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Prediction of future input explains lateral connectivity in primary visual cortex.
Neurons in primary visual cortex (V1) show a remarkable functional specificity in their pre- and postsynaptic partners. Recent work has revealed a variety of wiring biases describing how the short- and long-range connections of V1 neurons relate to their tuning properties. However, it is less clear whether these connectivity rules are based on some underlying principle of cortical organization. Here, we show that the functional specificity of V1 connections emerges naturally in a recurrent neural network optimized to predict upcoming sensory inputs for natural visual stimuli. This temporal prediction model reproduces the complex relationships between the connectivity of V1 neurons and their orientation and direction preferences, the tendency of highly connected neurons to respond more similarly to natural movies, and differences in the functional connectivity of excitatory and inhibitory V1 populations. Together, these findings provide a principled explanation for the functional and anatomical properties of early sensory cortex.
Basic Science and Pathogenesis
BACKGROUND: Alzheimer's (AD) and Parkinson's disease (PD) feature progressive neurodegeneration in a remarkably regionally selective manner. Post mortem studies have posited a role for cell autonomous mechanisms driving this, so we aimed to examine a live human induced pluripotent stem cell (iPSC) model to see whether it can replicate the phenomenon of selective neuronal vulnerability, so to better determine disease mechanisms and therapeutic targets. METHOD: iPSC-derived neurons offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD-related presenilin-1 mutations (n = 6), PD-related leucine rich repeat kinase 2 mutations (n = 6), and isogenic corrected (n = 4) and healthy controls (n = 4) have been differentiated into both cortical and midbrain dopaminergic neurons to enable comparison of pre-formed fibril induced pathology in different neuronal subtypes from the same patient. We then examined lysosomal number, morphology, degradation, pH, and calcium using live imaging assays, alongside mitochondrial biology, and electrophysiology to understand underlying drivers of vulnerability in the cell types. RESULT: Upon insult with alpha-synuclein PFFs, AD and PD dopaminergic neurons produce substantial Lewy-like pathology, whereas cortical neurons remain relatively resilient to alpha-synuclein aggregation, suggesting cell-type vulnerability. PSEN1-Intron-4-Deletion cortical neurons, however, had significantly elevated pathology. These lines displayed hyperactivity on microelectrode arrays and abnormal lysosomal biology, including increased LAMP1 and dysregulated calcium. PFF-insulted AD cortical neurons also have impaired neurite outgrowth, while PD cortical neurons are resilient. CONCLUSION: These preliminary results show relative vulnerability of AD against PD cortical neurons, and dopaminergic against cortical neurons to alpha-synuclein aggregates for the first time. These suggest the selective vulnerability to proteinopathy in these diseases is reflected by the iPSC neuronal model and support the notion that cell intrinsic factors like autophagy drive vulnerability.
Integration of somatosensory and motor-related information in the auditory system.
An ability to integrate information provided by different sensory modalities is a fundamental feature of neurons in many brain areas. Because visual and auditory inputs often originate from the same external object, which may be located some distance away from the observer, the synthesis of these cues can improve localization accuracy and speed up behavioral responses. By contrast, multisensory interactions occurring close to the body typically involve a combination of tactile stimuli with other sensory modalities. Moreover, most activities involving active touch generate sound, indicating that stimuli in these modalities are frequently experienced together. In this review, we examine the basis for determining sound-source distance and the contribution of auditory inputs to the neural encoding of space around the body. We then consider the perceptual consequences of combining auditory and tactile inputs in humans and discuss recent evidence from animal studies demonstrating how cortical and subcortical areas work together to mediate communication between these senses. This research has shown that somatosensory inputs interface with and modulate sound processing at multiple levels of the auditory pathway, from the cochlear nucleus in the brainstem to the cortex. Circuits involving inputs from the primary somatosensory cortex to the auditory midbrain have been identified that mediate suppressive effects of whisker stimulation on auditory thalamocortical processing, providing a possible basis for prioritizing the processing of tactile cues from nearby objects. Close links also exist between audition and movement, and auditory responses are typically suppressed by locomotion and other actions. These movement-related signals are thought to cancel out self-generated sounds, but they may also affect auditory responses via the associated somatosensory stimulation or as a result of changes in brain state. Together, these studies highlight the importance of considering both multisensory context and movement-related activity in order to understand how the auditory cortex operates during natural behaviors, paving the way for future work to investigate auditory-somatosensory interactions in more ecological situations.
