Analyse des signaux pour un dispositif de mesure et de stimulation du système nerveux central

- Un des enjeux actuels en Neurosciences est de pouvoir enregistrer simultanément les activités d'un grand nombre de cellules au sein de grands réseaux de neurones, et de pouvoir stimuler de manière dynamique ces réseaux afin d'en contrôler les activités. Le but du projet Neurocom est de réaliser un système multiélectrode haute densité intégré sur silicium, permettant d'enregistrer et de stimuler de grands réseaux de neurones in vitro. Ce dispositif sera constitué d'une microstructure d'électrodes stérilisable hybridée sur un circuit analogique intégré (préamplification, filtrage, multiplexage, stimulation), lui-même interfacé via une carte numérique de commande et acquisition reliée à un PC. Afin de pouvoir mieux appréhender les phénomènes bioélectriques et électrochimiques à l'interface capteur et donc mieux spécifier le cahier des charges et l'architecture du système, la maquette de test NEUROCOM1 a été conçue en électronique discrète et est actuellement utilisée pour conduire différents tests

Réflexions sur la notion d'échelle pour le terroir : Conséquences pour le classement des sites viticoles

National audienc

Dopamine synthesis during neuroinflammation: A focus on tetrahydrobiopterin

Poste

Tetrahydrobiopterin as a potential treatment for Alzheimer's disease: A study in 3xTg-AD mice

Alzheimer’s disease (AD) is a multifactorial disease, thus multi-target treatments are needed. Tetrahydrobiopterin (BH4) has been shown to be decreased in elderly and in AD patients. BH4 is an enzymatic cofactor required for the synthesis of serotonin (5-HT), dopamine (DA) and nitric oxide. It also exerts strong antioxidant and anti-inflammatory effects. Thus, BH4 administration could ameliorate monoaminergic neurotransmission but also other key physiological processes such as vascularization, metabolism, inflammatory and oxidative status. Surprisingly, despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been investigated. Thus, we hypothesized that BH4 administration can ameliorate both cognitive symptoms and AD neuropathology. Non-transgenic (NonTg) and 3xTg-AD mice, which display age-related behavior impairment, tau and Aβ neuropathologies, were subject to a high-fat diet (35% fat - HFD) or control diet (5% fat - CD) from 6 to 13 months in order to exacerbate inflammatory and metabolic disturbances. Then, mice were injected intraperitoneally with BH4 (15mg/kg) or control solution during ten days. To verify whether BH4 is a suitable therapeutic for the CNS, we first demonstrated that peripheral administration of BH4 (50mg/kg) was sufficient to double BH4 brain content within 3h. Using in-situ brain perfusion, we found that the brain uptake clearance (Clup) of BH4 was approximately 0.08μl/g/sec, consistent with a modest transfer across the BBB. For the first time, we report that ten days of chronic administration of BH4 induced a total rescue of memory impairment in 13-month-old 3xTg-AD mice as determined with the novel object recognition test. Interestingly, this improvement was observed even over a HFD background. Moreover, glucose intolerance induced by HFD in 3xTg-AD mice was completely reversed by BH4 treatment while no difference on diet consumption, mice weight and voluntary locomotion in open-field were observed. BH4 treatment had no effect on total or phosphorylated tau assessed in soluble and insoluble fractions extracted from the hippocampus. As BH4 is involved in monoamine synthesis, we also measured striatal DA and 5-HT content without detecting any significant changes. Amyloid pathology and pro-inflammatory cytokines measurements are currently ongoing. Overall, our data show that BH4 supplementation leads to a rescue in object recognition memory and metabolic impairments in the 3xTg-AD mouse model, without altering tau neuropathology

Exploring the effects of tetrahydrobiopterin on motivation, dopamine release and acute inflammation in mice

Inflammation can affect mesodopaminergic system and mediates depressive symptoms related to motivation and locomotion. Precisely, pro-inflammatory cytokines can alter dopamine synthesis and thus availability. Tetrahydrobiopterin (BH4) is the mandatory co-factor for phenylalanine and tyrosine hydroxylase activities and therefore essential for dopamine synthesis. Interestingly, inflammation can decrease BH4 by acting on its synthesis and degradation. So, lower BH4 level could participate to the dopaminergic and motivational deficits that occur frequently in chronic inflammatory conditions. Despite its importance, the effects of BH4 administration on dopamine synthesis and related behaviors have been poorly characterized. We hypothesized that BH4 administration can improve dopaminergic function and motivational processes and could be used to counteract inflammation-induced alterations. We first demonstrated that peripheral administration of BH4 (50mg/kg;intraperitoneally) was sufficient to double BH4 brain content within 3h. Using in-situ brain perfusion, we found that the brain uptake clearance (Clup) of BH4 was approximately 0.08μl/g/sec, consistent with a modest transfer across the blood brain barrier. BH4 injection neither changed the expression of main enzymes involved in BH4 and DA synthesis nor total striatal dopamine content. However, using in vivo microdialysis in freely moving mice, we showed that BH4 administration induced a slight increase in dopamine release in the nucleus accumbens during food presentation and a higher amphetamine-induced DA release (3mg/kg). Furthermore, BH4 injection increased motivation in a progressive ratio task in operant conditioning without affecting sucrose consumption and anhedonia. Surprisingly, BH4 injection led to a moderate decrease in spontaneous locomotion and to a blunted locomotor sensitization after second exposure to amphetamine. Last, BH4 injection reduced brain pro-inflammatory cytokines expression in an acute inflammation model induced by lLipopolysaccharide injection (830μg/kg). Here, we showed that increased BH4 content leads to increased dopamine release and motivation, and reduces the proinflammatory response to an acute inflammatory challenge. This suggests that BH4 could be a promising treatment for behavioral deficits related to dopaminergic disturbances related to inflammatory condition

Tetrahydrobiopterin administration facilitates amphetamine-induced dopamine release and motivation in mice

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.Impact de la composition lipidique membranaire sur la transmission dopaminergique dépendante du récepteur D2 et la motivationProgram Initiative d’Excellenc