir la sécrétion de l'incrétine intestinale glucagon-like peptide-1 (GLP-1) au niveau des cellules entéroendocrines L.Cependant, de récentes expériences ont montré que l’activation de TGR5 par des agonistes systémiques dans des modèles animaux peut induire des effets non souhaités tels qu’une augmentation du volume de la vésicule biliaire, des démangeaisons et des effets cardiovasculaires. Afin de s’affranchir des effets non désirés d’agonistes systémiques de TGR5, le projet s’est orienté vers le développement d’agonistes de TGR5 présentant une distribution tissulaire ciblée et limitée à l’intestin et dont la biodisponibilité orale serait très faible, voire nulle. Nous avons alors émis l’hypothèse qu’une activation de TGR5 limitée à l’épithélium intestinal sans exposition systémique permettrait d’obtenir des effets bénéfiques sur l’homéostasie du glucose via l’effet GLP-1 sécrétagogue, tout en minimisant les effets non souhaités sur d’autres tissus ou organes exprimant TGR5.A partir des études de relations structure-activités obtenues au laboratoire sur une série d’agonistes de TGR5, nous avons conçu des composés chimériques de la façon suivante : le pharmacophore responsable de l’activité sur le récepteur TGR5 est lié via un bras espaceur à des éléments structuraux appelés kinétophores qui ajustent les propriétés physicochimiques et pharmacocinétiques de nos agonistes pour limiter leur absorption intestinale. Ainsi, l’objectif de ce travail était d’obtenir des agonistes non systémiques de TGR5, puissants et originaux, exerçant leur action dans l’intestin afin de générer la preuve de concept in vivo de l’intérêt d’utiliser de tels agonistes dans le traitement du diabète de type 2.Une étude systématique de l’effet de kinétophores variés a été réalisée. Une trentaine de composés ont été synthétisés en 8 à 12 étapes permettant l’identification d’agonistes puissants et présentant des propriétés pharmacocinétiques en accord avec notre stratégie de composés topiques intestinaux. Des études in vivo ont ensuite permis de valider l’effet GLP-1 sécrétagogue de tels composés. Enfin, l’évaluation d’un des meilleurs composés dans un modèle murin de diabète nous a permis de valider l’hypothèse qu’un agoniste topique intestinal de TGR5 peut avoir un effet bénéfique sur l’homéostasie énergétique et glucidique. / The membrane receptor TGR5 (Takeda G Protein-coupled Receptor 5) is an ubiquitous receptor sensitive to bile acids. It is expressed in many tissues and organs including the intestine (in enteroendocrine L cells), the gallbladder, smooth and skeletal muscles, brown adipose tissue and in some immune cells. In vitro and in vivo studies in animals have shown beneficial effects of TGR5 activation on energy and glucose homeostasis. It is now commonly accepted that the beneficial effects of TGR5 on glucose homeostasis are, at least in part, mediated by its ability to promote the secretion of the intestinal incretin glucagon-like peptide-1 (GLP-1) in enteroendocrine L cells.However, recent experiments have shown that the activation of TGR5 by systemic agonists in animal models can induce unwanted effects such as increased gallbladder volume, itching and cardiovascular issues. In order to avoid the undesired effects of systemic agonists of TGR5, the project focused on the development of TGR5 agonists with an intestine targeted distribution and a very low oral bioavailability. Then, we hypothesized that the activation of TGR5 limited to the intestinal epithelium without systemic exposure would promote the beneficial effects on glucose homeostasis via the GLP-1 secretagogue effect, while minimizing systemic effects on other tissues or organs expressing TGR5.On the basis of structure-activity relationships on a series of TGR5 agonists developed in the laboratory, we have designed chimeric compounds as follows: the pharmacophore responsible for activity on the TGR5 receptor is bound, via a linker, at structural elements called kinetophores that fine-tune the physicochemical and pharmacokinetic properties of our agonists to limit their intestinal absorption. Thus, the aim of this work was to obtain powerful and original non-systemic TGR5 agonists acting in the intestine to generate the in vivo proof of concept of the therapeutic potential of such agonists in the treatment of type 2 diabetes.A systematic study of the effect of various kinetophores was performed. About thirty compounds have been synthesized in 8 to 12 steps allowing the identification of powerful agonists with pharmacokinetic properties in accordance with our strategy of topical intestinal compounds. In vivo studies were then used to validate the GLP-1 secretagogue effect of such compounds. Finally, evaluation of one of the best compounds in a murine model of diabetes allowed us to validate the hypothesis that a topical intestinal agonist of TGR5 can have a beneficial effect on energy and glucose homeostasis.

Congenital myasthenic syndromes (CMS) are a rare group of heterogeneous disorders, characterised by compromised neuromuscular transmission and symptoms of fatiguable muscle weakness. CMS is caused by mutations in genes that affect the structure and function of the neuromuscular junction (NMJ). In about 20% of CMS cases, patients have mutations in the gene DOK7; the protein product, DOK7, is crucial for maintaining the dense aggregation of acetylcholine receptor (AChR) clusters at the NMJ. DOK7-CMS patients do not respond to treatment with acetylcholinesterase inhibitors which are the first line treatment for most forms of CMS. Instead, a dramatic response to beta-2 adrenergic receptor (ADRB2) agonists, such as salbutamol, is observed. The aim of this project was to investigate the molecular mechanisms that underlie the beneficial effects of ADRB2 agonists. Firstly, NMJ functioning was modelled in vitro by studying AChR clusters formed on cultured C2C12 mouse myotubes in the presence of WT DOK7. Overexpression of mutant DOK7 led to a significant reduction in the number of AChR clusters, explaining the pathogenic effect of the mutation. Importantly, incubation of myotubes with salbutamol increased the number of AChR clusters and their stability. The results provide the first evidence that ADRB2 agonists directly affect proteins located at the NMJ. However, this disease model suffers from limitations. The rest of the thesis focussed on developing alternative cell culture models to explore the AChR clustering pathway. The first model combined optogenetics and fluorescence lifetime microscopy to study the effects of ADRB2 activation on AChR cluster stability in single live cells. The second used CRISPR/Cas9 genome editing tools to directly introduce Dok7 mutations to the genome of C2C12 cells, thereby overcoming some of the drawbacks associated with DOK7 overexpression. Further manipulations of these novel model systems will be used in the future to examine in more detail the molecular events underlying the pathogenic effects of DOK7 mutations and the mechanisms of ADRB2 agonists.

Doctor of Philosophy / Department of Animal Sciences and Industry / John A. Unruh / Sixty cows were utilized to investigate the use of zilpaterol, implanting, and concentrate feeding on performance, carcass traits, subprimal yield, steak retail display, and meat palatability of cows fed for 70 d. The 5 treatments were: 1) grass-fed on pasture (Grass); 2) concentrate-fed (C); 3) concentrate-fed and implanted (CI) with a trenbolone acetate/estradiol implant, DE); 4) concentrate-fed and fed zilpaterol beginning on d 38 of the feeding period (CZ); and 5) concentrate-fed, implanted and fed zilpaterol (CIZ). Hot carcass weights and dressing percentages were higher (P < 0.05) for all concentrate-fed cows than grass-fed cows. The CIZ cows had the largest and grass-fed cows the smallest longissimus muscle (LM) areas. Total subprimal weights were lightest for cuts from the grass-fed cows; and CIZ cows had greater weights than those from C cows. Sensory panelists found LM steaks from C and grass-fed cows were more tender than steaks from CZ and CIZ cows; and steaks from CI cows were more tender than steaks from CIZ cows. However, no tenderness differences were observed among treatments for knuckle (KN) steaks. In another study, carcasses from 31 fed cows and 24 fed steers were used to investigate the effects of aging (7 or 28 d) on LM retail display; aging and enhancement (blade tenderization and enhancement solution injection) on LM tenderness; and aging on enhanced KN, top blade, and top sirloin steaks. Steaks (LM) aged 7 d had less discoloration and were more color stable than steaks aged for 28 d. A sensory panel found enhanced-cow LM steaks were more tender than non-enhanced steaks; and aging for 28 d improved tenderness compared to 7 d aging for non-enhanced steaks only. Aging for 28 d compared to 7 d improved Warner-Bratzler shear (more tender) for enhanced cow top sirloin, steer top sirloin, and steer top blade steaks. Feeding cull cows a concentrate diet improved lean meat yields. When feeding a concentrate diet a combination of an implant and feeding zilpaterol can further increase lean meat yields. Enhancement provides an opportunity to improve tenderness of steaks from fed cows and steers.

Les récepteurs N-méthyl-D-aspartate (NMDA) sont des récepteurs ionotropiques du glutamate jouant un rôle clé dans la plasticité synaptique et les fonctions cognitives. En conséquence, la perturbation de leur activité est impliquée dans de nombreux troubles neurologiques et psychiatriques tels que l'épilepsie et la schizophrénie. La particularité de ces récepteurs est qu'ils nécessitent pour être activés la liaison simultanée de leur agoniste, le glutamate, et d'un co-agoniste. La glycine fut le premier co-agoniste identifié mais plus récemment, de nombreuses études ont révélé que la D-sérine joue également ce rôle dans de nombreuses régions cérébrales, notamment dans l'hippocampe. Toutefois il restait à définir si les fonctions de ces deux co-agonistes étaient régulées au cours du développement ou si elles étaient spécifiques à certaines synapses. Dans la première partie de mon travail, j'ai montré que la D-sérine est le co-agoniste préférentiel des synapses SC-CA1 matures alors que la glycine est le co-agoniste préférentiel des synapses mPP-DG. De plus, le remplacement des récepteurs NMDA composés de sous-unités GluN2B par des récepteurs contenant GluN2A au cours du développement post-natal survient au même moment qu'un changement dans l'identité du co-agoniste préférentiel des synapses SC-CA1. Dans la seconde partie de mon travail, je me suis intéressée à la contribution de la D-sérine en conditions pathologiques sur un modèle murin d'épilepsie chimio-induite par la pilocarpine. J'ai ainsi montré l'implication de la D-sérine dans l'activité épileptique initiée par la pilocarpine. / N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ionotropic receptors which play a crucial role in synaptic plasticity and cognitive functions. As a consequence, disturbance in their activity is correlated with a broad range of neurological and psychiatric disorders including epilepsy and schizophrenia. The major particularity of NMDA receptors is the requirement of simultaneous binding of their agonist, glutamate, and a co-agonist to be activated. Glycine was the first co-agonist identified but more recently several studies showed that D-serine is also playing this role in many brain areas including the hippocampus. Whether the identity of the co-agonist is synapse specific or developmentally regulated remains unexplored. In the first part of my work I showed that D-serine is the preferred co-agonist at SC-CA1 mature synapses while glycine is the preferred one at mPP-DG synapse. Moreover, we showed that during postnatal development, the replacement of GluN2B by GluN2A-containing NMDA receptors at SC-CA1 synapses parallels a change in the co-agonist identity from glycine to D-serine. In the second part of my work I investigated the contribution of D-serine in pathological conditions. By using a model of acute intoxication of pilocarpine, I demonstrated that D-serine is implicated in epileptiform activity initiated after pilocarpine perfusion.