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Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT.In vitroapplication of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

International audience; Warfare neurotoxicants such as sarin, soman or VX, are organophosphorus compounds which irreversibly inhibit cholinesterase. High-dose exposure with nerve agents (NA) is known to produce seizure activity and related brain damage, while less is known about the effects of acute sub-lethal dose exposure. The aim of this study was to characterize behavioral, brain activity and neuroinflammatory modifications at different time points after exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. In order to decipher the impacts of sub-lethal exposure, we chose 4 different doses of NIMP each corresponding to a fraction of the median lethal dose (LD50). First, we conducted a behavioral analysis of symptoms during the first hour following NIMP challenge and established a specific scoring scale for the intoxication severity. The intensity of intoxication signs was dose-dependent and proportional to the cholinesterase activity inhibition evaluated in mice brain. The lowest dose (0.3 LD50) did not induce significant behavioral, electrocorticographic (ECoG) nor cholinesterase activity changes. Animals exposed to one of the other doses (0.5, 0.7 and 0.9 LD50) exhibited substantial changes in behavior, significant cholinesterase activity inhibition, and a disruption of brainwave distribution that persisted in a dose-dependent manner. To evaluate long lasting changes, we conducted ECoG recording for 30 days on mice exposed to 0.5 or 0.9 LD50 of NIMP. Mice in both groups showed long-lasting impairment of theta rhythms, and a lack of restoration in hippocampal ChE activity after 1-month post-exposure. In addition, an increase in neuroinflammatory markers (IBA-1, TNF-α, NF-κB) and edema were transiently observed in mice hippocampus. Furthermore, a novel object recognition test showed an alteration of short-term memory in both groups, 1-month post-NIMP intoxication. Our findings identified both transient and long-term ECoG alterations and some long term cognitive impairments following exposure to sub-lethal doses of NIMP. These may further impact morphopathological alterations in the brain.

This review intends to provide an overview of the current knowledge on neurologic sequelae of COVID-19 and their possible etiology, and, based on available data, proposes possible improvements in current medical care procedures. We conducted a thorough review of the scientific literature on neurologic manifestations of COVID-19, the neuroinvasive propensity of known coronaviruses (CoV) and their possible effects on brain structural and functional integrity. It appears that around one third of COVID-19 patients admitted to intensive care units (ICU) for respiratory difficulties exhibit neurologic symptoms. This may be due to progressive brain damage and dysfunction triggered by severe hypoxia and hypoxemia, heightened inflammation and SARS-CoV-2 dissemination into brain parenchyma, as suggested by current reports and analyses of previous CoV outbreaks. Viral invasion of the brain may particularly target and alter brainstem and thalamic functions and, consequently, result in sensorimotor dysfunctions and psychiatric disorders. Moreover, data collected from other structurally homologous CoV suggest that SARS-CoV-2 infection may lead to brain cell degeneration and demyelination similar to multiple sclerosis (MS). Hence, current evidence warrants further evaluation and long-term follow-up of possible neurologic sequelae in COVID-19 patients. It may be particularly relevant to evaluate brainstem integrity in recovered patients, as it is suspected that this cerebral area may particularly be dysfunctional following SARS-CoV-2 infection. Because CoV infection can potentially lead to chronic neuroinflammation and progressive demyelination, neuroimaging features and signs of MS may also be evaluated in the long term in recovered COVID-19 patients., Highlights • Acute neurologic symptoms are observed in one third of COVID-19 patients • Neurotropism of SARS-CoV-2 is highly suspected • Brainstem damage may be a crucial driver for COVID-19-associated respiratory failure • COVID-19 is likely to trigger demyelination similarly to multiple sclerosis • Monitoring patients using Auditory Brainstem Responses and neuroimaging is warranted

