Methylphenidate (trade name: Ritalin) produced a more robust conditioned place male as compared to female juvenile rats. This effect was blocked by a D1 antagonist (SCH 23390), which resulted in a conditioned place aversion in male as compared to female rats. Effects on Brain-derived neurotrophic factor (BDNF) will be reported.

Human immunodeficiency virus type 1 (HIV-1) persists in certain CNS cell populations, despite peripheral control of the infection with modern antiretroviral therapy. Infected and/or activated cells release viral proteins, such as trans-activator of transcription (Tat) and various pro-inflammatory factors such as CCL5, creating a positive loop of neuro-inflammation. This serves as the basis for the resulting sublethal and lethal neuropathology that manifests as a spectrum of HIV-mediated CNS impairments, known as HIV-associated neurocognitive disorders (HAND). Opiates, which exist as an interlinked epidemic with HIV-1 infections, exacerbate these neurological effects through direct and indirect mechanisms that disrupt both glial and neuronal function. We hypothesize this is due to converging actions on the CCL5-CCR5 signaling axis by HIV-1 Tat and morphine co-exposure, primarily mediated at the level of the glia, whose consequent activation leads to neuronal damage. We performed repeated measure studies on mixed glia and neuron co-cultures obtained from C57Bl/6J and/or CCR5 knockout mice, treated with Tat and/or morphine for 72 hours. As established in prior studies, morphine worsened Tat-induced neurotoxicity in wild-type co-cultures; substitution of CCR5-null glia eliminated the interactive effects of Tat and morphine, but substitution of CCR5-null neurons did not. Overall, these results suggest that glial CCR5, but not neuronal CCR5, is a convergence point for the interactive effects of Tat and morphine that result in neuron loss. Additional experiments involving treatments with naloxone, a MOR antagonist, or the CCR5 antagonist maraviroc, confirmed each receptor’s role in mediating Tat + morphine toxicity. Quite surprisingly, in co-cultures of wild-type neurons and CCR5-null glia, morphine entirely protected neurons from the neurotoxic effects of Tat. We hypothesize that this effect may reflect an imbalance of neurotrophic factors, particularly BDNF and its neurotoxic precursor proBDNF, whose levels are altered in HIV+ and illicit drug-using patients and may contribute to changes in neuronal signaling and survival exhibited in HAND. Related behavioral tests of anxiety, motor and cognitive function – three areas of neurologic decline seen in HAND – were performed in inducible Tat-transgenic mice that were treated with maraviroc via oral gavage. Tat-mediated impairment was observed in the Barnes Maze, a measure of spatial memory, and was ameliorated by maraviroc. Finally, we assessed the role of CCR5 in mediating Tat and/or morphine effects on psychomotor sensitization and dendritic morphology. With both in vitro and in vivo studies, our findings support the hypothesis that CCR5 plays a central role in driving HIV-1 Tat and/or morphine-mediated neuronal damage.

Mammalian circadian rhythms are controlled by a clock located in the suprachiasmatic nucleus (SCN). The mechanisms through which light phase-shifts the SCN circadian clock are similar to those underlying memory formation and long-term potentiation (LTP). Several secreted proteins, including tissue-type plasminogen activator (tPA), plasminogen, and brain-derived neurotrophic factor (BDNF), have been implicated in this process. These same proteins are important for photic phase-shifts of the SCN circadian clock. Early night glutamate application to SCN containing brain slices resets the circadian clock. Our experiments find that the endogenous tPA inhibitor, plasminogen activator inhibitor 1(PAI-1), blocked these shifts in slices from wildtype mice but not mice lacking its stabilizing protein, vitronectin (VN). Plasmin, but not plasminogen, prevented inhibition by PAI-1. Both plasmin and active BDNF reversed alpha2-antiplasmin inhibition of glutamate-induced shifts. alpha2-Antiplasmin decreased the conversion of inactive to active BDNF in the SCN. Both tPA and BDNF allowed daytime glutamate-induced phase-resetting. Together, these data are the first to demonstrate expression of these proteases in the SCN, their involvement in modulating photic phase-shifts, and their activation of BDNF in the SCN, a potential ‘gating’ mechanism for photic phase-resetting. Using western-blot analyses of SCN tissue maintained in vitro, we find higher tPA, plasmin and mBDNF levels in the SCN at night vs. the day. Also, in vitro glutamate treatment of SCN tissue during early night increases tPA levels to ~2.5 times control levels, while similar treatments during late night and mid-day do not alter tPA expression. Glutamate treatment in the early night does not alter PAI-1, plasmin and BDNF levels. Co-treatment with glutamate and PAI-1 decreases plasmin levels (vs. glutamate treatment alone), while co-treatment with glutamate and alpha2-antiplasmin decreases the amount of pro- and mBDNF in the SCN relative to glutamate treatment alone. We also show that mBDNF levels are significantly lower in tPA knockout mice during both day and night. Together, these results support circadian clock modulation of BDNF and fibrinolytic protein levels in the SCN. They also suggest that glutamate modulates tPA expression in the SCN, while tPA and plasmin modulate BDNF expression.

IntroducciónLos Trastornos del Comportamiento Alimentario(TCA) son enfermedades mentales de gran relevancia social debido a la gravedad de la sintomatología y las dificultades en el tratamiento. En población no clínica existe un alto porcentaje de conductas alimentarias alteradas, consideradas de riesgo, que podrían agravarse convirtiéndose en un TCA. Por ello es importante conocer los factores que se relacionan con la evolución de estas conductas y sobretodo la implicación de esta evolución sobre el estado nutricional, en un periodo de crecimiento y madurez mental.Objetivo GeneralAnalizar el consumo alimentario, el desarrollo corporal, la actividad física, las características psicológicas y el polimorfismo G196A (Val66Met) del gen BDNF según la evolución del riesgo de TCA desde la preadolescencia a la adolescencia en ambos sexos.Material y métodosSe realizó un estudio epidemiológico prospectivo de dos años de duración en escolares de ambos sexos de la ciudad de Tarragona, estructurado en una fase inicial de cribado y en una de seguimiento de los sujetos seleccionados como casos (sujetos a riesgo de TCA) y controles, dividido en dos tiempos: preadolescencia (T1) y adolescencia (T2). En los dos tiempos se valoró individualmente: la composición corporal, la antropometría, el consumo alimentario cuantitativo, el diagnóstico de TCA y el polimorfismo genético. La actividad física, el estadio puberal, el nivel socioeconómico, la satisfacción corporal y la psicopatología asociada se evaluaron mediante cuestionarios.Conclusiones.El sexo femenino es un factor de riesgo en el mantenimiento del TCA. En su preadolescencia presentan un desarrollo puberal más avanzado junto a un IMC elevado. Esto provoca un cambio alimentario y una restricción energética progresiva que conduce a un riesgo nutricional, independientemente de que el riesgo de TCA se solucione. El riesgo de TCA se mantiene cuando se añaden en la adolescencia aspectos psicológicos como la insatisfacción corporal y las alteraciones emocionales. Las mujeres con mantenimiento de riesgo de TCA que tienen el polimorfismo son el grupo más vulnerable a la restricción energética en la adolescencia. / Eating Disorders (ED) are mental diseases of great social relevance due to the gravity of the sintomatología and the difficulties in the treatment. In nonclinical population a high percentage of altered eating conducts exists, considered of risk, that could worsen becoming to ED. For that reason it is important to know the factors that are related to the evolution of these conducts and coverall the implication of this evolution on the nutricional state, in a period of growth and mental maturity.AimTo analyze the food consumption, the corporal development, the physical activity, the psychological characteristics and polymorphism G196A (Val66Met) of gene BDNF according to the evolution of the TCA risk from the preadolescence to the adolescence in both sexes.Methods We performed two-year longitudinal epidemiological study in schoolchildren of both genders of the city of Tarragona, structured in an initial phase of sifting and one of follow-up of the subjects selected like cases (subject at risk of ED) and controls, divided in two times: preadolescence (T1) and adolescence (T2). In both times it was assessment individually: the corporal composition, the anthropometry, the quantitative food consumption, the diagnosis of ED and the genetic polymorphism. The physical activity, the puberal stage, the socioeconomic level, the corporal satisfaction and the associate psychopathology were assessment with questionnaires.Conclusions :Feminine sex is a factor of risk in the maintenance of the ED. In its preadolescence they present a more advanced puberal development next to BMI a high one. This causes an nourishing change and progressive a power restriction that leads to a nutricional risk, independently of which the ED risk is solved. The ED risk stays when psychological aspects like the corporal dissatisfaction and the emotional alterations are added in the adolescence. The women with maintenance of risk of ED that have the polymorphism are the most vulnerable group to the power restriction in the adolescence.

