Antipsychotiques, dopamine et glutamate, une relation à établir

Plus de 50 ans après leur découverte, nous savons encore très peu du mécanisme d’action des agents antipsychotiques. D’autre part, il est surprenant de constater que nous savons également bien peu de choses à propos du fonctionnement normal des systèmes de neurotransmission qui sont ciblés par ces molécules. Dans le cadre de cette brève réflexion, nous aborderons deux sujets principaux : d’une part, nous discuterons du mode d’action des antipsychotiques afin d’en arriver au constat qu’une meilleure compréhension de la plasticité structurale du cerveau induite par les antipsychotiques est nécessaire. D’autre part, nous lèverons le voile sur le comportement mystérieux d’une des populations neuronales ciblées par les antipsychotiques, à savoir les neurones produisant le neurotransmetteur dopamine. Nous verrons que des découvertes récentes ont montré que ces neurones sont en quelque sorte polygame, utilisant non seulement la dopamine, mais aussi le glutamate comme neurotransmetteur. Dans le contexte des théories récentes suggérant que la schizophrénie implique une perturbation à la fois de la neurotransmission dopaminergique et glutamatergique, cette découverte ouvre de nouvelles pistes quant aux relations entre schizophrénie, dopamine et glutamate.More than 50 years after their discovery, we still know very little about the mechanism of action of antipsychotic drugs. Moreover, it is surprising to realize that we also know very little about the basic functioning of the neuronal systems that are targeted by such pharmacological agents in the central nervous system. In this brief commentary, we will address two major issues: first, we will consider the mechanisms of action of antipsychotic drugs and reach the conclusion that a better understanding of the structural plasticity induced by chronic administration of such agents in the brain is required. Second, we will highlight some of the peculiar properties of one of the neuronal populations targeted by antipsychotics, namely the neurons that produce the neurotransmitter dopamine. We will see that recent discoveries have demonstrated that such neurons are in some ways polygamous, producing and releasing not only dopamine, but also glutamate as a neurotransmitter. In the context of recent theories suggesting that schizophrenia involves perturbations of not only dopamine but also glutamate-mediated neurotransmission, these recent findings open new opportunities in our quest to explain the complicated interrelations between schizophrenia, dopamine and glutamate.Más de 50 años después de su descubrimiento, sabemos todavía muy poco del mecanismo de acción de los agentes antipsicóticos. Por otra parte, es sorprendente constatar que también sabemos muy poco de las cosas al respecto del funcionamiento normal de los sistemas de neurotransmisión que son el blanco de estas moléculas. En el marco de esta breve reflexión, abordaremos dos temas principales: por una parte, trataremos el modo de acción de los antipsicóticos a fin de llegar a constatar que es necesaria una mejor comprensión de la plasticidad estructural del cerebro inducida por los antipsicóticos. Por otra parte, develaremos el comportamiento misterioso de una de las poblaciones neuronales blanco de los antipsicóticos, es decir, las neuronas que producen el neurotransmisor dopamina. Veremos que los descubrimientos recientes han mostrado que estas neuronas son de cierta forma polígamas, que no sólo utilizan la dopamina sino también el glutamato como neurotransmisor. En el contexto de las teorías recientes, que sugieren que la esquizofrenia implica una perturbación a la vez de la neurotransmisión dopaminérgica y glutaminérgica, este descubrimiento presenta pistas nuevas en cuanto a las relaciones entre esquizofrenia, dopamina y glutamato.Há mais de 50 anos após sua descoberta, ainda sabemos muito pouco sobre o mecanismo de ação dos agentes antipsicóticos. Por outro lado, é surpreendente constatar que também sabemos muito pouco a respeito do funcionamento normal dos sistemas de neurotransmissão que são escolhidos por estas moléculas. Dentro desta breve reflexão, abordaremos dois assuntos principais: por um lado, discutiremos o modo de ação dos antipsicóticos, a fim de chegar a uma constatação de que uma melhor compreensão da plasticidade estrutural do cérebro induzida pelos antipsicóticos é necessária. Por outro lado, esclareceremos sobre o comportamento misterioso de uma das populações neuronais buscadas pelos antipsicóticos, a saber, os neurônios que produzem o neurotransmissor dopamina. Veremos que descobertas recentes demonstraram que estes neurônios são, de alguma maneira, polígamos, utilizando não apenas a dopamina, mas também o glutamato como neurotransmissor. No contexto das teorias recentes que sugerem que a esquizofrenia implica em uma perturbação ao mesmo tempo da neurotransmissão dopaminérgica e glutamatérgica, esta descoberta abre novas pistas quanto às relações entre esquizofrenia, dopamina e glutamato

A Lyra2 FPGA Core for Lyra2REv2-Based Cryptocurrencies

Lyra2REv2 is a hashing algorithm that consists of a chain of individual hashing algorithms and it is used as a proof-of-work function in several cryptocurrencies that aim to be ASIC-resistant. The most crucial hashing algorithm in the Lyra2REv2 chain is a specific instance of the general Lyra2 algorithm. In this work we present the first FPGA implementation of the aforementioned instance of Lyra2 and we explain how several properties of the algorithm can be exploited in order to optimize the design.Comment: 5 pages, to be presented at the IEEE International Symposium on Circuits and Systems (ISCAS) 201

A Standalone FPGA-based Miner for Lyra2REv2 Cryptocurrencies

Lyra2REv2 is a hashing algorithm that consists of a chain of individual hashing algorithms, and it is used as a proof-of-work function in several cryptocurrencies. The most crucial and exotic hashing algorithm in the Lyra2REv2 chain is a specific instance of the general Lyra2 algorithm. This work presents the first hardware implementation of the specific instance of Lyra2 that is used in Lyra2REv2. Several properties of the aforementioned algorithm are exploited in order to optimize the design. In addition, an FPGA-based hardware implementation of a standalone miner for Lyra2REv2 on a Xilinx Multi-Processor System on Chip is presented. The proposed Lyra2REv2 miner is shown to be significantly more energy efficient than both a GPU and a commercially available FPGA-based miner. Finally, we also explain how the simplified Lyra2 and Lyra2REv2 architectures can be modified with minimal effort to also support the recent Lyra2REv3 chained hashing algorithm.Comment: 13 pages, accepted for publication in IEEE Trans. Circuits Syst. I. arXiv admin note: substantial text overlap with arXiv:1807.0576

Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function

<p>Abstract</p> <p>Background</p> <p>Neurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc).</p> <p>Results</p> <p>DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D₂autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D₂autoreceptors, quinpirole (1 μM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D₂receptor antagonist, sulpiride (5 μM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8–13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D₂autoreceptors. In addition, initial blockade of D₂autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8–13).</p> <p>Conclusion</p> <p>Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D₂autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.</p

Pendidikan Kewarganegaraan untuk Membangun Wawasan Global Warga Negara Muda

Penelitian ini bertujuan untuk menemukan nilai-nilai dasar yang perlu dikembangkan dalam pendidikan kewarganegaraan untuk membangun wawasan global warga negara muda. Penelitian menggunakan pendekatan kualitatif dengan metode grounded theory. Sumber data terdiri atas sumber kepustakaan dan responden yang dipilih dengan menggunakan metode purposive sampling.Teknik pengumpulan data menggunakan studi dokumentasi, wawancara, dan observasi. Analisis data menggunakan analisis induktif. Hasil penelitian menunjukkan bahwa nilai-nilai dasar yang perlu dikembangkan dalam pendidikan kewarganegaraan untuk membangun wawasan global warga negara muda dalam konteks Indonesia antara lain adalah ketuhanan, kemanusiaan, persatuan, kerakyatan, keadilan sosial, kompetisi, menghormati orang lain, kemerdekaan, dan perdamaian

Using dynamicN-mixture models to test cavity limitation on northern flying squirrel demographic parameters using experimental nest box supplementation

Dynamic N-mixture models have been recently developed to estimate demographic parameters of unmarked individuals while accounting for imperfect detection. We propose an application of the Dail and Madsen (2011: Biometrics, 67, 577–587) dynamic N-mixture model in a manipulative experiment using a before-after control-impact design (BACI). Specifically, we tested the hypothesis of cavity limitation of a cavity specialist species, the northern flying squirrel, using nest box supplementation on half of 56 trapping sites. Our main purpose was to evaluate the impact of an increase in cavity availability on flying squirrel population dynamics in deciduous stands in northwestern Quebec with the dynamic N-mixture model. We compared abundance estimates from this recent approach with those from classic capture–mark–recapture models and generalized linear models. We compared apparent survival estimates with those from Cormack–Jolly–Seber (CJS) models. Average recruitment rate was 6 individuals per site after 4 years. Nevertheless, we found no effect of cavity supplementation on apparent survival and recruitment rates of flying squirrels. Contrary to our expectations, initial abundance was not affected by conifer basal area (food availability) and was negatively affected by snag basal area (cavity availability). Northern flying squirrel population dynamics are not influenced by cavity availability at our deciduous sites. Consequently, we suggest that this species should not be considered an indicator of old forest attributes in our study area, especially in view of apparent wide population fluctuations across years. Abundance estimates from N-mixture models were similar to those from capture–mark–recapture models, although the latter had greater precision. Generalized linear mixed models produced lower abundance estimates, but revealed the same relationship between abundance and snag basal area. Apparent survival estimates from N-mixture models were higher and less precise than those from CJS models. However, N-mixture models can be particularly useful to evaluate management effects on animal populations, especially for species that are difficult to detect in situations where individuals cannot be uniquely identified. They also allow investigating the effects of covariates at the site level, when low recapture rates would require restricting classic CMR analyses to a subset of sites with the most captures

Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons

SummaryAlthough the mechanisms underlying the loss of neurons in Parkinson’s disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson’s disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP+ (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP+ but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson’s disease is directly due to their particular bioenergetic and morphological characteristics

On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease

Significant advances have been made uncovering the factors that render neurons vulnerable in Parkinson's disease (PD). However, the critical pathogenic events leading to cell loss remain poorly understood, complicating the development of disease-modifying interventions. Given that the cardinal motor symptoms and pathology of PD involve the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc), a majority of the work in the PD field has focused on this specific neuronal population. PD however, is not a disease of DA neurons exclusively: pathology, most notably in the form of Lewy bodies and neurites, has been reported in multiple regions of the central and peripheral nervous system, including for example the locus coeruleus, the dorsal raphe nucleus and the dorsal motor nucleus of the vagus. Cell and/or terminal loss of these additional nuclei is likely to contribute to some of the other symptoms of PD and, most notably to the non-motor features. However, exactly which regions show actual, well-documented, cell loss is presently unclear. In this review we will first examine the strength of the evidence describing the regions of cell loss in idiopathic PD, as well as the order in which this loss occurs. Secondly, we will discuss the neurochemical, morphological and physiological characteristics that render SNc DA neurons vulnerable, and will examine the evidence for these characteristics being shared across PD-affected neuronal populations. The insights raised by focusing on the underpinnings of the selective vulnerability of neurons in PD might be helpful to facilitate the development of new disease-modifying strategies and improve animal models of the disease

Glutamate Cotransmission in Cholinergic, GABAergic and Monoamine Systems: Contrasts and Commonalities

Multiple discoveries made since the identification of vesicular glutamate transporters (VGLUTs) two decades ago revealed that many neuronal populations in the brain use glutamate in addition to their “primary” neurotransmitter. Such a mode of cotransmission has been detected in dopamine (DA), acetylcholine (ACh), serotonin (5-HT), norepinephrine (NE) and surprisingly even in GABA neurons. Interestingly, work performed by multiple groups during the past decade suggests that the use of glutamate as a cotransmitter takes different forms in these different populations of neurons. In the present review, we will provide an overview of glutamate cotransmission in these different classes of neurons, highlighting puzzling differences in: (1) the proportion of such neurons expressing a VGLUT in different brain regions and at different stages of development; (2) the sub-cellular localization of the VGLUT; (3) the localization of the VGLUT in relation to the neurons’ other vesicular transporter; and (4) the functional role of glutamate cotransmission