With millions of intoxications each year and over 200,000 deaths, organophosphorus (OP) compounds are an important public health issue worldwide. OP poisoning induces cholinergic syndrome, with respiratory distress, hypertension, and neuron damage that may lead to epileptic seizures and permanent cognitive deficits. Existing countermeasures are lifesaving but do not prevent long-lasting neuronal comorbidities, emphasizing the urgent need for animal models to better understand OP neurotoxicity and identify novel antidotes. Here, using diisopropylfluorophosphate (DFP), a prototypic and moderately toxic OP, combined with zebrafish larvae, we first showed that DFP poisoning caused major acetylcholinesterase inhibition, resulting in paralysis and CNS neuron hyperactivation, as indicated by increased neuronal calcium transients and overexpression of the immediate early genes fosab, junBa, npas4b, and atf3. In addition to these epileptiform seizure-like events, DFP-exposed larvae showed increased neuronal apoptosis, which were both partially alleviated by diazepam treatment, suggesting a causal link between neuronal hyperexcitation and cell death. Last, DFP poisoning induced an altered balance of glutamatergic/GABAergic synaptic activity with increased NR2B-NMDA receptor accumulation combined with decreased GAD65/67 and gephyrin protein accumulation. The zebrafish DFP model presented here thus provides important novel insights into the pathophysiology of OP intoxication, making it a promising model to identify novel antidotes.

Numerous toxic compounds, either from natural or synthetic origin, can promote seizures, cerebral damage, and sometimes epilepsy. Although most of the studies have been performed mainly to study the toxicological mechanisms and deduce successful treatments, these compounds can also serve to set up models of broader impact. The chapter will review different classes of toxicants, namely inhibitors of acetylcholinesterase (organophosphorus compounds and methyl carbamates), mitochondrial toxins, chemicals acting on amino-acid receptors, actin-binding toxins, natural toxins acting on sodium and potassium channels, and cocaine.

Backgroud Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction. Methods With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors. Results We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia. Conclusions These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC , miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.

Despite the fact that the neurotransmitter dopamine was discovered more than 50 years ago, we still have limited knowledge of its physiological and pathological roles. Recent work has unveiled novel and surprising properties of dopamine neurons and of other key players involved in regulating the dopamine system. For example, the integration of the dopamine signal by its receptors depends on many proteins of diverse signaling pathways and also of other types of receptors that interact with and regulate dopamine receptors: many new promising interactions have been reported during the past few years. Also, we are beginning to discover that chronic treatment with dopamine receptor ligands or other molecules affecting dopaminergic pathways induce long-term molecular, structural and functional rearrangements that could ultimately force us to revisit the mechanism of action of established therapeutic agents. Finally, the discovery of glutamate co-release by dopamine neurons is leading us to reconsider some keys aspects of dopamine neuron physiology.

Mesencephalic dopamine (DA) neurons have been suggested to use glutamate as a cotransmitter. Here, we suggest a mechanism for this form of cotransmission by showing that a subset of DA neurons both in vitro and in vivo expresses vesicular glutamate transporter 2 (VGluT2). Expression of VGluT2 decreases with age. Moreover, when DA neurons are grown in isolation using a microculture system, there is a marked upregulation of VGluT2 expression. We provide evidence that expression of this transporter is normally repressed through a contact-dependent interaction with GABA and other DA neurons, thus providing a partial explanation for the highly restricted expression of VGluT2 in DA neurons in vivo. Our results demonstrate that the neurotransmitter phenotype of DA neurons is both developmentally and dynamically regulated. These findings may have implications for a better understanding of the fast synaptic action of DA neurons as well as basal ganglia circuitry.

BACKGROUND: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. METHODS: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. RESULTS: Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. CONCLUSIONS: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Fil: Rocchett, Jill. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Isingrini, Elsa. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Dal Bo, Gregory. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Sagheby, Sara. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Menegaux, Aurore. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Tronche, François. Centre National de la Recherche Scientifique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia Fil: Levesque, Daniel. Université de Montréal. Département de Pharmacie; Canadá Fil: Moquin, Luc. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Gratton, Alain. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Wong, Tak Pan. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Giros, Bruno. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá. Centre National de la Recherche Scientifique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia

Dopamine neurons have been suggested to use glutamate as a cotransmitter. To identify the basis of such a phenotype, we have examined the expression of the three recently identified vesicular glutamate transporters (VGLUT1-3) in postnatal rat dopamine neurons in culture. We found that the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3. In comparison, serotonin neurons express only VGLUT3. Single-cell RT-PCR experiments confirmed the presence of VGLUT2 mRNA in dopamine neurons. Arguing for phenotypic heterogeneity among axon terminals, we find that only a proportion of terminals established by dopamine neurons are VGLUT2-positive. Taken together, our results provide a basis for the ability of dopamine neurons to release glutamate as a cotransmitter. A detailed analysis of the conditions under which DA neurons gain or loose a glutamatergic phenotype may provide novel insight into pathophysiological processes that underlie diseases such as schizophrenia, Parkinson's disease and drug dependence.

Despite the fact that the neurotransmitter dopamine was discovered more than 50 years ago, we still have limited knowledge of its physiological and pathological roles. Recent work has unveiled novel and surprising properties of dopamine neurons and of other key players involved in regulating the dopamine system. For example, the integration of the dopamine signal by its receptors depends on many proteins of diverse signaling pathways and also of other types of receptors that interact with and regulate dopamine receptors: many new promising interactions have been reported during the past few years. Also, we are beginning to discover that chronic treatment with dopamine receptor ligands or other molecules affecting dopaminergic pathways induce long-term molecular, structural and functional rearrangements that could ultimately force us to revisit the mechanism of action of established therapeutic agents. Finally, the discovery of glutamate co-release by dopamine neurons is leading us to reconsider some keys aspects of dopamine neuron physiology.

Coexpression of tyrosine hydroxylase (TH) and vesicular glutamate transporter 2 (VGLUT2) mRNAs in the ventral tegmental area (VTA) and colocalization of these proteins in axon terminals of the nucleus accumbens (nAcb) have recently been demonstrated in immature (15-day-old) rat. After neonatal 6-hydroxydopamine (6-OHDA) lesion, the proportion of VTA neurons expressing both mRNAs and of nAcb terminals displaying the two proteins was enhanced. To determine the fate of this dual phenotype in adults, double in situ hybridization and dual immunolabeling for TH and VGLUT2 were performed in 90-day-old rats subjected or not to the neonatal 6-OHDA lesion. Very few neurons expressed both mRNAs in the VTA and substantia nigra (SN) of P90 rats, even after neonatal 6-OHDA. Dually immunolabeled terminals were no longer found in the nAcb of normal P90 rats and were exceedingly rare in the nAcb of 6-OHDAlesioned rats, although they had represented 28% and 37% of all TH terminals at P15. Similarly, 17% of all TH terminals in normal neostriatum and 46% in the dopamine neoinnervation of SN in 6-OHDA-lesioned rats were also immunoreactive for VGLUT2 at P15, but none at P90. In these three regions, all dually labeled terminals made synapse, in contradistinction to those immunolabeled for only TH or VGLUT2 at P15. These results suggest a regression of the VGLUT2 phenotype of dopamine neurons with age, following normal development, lesion, or sprouting after injury, and a role for glutamate in the establishment of synapses by these neurons. J. Comp. Neurol. 517:873– 891, 2009.

A wide range of indirect data obtained during the last two decades has suggested that monoamine neurons may co-release neurotransmitters. Ultrastructural investigations have consistently reported that these neurons, including dopamine, serotonin and norepinephrine neurons establish both junctional (i.e. synaptic) and non-junctional (i.e. non-synaptic) axon terminals. The hypothesis that some of these terminals can mediate synaptic glutamate release has received strong support from cell culture studies as well as indirect support from electrophysiological recordings obtained in slice preparations and in intact animals. The molecular identification of vesicular glutamate transporters (VGluTs) in recent years has provided a new impetus and a new strategy to confirm the glutamatergic phenotype of neurons. A number of recent results now confirm that while many serotonin neurons express VGluT3, a subset of norepinephrine and dopamine neurons express VGluT2, thus supporting the hypothesis of glutamate co-transmission. The possibility that the neurotransmitter repertoire of central monoamine neurons may be plastic during development and in the context of activity-dependent neuronal plasticity or disease is now a major direction of current research.