Exercise is often prescribed for patients with chronic pain, but there is little objective evidence supporting this recommendation. Therefore, we tested the effect of moderate aerobic exercise on the sensory hypersensitivity produced in an animal model of neuropathic pain. Male rats that underwent unilateral ligation of the L5 and L6 spinal nerves (SNL) were divided into exercise-trained or sedentary groups. Exercise training was performed using a treadmill, beginning 7 days after surgery, and continued 5 days a week for 5 weeks. Animals were exercised 30 min/day, at a speed of 14-16 m/min. Sensory testing was performed 23 hours after exercise training. Typical thermal and tactile hypersensitivity developed within 1 week after surgery. Treadmill training reversed thermal and tactile hypersensitivity in injured animals within 4 weeks, but had no effect on sham-operated or non-operated animals. One week after the cessation of exercise training, tactile hypersensitivity returned.The effects of exercise training on SNL-induced sensory hypersensitivity were reversed by the opioid receptor antagonist naloxone. Naloxone or naloxone methiodide reversed the effects of exercise when administered intracerebroventricularly (i.c.v.). Immunohistochemistry revealed increased immunostaining for B-endorphin and met-enkephalin in the periaquaductal grey (PAG) and rostral ventromedial medulla (RVM) regions of exercise-trained animals compared to sedentary animals. An ELISA immunoassay revealed a 31% increase in PAG B-endorphin content in exercise-trained SNL animals. More BDNF was also present in the brain's of exercise-trained animals compared to sedentary, specifically in the ventromedial hypothalamus, hippocampus, and outer rim of the PAG. Administering a BDNF sequestering agent reversed B-endorphin increases in the PAG of exercise-trained animals. Exercise-trained SNL animals treated with 25 ug BDNF sequestering agent (i.c.v.) had lower tactile thresholds compared to the exercise-trained vehicle group.These results support the recommendation of moderate aerobic exercise for patients suffering from neuropathic pain, and suggest that exercise-induced pain reversal results from the upregulation of endogenous opioids in the brainstem. Additionally, increased BDNF with exercise training may play a role in exercise-induced reversal of neuropathic pain by increasing the expression of endogenous opioids, but this needs to be verified further.

Huntington’s disease (HD) is an inherited neurodegenerative disorder that is caused by a mutation of a single gene, huntingtin. The disease is more commonly known for the characteristic choreiform movements that develop in the later, more advanced stages of the disease. However, cognitive deficits and psychiatric symptoms are frequently observed prior to the onset of the motor symptoms. Little is known about the pathological bases for the neuropsychiatric features which include increased irritability and heightened aggression. Depression affects 30-50% of HD patients and is the most commonly diagnosed psychiatric symptom. This is proportionally higher than in the general population and it is possible that inherent pathological changes in the HD brain render a HD-gene positive individual more susceptible to depression. / Using a variety of behavioural tests, the R6/1 transgenic mouse model of HD was found to display altered responses reflective of depression-related behaviour, indicating that the HD mutation confers a genetic susceptibility for developing depression. The behavioural alterations were more robust in female HD mice reflecting a possible sex-dependent manifestation of the depression symptoms in the human HD population that has yet to be investigated. The onset and rate of progression of HD is strongly influenced by the environment and the development of depression is similarly impacted upon by environmental factors (e.g. stress, negative life events). The experimental paradigms of environmental enrichment and wheel-running slow the development of motor and cognitive symptoms in R6/1 HD mice and the present study reports that both paradigms also correct the depression-related behavioural phenotype. This study also found that HD mice had muted responses to two common classes of antidepressant drugs, highlighting the need for a detailed examination of the efficacy of drug treatments in HD patients. / Depression susceptibility is linked to genetic variance in the human population and studies of gene candidates in mutant mice report the detection of behavioural phenotypes similar to the present study. The depression-related behavioural phenotype of the R6/1 HD model was found to be associated with early down-regulations in mRNA levels of the ii serotonin (5-HT) 1A and 5-HT 1B receptors in the cortex and the hippocampus. Additionally, female HD mice had reduced cortical 5-HT transporter gene expression. Collectively, these findings indicate that a disruption of serotonergic signaling in the HD brain contributes to the development of depression in HD. Brain-derived neurotrophic factor (BDNF) gene expression is down-regulated in the HD brain, however the expression pattern of exon-specific splice variants was previously unknown. This study reports that BDNF mRNA levels are reduced in the hippocampus by an early age but also reports that individual exon-specific transcripts are differentially down-regulated in males and females, although the functional relevance of this remains to be investigated. / Overall, this study has demonstrated that the R6/1 transgenic mouse model of HD is ideal for further investigating the occurrence of depression in pre-motor symptomatic HD. It has also identified alterations in gene expression of key components of neuronal signaling which might be linked to the molecular basis of depression.

?rea de concentra??o: Neuroimunoendocrinologia. / Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-04T18:24:18Z No. of bitstreams: 2 wellington_fabiano_gomes.pdf: 3823362 bytes, checksum: 39e0250b96c5bd95724cca2eef404fd7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-04T18:24:49Z (GMT) No. of bitstreams: 2 wellington_fabiano_gomes.pdf: 3823362 bytes, checksum: 39e0250b96c5bd95724cca2eef404fd7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-01-04T18:24:49Z (GMT). No. of bitstreams: 2 wellington_fabiano_gomes.pdf: 3823362 bytes, checksum: 39e0250b96c5bd95724cca2eef404fd7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014 / Funda??o de Amparo ? Pesquisa do estado de Minas Gerais (FAPEMIG) / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (Capes) / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / A osteartrite de joelho (OAj) ? uma doen?a que afeta principalmente os idosos e pode levar a grandes limita??es f?sicas e funcionais. No entanto, os efeitos espec?ficos da terapia por exerc?cios, especialmente a caminhada sobre o sistema imunol?gico, s?o desconhecidas. Portanto, este estudo teve como objetivo analisar o efeito de 12 semanas de caminhada (3x / semana) no perfil de leuc?citos, nos n?veis plasm?ticos de interleucina (IL-6), do fator de necrose tumoral alfa (TNF-?), dos receptores sol?veis de TNF-? (sTNFR1 e sTNFR2), e do fator neurotr?fico derivado do c?rebro (BDNF) a partir de plasma retirado do sangue perif?rico de mulheres idosas com OAj. Al?m disso, as avalia??es cl?nicas e funcionais (teste de WOMAC, teste de caminhada de 6 minutos, SF-36, a percep??o da dor) foram realizadas. Dezesseis mulheres (idade: 67 ? 4 anos, ?ndice de massa corporal: 28,07 ? 4,16 kg/m2) participaram de um programa de caminhada (36 sess?es de fisioterapia) e de um esfor?o f?sico (01 sess?o de fisioterapia). As vari?veis foram avaliadas antes e ap?s 12 semanas de treinamento com dura??o (30-55 min) e intensidade (70-80% da FCm?x) progressivamente maiores. As amostras de sangue coletadas foram analisadas com um contador de c?lulas, cit?metro de fluxo e pelo m?todo ELISA. As sess?es de fisioterapia resultaram em um aumento de 47% da qualidade de vida (p <0,05) e um aumento de 21% no VO2max (p <0,0001) em mulheres idosas com OAj. Al?m disso, houve uma redu??o nas c?lulas T CD4 + (antes 46,59 ? 7%, depois 44,58 ? 9%, p = 0,0189) e uma intensidade de fluoresc?ncia mais elevada para CD18 + CD4 + (antes 45,30 ? 10, depois de 64,27 ? 33, p = 0,0256) e CD18 + CD8 + (antes: 64,2 ? 27, depois de 85,02 ? 35, p = 0,0130). A ET aumentou a concentra??o plasm?tica de sTNR1; no entanto, diminuiu a concentra??o de plasma de sTNFR2, quando comparado com os n?veis em repouso de pacientes. O exerc?cio agudo afetou diferencialmente os n?veis de sTNFR1 dependente de quando as amostras foram tomadas, antes e ap?s o treinamento aer?bico. No entanto, os n?veis de sTNFR2 n?o foram afetados pelo treinamento. O exerc?cio agudo aumentou os n?veis de BDNF apenas antes do per?odo de treinamento de 12 semanas (p <0,001). Al?m disso, houve aumento das concentra??es plasm?ticas de BDNF (p <0,0001) e melhora em par?metros cl?nicos (funcional p <0,001; percep??o da dor p <0,01). A varia??o dos n?veis de receptores sol?veis correlacionou-se com a melhora funcional; no entanto, os marcadores inflamat?rios de osteoartrite (IL-6 e TNF-?) n?o foram afetados pelas 36 sess?es de fisioterapia. / Tese (Doutorado) ? Programa Multic?ntrico de P?s-Gradua??o em Ci?ncias Fisiol?gicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2014. / ABSTRACT Osteoarthritis of the knee (kOA) is a disease that mainly affects the elderly and can lead to major physical and functional limitations. However, the specific effects of exercise therapy (ET), specially walking and particularly on the immune system, are unknown. Therefore, this study aimed to analyze the effect of 12 weeks of walking (3x/week) on the leukocyte profile, levels of interleukin 6 (IL-6), tumor necrosis factor alpha, (TNF-?), soluble forms of the TNF-? receptor (sTNFR1 and sTNFR2), and brain-derived neurotrophic factor (BDNF) from plasma taken from the peripheral blood of elderly women with kOA. Additionally, clinical and functional assessments (WOMAC test, 6-min walk, SF-36, pain perception) were performed. Sixteen women (age: 67 ? 4 years, body mass index: 28.07 ? 4.16 kg/m2) participated in a walking program and physical exertion. The variables were assessed before and after 12 weeks of training with a progressively longer duration (30-55 min) and higher intensity (70-80% of HRmax). The blood samples were collected for analysis with a cell counter, the Scan Fac flow cytometer and were measured by ELISA. The ET resulted in a 47% enhancement of the self-reported quality of life (p <0.05) and a 21% increase in the VO2max (p <0.0001) in elderly women with kOA. Furthermore, there was a reduction in CD4+ cells (before 46.59?7%, after 44.58?9%, p=0.0189) and a higher fluorescence intensity for CD18+CD4+ (before 45.30 ? 10, after 64.27 ? 33, p=0.0256) and CD18+CD8+ (before: 64.2 ?27, after 85.02 ?35, p=0.0130). Aerobic training increased the plasma concentration of sTNR1; however, it decreased the plasma concentration of sTNFR2, when compared with levels of resting patients. Acute exercise differentially affects the levels of sTNFR1 dependent on when the samples were taken, before and after aerobic training. However, the levels of sTNFR2 were not affected by training. The acute exercise increased the levels of BDNF only before the 12-week training period (p<0.001). Moreover, the training augmented the plasma concentrations of BDNF (p<0.0001) and improved clinical parameters (functional p<0.001; pain perception p<0.01). The variation in the levels of soluble receptors correlated with functional improvement; however, the inflammatory osteoarthritis markers (IL-6 and TNF-?) were unaffected by the walking exercises, in physical therapy.

Submitted by Gabriel Keine Kuga (xgabriel@gmail.com) on 2018-09-13T16:26:51Z No. of bitstreams: 1 Dissertação - Gabriel Keine Kuga - PPG Ciencias da Motricidade.pdf: 2345917 bytes, checksum: 7b943b730b7884c42ec2e4a70eea0d04 (MD5) / Approved for entry into archive by Ana Paula Santulo Custódio de Medeiros null (asantulo@rc.unesp.br) on 2018-09-13T17:08:25Z (GMT) No. of bitstreams: 1 kuga_gk_me_rcla.pdf: 2335049 bytes, checksum: d95d86caf2a2ad20a26629e663df42d5 (MD5) / Made available in DSpace on 2018-09-13T17:08:25Z (GMT). No. of bitstreams: 1 kuga_gk_me_rcla.pdf: 2335049 bytes, checksum: d95d86caf2a2ad20a26629e663df42d5 (MD5) Previous issue date: 2018-07-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A insulina e o fator neurotrófico derivado do cérebro (BDNF) no hipocampo promovem a plasticidade sináptica e a formação da memória no hipocampo. Por outro lado, o envelhecimento está relacionado ao declínio cognitivo e é o principal fator de risco para a doença de Alzheimer (DA). No entanto, a comunidade científica tem feito grande esforço para elucidar os mecanismos moleculares responsáveis pela patogênese da DA que são disparados pelo envelhecimento. A Proteina Tirosina Fosfatase 1B (PTP1B) está relacionada a vários processos deletérios nos neurônios e pode ser alvo promissor para novas terapias, e também regulada pelo exercício físico. Neste contexto, nosso estudo teve como objetivo investigar as alterações relacionadas com o envelhecimento sobre o conteúdo de PTP1B, sinalização da insulina e conteúdo de β-amilóide no hipocampo de ratos de meia-idade, bem como o possível efeito terapêutico do exercício físico. Ratos Wistar jovens (3 meses de idade) e de meia-idade (sedentários e exercitados) (17 meses de idade) foram submetidos ao teste do Labirinto Aquático de Morris (MWM), ao teste de tolerância à glicose e à análise molecular do tecido hipocampal através da técnica de Western Blot. Os dados foram analisados através da Análise de Variância (ANOVA) one-way com nível de significância estabelecido abaixo de 0,05. Os ratos realizaram protocolo de exercício físico de natação durante 5 dias consecutivos, com 2 horas de duração por dia. Através dos resultados, verificou-se que o envelhecimento resultou em aumento do peso corporal e intolerância à glicose, bem como diminuiu o processo de aprendizagem no MWM. Observou-se também que os ratos de meia-idade têm níveis mais altos de PTP1B, e isso está relacionado a menor fosforilação de Substrato do Receptor de Insulina-1 (IRS-1), Proteína Kinase B (Akt), Glicogênio Sintase Kinase β (GSK3β), e Receptor Tirosina Kinase Beta (TrkB). Além disso, o processo de envelhecimento aumentou o conteúdo β-amilóide no hipocampo. Por outro lado, o exercício físico foi eficiente em melhorar a tolerância à glicose e o desempenho no MWM, bem como em restaurar a fosforilação da Akt e reduzir o conteúdo de β-amilóide. Em conclusão, este estudo fornece novas evidências de que o conteúdo de PTP1B no hipocampo está aumentada com o envelhecimento e isto está relacionado com alterações cognitivas, e, por outro lado, o exercício físico atenua esse processo em ratos envelhecidos. / The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promote synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer’s Disease (DA). Nevertheless, a great effort has been made by the scientific community to elucidate the molecular mechanism of aging-related DA pathogenesis. The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies, like as physical exercise. In this context, our study aims to investigate the age-related changes in hippocampal PTP1B content, insulin signaling, β-amyloid content in the hippocampus of middle-aged rats, and the possible therapeutic effect of exercise. Young (3 months-old) and Middle-aged (17 months-old) Wistar rats were submitted to Morris-water maze (MWM) test, glucose tolerance test, and to molecular analysis in the hippocampus. The rats performed a 2-hour swim physical exercise protocol for 5 consecutive days. Aging resulted in increased body weight, and glucose intolerance and decreases learning process in MWM. Interestingly, the Middle-Aged rats have higher levels of PTPB, and this is related to lower phosphorylation of Insulin Receptor Substrate-1 (IRS-1), Protein Kinase B (Akt), Glycogen Syntase Kinase β (GSK3β), and Tyrosine Kinase Receptor Beta (TrkB). Also, the aging process increased β-amyloid content in the hippocampus. On the other hand, the physical exercise was efficient to improve glucose tolerance and MWM performance, as well as to restore Akt phosphorylation and reduce β-amyloid content. In conclusion, this study provides new evidence that PTP1B content in the hippocampus is increased with aging and this is related to cognitive alterations, and physical exercise can attenuate this process in middle-aged rats.

De nombreuses données indiquent qu’un petit poids à la naissance, résultant en partie d’une sous-nutrition materno-fœtale, est associé à une augmentation de la morbidité et de la mortalité durant la période néonatale, et conduit également à un risque accru de développer à l'âge adulte un syndrome métabolique (diabète de type 2, obésité, hypertension artérielle et dyslipidémie). Les mécanismes de cette programmation prénatale sont encore mal connus et impliqueraient plusieurs molécules et systèmes physiologiques distincts. De nombreuses études suggèrent que le placenta serait impliqué dans la programmations de ces pathologies métaboliques. En effet, celui-ci constitue un organe de communication entre la mère et son fœtus et participe à la régulation de l'homéostasie fœtale. En raison de la proportion croissante de femmes présentant des troubles de la nutrition durant la grossesse et en lien avec leurs répercussions potentielles chez la descendance, il est nécessaire de mieux comprendre les interactions entre l’alimentation maternelle et l’unité fœto-placentaire et d’identifier les mécanismes impliqués dans les altérations de la croissance fœtale. En conséquent, le placenta constitue un organe de choix pour étudier les interactions entre l’alimentation maternelle et le fœtus au cours de la grossesse. Durant cette thèse, nous avons tenté d’identifier de nouvelles voies moléculaires placentaires impliquées dans le contrôle de la croissance fœtale chez le rat, puis d'étudié l'expression de ces facteurs dans des placentas humains provenant de grossesses impliquant des anomalies de la croissance fœtale. Comme la malnutrition maternelle constitue une part importante dans l'étiologie de la restriction de croissance intra-utérine (RCIU), nous avons utilisé un modèle expérimental effectué chez le rat, qui consiste en une réduction (de 50% à 70%) de la ration alimentaire quotidienne maternelle durant la gestation. Ces régimes conduisent à des troubles de la croissance de l'unité fœto-placentaire révélés par des réductions drastiques du poids du placenta et des poids de naissance à terme. Afin d'identifier de nouvelles voies placentaires impliquées dans RCIU, nous avons utilisé deux méthodologies différentes: une approche protéomique et une évaluation de deux protéines récemment caractérisées.Premièrement, nous avons étudié le protéome placentaire chez le rat RCIU provenant de mères dénutris par une analyse protéomique (2D-PAGE et spectrométrie de masse). Cette stratégie nous a permis de découvrir de nouvelles voies modulées par le RCIU et, étonnamment, des modulations importantes ont été observées pour plusieurs protéines mitochondriales, suggérant un effet ciblé de la dénutrition sur ces organites. Par la suite, en utilisant diverses techniques d'analyses moléculaires, protéomiques et fonctionnelles, nous avons montré que ces organites élaborent une réponse adaptative à la restriction alimentaire maternelle qui pourrait avoir des conséquences sur la régulation de la croissance fœtale. Deuxièmement, nous avons étudié deux autres protéines atypiques: le brain-derived neurotrophic factor et l'hormone apéline. Nos résultats suggèrent que ces deux facteurs pourraient être impliqués, au niveau placentaire, dans le contrôle de la croissance fœtale à la fois chez le rat et chez l'homme. En conclusion, comme les techniques cliniques actuelles ne permettent pas de diagnostiquer avec précision un RCIU, nos résultats pourraient permettre une meilleure compréhension de la physiopathologie placentaire et permettre de développer de nouveaux marqueurs de diagnostique et/ou de traitement dans le but d'améliorer la croissance placentaire et fœtale en conditions pathologiques. / Growing evidences indicate that a small birthweight, resulting from maternal malnutrition or others prenatal alterations, is associated with an increased neonatal morbidity and mortality and may lead to higher propensity to develop a metabolic syndrome (including type 2 diabetes, obesity, hypertension and dyslipidemia) in adulthood. However, the physiopathological mechanisms acting in utero on the programming of the offspring's metabolic profile