Neuroglial ATP release through innexin channels controls microglial cell movement to a nerve injury

Microglia, the immune cells of the central nervous system, are attracted to sites of injury. The injury releases adenosine triphosphate (ATP) into the extracellular space, activating the microglia, but the full mechanism of release is not known. In glial cells, a family of physiologically regulated unpaired gap junction channels called innexons (invertebrates) or pannexons (vertebrates) located in the cell membrane is permeable to ATP. Innexons, but not pannexons, also pair to make gap junctions. Glial calcium waves, triggered by injury or mechanical stimulation, open pannexon/innexon channels and cause the release of ATP. It has been hypothesized that a glial calcium wave that triggers the release of ATP causes rapid microglial migration to distant lesions. In the present study in the leech, in which a single giant glial cell ensheathes each connective, hydrolysis of ATP with 10 U/ml apyrase or block of innexons with 10 µM carbenoxolone (CBX), which decreased injury-induced ATP release, reduced both movement of microglia and their accumulation at lesions. Directed movement and accumulation were restored in CBX by adding ATP, consistent with separate actions of ATP and nitric oxide, which is required for directed movement but does not activate glia. Injection of glia with innexin2 (Hminx2) RNAi inhibited release of carboxyfluorescein dye and microglial migration, whereas injection of innexin1 (Hminx1) RNAi did not when measured 2 days after injection, indicating that glial cells’ ATP release through innexons was required for microglial migration after nerve injury. Focal stimulation either mechanically or with ATP generated a calcium wave in the glial cell; injury caused a large, persistent intracellular calcium response. Neither the calcium wave nor the persistent response required ATP or its release. Thus, in the leech, innexin membrane channels releasing ATP from glia are required for migration and accumulation of microglia after nerve injury

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

Abstract There is emerging evidence of the beneficial role of the melatonin system in a wide range of psychiatric and neurologic disorders, including anxiety, depression, and epilepsy. Although melatoninergic drugs have chronobiotic and antioxidant properties that positively influence circadian rhythm desynchronization and neuroprotection in neurodegenerative disorders, studies examining the use of melatonin for epilepsy's comorbid psychiatric and neurological symptomatology are still limited. Preclinical and clinical findings on the beneficial effects of the melatonin system on anxiety, depression, and epilepsy suggest that melatoninergic compounds might be effective in treating comorbid behavioral complications in epilepsy beyond regulation of a disturbed sleep-wake cycle

