Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate realistic models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems

Left atrial appendage occlusion in the absence of intraprocedural product specialist monitoring: is it time to proceed alone? Results from a multicenter real-world experience

BackgroundPercutaneous left atrial appendage occlusion (LAAO) presents many technical complex features, and it is often performed under the intraprocedural surveillance of a product specialist (PS). Our aim is to assess whether LAAO is equally safe and effective when performed in high-volume centers without PS support.MethodsIntraprocedural results and long-term outcome were retrospectively assessed in 247 patients who underwent LAAO without intraprocedural PS monitoring between January 2013 and January 2022 at three different hospitals. This cohort was then matched to a population who underwent LAAO with PS surveillance. The primary end point was all-cause mortality at 1 year. The secondary end point was a composite of cardiovascular mortality plus nonfatal ischemic stroke occurrence at 1 year.ResultsOf the 247 study patients, procedural success was achieved in 243 patients (98.4%), with only 1 (0.4%) intraprocedural death. After matching, we did not identify any significant difference between the two groups in terms of procedural time (70 ± 19 min vs. 81 ± 30 min, p = 0.106), procedural success (98.4% vs. 96.7%, p = 0.242), and procedure-related ischemic stroke (0.8% vs. 1.2%, p = 0.653). Compared to the matched cohort, a significant higher dosage of contrast was used during procedures without specialist supervision (98 ± 19 vs. 43 ± 21, p < 0.001), but this was not associated with a higher postprocedural acute kidney injury occurrence (0.8% vs. 0.4%, p = 0.56). At 1 year, the primary and the secondary endpoints occurred in 21 (9%) and 11 (4%) of our cohort, respectively. Kaplan–Meier curves showed no significant difference in both primary (p = 0.85) and secondary (p = 0.74) endpoint occurrence according to intraprocedural PS monitoring.ConclusionsOur results show that LAAO, despite the absence of intraprocedural PS monitoring, remains a long-term safe and effective procedure, when performed in high-volume centers

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Single Neuron Optimization as a Basis for Accurate Biophysical Modeling: The Case of Cerebellar Granule Cells

In realistic neuronal modeling, once the ionic channel complement has been defined, the maximum ionic conductance (Gi-max) values need to be tuned in order to match the firing pattern revealed by electrophysiological recordings. Recently, selection/mutation genetic algorithms have been proposed to efficiently and automatically tune these parameters. Nonetheless, since similar firing patterns can be achieved through different combinations of Gi-max values, it is not clear how well these algorithms approximate the corresponding properties of real cells. Here we have evaluated the issue by exploiting a unique opportunity offered by the cerebellar granule cell (GrC), which is electrotonically compact and has therefore allowed the direct experimental measurement of ionic currents. Previous models were constructed using empirical tuning of Gi-max values to match the original data set. Here, by using repetitive discharge patterns as a template, the optimization procedure yielded models that closely approximated the experimental Gi-max values. These models, in addition to repetitive firing, captured additional features, including inward rectification, near-threshold oscillations, and resonance, which were not used as features. Thus, parameter optimization using genetic algorithms provided an efficient modeling strategy for reconstructing the biophysical properties of neurons and for the subsequent reconstruction of large-scale neuronal network model

Impact of Insulin Degludec/Liraglutide Fixed Combination on the Gut Microbiomes of Elderly Patients With Type 2 Diabetes: Results From A Subanalysis of A Small Non-Randomised Single Arm Study

In elderly Type 2 Diabetes (T2D) patients the relationship between the destabilization of gut microbiome and reversal of dysbiosis via glucose lowering drugs has not been explored. We investigated the effect of 6 months therapy with a fixed combination of Liraglutide and Degludec on the composition of the gut microbiome and its relationship with Quality of Life, glucose metabolism, depression, cognitive function, and markers of inflammation in a group of very old T2D subjects (n=24, 5 women, 19 men, mean age=82 years). While we observed no significant differences in microbiome biodiversity or community among study participants (N = 24, 19 men, mean age 82 years) who responded with decreased HbA1c (n=13) versus those who did not (n=11), our results revealed a significant increase in Gram-negative Alistipes among the former group (p=0.013). Among the responders, changes in the Alistipes content were associated directly with cognitive improvement (r=0.545, p=0.062) and inversely with TNF alpha levels (r=-0.608, p=0.036). Our results suggest that this combination drug may have a significant impact on both gastrointestinal microbes and cognitive function in elderly T2D individuals

Stellate cell computational modeling predicts signal fltering in the molecular layer circuit of cerebellum

The functional properties of cerebellar stellate cells and the way they regulate molecular layer activity are still unclear. We have measured stellate cells electroresponsiveness and their activation by parallel fber bursts. Stellate cells showed intrinsic pacemaking, along with characteristic responses to depolarization and hyperpolarization, and showed a marked short-term facilitation during repetitive parallel fber transmission. Spikes were emitted after a lag and only at high frequency, making stellate cells to operate as delay-high-pass flters. A detailed computational model summarizing these physiological properties allowed to explore diferent functional confgurations of the parallel fber—stellate cell—Purkinje cell circuit. Simulations showed that, following parallel fber stimulation, Purkinje cells almost linearly increased their response with input frequency, but such an increase was inhibited by stellate cells, which leveled the Purkinje cell gain curve to its 4 Hz value. When reciprocal inhibitory connections between stellate cells were activated, the control of stellate cells over Purkinje cell discharge was maintained only at very high frequencies. These simulations thus predict a new role for stellate cells, which could endow the molecular layer with low-pass and band-pass fltering properties regulating Purkinje cell gain and, along with this, also burst delay and the burst-pause responses pattern

Carotid intimal medial thickness in rotating night shift is related to {IL}1\upbeta/{IL}6 axis

Background and aims: Sleep disturbances may promote glucose abnormalities and inflammatory burden among shift workers. Therefore, precocious subclinical atherosclerotic process might develop in healthy shift workers even without known metabolic and cardiovascular risk factors.Methods and results: We measured anthropometric parameters, glucose, lipids, inflammation and common carotid Intimal Medial Thickness (cIMT) in rotating-night shift workers (r-NSW, n = 88, age = 40.3 +/- 7.8 y) in comparison with former-night shift workers (f-NSW, n = 35, age = 44.2 +/- 6.4 y) and with day-only workers (DW, n = 64, age = 44.1 +/- 8.9 y).R-NSW and f-NSW showed significantly higher cIMT and high sensitivity C-Reactive Protein (hs-CRP) respect to DW (p = 0.043 and p = 0.025, respectively). IL-1 beta levels were higher in r-NSW than in DW and f-NSW (p = 0.043) and significantly correlated with IL6 (r = 0.365, p < 0.001). In addition, r-NSW and f-NSW had higher HbA1c levels in comparison with DW (p = 0.047). Carotid-IMT was significantly related to night shift work (p = 0.023), with age (p < 0.001), with HOMA IR (p = 0.009), with insulin (p = 0.006) with HbA1c (p = 0.002), with LDL cholesterol (p < 0.001), with diastolic BP (p < 0.001), with WBC (p = 0.002) and with IL6 (p = 0.004). After performing a multivariate analysis night shift work remained statistically related to cIMT (B = 2.633, 95%CI = 0.489-4.776, p = 0.016).Conclusions: Our result described a possible link bridging night shift work, inflammation and carotid Intimal Medial Thickness. Future studies are warranted to understand if carotid atherosclerosis process should be mainly driven by the IL1 beta/IL6 citokine axis connected to sleep disturbances. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved

Successful Urgent Liver Retransplantation for Donor-Transmitted Hepatocellular Carcinoma

Letter to Edito