Transmission of trisomy decreases with maternal age in mouse models of Down syndrome, mirroring a phenomenon in human Down syndrome mothers

Genotyping Tc1. An example picture of a gel used during genotyping. Two lines refer to a Tc1 positive trisomic pup. One line refers to a disomic pup. (EPS 1781 kb

Intrinsic excitability in layer IV-VI anterior insula to basolateral amygdala projection neurons correlates with the confidence of taste valence encoding.

Avoiding potentially harmful, and consuming safe food is crucial for the survival of living organisms. However, the perceived valence of sensory information can change following conflicting experiences. Pleasurability and aversiveness are two crucial parameters defining the perceived valence of a taste and can be impacted by novelty. Importantly, the ability of a given taste to serve as the conditioned stimulus (CS) in conditioned taste aversion (CTA), is dependent on its valence. Activity in anterior insula (aIC) layer IV-VI pyramidal neurons projecting to the basolateral amygdala (BLA) is correlated with, and necessary for CTA learning and retrieval, as well as the expression of neophobia towards novel tastants, but not learning taste familiarity. Yet, the cellular mechanisms underlying the updating of taste valence representation in this specific pathway are poorly understood. Here, using retrograde viral tracing and whole -cell patch-clamp electrophysiology in trained mice, we demonstrate that the intrinsic properties of deep-lying layer IV-VI, but not superficial layer I-III aIC-BLA neurons, are differentially modulated by both novelty and valence, reflecting the subjective predictability of taste valence arising from prior experience. These correlative changes in the profile of intrinsic properties of LIV-VI aIC-BLA neurons were detectable following both simple taste experiences, as well as following memory retrieval, extinction learning and reinstatement.Significance statementLearning to form aversive or safe taste memories is dependent on genetic predisposition as well as previous experiences. In mice, anterior insula neurons projecting to the basolateral amygdala (aIC-BLA) are indispensable for learning and retrieving learned taste aversion. Kolatt Chandran et al. demonstrate that the intrinsic properties of aIC-BLA neurons, represent the certainty of taste valence prediction, but not percept. Predictive valence-specific changes are reflected through excitability, being low when taste outcome is highly predictive (i.e., following aversive taste memory retrieval or unreinforced familiarization), and high when taste valence is uncertain (i.e., following novelty or aversive taste memory extinction). In addition, the results propose a neuronal mechanism underlying the long delay between taste and visceral discomfort in conditioned taste aversion

Total serum cholinesterase activity predicts hemodynamic changes during exercise and associates with cardiac troponin detection in a sex-dependent manner.

BACKGROUND: Imbalanced autonomic nervous system (ANS) activity is associated with poor cardiovascular outcome. However, clinically validated biomarkers to assess parasympathetic function are not yet available. We sought to evaluate parasympathetic dysfunction by measuring serum cholinesterase activity and to determine its relationship to high sensitive cardiac troponin T (hs-cTnT) as well as traditional non-invasive parameters of ANS function during exercise in apparently healthy individuals. METHODS: We enrolled 1526 individuals (mean age 49 ± 11 yr., 75% men) from the Tel Aviv Medical Center Inflammation Survey (TAMCIS). We used the acetylcholine (ACh) analog acetylthiocholine (ATCh) as a substrate that is hydrolyzed by both ACh degrading enzymes and reflects the total serum capacity for acetylcholine hydrolysis, referred to as cholinergic status (CS). All subjects performed a cardiac stress test reviewed on the spot by a cardiologist and multiple physiological and metabolic parameters including hs-cTnT were measured. RESULTS: CS values at rest predicted multiple exercise-hemodynamic changes. Heart rate recovery after exercise was inversely correlated to CS values (p  5 ng/L) presented with elevated CS levels compared to women with undetectable levels; 1423 ± 272.5 vs 1347 ± 297.9 (p = 0.02). An opposite trend was observed in men. Metabolic dysfunction parameters were also associated with CS elevation in both men and women. CONCLUSIONS: Parasympathetic dysfunction assessed by total serum cholinesterase activity predicts hemodynamic changes during exercise. CS is also associated with hs-cTnT detection in women and inversely so in men. Future studies to assess the potential clinical use of this new sex-specific biomarker in cardiovascular disease risk stratification are warranted

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Proteins and Transcriptional Dysregulation of the Brain Extracellular Matrix in Parkinson’s Disease: A Systematic Review

The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational, and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect cellular functions and may result in disease. However, most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix in disease pathogenesis. Thus, due to the ECM’s diversified biological roles, increasing interest in its involvement in disease, and the lack of sufficient compiled evidence regarding its relationship with Parkinson’s disease (PD) pathology, we aimed to compile the existing evidence to boost the current knowledge on the area and provide refined guidance for the future research. Here, in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google Scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson’s disease (PD). A literature search was conducted up until 10 February 2023. The overall hits from the database and manual search for proteomic and transcriptome studies were 1243 and 1041 articles, respectively. Following a full-text review, 10 articles from proteomic and 24 from transcriptomic studies were found to be eligible for inclusion. According to proteomic studies, proteins such as collagens, fibronectin, annexins, and tenascins were recognized to be differentially expressed in Parkinson’s disease. Transcriptomic studies displayed dysregulated pathways including ECM–receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson’s disease. A limited number of relevant studies were accessed from our search, indicating that much work remains to be carried out to better understand the roles of the ECM in neurodegeneration and Parkinson’s disease. However, we believe that our review will elicit focused primary studies and thus support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson’s disease

Stronger Privacy Preserving Projections for Multi-Agent Planning

Collaborative privacy-preserving planning (CPPP) is a multi-agent planning task in which agents need to achieve a common set of goals without revealing certain private information. In many CPPP algorithms the individual agents reason about a projection of the multiagent problem onto a single-agent classical planning problem. For example, an agent can plan as if it controls the public actions of other agents, ignoring their unknown private preconditions and effects, and use the cost of this plan as a heuristic for the cost of the full, multi-agent plan. Using such a projection, however, ignores some dependencies between agents’ public actions. In particular, it does not contain dependencies between actions of other agents caused by their private facts. We propose a projection in which these private dependencies are maintained. The benefit of our dependency-preserving projection is demonstrated by using it to produce high level plans in a new privacy preserving planner that is able to solve more benchmark problems than any other state-of-the-art privacy preserving planner. This more informed projection does not explicitly share private information. In addition, we show that even if an adversary agent knows that an agent has some private objects of a given type (e.g., trucks), it cannot infer how many such private objects the agent controls. This introduces a novel strong form of privacy that is motivated by real-world requirements

Involvement of Potassium and Cation Channels in Hippocampal Abnormalities of Embryonic Ts65Dn and Tc1 Trisomic Mice

Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca2+]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in Δf / f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after-hyperpolarization amplitude. Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype

Multi Agent Path Finding under Obstacle Uncertainty

In multi-agent path finding (MAPF), several agents must move from their current positions to their target positions without colliding. Prior work on MAPF commonly assumed perfect knowledge of the environment. We consider a MAPF setting where this is not the case, and the planner does not know a-priori whether some positions are blocked or not. To sense whether such a position is traversable, an agent must move close to it and adapt its behavior accordingly. In this work we focus on solving this type of MAPF problem, for cases where planning is centralized but cannot be done during execution. In this setting, a solution can be formulated as a plan tree for each agent, branching on the observations. We propose algorithms for finding such plans trees for two modes of executions: centralized, where the agents share information concerning observed obstacles during execution, a decentralized, where such communication is not allowed. The proposed algorithms are complete and can be configured to optimize solution cost, measured for either the best case or the worst case. We implemented these algorithms and provide experimental results demonstrating how our approach scales with respect to the number of agents and the number of positions we are uncertain about. The results show that our algorithms can solve non-trivial problems, but also highlight that this type of MAPF problems is significantly harder than classical MAPF