remain confused and may implicate numerous molecules and physiological systems. Several data suggest that the placental alterations may have long-lasting consequences and could thus contribute to the programming of adult metabolic diseases. The placenta is the primary means of communication and nutrient delivery to the fetus and is also involved in fetal homeostasis. Thus, the placenta may constitute an appropriate organ for investigating how differences in maternal food consumption are sensed by the fetus along the pregnancy. Because of the increasing proportion of women eating inadequately during pregnancy and because such nutritional disturbances may have huge repercussions on adult health of the offspring, we urgently have to better understand how the placenta elaborates adaptive responses to maternal food intake modulations. My PhD aimed at identifying new placental pathways implicated in fetal growth restriction in rat, and investigated in human placental samples, the expression of these factors in pregnancies with fetal growth disturbances.As maternal malnutrition constitutes an important part in the etiology of intrauterine growth restriction (IUGR), we used an experimental model performed in rats which consists of a reduction (from 50% to 70%) of the daily maternal food intake during the gestation. These regimens lead to profound growth disturbances of the feto-placental unit revealed by drastic reductions of both placental and birth weights at term. To identify new placental pathways implicated in IUGR, we have used two different strategies: a proteomic approach and the evaluation of two proteins recently characterized in the placenta.First, we investigated the placental proteome in IUGR rats from undernourished mothers using 2D-PAGE electrophoresis and mass spectrometry identification. This strategy allowed the discovery of new pathways modulated by IUGR. Surprisingly, major modulations were observed for several proteins localized in mitochondria, suggesting specific effects of maternal undernutrition on these organelles. Thereafter, using multiple molecular, proteomic and functional analyses, we have shown that these organelles develop adaptive responses to maternal nutrient restriction that may have functional consequences on the regulation of the fetal growth. Secondly, we studied two others atypical proteins: the brain-derived neurotrophic factor and the hormone apelin. Our findings suggest that both of these factors may be implicated in the control of fetal growth at the placental level in rat and putatively in human. As actual clinical methods do not permit to diagnose precisely fetal growth disturbances, our results may permit to better understand the placental physiological pathways implicated during these pathologies and could lead to the development of markers and/or treatments in order to improve both placental functions and fetal growth.

It is now well accepted that there is a close relationship between noradrenergic and dopaminergic neurons in the brain, especially referring to the modulation of the locus coeruleus–norepinephrine (LC-NE) system on dopamine transmission. The disturbance of this modulation may contribute to neurodegeneration of dopaminergic neurons in Parkinson’s disease. In this article, we briefly review evidence related to such modulation. Firstly, we illustrated the noradrenergic innervation and functional implication for the LC-NE system and nigra–striatum dopaminergic system. Furthermore, we depicted neuroprotective effects of the LC-NE on dopaminergic neurons in vivo and in vitro. Moreover, we present data implicating the potential mechanisms underlying the modulation of the LC-NE system on dopaminergic neurons, in particular the effects of NE as a neurotrophic factor and through its ability to stimulate the expression of other neurotrophic factors, such as the brain-derived neurotrophic factor. Finally, we discussed other mechanisms intrinsic to NE’s effects. A better understanding of the noradrenergic modulation on dopaminergic neurons may be rewarding by significant advances in etiologic study and promising treatment of Parkinson’s disease.