Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition.

Prefrontal cortex (PFC) is postulated to exert "top-down control" on information processing throughout the brain to promote specific behaviors. However, pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down control of hippocampal information processing remains sparse. Here we describe monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide-expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal-hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal encoding of object locations and augment object-induced increases in spatial information. Correspondingly, activating or inhibiting these projections promotes or suppresses object exploration, respectively. Together, these results elucidate a top-down prefrontal pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

Cortical Layer-Dependent Signaling in Cognition: Three Computational Modes of the Canonical Circuit.

The cerebral cortex performs computations via numerous six-layer modules. The operational dynamics of these modules were studied primarily in early sensory cortices using bottom-up computation for response selectivity as a model, which has been recently revolutionized by genetic approaches in mice. However, cognitive processes such as recall and imagery require top-down generative computation. The question of whether the layered module operates similarly in top-down generative processing as in bottom-up sensory processing has become testable by advances in the layer identification of recorded neurons in behaving monkeys. This review examines recent advances in laminar signaling in these two computations, using predictive coding computation as a common reference, and shows that each of these computations recruits distinct laminar circuits, particularly in layer 5, depending on the cognitive demands. These findings highlight many open questions, including how different interareal feedback pathways, originating from and terminating at different layers, convey distinct functional signals.

Aneuploidy Causes Non-genetic Individuality.

Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell-cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting that subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.

Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease.

Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particularly vulnerable to oxidative damage, mainly because of its unique lipid composition, resulting in an amplified cascade of redox reactions that target several cellular components/functions ultimately leading to neurodegeneration. The present review highlights the "OS hypothesis of AD," including amyloid beta-peptide-associated mechanisms, the role of lipid and protein oxidation unraveled by redox proteomics, and the antioxidant strategies that have been investigated to modulate the progression of AD. Collected studies from our groups and others have contributed to unraveling the close relationships between perturbation of redox homeostasis in the brain and AD neuropathology by elucidating redox-regulated events potentially involved in both the pathogenesis and progression of AD. However, the complexity of AD pathological mechanisms requires an in-depth understanding of several major intracellular pathways affecting redox homeostasis and relevant for brain functions. This understanding is crucial to developing pharmacological strategies targeting OS-mediated toxicity that may potentially contribute to slow AD progression as well as improve the quality of life of persons with this severe dementing disorder.

Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome.

Down syndrome (DS) is typically caused by triplication of chromosome 21. Phenotypically, DS presents with developmental, neurocognitive, and immune features. Epidemiologically, individuals with DS have less frequent viral infection, but when present, these infections lead to more severe disease. The potent antiviral cytokine type I Interferon (IFN-I) receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21. While increased IFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessive negative feedback. This led to a hypo-response to subsequent IFN-I stimuli and an ensuing viral susceptibility in DS compared to control cells. Upregulation of IFNAR2 expression phenocopied the DS IFN-I dynamics independent of trisomy 21. CD14+ monocytes from individuals with DS exhibited markers of prior IFN-I exposure and had muted responsiveness to ex vivo IFN-I stimulation. Our findings unveil oscillations of hyper- and hypo-response to IFN-I in DS, predisposing individuals to both lower incidence of viral disease and increased infection-related morbidity and mortality.

Next generation single-molecule techniques: Imaging, labeling, and manipulation in vitro and in cellulo.

Owing to their unique abilities to manipulate, label, and image individual molecules in vitro and in cellulo, single-molecule techniques provide previously unattainable access to elementary biological processes. In imaging, single-molecule fluorescence resonance energy transfer (smFRET) and protein-induced fluorescence enhancement in vitro can report on conformational changes and molecular interactions, single-molecule pull-down (SiMPull) can capture and analyze the composition and function of native protein complexes, and single-molecule tracking (SMT) in live cells reveals cellular structures and dynamics. In labeling, the abilities to specifically label genomic loci, mRNA, and nascent polypeptides in cells have uncovered chromosome organization and dynamics, transcription and translation dynamics, and gene expression regulation. In manipulation, optical tweezers, integration of single-molecule fluorescence with force measurements, and single-molecule force probes in live cells have transformed our mechanistic understanding of diverse biological processes, ranging from protein folding, nucleic acids-protein interactions to cell surface receptor function.

Neocortical Layer 1: An Elegant Solution to Top-Down and Bottom-Up Integration.

Many of our daily activities, such as riding a bike to work or reading a book in a noisy cafe, and highly skilled activities, such as a professional playing a tennis match or a violin concerto, depend upon the ability of the brain to quickly make moment-to-moment adjustments to our behavior in response to the results of our actions. Particularly, they depend upon the ability of the neocortex to integrate the information provided by the sensory organs (bottom-up information) with internally generated signals such as expectations or attentional signals (top-down information). This integration occurs in pyramidal cells (PCs) and their long apical dendrite, which branches extensively into a dendritic tuft in layer 1 (L1). The outermost layer of the neocortex, L1 is highly conserved across cortical areas and species. Importantly, L1 is the predominant input layer for top-down information, relayed by a rich, dense mesh of long-range projections that provide signals to the tuft branches of the PCs. Here, we discuss recent progress in our understanding of the composition of L1 and review evidence that L1 processing contributes to functions such as sensory perception, cross-modal integration, controlling states of consciousness, attention, and learning.

The immune system in Down Syndrome: Autoimmunity and severe infections.

Over 200,000 individuals in the United States alone live with Down Syndrome (DS), the most common genetic disorder associated with intellectual disability. DS has a constellation of features across the body, including dysregulation of the immune system. Individuals with DS have both a higher frequency of autoimmunity and more severe infections than the general population, highlighting the importance of understanding the immune system in this population. Individuals with DS present with dysregulation of both the innate and adaptive immune systems. Elevated cytokine levels, increased type I and type II IFN signaling, a shift toward memory phenotypes in T cells, and a decrease in the size of the B-cell compartment are observed in individuals with DS, which contribute to both autoinflammation and severe infections. Herein, we discuss the current knowledge of the immune system in individuals with Down Syndrome as well as ideas of necessary further investigations to decipher the mechanisms by which trisomy 21 leads to immune dysregulation, with the ultimate goal of identifying clinical targets to improve treatment.

Assessing autosomal aneuploidy in ancient genomes.

Using genetic methods, aneuploidies can be detected in ancient human remains, which is so far the only way to reliably prove their existence in the past. As highlighted in recent studies by Rohrlach et al. and by Anastasiadou et al., this initial step enables a deeper exploration of the history of rare diseases, encompassing the social and historical contexts of the afflicted individuals.

AUTACs: Cargo-Specific Degraders Using Selective Autophagy.

Protein silencing represents an essential tool in biomedical research. Targeted protein degradation (TPD) strategies exemplified by PROTACs are rapidly emerging as modalities in drug discovery. However, the scope of current TPD techniques is limited because many intracellular materials are not substrates of proteasomal clearance. Here, we described a novel targeted-clearance strategy (autophagy-targeting chimera [AUTAC]) that contains a degradation tag (guanine derivatives) and a warhead to provide target specificity. As expected from the substrate scope of autophagy, AUTAC degraded fragmented mitochondria as well as proteins. Mitochondria-targeted AUTAC accelerated both the removal of dysfunctional fragmented mitochondria and the biogenesis of functionally normal mitochondria in patient-derived fibroblast cells. Cytoprotective effects against acute mitochondrial injuries were also seen. Canonical autophagy is viewed as a nonselective bulk decomposition system, and none of the available autophagy-inducing agents exhibit useful cargo selectivity. With its target specificity, AUTAC provides a new modality for research on autophagy-based drugs.

Consequences of trisomy syndromes - 21 and beyond.

