Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and effect of perineuronal net loss.

Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in β band) in slices of the mouse anterior cingulate cortex (ACC). We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets (PNNs) enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia (SZ) patients who display prefrontal anomalies of both the dopaminergic system and the PNNs

Synthetic Peptides as an Alternative Tool for the Diagnosis of Cryptococcosis

Cryptococcosis is an important systemic mycosis that threatens the lives of humans and animals. The disease is caused by two species of the genus Cryptococcus: Cryptococcus neoformans and Cryptococcus gattii. The diagnosis of cryptococcosis is made through microscopy, fungal culture followed by biochemical tests, and detection of the cryptococcal capsular antigen (CrAg). Despite the existence of an established diagnostic protocol, the search for new diagnostic tests is necessary due to the high incidence of the disease, with estimates of approximately 1 million cases of cryptococcal meningitis per year and more than 600,000 deaths in patients infected with human immunodeficiency virus (HIV), the potential for C. gattii to cause the disease in immunocompetent individuals, and the disease’s rapid worldwide dissemination. With the development of biotechnology, synthetic peptides have opened up new possibilities as a source of pure epitopes and molecules for the diagnosis of various diseases, based on the detection of circulating antibodies. Synthetic peptides can also be used for the development of vaccines. Studies on Leishmaniasis, Chagas disease, paracoccidioidomycosis, tuberculosis, and, more recently, on cryptococcosis, among others, have shown that this approach shows potential for the early diagnosis of the disease, thus reducing the morbi-lethality of individuals affected by this infection and ultimately changing their prognosis

Nucleotide Frequencies in Human Genome and Fibonacci Numbers

This work presents a mathematical model that establishes an interesting connection between nucleotide frequencies in human single-stranded DNA and the famous Fibonacci's numbers. The model relies on two assumptions. First, Chargaff's second parity rule should be valid, and, second, the nucleotide frequencies should approach limit values when the number of bases is sufficiently large. Under these two hypotheses, it is possible to predict the human nucleotide frequencies with accuracy. It is noteworthy, that the predicted values are solutions of an optimization problem, which is commonplace in many nature's phenomena.Comment: 12 pages, 2 figure

Including diverse knowledges and worldviews in environmental assessment and planning: : the Brazilian Amazon Kaxinawá Nova Olinda Indigenous Land case

The concepts of ‘ecosystem services’ (ES) and ‘nature’s contributions to people’ (NCP) inform environmental frameworks that set out to include Indigenous and Local Knowledge systems (ILK) and worldviews in policy and planning processes. These frameworks aim to enhance biodiversity conservation and human well-being in a legitimate and effective way. In this article, we explore how the concept of People’s Contributions to Nature (PCN) is complementary to NCP. We use it to investigate challenges that planners and locals face in realizing the legitimate inclusion of diverse knowledges and worldviwes that account for people and ecosystems in a relational way. We introduce a case study where planners drew on ES and NCP and used participatory methods to implement a REDD+ policy in the Kaxinawá Nova Olinda Indigenous Land (Acre-Brazil). We find that both Kaxinawás and planners emphasize both NCP and PCN in their discourses. Nevertheless, differences between knowledge systems and disciplines, uneven power relations between Kaxinawás and planners, and an under-consideration of PCN by global frameworks challenge the legitimate inclusion of the Kaxinawá knowlege and worldviews to craft assessment and planning. We conclude that by explicitly addressing these challenges, science-policy interfaces can further advance knowledge legitimacy and policy effectiveness

Differential Geometry applied to Acoustics : Non Linear Propagation in Reissner Beams

Although acoustics is one of the disciplines of mechanics, its "geometrization" is still limited to a few areas. As shown in the work on nonlinear propagation in Reissner beams, it seems that an interpretation of the theories of acoustics through the concepts of differential geometry can help to address the non-linear phenomena in their intrinsic qualities. This results in a field of research aimed at establishing and solving dynamic models purged of any artificial nonlinearity by taking advantage of symmetry properties underlying the use of Lie groups. The geometric constructions needed for reduction are presented in the context of the "covariant" approach.Comment: Submitted to GSI2013 - Geometric Science of Informatio

A lack of GluN2A-containing NMDA receptors confers a vulnerability to redox dysregulation: Consequences on parvalbumin interneurons, and their perineuronal nets.

The GluN2A subunit of NMDA receptors (NMDARs) plays a critical role during postnatal brain development as its expression increases while Glun2B expression decreases. Mutations and polymorphisms in GRIN2A gene, coding for GluN2A, are linked to developmental brain disorders such as mental retardation, epilepsy, schizophrenia. Published data suggest that GluN2A is involved in maturation and phenotypic maintenance of parvalbumin interneurons (PVIs), and these interneurons suffer from a deficient glutamatergic neurotransmission via GluN2A-containing NMDARs in schizophrenia. In the present study, we find that although PVIs and their associated perineuronal nets (PNNs) appear normal in anterior cingulate cortex of late adolescent/young adult GRIN2A KO mice, a lack of GluN2A delays PNN maturation. GRIN2A KO mice display a susceptibility to redox dysregulation as sub-threshold oxidative stress and subtle alterations in antioxidant systems are observed in their prefrontal cortex. Consequently, an oxidative insult applied during early postnatal development increases oxidative stress, decreases the number of parvalbumin-immunoreactive cells, and weakens the PNNs in KO but not WT mice. These effects are long-lasting, but preventable by the antioxidant, N-acetylcysteine. The persisting oxidative stress, deficit in PVIs and PNNs, and reduced local high-frequency neuronal synchrony in anterior cingulate of late adolescent/young adult KO mice, which have been challenged by an early-life oxidative insult, is accompanied with microglia activation. Altogether, these indicate that a lack of GluN2A-containing NMDARs alters the fine control of redox status, leading to a delayed maturation of PNNs, and conferring vulnerability for long-term oxidative stress, microglial activation, and PVI network dysfunction

Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis.

Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia