Conception et évaluation de nouvelles méthodes pour améliorer les performances des réseaux de nano-communication

Abstract : The field of nanotechnology has undergone very rapid and fascinating development in recent years. This rapid and impressive advance has led to new applications of nanotechnology in the biomedical and military industries, making it a key area of research in multidisciplinary fields. However, the individual processing capacity of nanodevices is very limited, hence the need to design nanonetworks that allow the nanodevices to share information and to cooperate with each other. There are two solutions to establish a nanocommunication system: either by adapting the classical electromagnetic communication to the requirements of nano scale, or by using biological nanosystems inspired by nature such as the molecular communication proposed in the literature. In this thesis, we are interested in the second solution, which is exploiting the potential of biological nanosystems used by nature since billions of years to design biocompatible nanonetworks that can be used inside the human body for medical applications. Nevertheless, the use of this new paradigm is not without challenges. The very low achievable throughput and the Inter-Symbol Interference (ISI) are the most influential problems on the quality of molecular communication. The main objective of this thesis is to design and evaluate new methods inspired by nature in order to enhance the performance of nano-communication systems. To do this, the work is divided into three main parts. In the first part, we enhance the performance of molecular communication by proposing a new method that uses a photolysis-reaction instead of using enzyme to better attenuate ISI. We also propose an optimization of the receiver used in MIMO systems by judiciously choosing the parameters used in its design to reduce the influence of path loss on the quality of the system. The second part proposes a new wired nano-communication system based on self-assembled polymers that build an electrically conductive nanowire to connect the nanodevices to each other. The use of electrons as information carriers drastically increases the achievable throughput and reduces the delay. We study the dynamic process of self-assembly of the nanowire and we propose a bio-inspired receiver that detects the electrons sent through the conductive nanowire and converts them into a blue light. The third part applies the proposed wired nano-communication system to design an architecture ofWired Ad hoc NanoNETworks (WANNET) with a physical layer, Medium Acess Control (MAC) layer and application layer. We also calculate the maximum throughput and we evaluate the performance of the system.Le domaine des nanotechnologies a connu un développement très rapide et fascinant ces dernières années. Cette avancée rapide et impressionnante a conduit à de nouvelles applications dans les industries biomédicale et militaire, ce qui en fait un champ clé de recherche dans des domaines multidisciplinaires. Cependant, la capacité de traitement individuelle des nanodispositifs est très limitée, d'où la nécessité de concevoir des nanoréseaux qui permettent aux nanodispositifs de partager des informations et de coopérer entre eux. Il existe deux solutions pour mettre en place un système de nano-communication: soit en adaptant la communication électromagnétique classiques aux exigences de la nano échelle, soit en utilisant des nanosystèmes inspirés de la nature comme la communication moléculaire. Dans cette thèse, nous nous intéressons à la deuxième solution, qui exploite le potentiel des nanosystèmes biologiques utilisés par la nature depuis des milliards d'années pour concevoir des nanoréseaux biocompatibles pouvant être utilisés à l'intérieur du corps humain pour des applications médicales. Néanmoins, l'utilisation de ce nouveau paradigme n'est pas sans défis. Le très faible débit réalisable et l'Interférence Entre Symboles (IES) sont les problèmes les plus influents sur la qualité de la communication moléculaire. L'objectif principal de cette thèse est de concevoir et d'évaluer de nouvelles méthodes inspirées de la nature afin d'améliorer les performances des systèmes de nano-communication. Pour ce faire, le travail est divisé en trois parties principales. Dans la première partie, nous améliorons les performances de la communication moléculaire en proposant une nouvelle méthode qui utilise une réaction de photolyse pour mieux atténuer l'IES. Nous proposons également une optimisation du receveur utilisé dans les systèmes MIMO en choisissant judicieusement les paramètres utilisés dans sa conception pour réduire l'influence de l'atténuation de trajet sur la qualité du système. La deuxième partie propose un nouveau système de nano-communication filaire basé sur des polymères auto-assemblés qui construisent un nanofil électriquement conducteur pour connecter les nanodispositifs les uns aux autres. L'utilisation d'électrons comme supports d'informations augmente considérablement le débit réalisable et réduit le délai. Nous étudions le processus dynamique d'auto-assemblage du nanofil et nous proposons un receveur bio-inspiré qui détecte les électrons envoyés et les convertit en une lumière bleue. La troisième partie applique le système de nano-communication filaire proposé pour concevoir une architecture d'un nanoréseau ad hoc filaire (Wired Ad hoc NanoNETworks) WANNET avec une couche physique, une couche de contrôle d'accès moyen (Medium Access Control) MAC et une couche d'application. Nous calculons également le débit maximum et nous évaluons les performances du système

Toward a Wired Ad Hoc Nanonetwork

Nanomachines promise to enable new medical applications, including drug delivery and real time chemical reactions' detection inside the human body. Such complex tasks need cooperation between nanomachines using a communication network. Wireless Ad hoc networks, using molecular or electromagnetic-based communication have been proposed in the literature to create flexible nanonetworks between nanomachines. In this paper, we propose a Wired Ad hoc NanoNETwork (WANNET) model design using actin-based nano-communication. In the proposed model, actin filaments self-assembly and disassembly is used to create flexible nanowires between nanomachines, and electrons are used as carriers of information. We give a general overview of the application layer, Medium Access Control (MAC) layer and a physical layer of the model. We also detail the analytical model of the physical layer using actin nanowire equivalent circuits, and we present an estimation of the circuit component's values. Numerical results of the derived model are provided in terms of attenuation, phase and delay as a function of the frequency and distances between nanomachines. The maximum throughput of the actin-based nanowire is also provided, and a comparison between the maximum throughput of the proposed WANNET, vs other proposed approaches is presented. The obtained results prove that the proposed wired ad hoc nanonetwork can give a very high achievable throughput with a smaller delay compared to other proposed wireless molecular communication networks.Comment: submitted to IEEE International Conference on Communications 2020 (ICC 2020

The Role of Hippocampal and Medial Prefrontal Interactions in the Estrogenic Regulation of Memory

Dendritic spine plasticity is thought to be essential for the formation and storage of memories. The sex-steroid hormone 17-estradiol (E2) increases dendritic spine density in 2 brain regions necessary for memory formation, the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC), but the mechanisms through which it does so remain largely unknown. Further, the extent to which these brain regions interact to mediate E2’s effects on memory is also unclear. Recently, we found that infusion of E2 directly into the DH also increases dendritic spine density in the DH and mPFC, and that these effects depend upon rapid activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) cell-signaling pathways in the DH (Tuscher et al., 2016). These intriguing findings highlighted a previously unexplored interaction between the DH and mPFC that may have important implications for understanding how E2 regulates memory. As such, these data led us to question what the role of the mPFC is during object memory formation, and whether interactions between the DH and mPFC are necessary for the E2-induced memory enhancements we have previously observed in our object memory tasks (Fernandez et al., 2008, Boulware et al., 2013, Fortress et al., 2013). Therefore the overall goal of the dissertation was to examine the role of the DH and mPFC in object memory consolidation both in the presence and absence of exogenous E2 infusions, and to examine how E2 regulates spine density changes in these regions, which may ultimately strengthen the synaptic connections involved in the formation of such memories. To this end, we first utilized inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inactivate the DH, the mPFC, or both brain regions simultaneously immediately after novel object training to assess the role of each of these regions individually and in combination during object memory consolidation. Next, we asked whether E2 can act directly in the mPFC to enhance object memory consolidation and increase spine density in the mPFC and DH. Finally, we combined DREADD-mediated inhibition of the mPFC with direct infusion of E2 into the DH to examine whether DH-mPFC interactions are necessary for the beneficial mnemonic effects of DH infused E2. Our results collectively suggest that individual and simultaneous activation of both the DH and mPFC is required for the successful consolidation of object recognition and spatial memories. We also found that infusion of E2 directly into the mPFC increases mPFC apical spine density and facilitates object memory consolidation. Finally, we demonstrate that activation of the mPFC is necessary for the memory-enhancing effects of DH-infused E2. Together, these studies provide critical insight into how the DH and mPFC work in concert to facilitate E2-mediated memory enhancement in female mice. Further, this work will enable future studies investigating circuit and cellular-level questions regarding how E2 mediates cognition across the lifespan

Dopamine and the Temporal Dependence of Learning and Memory

Animal behavior is largely influenced by the seeking out of rewards and avoidance of punishments. Positive or negative reinforcements, like a food reward or painful shock, impart meaningful valence onto sensory cues in the animal’s environment. The ability of animals to form associations between a sensory cue and a rewarding or punishing reinforcement permits them to adapt their future behavior to maximize reward and minimize punishments. Animals rely on the timing of events to infer the causal relationships between cues and outcomes –– sensory cues that precede a painful shock in time become associated with its onset and are imparted with negative valence, whereas cues that follow the shock in time are instead associated with its cessation and imparted with positive valence. While the temporal requirements for associative learning have been well characterized at the behavioral level, the molecular and circuit mechanisms for this temporal sensitivity remain incompletely understood. Using the simple architecture of the mushroom body, an olfactory associative learning center in Drosophila, I examined how the relative timing of olfactory inputs and dopaminergic reinforcement signals is encoded at the molecular, synaptic, and circuit level to give rise to learned odor associations. I show that in Drosophila, opposing olfactory associations can be formed and updated on a trial-by-trial basis depending on the temporal relationship between an odor cue and dopaminergic reinforcement during conditioning. Additionally, both negative and positive reinforcements equivalently instruct appetitive and aversive olfactory associations –– odors preceding a negative reinforcement or following a rewarding reinforcement acquire an aversive valence, while odors instead following a negative reinforcement or preceding a rewarding reinforcement become attractive. Furthermore, functional imaging revealed that synapses within the mushroom body are bidirectionally modulated depending on the temporal ordering of odor and dopaminergic reinforcement, leading to synaptic depression when an odor precedes dopaminergic activity or synaptic facilitation when dopaminergic activity instead precedes an odor. Through the synchronous recording of neural activity and behavior, I found that the bidirectional regulation of synaptic transmission within the mushroom body directly correlates with the emergence of learned olfactory behaviors. This temporal sensitivity arises from two dopamine receptors, DopR1 and DopR2, that couple to distinct second-messengers and direct either synaptic depression or potentiation. Loss of either receptor renders the synapses of the mushroom body capable of only unidirectional plasticity and prevents the behavioral flexibility of writing opposing associations depending on the temporal structure of conditioning. Together, these results reveal how the distinct intracellular signaling pathways of two dopamine receptors can detect the order of events within an associative learning circuit to instruct opposing forms of synaptic and behavioral plasticity, providing a mechanism for animals to use both the onset and offset of a reinforcement signal to instruct distinct associations. Additionally, this bidirectional modulation allows animals to flexibly update olfactory associations on a trial-bytrial basis when temporal relationships are altered, permitting them to contend with a complex and changing sensory world

Characterization of Ambra1 heterozygous mice as genetic mouse model of female-specific autism

Autism is known as a heritable neurodevelopmental disorder, diagnosed prior to the age of three years in humans based on three major domains: (1) impairment in social interaction (2) communication deficits (3) restricted interests and repetitive behaviors. Since it is a very heterogeneous disorder with various causes and different combinations of phenotypes, it is also called autism spectrum disorder (ASD). Monogenic heritable forms of ASD enable us to develop genetic mouse models of autism in order to obtain mechanistic insight in this disorder. Ambra1 is a positive regulator of Beclin1, a major player in the formation of autophagosomes during the process of autophagy. While Ambra1 null mutation leads to embryonic lethality, we could show that Ambra1 heterozygous mice (Ambra1+/-) display autism-like behavior only in females. Purpose of this thesis was therefore to characterize this mouse line further. It turned out that communication deficits, measured by ultrasound vocalization, start in the neonatal stage of females, while physical or neurological development is normal in Ambra1+/-. Female Ambra1 mutants had a stronger reduction in Ambra1 expression than male mutants, which gives first hints of the female-specific autism-like behavior in this mouse line. Mild enlargement of whole brain and hippocampus was detected in both Ambra1+/- males and females, with no change of ventricle size. Since β-galactosidase, used as reporter expressed under the Ambra1 promoter, was found only in neuronal cells, I focused on understanding the neural mechanism of its phenotype. Short-term and long-term synaptic plasticity in the hippocampus was normal for males and females of both genotypes. However, the power of gamma oscillations (γ-power), indicative of change in the balance of excitation and inhibition, was age-dependently altered in Ambra1+/- females only. However, this difference was not detected in male. Moreover, increased susceptibility to seizures, a known comorbid condition of ASD was restricted to females, suggesting an association between autism-like behavior, gamma oscillation and seizure propensity in female Ambra1+/- mice. Next, I approached the neuronal substrate of these three phenotypes by morphological analysis of hippocampal pyramidal neurons, such as dendritic arborization and synapse number. A genotype-associated difference of dendritic arborization was detected in neither males nor females. The quantification of spines or synapses and cellular electrophysiology are still on-going. First signals point to an imbalance between excitation and inhibition as a cause of the female autism-like behavior in Ambra1+/- mice

Characterization of Ambra1 heterozygous mice as genetic mouse model of female-specific autism

Autism is known as a heritable neurodevelopmental disorder, diagnosed prior to the age of three years in humans based on three major domains: (1) impairment in social interaction (2) communication deficits (3) restricted interests and repetitive behaviors. Since it is a very heterogeneous disorder with various causes and different combinations of phenotypes, it is also called autism spectrum disorder (ASD). Monogenic heritable forms of ASD enable us to develop genetic mouse models of autism in order to obtain mechanistic insight in this disorder. Ambra1 is a positive regulator of Beclin1, a major player in the formation of autophagosomes during the process of autophagy. While Ambra1 null mutation leads to embryonic lethality, we could show that Ambra1 heterozygous mice (Ambra1+/-) display autism-like behavior only in females. Purpose of this thesis was therefore to characterize this mouse line further. It turned out that communication deficits, measured by ultrasound vocalization, start in the neonatal stage of females, while physical or neurological development is normal in Ambra1+/-. Female Ambra1 mutants had a stronger reduction in Ambra1 expression than male mutants, which gives first hints of the female-specific autism-like behavior in this mouse line. Mild enlargement of whole brain and hippocampus was detected in both Ambra1+/- males and females, with no change of ventricle size. Since β-galactosidase, used as reporter expressed under the Ambra1 promoter, was found only in neuronal cells, I focused on understanding the neural mechanism of its phenotype. Short-term and long-term synaptic plasticity in the hippocampus was normal for males and females of both genotypes. However, the power of gamma oscillations (γ-power), indicative of change in the balance of excitation and inhibition, was age-dependently altered in Ambra1+/- females only. However, this difference was not detected in male. Moreover, increased susceptibility to seizures, a known comorbid condition of ASD was restricted to females, suggesting an association between autism-like behavior, gamma oscillation and seizure propensity in female Ambra1+/- mice. Next, I approached the neuronal substrate of these three phenotypes by morphological analysis of hippocampal pyramidal neurons, such as dendritic arborization and synapse number. A genotype-associated difference of dendritic arborization was detected in neither males nor females. The quantification of spines or synapses and cellular electrophysiology are still on-going. First signals point to an imbalance between excitation and inhibition as a cause of the female autism-like behavior in Ambra1+/- mice