IST Austria Thesis

Distinguishing between similar experiences is achieved by the brain in a process called pattern separation. In the hippocampus, pattern separation reduces the interference of memories and increases the storage capacity by decorrelating similar inputs patterns of neuronal activity into non-overlapping output firing patterns. Winners-take-all (WTA) mechanism is a theoretical model for pattern separation in which a "winner" cell suppresses the activity of the neighboring neurons through feedback inhibition. However, if the network properties of the dentate gyrus support WTA as a biologically conceivable model remains unknown. Here, we showed that the connectivity rules of PV+interneurons and their synaptic properties are optimizedfor efficient pattern separation. We found using multiple whole-cell in vitrorecordings that PV+interneurons mainly connect to granule cells (GC) through lateral inhibition, a form of feedback inhibition in which a GC inhibits other GCs but not itself through the activation of PV+interneurons. Thus, lateral inhibition between GC–PV+interneurons was ~10 times more abundant than recurrent connections. Furthermore, the GC–PV+interneuron connectivity was more spatially confined but less abundant than PV+interneurons–GC connectivity, leading to an asymmetrical distribution of excitatory and inhibitory connectivity. Our network model of the dentate gyrus with incorporated real connectivity rules efficiently decorrelates neuronal activity patterns using WTA as the primary mechanism. This process relied on lateral inhibition, fast-signaling properties of PV+interneurons and the asymmetrical distribution of excitatory and inhibitory connectivity. Finally, we found that silencing the activity of PV+interneurons in vivoleads to acute deficits in discrimination between similar environments, suggesting that PV+interneuron networks are necessary for behavioral relevant computations. Our results demonstrate that PV+interneurons possess unique connectivity and fast signaling properties that confer to the dentate gyrus network properties that allow the emergence of pattern separation. Thus, our results contribute to the knowledge of how specific forms of network organization underlie sophisticated types of information processing

Excitement about inhibitory presynaptic terminals

Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression. Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression

Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus

Parvalbumin-positive (PV+) GABAergic interneurons in hippocampal microcircuits are thought to play a key role in several higher network functions, such as feedforward and feedback inhibition, network oscillations, and pattern separation. Fast lateral inhibition mediated by GABAergic interneurons may implement a winner-takes-all mechanism in the hippocampal input layer. However, it is not clear whether the functional connectivity rules of granule cells (GCs) and interneurons in the dentate gyrus are consistent with such a mechanism. Using simultaneous patch-clamp recordings from up to seven GCs and up to four PV+ interneurons in the dentate gyrus, we find that connectivity is structured in space, synapse-specific, and enriched in specific disynaptic motifs. In contrast to the neocortex, lateral inhibition in the dentate gyrus (in which a GC inhibits neighboring GCs via a PV+ interneuron) is ~ 10-times more abundant than recurrent inhibition (in which a GC inhibits itself). Thus, unique connectivity rules may enable the dentate gyrus to perform specific higher-order computation

How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network

Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks

Cross-cultural adaptation and psychometric evaluation of the early childhood oral health impact scale (ECOHIS) in chilean population

The Early Childhood Oral Health Impact Scale (ECOHIS) measures the impact of dental diseases on Oral Health-Related Quality of Life both in children and their families. The aim of this study was to develop a Chilean Spanish version of the ECOHIS that is conceptually equivalent to the original and to assess its acceptability, reliability and validity in the preschool population of Chile. The Chilean version of the ECOHIS was obtained through a process including forward and back-translation, expert panel, and cognitive debriefing interviews. To assess metric properties, a cross-sectional study was carried out in Carahue, Southern Chile (April-October 2016). Children younger than six years old without systemic diseases, disabilities or chronic medication from eleven public preschools were included. Parents were invited to complete the Chilean version of the ECOHIS, PedsQL™4.0 Generic Core and PedsQL Oral Health scales, and to answer global questions about their children's general and oral health. A subsample was administrated ECOHIS a second time 14-21 days after. A clinical examination was performed to assess dental caries, malocclusion, and traumatic dental injuries. Reliability was evaluated using measures of internal consistency (Cronbach's alpha) and reproducibility (Intraclass correlation coefficient - ICC). Construct validity was assessed by testing hypotheses based on available evidence about known groups and relationships between different instruments. The content comparison of the back-translation with the original ECOHIS showed that all items except one were conceptually and linguistically equivalent. The cognitive debriefing showed a suitable understanding of the Chilean version by the parents. In the total sample (n = 302), the ECOHIS total score median was 1 (IQR 6), floor effect was 41.6%, and ceiling effect 0%. Cronbach's alpha was 0.89 and the ICC was 0.84. The correlation between ECOHIS and PedsQL™4.0 Generic Core was weak (r = 0.21), while it was strong-moderate (r = 0.64) with the PedsQL Oral Health scale. In the known groups comparison, the ECOHIS total score was statistically higher in children with poor than excellent/very good oral health (median 11.6 vs 0, p < 0.01), and in the high severity than in the caries-free group (median 8 vs 0.5, p < 0.01). No differences were found according to malocclusion and traumatic dental injuries groups. These results supported the feasibility, reliability and validity of the Chilean version of ECOHIS questionnaire for preschool children through proxy

Association between walking pace and diabetes: findings from the Chilean National Health Survey 2016-2017

Background: Walking pace is a well-known indicator of physical capability, but it is also a strong predictor of type 2 diabetes (T2D). However, there is a lack of evidence on the association between walking pace and T2D, specifically, within developing countries such as Chile. Aim: To investigate the association between self-reported walking pace and T2D in the Chilean adult population. Methods: 5520 Chilean participants (aged 15 to 90 years, 52.1% women) from the Chilean National Health Survey 2016–2017 were included in this cross-sectional study. Both walking pace (slow, average, and brisk) and diabetes data were collected through self-reported methods. Fasting blood glucose (reported in mg/dl) and glycosylated haemoglobin A (HbA1c) scores were determined via blood exams. Results: In the unadjusted model, and compared to people who reported a slow walking pace, those with average and brisk walking pace had lower blood glucose levels (β = −7.74 mg/dL (95% CI: −11.08 to −4.40) and β = −11.05 mg/dL (95% CI: −14.36 to −7.75), respectively) and lower HbA1c (β = −0.34% (95% CI: −0.57 to −0.11) and β= −0.72% (95% CI: −0.94 to −0.49)), respectively. After adjusting for sociodemographic, Body Mass Index and lifestyle factors, the association between glycaemia and HbA1c remained only for brisk walkers. Both the average and brisk walker categories had lower odds of T2D (OR: 0.59 (95% CI: 0.41 to 0.84) and (OR 0.48 (95% CI: 0.30 to 0.79), respectively). Conclusion: Brisk walkers were associated with lower blood glucose and HbA1c levels. Moreover, average to brisk walking pace also showed a lower risk for T2D

Contribución de la producción animal en pequeña escala al desarrollo rural

La producción y el consumo de productos de origen animal han experimentado un rápido crecimiento en todo el mundo, y se prevé que continuarán aumentando. Se considera que la mayor parte del incremento en la producción provendrá de sistemas de producción en pequeña escala, que representan el medio de vida de hasta un 70% de la población rural pobre del mundo.1 La producción animal en pequeña escala se reconoce en todo el mundo como un elemento que contribuye al alivio de la pobreza en el medio rural, mediante generación de ingresos, oportunidades de ocupación y dinamismo del uso de los recursos disponibles. Por lo tanto, es de suma importancia conocer las dinámicas de estos sistemas de producción animal y su contribución al desarrollo rural en México. Investigadores y extensionistas deben priorizar las demandas de la producción animal en las comunidades rurales, ya que la producción animal en pequeña escala ha contribuido a mejorar la calidad de vida y a disminuir la vulnerabilidad de las familias productoras. En el México prehispánico la población sólo criaba xoloitzcuintle y guajolotes como animales domésticos, y complementaba en proteínas su dieta con la caza y la pesca. Sin embargo, con la llegada de los españoles en 1521 llegaron también los primeros bovinos a la Nueva España, que se reprodujeron con suma rapidez. La carne de bovino llegó a constituir una parte sustancial de la dieta alimenticia de toda la población.2 A pesar de que al inicio la producción animal era casi nula, ésta empezó a desarrollarse rápidamente y en la actualidad representa un pilar importante para el desarrollo rural en las familias campesinas de nuestro país, pues es vista como una fuente de ingreso

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure