Maternal immune activation disrupts dopamine system in the offspring

Background: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. Methods: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. Results: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. Conclusions: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human patholog

Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain and provide a potential new target for the treatment of nicotine addictio

Meta-review of systematic and meta-analytic reviews on family psychoeducation for schizophrenia

The purpose of family psychoeducation is to increase patients’ and their families’ knowledge and understanding of their illness and treatment. Improved knowledge of schizophrenia is expected to enable people to cope better with their illness. The aim of this review is to summarize and appraise evidence from published systematic and meta-analytic reviews on family psychoeducation in schizophrenia. Thorough search and analysis of reviews on efficacy of family psychoeducation in schizophrenia were carried out in PubMed/Medline (19872015), Ovid/Psych Info (1987-2015), and the Cochrane Database of Systematic Reviews. We included only reviews reporting quantitative summary statistics on studies carried out in patients with schizophrenia and written in English. Review methodology was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Double check by two independent assessors was applied. Nine reviews meeting inclusion/exclusion criteria were included in the meta-review. Risk of relapse was reduced in protocols that included family members, whether conducted in single family or in multifamily group sessions. However, effectiveness seems not to be maintained at follow-up. Hospital admission/re-hospitalization was less influenced by family psychoeducation, and no reproducible effect on compliance/medication adherence was found. Overall, quality of evidence on the effectiveness of family psychoeducation in schizophrenia is poo

Prevalence and correlates of DSM-5 major depressive and related disorders in the community.

Although the DSM-5 has suggested the two new categories of Persistent Depressive Disorders (PDD) and Other Specified Depressive Disorders (OSDD), no study so far has applied the DSM-5 criteria throughout the range of depressive disorders. The aims of the present study were to 1) establish the lifetime prevalence of specific depressive disorders according to the new DSM-5 definitions in a community sample, and 2) determine their clinical relevance in terms of socio-demographic characteristics, comorbidity, course and treatment patterns. The semi-structured Diagnostic Interview for Genetic Studies was administered by masters-level psychologists to a random sample of an urban area (n=3720). The lifetime prevalence was 15.2% for PDD with persistent major depressive episode (MDE), 3.3% for PDD with pure dysthymia, 28.2% for Major Depressive Disorder (MDD) and 9.1% for OSDD. Subjects with PDD with persistent MDE were the most severely affected, followed by those with recurrent MDD, single episode MDD, PDD with pure dysthymia and OSDD and finally those without depressive disorders. Our data provide further evidence for the clinical significance of mild depressive disorders (OSDD), but cast doubt on the pertinence of lumping together PDD with persistent MDE and the former DSM-IV dysthymic disorder within the new PDD category

Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in sardinian alcohol-preferring rats

The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intak

Democracy in the Democratic Republic of Congo: Myth or Reality?

Democracy is a regime by which the people impose their veto by choosing their representatives for a defined time on the basis of a social program that adapts to the socio-political realities of the primary sovereign In the case of the DRC we are in fact proposing the foundation of the Congolese state which must start from democracy to impose a state with strong and enlightened leadership authoritarianism a bit like what happened in Russia with Putin and in Mao s China because for us not only does it correspond to a Western-type regime corresponding to the way of life the understanding of things and adaptations to Western realities and behavior but it is the result or the reflection of the States already mature developed which have already laid the foundations for development is where state institutions and entities are seated A State where the leaders and the people are well prepared educated in development and democratic values by defining its prerogatives its needs to love and protect national interest

Internationalisation Du Processus Electoral En Republique Democratique Du Congo

The Congolese State for several decades through a crisis of self-management This crisis deeply affects all sectors of national life and does not allow it to play a significant influence on the national continental or international scene The foreign presence in the Democratic Republic of Congo and the pressures of the international community in the face of the democracy desired by it could be justified not only in a political but also in an economic context It is a question of imposing in a political but also economic context It is a question of imposing the leaders who must allow the great powers to illegally exploit natural resources and to impose Western ideolog

Ingérence Occidentale Comme Facteur Du Sous-Développement De La République Démocratique Du Congo Et L’élimination Des Nationalistes Patriotes Congolais

L’influence de puissances étrangères en République Démocratique du Congo et des pressions de la communauté internationale face la démocratisation du pays pourrait se justifier non seulement dans un contexte politique, mais aussi économique. Il s’agit d’imposer des dirigeants qui doivent permettre aux grandes puissances d’exploiter impunément les richesses naturelles et d’imposer l’idéologie occidentale. Cette ingérence occidentale pourrait se justifier par la présence permanente des pays de grandes puissances au travers les organisions, les acteurs tant nationaux qu’internationaux sans oubliés le financement et appui des multinationaux. L’incapacité de la République Démocratique du Congo de s’approprier son propre processus de démocratisation et l’inconscience des dirigeants congolais ouvrent la voie aux dominations des puissances étrangères dans le contexte de maintenir une gouvernance politique chaotique. La politique occidentale au Congo-Kinshasa consisterait à la domination et l’exploitation du pays en multipliant et en changeant les concepts mais dans la pratique soutenue par la même stratégie de dominer et d’exploiter le pays. La présence de l’homme blanc en République Démocratique du Congo serait à l’origine du sous-développement et la souffrance des autochtones en considérant la traite humaine, l’esclavagisme, le pillage des ressources naturelles, la colonisation, l’indépendance, la mondialisation, la démocratie du type occidental. Etc. cela ouvre la voie au système du sous-développés administratif, politique et économique.

The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABA_A receptor-mediated inhibition

Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics. Inhibition of TC neurons is mediated predominantly by a combination of phasic and tonic inhibition, together with a recently described ‘spillover’ mode of inhibition, generated by the dynamic recruitment of extrasynaptic γ-aminobutyric acid (GABA)(A) receptors (GABA(A)Rs). Previous studies demonstrated that the intravenous anaesthetic etomidate enhances tonic and phasic inhibition in TC relay neurons, but it is not known how etomidate may influence spillover inhibition. Moreover, it is unclear how etomidate influences the excitability of TC neurons. Thus, to investigate the relative contribution of synaptic (α1β2γ2) and extrasynaptic (α4β2δ) GABA(A)Rs to the thalamic effects of etomidate, we performed whole-cell recordings from mouse TC neurons lacking synaptic (α1(0/0)) or extrasynaptic (δ(0/0)) GABA(A)Rs. Etomidate (3 μm) significantly inhibited action-potential discharge in a manner that was dependent on facilitation of both synaptic and extrasynaptic GABA(A)Rs, although enhanced tonic inhibition was dominant in this respect. Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABA(A)Rs, which was significantly prolonged in the presence of etomidate. Thus, etomidate greatly enhanced the transient suppression of TC spike trains by evoked inhibitory postsynaptic potentials. Collectively, these results suggest that the deactivation of thalamus observed during etomidate-induced anaesthesia involves potentiation of tonic and phasic inhibition, and implicate amplification of spillover inhibition as a novel mechanism to regulate the gating of sensory information through the thalamus during anaesthetic states

Anti-IL5 Drugs in COVID-19 Patients: Role of Eosinophils in SARS-CoV-2-Induced Immunopathology

SARS-CoV-2 infection stimulates a complex activation of the immune system. Eosinophils belong to the host’s defense equipment against respiratory viruses. In the first phase of the infection, eosinophils contribution is probably appropriate and beneficial, as they facilitate the suppression of the viral replication. However, in severe COVID-19 patients, during the second and third phases of the disease, eosinophils may participate in a maladaptive immune response and directly contribute to immunopathology. In fact, in severe patients, the immune response is prevalently T helper 1 type, but T helper 2 is also present. Eosinophils’ expansion and activation are stimulated by Type 2 cytokines, especially IL-5. Moreover, bronchial asthma, in which eosinophils play a central role, seems not to be a major risk factor for severe COVID-19. Among possible explanations, asthmatic patients are often treated with corticosteroids, which have been demonstrated to reduce the progression to critical COVID-19 in hospitalized patients. In addition to steroids, severe asthmatic patients are currently treated with biological drugs that target Type 2 immune response. Because IL-5 is necessary for the growth, survival, and activation of eosinophils, IL-5 inhibitors, such as mepolizumab, decrease the peripheral blood count of eosinophils, but do not influence eosinophils activation in the airway. In severe COVID-19 patients, the blockade of eosinophils’ activation might contrast harmful immunity