There is solid electron microscopic data demonstrating the existence of dopamine (DA) axon terminals (varicosities) with or without synaptic membrane specializations (junctional complexes) in many parts of the CNS, and notably in neostriatum and nucleus accumbens. The dual morphological character of these DA innervations has led to the suggestion that the meso-telencephalic DA system operates by diffuse (or volume) as well as by classical synaptic transmission. In the last decade, electrophysiological and neurochemical evidence has also accumulated indicating that monoamine neurons in various parts of the CNS, and particularly the mesencephalic DA neurons, might release glutamate as a co-transmitter. Following the identification of the vesicular transporters for glutamate (VGluT), in situ hybridization and RT-PCR studies carried out on isolated neurons or standard tissue cultures, and more recently in vivo, have shown that VGluT2 mRNA may be expressed in a significant proportion of mesencephalic DA neurons, at least in the ventral tegmental area. A current study also suggests that the co-expression of tyrosine hydroxylase (TH) and VGluT2 by these neurons is regulated during embryonic development, and may be derepressed or reactivated postnatally following their partial destruction by neonatal administration of 6-hydroxydopamine (6-OHDA). In both 15 day-old and adult rats subjected or not to the neonatal 6-OHDA lesion, concurrent electron microscopic examination of the nucleus accumbens after dual immunocytochemical labeling for TH and VGluT2 reveals the co-existence of the two proteins in a significant proportion of these axon terminals. Moreover, all TH varicosities which co-localize VGluT2 are synaptic, as if there was a link between the potential of DA axon terminals to release glutamate and their establishment of synaptic junctions. Together with the RT-PCR and in situ hybridization data demonstrating the co-localization of TH and VGluT2 mRNA in mesencephalic neurons of the VTA, these observations raise a number of fundamental questions regarding the functioning of the meso-telencephalic DA system in healthy or diseased brain.

Background Microglia can adopt different morphologies, ranging from a highly ramified to an amoeboid-like phenotype. Although morphological properties of microglia have been described in rodents, little is known about their fine features in humans. The aim of this study was to characterize the morphometric properties of human microglia in gray and white matter of dorsal anterior cingulate cortex (dACC), a region implicated in behavioral adaptation to neuroinflammation. These properties were compared to those of murine microglia in order to gain a better appreciation of the differences displayed by these cells across species. Methods Postmortem dACC samples were analyzed from 11 individuals having died suddenly without any history of neuroinflammatory, neurodegenerative, nor psychiatric illness. Tissues were sectioned and immunostained for the macrophage marker Ionized calcium binding adaptor molecule 1 (IBA1). Randomly selected IBA1-immunoreactive (IBA1-IR) cells displaying features corresponding to commonly accepted microglial phenotypes (ramified, primed, reactive, amoeboid) were reconstructed in 3D and all aspects of their morphologies quantified using the Neurolucida software. The relative abundance of each morphological phenotype was also assessed. Furthermore, adult mouse brains were similarly immunostained, and IBA1-IR cells in cingulate cortex were compared to those scrutinized in human dACC. Results In human cortical gray and white matter, all microglial phenotypes were observed in significant proportions. Compared to ramified, primed microglia presented an average 2.5 fold increase in cell body size, with almost no differences in branching patterns. When compared to the primed microglia, which projected an average of six primary processes, the reactive and amoeboid phenotypes displayed fewer processes and branching points, or no processes at all. In contrast, the majority of microglial cells in adult mouse cortex were highly ramified. This was also the case following a postmortem interval of 43 hours. Interestingly, the morphology of ramified microglia was strikingly similar between species. Conclusions This study provides fundamental information on the morphological features of microglia in the normal adult human cerebral cortex. These morphometric data will be useful for future studies of microglial morphology in various illnesses. Furthermore, this first direct comparison of human and mouse microglia reveals that these brain cells are morphologically similar across species, suggesting highly conserved functions.

Acetylcholinesterases (AchE) are enzymes widely spread in the central nervous system (CNS) that allow the recycling of acetylcholine (Ach). The use of reversible/irreversible inhibitors of these enzymes prevents the degradation of Ach. Depending on the context of their use, AchE inhibitors can have a beneficial or detrimental impact on brain mechanisms. In the last decades, a class of irreversible AchE inhibitors considered as warfare nerve agents such as sarin gas have been used in various military conflicts and/or in several attacks against civilian populations. They cause an excessive accumulation of Ach in the SNC of people who have been in contact with them, which is considered as intoxication. The hyperexcitability of the CNS following intoxication generates a succession of symptoms that can be detected either in the short or long term, depending on the dose of the nerve agent. Studies following the Tokyo attacks in 1995 showed that even a low dose of toxic that did not cause the emergence of immediate symptoms was capable of generating cognitive disorders, particularly memory impairment, several years after exposure. However, the mechanisms underlying such disorders are still not well understood. AchE can also be used in a therapeutic context. Indeed, in Alzheimer's disease, a decrease in Ach levels are observed. Therefore, reversible AchE inhibitors such as Donepezil (DPZ) are used to maintain normal levels of Ach in the brain, thus allowing a proper brain functioning. The studies carried out in this thesis aimed to determine the effect of these AchE inhibitors on various brain mechanisms. The first study investigated the impact of high and low dose administration of an organophosphate (NIMP; analogue of sarin gas), an irreversible AchE inhibitor, on neuroinflammation using in vivo [¹⁸F]DPA-714 PET imaging. Longitudinal in vivo monitoring of neuroinflammation over several months allowed to identify a therapeutic window for neuroprotective treatment. For the second study a preclinical model of Alzheimer's disease (AD) was employed in order to evaluate in vivo the effects of Donepezil treatment on cerebral glucose metabolism using [¹⁸F]FDG PET. Various pathophysiological mechanisms (neuroinflammation, abnormal accumulation of misfolded proteins (AD)...) are associated with neurological diseases and may impact the blood-brain barrier (BBB) integrity. It is therefore essential to develop tools to quantify BBB permeability in vivo. In this context, a third project combining focused ultrasound and PET was set up in order to investigate the potential of [¹⁸F]FDS PET imaging as a quantitative biomarker of BBB integrity in vivo. In the course of this thesis, PET imaging allowed to investigate different brain functions (neuroinflammation, cerebral glucose metabolism, integrity of the BBB) in order to assess i) changes in brain mechanisms in a longitudinal manner, ii) a therapeutic follow-up and iii) validate a new biomarker., Les acétylcholinestérases (AchE) sont des enzymes largement distribuées au sein du système nerveux central (SNC) permettant le recyclage de l’acétylcholine (Ach). L’utilisation d’inhibiteurs réversibles/irréversibles de ces dernières empêchent la dégradation de l’Ach. Suivant le contexte d’utilisation, les inhibiteurs des AchE peuvent avoir un impact bénéfique ou néfaste sur les mécanismes cérébraux. Ces dernières décennies, une classe d’inhibiteurs irréversibles des AchE considérés comme des neurotoxiques de guerre tel que le gaz sarin ont été utilisés lors de divers conflits militaires et/ou lors d’attaques ciblant les populations civiles. Ils provoquent une accumulation anormalement élevée d’Ach au sein du SNC des personnes ayant été en contact avec ces derniers, on parle alors d’intoxication. L’hyperexcitabilité du SNC suite à l’intoxication engendre une succession de symptômes détectables soit sur le court ou le long terme selon la dose de toxique à laquelle les personnes ont été exposés. Des études suite aux attentats de Tokyo en 1995 ont mis en évidence que même une faible dose de toxique ne provoquant pas l’apparition de symptômes immédiats était capable de générer des troubles cognitifs notamment mnésiques des années post-exposition. Cependant les mécanismes sous-jacents à de tels troubles restent encore méconnus. L’utilisation des inhibiteurs d’AchE est aussi possible dans un contexte thérapeutique. En effet, dans la maladie d’Alzheimer une diminution des taux d’Ach est observée. Des inhibiteurs cette fois-ci réversibles des AchE comme le Donépézil (DPZ) sont alors utilisés pour maintenir des taux normaux d’Ach dans le cerveau permettant ainsi son bon fonctionnement. Les études réalisées au cours de cette thèse ont pour but de déterminer l’effet de ces inhibiteurs d’AchE sur divers mécanismes cérébraux. La première étude a permis d’analyser l’impact de l’administration d’une forte et d’une faible dose d’un organophosphoré (NIMP ; analogue du gaz sarin), un inhibiteur irréversible des AchE, sur la neuroinflammation en imagerie TEP in vivo via l’utilisation du radiotraceur [¹⁸F]DPA-714. Le suivi de la neuroinflammation in vivo sur plusieurs mois a permis de déterminer une fenêtre thérapeutique d’action pour tester un traitement neuroprotecteur. Pour la deuxième étude un modèle préclinique de la maladie d’Alzheimer (MA) a été employé afin d’évaluer in vivo les effets d’un traitement avec le Donépézil sur le métabolisme cérébral du glucose en utilisant l’imagerie TEP au [¹⁸F]FDG. Divers mécanismes pathophysiologiques (neuroinflammation, accumulation anormale de protéines mal conformées (MA)…) sont associés aux maladies neurologiques et peuvent impacter l’étanchéité de la barrière hématoencéphalique (BHE). Il est donc primordial d’avoir des outils permettant la quantification de la perméabilité de la BHE in vivo. Dans ce cadre, un troisième projet utilisant la technique des ultrasons focalisés mis au point au laboratoire a permis de repositionner l’imagerie TEP au [¹⁸F]-2- fluoro-2-désoxy-sorbitol ([¹⁸F]FDS) comme biomarqueur quantitatif de l’intégrité de la BHE in vivo. Au cours de cette thèse l’imagerie TEP a permis d’investiguer différents fonctionnalités cérébrales (neuroinflammation, métabolisme cérébral du glucose, intégrité de la BHE) afin de i) réaliser un suivi longitudinal, ii) un suivi thérapeutique et iii) valider un nouveau biomarqueur.

Acetylcholinesterases (AchE) are enzymes widely spread in the central nervous system (CNS) that allow the recycling of acetylcholine (Ach). The use of reversible/irreversible inhibitors of these enzymes prevents the degradation of Ach. Depending on the context of their use, AchE inhibitors can have a beneficial or detrimental impact on brain mechanisms. In the last decades, a class of irreversible AchE inhibitors considered as warfare nerve agents such as sarin gas have been used in various military conflicts and/or in several attacks against civilian populations. They cause an excessive accumulation of Ach in the SNC of people who have been in contact with them, which is considered as intoxication. The hyperexcitability of the CNS following intoxication generates a succession of symptoms that can be detected either in the short or long term, depending on the dose of the nerve agent. Studies following the Tokyo attacks in 1995 showed that even a low dose of toxic that did not cause the emergence of immediate symptoms was capable of generating cognitive disorders, particularly memory impairment, several years after exposure. However, the mechanisms underlying such disorders are still not well understood. AchE can also be used in a therapeutic context. Indeed, in Alzheimer's disease, a decrease in Ach levels are observed. Therefore, reversible AchE inhibitors such as Donepezil (DPZ) are used to maintain normal levels of Ach in the brain, thus allowing a proper brain functioning. The studies carried out in this thesis aimed to determine the effect of these AchE inhibitors on various brain mechanisms. The first study investigated the impact of high and low dose administration of an organophosphate (NIMP; analogue of sarin gas), an irreversible AchE inhibitor, on neuroinflammation using in vivo [¹⁸F]DPA-714 PET imaging. Longitudinal in vivo monitoring of neuroinflammation over several months allowed to identify a therapeutic window for neuroprotective treatment. For the second study a preclinical model of Alzheimer's disease (AD) was employed in order to evaluate in vivo the effects of Donepezil treatment on cerebral glucose metabolism using [¹⁸F]FDG PET. Various pathophysiological mechanisms (neuroinflammation, abnormal accumulation of misfolded proteins (AD)...) are associated with neurological diseases and may impact the blood-brain barrier (BBB) integrity. It is therefore essential to develop tools to quantify BBB permeability in vivo. In this context, a third project combining focused ultrasound and PET was set up in order to investigate the potential of [¹⁸F]FDS PET imaging as a quantitative biomarker of BBB integrity in vivo. In the course of this thesis, PET imaging allowed to investigate different brain functions (neuroinflammation, cerebral glucose metabolism, integrity of the BBB) in order to assess i) changes in brain mechanisms in a longitudinal manner, ii) a therapeutic follow-up and iii) validate a new biomarker., Les acétylcholinestérases (AchE) sont des enzymes largement distribuées au sein du système nerveux central (SNC) permettant le recyclage de l’acétylcholine (Ach). L’utilisation d’inhibiteurs réversibles/irréversibles de ces dernières empêchent la dégradation de l’Ach. Suivant le contexte d’utilisation, les inhibiteurs des AchE peuvent avoir un impact bénéfique ou néfaste sur les mécanismes cérébraux. Ces dernières décennies, une classe d’inhibiteurs irréversibles des AchE considérés comme des neurotoxiques de guerre tel que le gaz sarin ont été utilisés lors de divers conflits militaires et/ou lors d’attaques ciblant les populations civiles. Ils provoquent une accumulation anormalement élevée d’Ach au sein du SNC des personnes ayant été en contact avec ces derniers, on parle alors d’intoxication. L’hyperexcitabilité du SNC suite à l’intoxication engendre une succession de symptômes détectables soit sur le court ou le long terme selon la dose de toxique à laquelle les personnes ont été exposés. Des études suite aux attentats de Tokyo en 1995 ont mis en évidence que même une faible dose de toxique ne provoquant pas l’apparition de symptômes immédiats était capable de générer des troubles cognitifs notamment mnésiques des années post-exposition. Cependant les mécanismes sous-jacents à de tels troubles restent encore méconnus. L’utilisation des inhibiteurs d’AchE est aussi possible dans un contexte thérapeutique. En effet, dans la maladie d’Alzheimer une diminution des taux d’Ach est observée. Des inhibiteurs cette fois-ci réversibles des AchE comme le Donépézil (DPZ) sont alors utilisés pour maintenir des taux normaux d’Ach dans le cerveau permettant ainsi son bon fonctionnement. Les études réalisées au cours de cette thèse ont pour but de déterminer l’effet de ces inhibiteurs d’AchE sur divers mécanismes cérébraux. La première étude a permis d’analyser l’impact de l’administration d’une forte et d’une faible dose d’un organophosphoré (NIMP ; analogue du gaz sarin), un inhibiteur irréversible des AchE, sur la neuroinflammation en imagerie TEP in vivo via l’utilisation du radiotraceur [¹⁸F]DPA-714. Le suivi de la neuroinflammation in vivo sur plusieurs mois a permis de déterminer une fenêtre thérapeutique d’action pour tester un traitement neuroprotecteur. Pour la deuxième étude un modèle préclinique de la maladie d’Alzheimer (MA) a été employé afin d’évaluer in vivo les effets d’un traitement avec le Donépézil sur le métabolisme cérébral du glucose en utilisant l’imagerie TEP au [¹⁸F]FDG. Divers mécanismes pathophysiologiques (neuroinflammation, accumulation anormale de protéines mal conformées (MA)…) sont associés aux maladies neurologiques et peuvent impacter l’étanchéité de la barrière hématoencéphalique (BHE). Il est donc primordial d’avoir des outils permettant la quantification de la perméabilité de la BHE in vivo. Dans ce cadre, un troisième projet utilisant la technique des ultrasons focalisés mis au point au laboratoire a permis de repositionner l’imagerie TEP au [¹⁸F]-2- fluoro-2-désoxy-sorbitol ([¹⁸F]FDS) comme biomarqueur quantitatif de l’intégrité de la BHE in vivo. Au cours de cette thèse l’imagerie TEP a permis d’investiguer différents fonctionnalités cérébrales (neuroinflammation, métabolisme cérébral du glucose, intégrité de la BHE) afin de i) réaliser un suivi longitudinal, ii) un suivi thérapeutique et iii) valider un nouveau biomarqueur.