On the scalability and security of distributed multiplayer online games

Multiplayer Online Games (MOGs) are an extremely popular online technology, one that produces billions of dollars in revenues. Yet, providing scalable, fast, and cheat-resistant games is challenging. In this thesis we propose solutions to some of these challenges.The underlying architecture plays a crucial role in enabling the games to meet the scalability, response time, and low cost requirements that are of utmost importance in designing a successful massively multiplayer online game. Peer-to-peer architectures where the game runs exclusively on client machines, and hybrid approaches, where some tasks run on the clients while a central server controls other aspects, have, due to their distributed and collaborative nature, low infrastructure costs, and can achieve high scalability. They can also achieve fast response times by creating direct connections between players. However, they introduce their own challenges such as cheating. As one contribution of this thesis, we provide a comprehensive overview of current peer-to-peer and hybrid solutions for massively multiplayer games using a uniform terminology.Most of the solutions we studied fail to meet one of the following main requirements: (1) fast response time, (2) scalability, (3) cheat-resistance. This thesis makes several proposals that address these requirements: Watchmen, mobile security, AntReckoning, and AntAI.Watchmen is the first distributed scalable protocol designed with cheat detection and prevention in mind that supports fast paced games. It is based on a randomized dynamic proxy scheme for both the dissemination and verification of actions. We show that Watchmen, while scaling to hundreds of players and meeting the tight latency requirements of first person shooter games, is able to significantly reduce opportunities to cheat, even in the presence of collusion. In the context of cheating we also look at the fast rising genre of mobile games. We discuss existing and potential new avenues of cheating that can occur in such mobile environment, and suggest several solutions to improve security based on existing and novel services that are or can be offered by carriers, ecosystems, and developers.AntReckoning is a dead-reckoning algorithm, inspired from ant colonies, which models players' interests to predict their movements. It helps our architecture by allowing us to send updates at lower frequencies and with more accurate predictions which in turn improves the scalability and the quality of experience of the players. AntReckoning incorporates a player's interest in specific locations, objects, and avatars in the equations of motion in the form of attraction forces. In practice, these points of interest generate pheromones, which spread and fade in the game world, and are a source of attraction. AntReckoning greatly improves the accuracy of traditional dead reckoning techniques and can decrease the upload bandwidth by up to a third of overall traffic.Interest modeling can also be used to improve the performance of non-player characters in games. In our AntAI project, we detail how movements, interactions, use of items, and relying on static decision-making schemes result in markedly different behaviors from humans in a popular fist-person shooter game. From there, we propose a framework relying on our pheromone maps, which can lead to a more adaptive human-like behavior.Altogether, this thesis presents components that we believe are key elements for a scalable, cheat-resistant, and fast multiplayer online game architecture.Les jeux multijoueurs en ligne constituent à l’heure actuelle une technologie en ligne très populaire qui génère des milliards de dollars en revenus. En dépit de cela, offrir des jeux qui sont à la fois extensibles, rapides et résistants à la tricherie est toujours un défi. Dans cette thèse, nous proposons des solutions à certains de ces défis.L’architecture sous-jacente joue un rôle crucial lorsque l’on souhaite développer des jeux qui rencontrent des contraintes d’extensibilité, de faible temps de réponse et de faible coût. Ces contraintes sont d’une importance capitale si l’on souhaite que le jeu massivement multijoueurs en ligne ainsi développé devienne un succès. Les architectures pair-à-pair, où le jeu s’exécute uniquement sur les machines des clients (joueurs), ainsi que les approches hybrides, où certaines tâches du jeu s’exécutent sur les machines des clients tandis qu’un serveur central gère d’autres aspects du jeu, permettent, de par leur nature distribuée et collaborative, d’atteindre une haute extensibilité tout en minimisant les coûts d’infrastructure. Ces architectures permettent également d’atteindre des temps de réponse élevés en établissant des connexions directes entre les joueurs. Cependant, elles introduisent également certains défis à résoudre tels que la possibilité de tricher. En tant que contribution à cette thèse, nous exposons une vue d’ensemble exhaustive des solutions pair-à-pair et hybrides courantes pour les jeux massivement multijoueurs en ligne utilisant une technologie uniforme.La plupart des solutions que nous avons étudié ne respectent pas l’une des exigences principales suivantes: (1) temps de réponse rapide, (2) extensibilité, (3) résistance à la tricherie. Cette thèse décrit les différents projets sur lesquels nous avons travaillé qui visent à mettre en oeuvre ces exigences: Watchmen, sécurité mobile (mobile security), AntReckoning et AntAI.Watchmen est le premier protocole extensible et distribué conçu spécifiquement pour la détection et la prévention de la tricherie qui prend en charge les jeux à rythme rapide (fast-paced). Ce protocole est basé sur un schéma d’assignation dynamique aléatoire de noeuds-relais (proxie) pour effectuer tant la dissémination que la vérification des actions. Nous démontrons que Watchmen est en mesure de réduire de manière significative les possibilités de tricherie, même en présence de collusion et ce, tout en prenant en charge des centaines de joueurs et en rencontrant les exigences strictes de latence imposées par les jeux de tirs à la première personne. Dans le contexte de la tricherie, nous nous attardons également aux jeux mobiles. Nous discutons des possibilités existantes et des nouvelles avenues potentielles de tricherie qui peuvent survenir dans des environnements mobiles et nous suggérons différentes solutions pour améliorer la sécurité. Ces solutions sont basées sur des services existants ou nouveaux qui sont ou qui pourrait être offerts par les opérateurs, écosystèmes et développeurs.AntReckonning est un algorithme de navigation à l’estime (dead-reckoning) inspiré des colonies de fourmis qui modèle les intérêts des joueurs pour prédire leurs mouvements. Ce modèle est bénéfique pour notre architecture puisqu’il nous permet de transmettre les mises à jour à des fréquences inférieures et avec des prédictions plus précises, ce qui permet d’améliorer l’extensibilité et la qualité de l’expérience des joueurs. AntReckoning incorpore l’intérêt des joueurs pour des emplacements, objets et avatars spécifiques au sein d’équations de mouvement en tant que forces d’attraction. En pratique, ces points d’intérêt génèrent des phéromones qui se diffusent et s’estompent dans le monde virtuel du jeu et qui sont des sources d’attraction. AntReckoning améliore de manière significative la précision des techniques de navigation à l’estime traditionnelles et peut réduire la bande passante de téléversement (upload) jusqu’à concurrence de un tiers du trafic total

Response Acquisition and Fixed-Ratio Escalation Based on Interresponse Times in Rats

The effectiveness of a fixed-ratio (FR) escalation procedure, developed by Pinkston and Branch (2004) and based on interresponse times (IRTs), was assessed during lever-press acquisition. Forty-nine experimentally naïve adult male Long Evans rats were deprived of food for 24 hr prior to an extended acquisition session. Before the start of the session, three food pellets were placed in the magazine. Otherwise, no magazine training, shaping, nor autoshaping procedure was employed. The first 20 presses each resulted in the delivery of a 45-mg food pellet. Then, the FR increased (2, 4, 8, 11, 16, 20, 25, 30) when each IRT in the ratio was less than 2 s during three consecutive ratios. Sessions lasted 13 hr or until 500 pellets were earned. On average, rats reached a terminal ratio of 11 (mean) or 16 (median) during the first session. Seven rats reached the maximum value of FR 30 and only one rat did not acquire the response. In most rats, a break-and-run pattern of responding characteristic of FR schedules began to develop in this acquisition session. Subsequently, the ratio-escalation procedure continued during daily 2-hr sessions. In these sessions, the starting ratio requirement was set at the terminal ratio reached in the previous session. Using this procedure, over half (26) of the rats reached the FR 30 requirement by the fourth session. These data demonstrate that a ratio-escalation procedure based on IRTs provides a time-efficient way of establishing ratio responding