The mechanisms underlying pathologies in Down syndrome remain poorly understood. In this forum article we compare the cellular phenotypes of chromosome 21 trisomy with other trisomic cells. We argue that both effects of the extra chromosome 21 and the global consequences of chromosome gain must be considered to understand complex pathologies of Down syndrome.

Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes.

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes.

Are Internal Fragments Observable in Electron Based Top-Down Mass Spectrometry?

Protein tandem mass spectrometry (MS/MS) often generates sequence-informative fragments from backbone bond cleavages near the termini. This lack of fragmentation in the protein interior is particularly apparent in native top-down mass spectrometry (MS). Improved sequence coverage, critical for reliable annotation of posttranslational modifications and sequence variants, may be obtained from internal fragments generated by multiple backbone cleavage events. However, internal fragment assignments can be error prone due to isomeric/isobaric fragments from different parts of a protein sequence. Also, internal fragment generation propensity depends on the chosen MS/MS activation strategy. Here, we examine internal fragment formation in electron capture dissociation (ECD) and electron transfer dissociation (ETD) following native and denaturing MS, as well as LC/MS of several proteins. Experiments were undertaken on multiple instruments, including quadrupole time-of-flight, Orbitrap, and high-field Fourier-transform ion cyclotron resonance (FT-ICR) across four laboratories. ECD was performed at both ultrahigh vacuum and at similar pressure to ETD conditions. Two complementary software packages were used for data analysis. When feasible, ETD-higher energy collision dissociation MS3 was performed to validate/refute potential internal fragment assignments, including differentiating MS3 fragmentation behavior of radical versus even-electron primary fragments. We show that, under typical operating conditions, internal fragments cannot be confidently assigned in ECD or ETD. On the other hand, such fragments, along with some b-type terminal fragments (not typically observed in ECD/ETD spectra) appear at atypical ECD operating conditions, suggesting they originate from a separate ion-electron activation process. Furthermore, atypical fragment ion types, e.g., x ions, are observed at such conditions as well as upon EThcD, presumably due to vibrational activation of radical z-type ions.

The hidden order of Turing patterns in arid and semi-arid vegetation ecosystems.

Vegetation Turing patterns play a critical role in the ecological functioning of arid and semi-arid ecosystems. However, the long-range spatial features of these patterns have been neglected compared to short-range features like patch shape and spatial wavelength. Drawing inspiration from hyperuniform structures in material science, we find that the arid and semi-arid vegetation Turing pattern exhibits long-range dispersion similar to hyperuniformity. As the degree of hyperuniformity of the vegetation Turing pattern increases, so does the water-use efficiency of the vegetation. This finding supports previous studies that suggest that Turing patterns represent a spatially optimized self-organization of ecosystems for water acquisition. The degree of hyperuniformity of Turing-type ecosystems exhibits significant critical slowing down near the tipping point, indicating that these ecosystems have non-negligible transient dynamical behavior. Reduced rainfall not only decreases the resilience of the steady state of the ecosystem but also slows down the rate of spatial optimization of water-use efficiency in long transient regimes. We propose that the degree of hyperuniformity indicates the spatial resilience of Turing-type ecosystems after strong, short-term disturbances. Spatially heterogeneous disturbances that reduce hyperuniformity lead to longer recovery times than spatially homogeneous disturbances that maintain hyperuniformity.

Human-like scene interpretation by a guided counterstream processing.

In modeling vision, there has been a remarkable progress in recognizing a range of scene components, but the problem of analyzing full scenes, an ultimate goal of visual perception, is still largely open. To deal with complete scenes, recent work focused on the training of models for extracting the full graph-like structure of a scene. In contrast with scene graphs, humans' scene perception focuses on selected structures in the scene, starting with a limited interpretation and evolving sequentially in a goal-directed manner [G. L. Malcolm, I. I. A. Groen, C. I. Baker, Trends. Cogn. Sci. 20, 843-856 (2016)]. Guidance is crucial throughout scene interpretation since the extraction of full scene representation is often infeasible. Here, we present a model that performs human-like guided scene interpretation, using an iterative bottom-up, top-down processing, in a "counterstream" structure motivated by cortical circuitry. The process proceeds by the sequential application of top-down instructions that guide the interpretation process. The results show how scene structures of interest to the viewer are extracted by an automatically selected sequence of top-down instructions. The model shows two further benefits. One is an inherent capability to deal well with the problem of combinatorial generalization-generalizing broadly to unseen scene configurations, which is limited in current network models [B. Lake, M. Baroni, 35th International Conference on Machine Learning, ICML 2018 (2018)]. The second is the ability to combine visual with nonvisual information at each cycle of the interpretation process, which is a key aspect for modeling human perception as well as advancing AI vision systems.

Hierarchical Gradients of Encoded Spatial and Sensory Information in the Neocortex Are Attenuated by Dorsal Hippocampal Lesions.

During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs.

The serine protease inhibitor HAMpin-1 produced by the ectoparasite Hyalomma anatolicum salivary gland modulates the host complement system.

Ticks are notable vectors of diseases affecting both humans and animals, with Hyalomma anatolicum being of particular significance due to its wide distribution and capability to transmit a variety of pathogens, including Theileriaannulata and Crimean-Congo haemorrhagic fever virus. This study aimed to investigate the inhibitory effects of H. anatolicum salivary gland extract (HaSGE) and the identification of its key component on the complement system of the host's innate immune defense. We demonstrated that HaSGE exerts a dose-dependent inhibition on the complement activation in a host-specific manner. Mechanistic studies revealed that HaSGE interferes with deposition and cleavage of complement proteins C3 and C5, thus preventing the formation of the membrane attack complex. Further, we identified a serine protease inhibitor, Hyalomma anatolicum serpin-1 (HAMpin-1), from the HaSGE through proteomic analysis and characterized its structure, function, and interaction with complement proteins. HAMpin-1 exhibited potent inhibitory activity against chymotrypsin and cathepsin-G, and notably, it is the first serpin from ticks shown to inhibit the classical and lectin pathways of the complement system. The expression of HAMpin-1 was highest in the salivary glands, suggesting its crucial role in blood feeding and immune evasion. Our findings revealed one of the potential mechanisms used by H. anatolicum to modulate host immune responses at the interface, offering new insights into tick-host interactions.

Following the Evolutionary Paths of Dscam1 Proteins toward Highly Specific Homophilic Interactions.

Many adhesion proteins, evolutionarily related through gene duplication, exhibit distinct and precise interaction preferences and affinities crucial for cell patterning. Yet, the evolutionary paths by which these proteins acquire new specificities and prevent cross-interactions within their family members remain unknown. To bridge this gap, this study focuses on Drosophila Down syndrome cell adhesion molecule-1 (Dscam1) proteins, which are cell adhesion proteins that have undergone extensive gene duplication. Dscam1 evolved under strong selective pressure to achieve strict homophilic recognition, essential for neuronal self-avoidance and patterning. Through a combination of phylogenetic analyses, ancestral sequence reconstruction, and cell aggregation assays, we studied the evolutionary trajectory of Dscam1 exon 4 across various insect lineages. We demonstrated that recent Dscam1 duplications in the mosquito lineage bind with strict homophilic specificities without any cross-interactions. We found that ancestral and intermediate Dscam1 isoforms maintained their homophilic binding capabilities, with some intermediate isoforms also engaging in promiscuous interactions with other paralogs. Our results highlight the robust selective pressure for homophilic specificity integral to the Dscam1 function within the process of neuronal self-avoidance. Importantly, our study suggests that the path to achieving such selective specificity does not introduce disruptive mutations that prevent self-binding but includes evolutionary intermediates that demonstrate promiscuous heterophilic interactions. Overall, these results offer insights into evolutionary strategies that underlie adhesion protein interaction specificities.

Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension.

Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A/PPARG/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.

Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders.

Those with Down syndrome (DS)-trisomy for chromosome 21-are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.