ARSACS: Clinical Features, Pathophysiology and iPS-Derived Models.
Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease caused by mutations in the SACS gene. The first two mutations were identified in French Canadian populations 20 years ago. The disease is now known as one of the most frequent recessive ataxias worldwide. Prominent features include cerebellar ataxia, pyramidal spasticity, and neuropathy. Neuropathological findings revealed cerebellar atrophy of the superior cerebellar vermis and the anterior vermis associated with Purkinje cell death, pyramidal degeneration, cortical atrophy, loss of motor neurons, and demyelinating neuropathy. No effective therapy is available for ARSACS patients but, in the last two decades, there have been significant advances in our understanding of the disease. New approaches in ARSACS, such as the reprogramming of induced pluripotent stem cells derived from patients, open exciting perspectives of discoveries. Several research questions are now emerging. Here, we review the clinical features of ARSACS as well as the cerebellar aspects of the disease, with an emphasis on recent fields of investigation.
Sonic hedgehog medulloblastoma cells in co-culture with cerebellar organoids converge towards in vivo malignant cell states
Abstract Background In the malignant brain tumour sonic hedgehog medulloblastoma (SHH-MB) the properties of cancer cells are influenced by their microenvironment, but the nature of those effects and the phenotypic consequences for the tumour are poorly understood. The aim of this study was to identify phenotypic properties of SHH-MB cells that were driven by the non-malignant tumour microenvironment. Methods Human induced pluripotent cells (iPSC) were differentiated to cerebellar organoids to simulate the non-maliganant tumour microenvironment. Tumour spheroids were generated from two distinct, long-established SHH-MB cell lines which were co-cultured with cerebellar organoids. We profiled the cellular transcriptomes of malignant and non-malignant cells by performing droplet-based single-cell RNA-sequencing (scRNA-seq). The transcriptional profiles of tumour cells in co-culture were compared with those of malignant cell monocultures and with public SHH-MB datasets of patient tumours and patient-derived orthotopic xenograft (PDX) mouse models. Results SHH-MB cell lines in organoid co-culture adopted patient tumour-associated phenotypes and showed increased heterogeneity compared to monocultures. Sub-populations of co-cultured SHH-MB cells activated a key marker of differentiating granule cells, NEUROD1 that was not observed in tumour monocultures. Other sub-populations expressed transcriptional determinants consistent with a cancer stem cell (CSC)-like state that resembled cell states identified in vivo. Conclusion For SHH-MB cell lines in co-culture, there was a convergence of malignant cell states towards patterns of heterogeneity in patient tumours and PDX models implying these states were non-cell autonomously induced by the microenvironment. Therefore, we have generated an advanced, novel in vitro model of SHH-MB with potential translational applications.
Establishment of early embryonic lineages and the basic body plan
Embryonic development transforms an apparently featureless fertilized egg into the complex form of the fetus. Several important processes need to occur in a coordinated manner to achieve this. First among them is the proliferation of cells, with every cell of the body being derived through the repeated division of the zygote and its descendants. These cells undergo a process of gradual specialization, so that their structure and physiology can be tuned to a variety of different functions. This is coordinated with patterning, which ensures that this emerging cellular heterogeneity within tissues is temporally and spatially organized. Patterning is primarily achieved through modulating the transcriptional state of the cells within tissues. Morphogenesis shapes these tissues to generate the basic body plan and the various organ primordia. This is brought about through coordinated movement, generation of forces, and the modulation of biomechanical properties of the component cells of embryonic tissues. In this chapter, we give a broad outline of the patterning and morphogenetic events that occur from fertilization up to the end of gastrulation. We describe the origin of the tissues that go on to lay the foundations of the various organ systems and how the basic body plan of the fetus is established. As a companion to the Kaufman atlas, this chapter focuses on the developmental origin of anatomical features of the mouse embryo. Wherever possible, we draw comparisons to what is known about human development.
Kaufman’s Atlas of Mouse Development Supplement
Kaufman's Atlas of Mouse Development Supplement, Second Edition continues the stellar reputation of the original Atlas by providing updated, in-depth anatomical content and morphological views of organ systems. The book explores the developmental origins of the organ systems, following the original atlas as a continuation of the standard in the field for developmental biologists and researchers across biological and biomedical sciences studying mouse development. In this new edition, each chapter has been updated to include the latest research, along with while new chapters on the functional aspects of mouse and human heart development, the immune system, and the inner ear. These additions ensure an up-to-date resource for all biomedical scientists who use the mouse as a model species for understanding the normal and abnormal development of human systems.
Introduction
The original Atlas of Mouse Development by Mathew Kaufman was published in the year 1989. In this chapter, we introduce the supplement to this definitive atlas, bringing the description of mouse embryo development up-to-date in light of the new knowledge and understanding of the molecular underpinnings.
The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis.
Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/- bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/- chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.
Brain development
Mouse models have been central to achieving our current understanding of the molecular and cellular mechanisms governing brain development. Brain morphogenesis follows an integrated series of developmental steps: neural induction, neurulation, proliferation, migration, differentiation, regionalization, axonal outgrowth, synaptogenesis, and apoptosis. Newly generated cells migrate radially and tangentially from their sites of origin in primordial brain divisions to generate increasingly mature structures through pre- and postnatal development, with emphasis here given to the cerebral cortex and cerebellum. Immense neuronal diversity is achieved by graded and combinatorial gene expression in various sectors of proliferative cell populations over time. Complex intrinsic and extrinsic factors, such as thalamocortical and corticofugal signaling, update and adapt the brain's functional architecture particularly during critical periods. Studies using transgenic mouse models and advances in both adult and developmental mouse brain atlases will continue to elucidate mechanisms governing normal and pathological mammalian brain development.
Bright and stable anti-counterfeiting devices with independent stochastic processes covering multiple length scales.
Physical unclonable functions (PUFs) are considered the most promising approach to address the global issue of counterfeiting. Current PUF devices are often based on a single stochastic process, which can be broken, especially since their practical encoding capacities can be significantly lower than the theoretical value. Here we present stochastic PUF devices with features across multiple length scales, which incorporate semiconducting polymer nanoparticles (SPNs) as fluorescent taggants. The SPNs exhibit high brightness, photostability and size tunability when compared to the current state-of-the-art taggants. As a result, they are easily detectable and highly resilient to UV radiation. By embedding SPNs in photoresists, we generate PUFs consisting of nanoscale (distribution of SPNs within microspots), microscale (fractal edges on microspots), and macroscale (random microspot array) designs. With the assistance of a deep-learning model, the resulting PUFs show both near-ideal performance and accessibility for general end users, offering a strategy for next-generation security devices.
Conserved patterns of transcriptional dysregulation, heterogeneity, and cell states in clear cell kidney cancer.
Clear cell kidney cancers are characterized both by conserved oncogenic driver events and by marked intratumor genetic and phenotypic heterogeneity, which help drive tumor progression, metastasis, and resistance to therapy. How these are reflected in transcriptional programs within the cancer and stromal cell components remains an important question with the potential to drive novel therapeutic approaches to treating cancer. To better understand these programs, we perform single-cell transcriptomics on 75 multi-regional biopsies from kidney tumors and normal kidney. We identify conserved patterns of transcriptional dysregulation and their upstream regulators within the tumor and associated vasculature. We describe recurrent subclonal transcriptional consequences of Chr14q loss linked to metastatic potential. We identify prognostically significant conserved patterns of intratumor transcriptional heterogeneity. These reflect co-existing cell states found in both cancer cells and normal kidney cells, indicating that rather than arising from genetic heterogeneity they are a consequence of lineage plasticity.
Effects of noise and metabolic cost on cortical task representations.
Cognitive flexibility requires both the encoding of task-relevant and the ignoring of task-irrelevant stimuli. While the neural coding of task-relevant stimuli is increasingly well understood, the mechanisms for ignoring task-irrelevant stimuli remain poorly understood. Here, we study how task performance and biological constraints jointly determine the coding of relevant and irrelevant stimuli in neural circuits. Using mathematical analyses and task-optimized recurrent neural networks, we show that neural circuits can exhibit a range of representational geometries depending on the strength of neural noise and metabolic cost. By comparing these results with recordings from primate prefrontal cortex (PFC) over the course of learning, we show that neural activity in PFC changes in line with a minimal representational strategy. Specifically, our analyses reveal that the suppression of dynamically irrelevant stimuli is achieved by activity-silent, sub-threshold dynamics. Our results provide a normative explanation as to why PFC implements an adaptive, minimal representational strategy.