L’activateur tissulaire du plasminogène est une sérine protéase initialement découverte dans le compartiment vasculaire et qui joue un rôle prépondérant dans le processus de fibrinolyse. De manière intéressante, le tPA est également présent dans le parenchyme cérébral, où il est notamment exprimé par les neurones. Le tPA est impliqué dans de nombreuses fonctions cérébrales dont la plasticité synaptique, les processus de mémoire et d’apprentissage ainsi que dans la survie et la mort neuronales. Le tPA est capable d’augmenter la signalisation calcique induite par une activation des récepteurs N-Méthyl-D-Aspartate (NMDAR) : un mécanisme à la base de la plasticité synaptique mais également de la mort neuronale excitotoxique. Cependant, il peut également activer les récepteurs du facteur de croissance épidermique (EGFR) pour induire un effet anti-apoptotique sur les neurones. Afin de mieux comprendre les différentes fonctions du tPA sur les neurones, nous nous sommes intéressés à la distribution et au trafic intracellulaire du tPA. Pour cela, nous avons créé un nouvel outil afin d’imager le tPA dans les neurones en temps réel: un plasmide codant pour une protéine fusion, le tPA-HaloTag®.Premièrement, nos résultats montrent que le tPA est présent dans les axones et les dendrites des neurones corticaux matures en culture et qu’il est majoritairement présent dans le compartiment post-synaptique. Cette étude a également permis de voir que le tPA est stocké et libéré par des vésicules d’exocytose VAMP2, qu’il peut être endocyté par des vésicules Rab5, recyclé par des vésicules Rab11 et dégradé par des vésicules Rab7. Deuxièmement, nous avons montré que le tPA est présent dans les mêmes vésicules synaptiques que le facteur neurotrophique issu du cerveau (BDNF) : une neurotrophine importante pour le bon fonctionnement cérébral et dont la maturation dépend de l’activité protéolytique du tPA. Ce travail fournit une meilleure compréhension du rôle et de la distribution du tPA dans les neurones et ouvre de nouvelles voies de recherche dans l’implication de du tPA et du BDNF dans la survie neuronale. / Tissue-type Plasminogen Activator (tPA) is a serine protease, firstly discovered for its fibrinolytic role in the vascular compartment. Interestingly, tPA is also present in the brain parenchyma, being notably expressed by neurons. tPA displays important roles in synaptic plasticity(Danny Baranes et al., 1998; Melchor and Strickland, 2006), learning, memory processes(R Madani et al., 1999; R Pawlak et al., 2002), neuronal survival and death. tPA is able to promote N-Methyl-D-Aspartate Receptors (NMDAR)-induced calcium influx, promoting synaptic plasticity or excitotoxic neuronal death. tPA is also able to activate Epidermal Growth Factor Receptors (EGFR), a mechanism mediating its anti-apoptotic effect. To better understand the different functions of tPA on neurons, we studied the pattern of distribution and trafficking of neuronal tPA. For that, we designed a new tool to image tPA in living neurons: a plasmid encoding for a tPA-HaloTag® fusion protein. We first found that tPA is present in both axons and dendrites of mature cultured cortical neurons and preferentially at the post-synaptic part. Our results also showed that tPA is stored and released by VAMP2 exocytotic vesicles, and can be endocytosed by Rab5 vesicles, recycled by Rab11 vesicles and degraded by Rab7 vesicles. Furthermore, tPA is localized and sorted in the same vesicles than Brain-Derived Neurotrophic Factor (BDNF), one of the most important neurotrophins, Interestingly, BDNF maturation is dependent of tPA proteolytic activity. This work provides a better understanding of the role and distribution of tPA in living neurons and opens new avenues into the involvement of tPA and BDNF in neuronal survival.

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.

This review details the manner in which the central nervous system regulates metabolic homeostasis in normal weight and obese rodents and humans. It includes a review of the homeostatic contributions of neurons located in the hypothalamus, the midbrain and limbic structures, the pons and the medullary area postrema, nucleus tractus solitarius, and vagus nucleus, and details how these brain regions respond to circulating levels of orexigenic hormones, such as ghrelin, and anorexigenic hormones, such as glucagon-like peptide 1 and leptin. It provides an insight as to how high intensity exercise may improve homeostatic control in overweight and obese subjects. Finally, it provides suggestions as to how further progress can be made in controlling the current pandemic of obesity and diabetes.

Depression is a very common public disease that can lead to social and economic burdens in the society and has been shown to increase in recent decades. The symptoms that define depression are melancholic mood, loss of interest in previously enjoyable activities, loss of joy and loss of energy (greater fatigue than usual). More serious symptoms are thoughts of death and eventually even suicide. The pathophysiology is complicated and not yet fully understood. One of the hypotheses is the monoamine hypothesis, which states that the concentrations of serotonin, dopamine and norepinephrine are depleted in depressed patients and that this is the reason why antidepressant drugs work to many people. Another hypothesis states the role of neuroplasticity (e.g., neurogenesis) in depression. Neuroplasticity can be stimulated by various neurotrophins (e.g., BDNF, Brain derived neurotrophic factor) which in turn have been shown to be stimulated by physical activity. The stimulation of neuroplasticity in some regions in the brain (e.g., hippocampus) leads to antidepressant effects.  The purpose of the work was to, based on literature studies, investigate whether mild to moderate depression can be treated with physical activity as alternative treatment instead of antidepressant drugs. This literature study is based on articles from the databases PubMed.  A total of four studies have been reviewed and were Randomized controlled trial (RCT)- studies comparing physical activity with antidepressant drugs. All studies showed a clear reduction in depressive symptoms in participants who exercised. Exercise has been shown to have similar effects as drug use. The advantages of exercise compared to drug use include fewer side effects, no drug-drug interactions and additional health benefits. The disadvantage is poorer compliance and added costs of group training or help from professional staff.  The conclusion that is drawn is that exercise could very well be offered as an alternative to treatment and has promising conditions. However, additional larger studies with more statistically significant results examining the difference between physical activity and antidepressant drugs should be done as well as studies that provide a better understanding of the pathophysiology which in turn could lead to better treating options. / Depression är en mycket vanlig folksjukdom som kan leda till både social och ekonomisk börda i samhället och har visats öka de senaste decennierna. Symtomen som definierar depression är sänkt grundstämning med onormal nedstämdhet, intresseförlust, glädjeförlust och energiförlust (större uttröttbarhet än vanligt). Mer allvarliga symtom är tankar på död och självmord. Patofysiologin är komplicerad och ännu inte helt klarlagd. En av hypotesen är monoaminohypotesen, och går ut på att koncentrationerna av serotonin, dopamin och noradrenalin är uttömda hos deprimerade patienter samt att det är orsaken till att antidepressiva läkemedel fungerar hos många. En annan hypotes är neuroplasticitetens (bl.a. neurogenes) roll i depressionen. Neuroplasticiteten kan stimuleras av olika neurotrofiner (BDNF) som i sin tur har visats stimuleras av fysisk aktivitet. Denna stimulering ger upphov till antidepressiva effekter. Syftet med arbetet var att, baserat på litteraturstudier, undersöka om mild till måttlig depression kan behandlas med fysisk aktivitet som alternativbehandling istället för antidepressiva läkemedel. Denna litteraturstudie var baserad på artiklar från databaserna PubMed. Fyra studier hade sammanlagt granskats, där dessa var RCT-studier som jämförde fysisk aktivitet med antidepressiva läkemedel. Samtliga studier visade en tydlig minskning av depressiva symtom hos deltagare som tränat. Träning har även visats ge liknande effekter som läkemedelsanvändning. Fördelarna med träning jämfört med läkemedelsanvändning är bl.a. färre biverkningar, inga läkemedel-läkemedel interaktioner samt fler hälsofördelar. Nackdelen är sämre följsamhet och eventuella kostnader vid gruppträning eller hjälp från professionell personal. Slutsatsen som dras är att träning mycket väl skulle kunna erbjudas som en alternativbehandling då det har visats ge likvärdiga effekter som antidepressiva läkemedel. Fler större studier med fler statistiskt signifikanta resultat som undersöker skillnaden mellan fysisk aktivitet och antidepressiva läkemedel bör dock göras, samt studier som ger bättre förståelse för patofysiologin.

Exercise alone is an efficacious intervention for depression, but few studies have identified the benefits of using exercise to augment other psychosocial treatments. The purpose of the current series of studies was to examine the feasibility, acceptability, efficacy, and potential mechanism of the augmentation of behavioral activation (BA) with exercise. The starting point for this series was a meta-analysis of the strength and reliability of brain-derived neurotrophic factor (BDNF) as a putative mechanism of the mood and cognitive effects of exercise. Evaluating 29 studies, I found: (1) a moderate effect for BDNF increases following acute exercise, (2) a moderate effect for the intensification of this effect following a program of exercise, and (3) a small effect on resting BDNF following a program of exercise. Given these effects, I hypothesized that exercise added to BA would improve mood beyond that for BA combined with a control condition and that changes in BDNF would mediate these effects. In a clinical trial, 32 sedentary, depressed patients received 9 sessions of BA over 12 weeks and were randomized to receive an exercise or control (stretching) augmentation. Assessments of depression, quality of life, distress intolerance, perceived stress, cognition (memory, attention), and amount of exercise were conducted across the treatment period. Results demonstrated strong credibility ratings and completion rates comparable to other exercise interventions. The randomized treatment failed to lead to differential exercise between groups; all participants exercised more over time. Similarly, participants, regardless of condition, significantly improved on all outcome measures over time. BDNF significantly increased following acute exercise. However, the amount of exercise completed over time was not significantly related to changes in BDNF across acute episodes, nor did resting BDNF significantly improve over time. Nonetheless, effect sizes for these changes were in the moderate range, reflecting values for the literature as a whole. Finally, contrary to my hypothesis, BDNF changes were not associated with subsequent improvement in depression symptoms. Results from this trial raise questions whether BA may be a powerful enough intervention to increase exercise, thus explicit exercise prescriptions may not be necessary for patients receiving this intervention.

Early life stress has been found to be a strong predictor of depression severity, with genetic risk factors such as the serotonin transporter promotor (5-HTTLPR) and brain derived neurotrophic factor (BDNF) polymorphisms moderating depression development. Our investigation aims to extend these findings to examine the impact of depression severity, genetic risk factors, and childhood maltreatment on neuronal connectivity changes using tract based spatial statistics (TBSS) and probabilistic tractography. Fifty-five medication-free patients with major depressive disorder (MDD) [x̅ age: 36.4, M/F: 22/33] and 18 controls [x̅ age: 33.2, M/F: 8/10] underwent diffusion tensor imaging scanning, genotyping and completed the Childhood Trauma Questionairre. Corrected TBSS findings revealed trends toward significantly reduced FA in the right anterior internal capsule [p=0.051], fornix [p=0.085] and right anterior corona radiata [p=0.084] in the MDD group. Probabilistic tractography analysis examined fractional anisotropy (FA) in the cingulum bundle, uncinate fasciculus and superior longitudinal fasciculus. Individuals scoring high in depression severity and who experienced severe childhood physical neglect (PN) and emotional neglect (EN) had higher FA in the uncinate [PN: p=0.003, EN: p=0.029] and superior longitudinal fasciculus [PN: p=0.0748], with BDNF and 5-HTTLPR moderating these associations. BDNF polymorphisms also exhibited a stronger impact on uncinate FA in individuals with high depression severity, with val-BDNF exhibiting higher FA than met carriers [p=0.021]. In conclusion, MDD patients exhibit widespread decreases in FA across many neural regions. Furthermore, the impact that depression severity has on FA is considerably influenced by early life neglect. / Thesis / Master of Science (MSc)

Background: Adenosine A2a receptors form a mutually inhibitory heteromeric complex with dopamine D2 receptors such that each receptor exhibits lower sensitivity to its agonist after the opposing receptor agonist is bound. This study analyzed the effects of CGS 21680, an adenosine A2A agonist, on nicotine conditioned place preference (CPP) in adolescence using a rodent model of schizophrenia (SZ). Methods: Rats were treated from postnatal day (P) 1 to P21 with saline or the dopamine D2/D3 agonist quinpirole (NQ treatment) and raised to P41. After an initial preference test, rats were conditioned with saline or nicotine (0.6 mg/kg base) from P43 to P51. CGS 21680 (0.03 or 0.09 mg/kg) was given 15 minutes before nicotine was administered. The post-conditioning test was administered on P52. On P53, the nucleus accumbens (NAcc) was analyzed for brain-derived neurotrophic factor (BDNF) and glial cell-lined neurotrophic factor (GDNF). Results: Results revealed that NQ treatment enhanced nicotine CPP, and both doses of CGS 21680 alleviated this enhancement. Nicotine also resulted in a CPP in controls, which was alleviated by both doses of CGS 21680. BDNF closely followed the behavioral results: CGS 21680 alleviated the enhancement in NAcc BDNF in NQ-treated animals, and eliminated the increase in NAcc BDNF produced by nicotine in controls. NQ-treated animals conditioned to nicotine resulted in an increase of NAcc GDNF, but this was eliminated by CGS 21680. Both BDNF and GDNF correlated with CPP performance. Conclusions: Results revealed that an adenosine A2A agonist decreased the rewarding aspects of nicotine and its accompanying neural plasticity changes in a model of SZ.

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