Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.

Both sustained attention (SA) and executive functioning (EF) are critical for adaptive behavior and compromised across a range of psychiatric disorders, yet their etiological relationships remain underexplored. Here, we report the first multivariate characterization of molecular genetic influences on SA (vigilance, lapse recovery cost, lapse propensity) and EF (processing speed, response selection, working memory). In collaboration with 23andMe, we report previously unpublished genome-wide association studies of these phenotypes in a single cohort of more than 20,000 individuals enriched for diagnoses of major depressive disorder and bipolar disorder. We used Genomic Structural Equation Modeling to formally model patterns of genetic covariance among these task-based measures of cognition, and their relationships with other cognitive, clinical, and imaging-derived phenotypes. We identified two distinct latent genetic factors: one influencing EF and one influencing SA. Both the EF and SA factors were genetically correlated with cognitive and clinical phenotypes, with each latent factor uniquely linked to liability for psychiatric disorders, including attention-deficit/hyperactivity disorder. However, genetic correlations with imaging-derived neuroanatomical phenotypes were modest and non-significant after correction for multiple comparisons. Collectively, these results provide an initial multivariate genetic characterization of SA and EF, though replication in larger and more diverse samples will be important. They suggest that genetic influences on sustained attention are generally distinct from those that influence executive function. The EF and SA factors show distinct patterns of genetic overlap with multiple cognitive and psychiatric outcomes, underscoring the need for more granular cognitive phenotyping to generate new insights into the genetic architecture of cognition and the etiology of psychopathology.

Microglia function as brain-resident innate immune cells that maintain brain health and play a critical role in resolving Alzheimer´s Disease (AD) pathology. TREM2 modulates microglia responses to neutralize misfolded proteins and ultimately restore neuronal function. MTX46943 is a novel, potent, selective, safe and brain-penetrant TREM2 small molecule agonist developed for the treatment of early AD. We show here key features of the mechanism and efficacy of MTX46943 in activating microglia and reducing AD pathology following chronic treatment in vivo . TREM2 agonist-induced receptor complex dynamics and downstream functional effects were assessed in vitro in CHO, HEK, THP-1 and hIPSC derived microglia cells by nanoBiT, Western blot, alphaLISA, cell migration and phagocytosis assays. Differences in receptor activation between agonist modalities were studied by comparing MTX46943 with TREM2 agonist antibodies. The impact of MTX46943 on amyloid pathology in vivo was tested with 3-month treatment of 5xFAD // hTREM2 knock-in mice followed by human microglia and brain tissue isolation for qPCR, single-cell RNA sequencing and immunostaining analyses. MTX46943-mediated TREM2 activation leads to TREM2/DAP12 receptor complex formation and stabilizes surface location required for downstream signaling and microglia activation. These effects are differentiated from TREM2 agonistic antibodies and are required for downstream microglial activation. In vivo , human TREM2 is expressed by pathology-associated microglia and induced by amyloid plaques. Chronic, systemic treatment with MTX46943 leads to re-programming of microglia in the presence of amyloid pathology which in turn leads to reduction of neurotoxic amyloid beta species. Effects were observed at compound exposure levels in the brain consistent with MTX46943 in vitro potency. Muna Therapeutics is advancing MTX46943, a selective, potent, safe and brain exposed small molecule TREM2 agonist into clinical studies for the treatment of early AD. We demonstrate here key differentiated aspects of the mechanism by which MTX46943 targets TREM2 and induces microglial re-programming via receptor complex formation and stabilization. Chronic treatment of MTX46943 robustly and significantly reduces brain amyloid pathology at doses shown to promote peripheral and central biomarker responses. The present studies collectively support the best-in-class therapeutic potential of MTX46943 for the treatment of Alzheimer´s disease.

Background:Attentional control is a critical component of executive functioning involved in numerous psychiatric and neurological disorders, yet its etiological relationships with many cognitive and behavioral phenotypes remain underexplored. Methods:We conducted the first multivariate characterization of molecular genetic influences on attentional control and other executive processes in a cohort of more than 20,000 individuals enriched for mood disorders. We used Genomic Structural Equation Modeling to formally model patterns of genetic covariance among these task-based measures of cognition, as well as their relationships with other cognitive, clinical, and imaging-derived phenotypes. Results:We identified two independent latent genetic factors: one broadly influencing executive function and one narrowly influencing attentional control. Both the Common Executive Function (CEF) and Attentional Control (AC) factors were genetically correlated with cognitive and clinical phenotypes, with each latent factor uniquely linked to liability for psychiatric disorders. For example, we observed myriad relationships between the factors and psychopathology, including robust and conditionally independent genetic associations with ADHD. However, despite clear links to brain-related phenotypes, genetic correlations with imaging-derived phenotypes themselves were modest and non-significant after correcting for multiple comparisons. Conclusions:Overall, the results of our study suggest that genetic influences on attentional control are generally distinct from those that influence broader aspects of executive function. The CEF and AC factors show distinct patterns of genetic overlap with multiple cognitive and psychiatric outcomes, underscoring the need for more detailed phenotyping of cognition to generate new insights into the etiology of psychopathology.

Pharmacological activation of TREM2 represents a novel therapeutic approach to slow Alzheimer´s disease (AD) progression. Mutations in microglial gene, TREM2, confers increased risk to developing late-onset AD. Moreover, animal studies demonstrate the loss-of-of function variants or complete absence of Trem2 aggravates amyloid pathology. Genetic ablation of TREM2 function has been shown to lock microglia in a homeostatic state, preventing a switch to the disease-associated state supporting the phagocytic clearance of misfolded proteins and cellular debris. Due to low gene sequence and protein structure homology between mouse and human TREM2, as well as phenotypical disparities between mouse and human microglia, monitoring the impact of TREM2 activation in vivo requires humanized animal models. Here we studied the impact of TREM2 agonism on xenografted human microglia in a mouse model of amyloid pathology. We systematically treated 7-month-old transgenic App NL-G-F mice transplanted with human embryonic-stem-cell-derived microglia with TREM2 small molecule agonists. Human microglia were sorted from the brain and subsequently assessed using multi-omics technologies. The activation of TREM2 lead to increased expression of cytokines and chemokines in xenografted human microglia in the presence of amyloid pathology in App NL-G-F , but not in wild-type mice. Other changes in the transcriptome profile indicated shifts in microglia populations in TREM2-agonist-treated App NL-G-F mice. These effects were observed at exposures consistent with activation of TREM2 in vitro assessed by pSYK and sTREM2 levels. All together, we show the human microglia xenograft mouse model is a valuable tool to study the impact of pharmacological TREM2 activation in the presence of AD neuropathology.

There is a wealth of research showing that deficits in executive function constitute a key transdiagnostic symptom that contributes to dysfunction and impairment across the spectrum of psychiatric illness. However, executive function is a multidimensional construct, comprising a multitude of distinct cognitive processes. Work in cognitive science has contributed greatly to our understanding of the latent phenotypic structure of executive function. In parallel, neuropsychiatric research has begun to map latent domains of executive cognition to domains of psychopathology with increasing precision. However, we still know little about the latent genetic structure of executive function and its links to psychiatric symptoms. Here, we used the Genomic Structural Equation Modeling (Genomic SEM) framework to examine the genetic architecture of a diverse set of cognitive measures (indexing processing speed, cognitive flexibility, response selection, working memory, performance monitoring, sustained attention, and response inhibition) in the AFFECT study, a large online cohort enriched for mood disorders (N ∼50k). Factor analysis indicated a two-factor solution. One latent factor (F1) reflected genetic variation associated with a broad suite of low-level executive processes. By contrast, the other factor (F2) reflected genetic variability linked to a more specific and higher-order aspect of executive function: goal-directed attentional control in contexts requiring the inhibition of prepotent responses. Notably, these factors were only weakly correlated with one another (rg = 0.28, p=0.06). Genetic correlation analyses indicated that F1 and F2 were differentially related to distinct dimensions of psychopathology: major depressive disorder and bipolar disorders showed consistently higher genetic correlations with F2 (rg: 0.26 - 0.60) than F1 (rg: 0.13 - 0.18). Compared to F2, F1 showed significantly stronger genetic correlations with aggression (rg=0.42, se=0.14, p=0.002), drug-use (rg=0.40, se=0.16, p=0.01), disturbed sleep (rg=0.34, se=0.16, p=0.03) and mania severity (rg=0.32, se=0.15, p=0.04). These results illuminate the latent genetic structure of executive function and highlight the importance of considering the contribution of common and genetic dimensions of cognition in predisposing distinct domains of psychiatric symptoms.

Human genetics point towards a key role of microglia and microglia expressed genes like TREM2 in neuroinflammation and AD pathology, yet our understanding of microglia spatial and temporal dynamics, therapeutic directionality and translational biomarkers remains limited.

There has recently been marked progress in identifying genetic risk factors for major depression (MD) and bipolar disorder (BD); however, few systematic efforts have been made to elucidate heterogeneity that exists within and across these diagnostic taxa. The Affective disorders, Environment, and Cognitive Trait (AFFECT) study presents an opportunity to identify and associate the structure of cognition and symptom-level domains across the mood disorder spectrum in a prospective study from a diverse US population. Participants were recruited from the 23andMe, Inc research participant database and through social media; self-reported diagnosis of MD or BD by a medical professional and medication status data were used to enrich for mood-disorder cases. Remote assessments were used to acquire an extensive range of phenotypes, including mood state, transdiagnostic symptom severity, task-based measures of cognition, environmental exposures, personality traits. In this paper we describe the study design, and the demographic and clinical characteristics of the cohort. In addition we report genetic ancestry, SNP heritability, and genetic correlations with other large cohorts of mood disorders. A total of 48,467 participants were enrolled: 14,768 with MD, 9864 with BD, and 23,835 controls. Upon enrollment, 47% of participants with MD and 27% with BD indicated being in an active mood episode. Cases reported early ages of onset (mean = 13.2 and 14.3 years for MD and BD, respectively), and high levels of recurrence (78.6% and 84.9% with >5 episodes), psychotherapy, and psychotropic medication use. SNP heritability on the liability scale for the ascertained MD participants (0.19–0.21) was consistent with the high level of disease severity in this cohort, while BD heritability estimates (0.16–0.22) were comparable to reports in other large scale genomic studies of mood disorders. Genetic correlations between the AFFECT cohort and other large-scale cohorts were high for MD but not for BD. By incorporating transdiagnostic symptom assessments, repeated measures, and genomic data, the AFFECT study represents a unique resource for dissecting the structure of mood disorders across multiple levels of analysis. In addition, the fully remote nature of the study provides valuable insights for future virtual and decentralized clinical trials within mood disorders.

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases.

Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.

Background Of the 108 Schizophrenia (SZ) risk-loci discovered through genome-wide association studies (GWAS), 96 are not altering the sequence of any protein. Evidence linking non-coding risk-SNPs and genes may be established using expression quantitative trait loci (eQTL). However, other approaches such allelic expression quantitative trait loci (aeQTL) also may be of use. Methods We applied both the eQTL and aeQTL analysis to a biobank of deeply sequenced RNA from 680 dorso-lateral pre-frontal cortex (DLPFC) samples. For each of 340 genes proximal to the SZ risk-SNPs, we asked how much SNP-genotype affected total expression (eQTL), as well as how much the expression ratio between the two alleles differed from 1:1 as a consequence of the risk-SNP genotype (aeQTL). Results We analyzed overlap with comparable eQTL-findings: 16 of the 30 risk-SNPs known to have gene-level eQTL also had gene-level aeQTL effects. 6 of 21 risk-SNPs with known splice-eQTL had exon-aeQTL effects. 12 novel potential risk genes were identified with the aeQTL approach, while 55 tested SNP-pairs were found as eQTL but not aeQTL. Of the tested 108 loci we could find at least one gene to be associated with 21 of the risk-SNPs using gene-level aeQTL, and with an additional 18 risk-SNPs using exon-level aeQTL. Conclusion Our results suggest that the aeQTL strategy complements the eQTL approach to susceptibility gene identification.

Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light–dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light–dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.

Background: Sub-anesthetic doses of the non-competitive N-methyl-o-aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas. Methods: Single units and local field potentials were recorded in chloral hydrate anesthetized male Wistar rats. The effects of cumulative ketamine doses (0.25-5 mg/kg, i.v.) on neuronal discharge and oscillatory activity were examined in RtN, mediodorsal and centromedial (MD/CM) thalamic nuclei, and layer VI of the medial prefrontal cortex (mPFC). Results: Ketamine (1, 2 and 5 mg/kg, i.v.) significantly decreased the discharge of MD/CM, RtN and layer VI mPFC pyramidal neurons. Simultaneously, ketamine decreased the power of low frequency oscillations in all areas examined and increased gamma oscillations in mPFC and MD/CM. Lower ketamine doses (025 and 0.5 mg/kg, i.v.) were ineffective. Conclusions: As observed for PCP, ketamine markedly inhibited the activity of RtN neurons. However, unlike PCP, this effect did not translate into a disinhibition of MD/CM and mPFC excitatory neurons, possibly due to a more potent and simultaneous blockade of NMDA-Rs by ketamine in MD/CM and mPFC neurons. Hence, the present in vivo results show that ketamine evokes an early transient inhibition of neuronal discharge in thalamo-cortical networks, following its rapid pharmacokinetics, which is likely associated to its psychotomimetic effects. The prolonged increase in gamma oscillations may underlie its antidepressant action. (C) 2018 Elsevier Ltd. All rights reserved.

Clinical depression is accompanied by changes in sleep patterning, which is controlled in a circadian fashion. It is thus desirable that animal models of depression mirror such diurnally-specific state alterations, along with other behavioral and physiological changes. We previously found several changes in behavior indicative of a depression-like phenotype in offspring of rats subjected to repeated, variable prenatal stress (PNS), including increased locomotor activity during specific periods of the circadian cycle. We, therefore, investigated whether PNS rats also exhibit alterations in sleep/wakefulness behavior around the change from light-to-dark phase. Control and PNS Sprague-Dawley rats were implanted with electrodes for continuous monitoring of electroencephalic activity used to determine behavioral state. The distribution of slow-wave sleep (SWS), rapid eye movement sleep (REMS) and wakefulness was compared for periods before and after lights were turned off, between baseline conditions and after exposure to an acute stressor. Both REMS and SWS amounts were increased in PNS rats relative to control animals in the beginning of the dark phase. REMS changes were due to an increase in REMS bout number, rather than in bout duration. During this circadian time period, we did not find any sex differences in the state changes. These results indicate that PNS affects baseline sleep patterning in both male and female rats around active-phase onset.

Background Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. Methods We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Results Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ9-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Conclusions Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.

Trabajo presentado en el Neuroscience 2017, celebrado en Washington del 11 al 15 de noviembre de 2017

Vision and AHRS (attitude and heading reference system) sensors fusion strategy is prevalent in recent years for the legged robot's SLAM (Simultaneous Localization and Mapping), due to its low cost and effectiveness in the global positioning system. In this paper, a new adaptive estimation algorithm is proposed to achieve the robot SLAM by fusing binocular vision and AHRS sensors. A novel acceleration algorithm for SIFT implementation based on Compute Unified Device Architecture (CUDA) is presented to detect the matching feature points in 2D images. All the steps of SIFT were specifically distributed and implemented by CPU or GPU, according to the step's characteristics to make full use of computational resources. The registration of the 3D feature point cloud is performed by using the iterative closest point (ICP) algorithm. Our GPU-based SIFT implementation can run at the speed of 30 frames per second (fps) on most images with 900 × 750 resolution in the test. Compared to other methods, our algorithm is simple to implement and suitable for parallel processing. It can be easily integrated into mobile robot’s tasks like navigation or object tracking, which need the real-time localization information. Experiments results showed that in the unknown indoor environments, the proposed algorithm`s operation is stable and the positioning accuracy is high.

The kinetochore drives chromosome segregation at cell division. It acts as a physical link between chromosomes and dynamic microtubules, and as a signaling hub detecting and processing microtubule attachments to control anaphase onset. The mammalian kinetochore is a large macromolecular machine that forms a dynamic interface with the many microtubules that it binds. While we know most of the kinetochore’s component parts, how they work together to give rise to its robust functions remains poorly understood. Here we highlight recent findings that shed light on this question, driven by an expanding physical and molecular toolkit. We present emerging principles that underlie the kinetochore’s robust microtubule grip, such as redundancy, specialization, and dynamicity, and present signal processing principles that connect this microtubule grip to robust computation. Throughout, we identify open questions, and define simple engineering concepts that provide insight into kinetochore function.