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Investigating the role of elastin and extracellular matrix damage in cardiovascular calcification.
Although calcification in the cardiovascular system is highly studied, the mechanisms behind it are not well understood. Current proposed mechanisms focus on cellular processes leading to, or controlling the unwanted mineralization in soft tissues. However, extracellular components such as collagen and elastin fundamentally regulate the mechanical properties of heart tissues. Here, we report on a toolkit to control the composition of tissues through the selective digestion of extracellular matrix (ECM) components, which can be used to design disease-specific in vitro models. Using this technique, we show that elastin as well as matrix tissue damage may play major role in cardiovascular calcification. This study highlights a novel approach to understand the role of proteins in soft tissue calcifications and may lead to the development of strategies to treat and prevent these unwanted pathological disorders.
Policy complexity suppresses dopamine responses.
Limits on information processing capacity impose limits on task performance. We show that male and female mice achieve performance on a perceptual decision task that is near-optimal given their capacity limits, as measured by policy complexity (the mutual information between states and actions). This behavioral profile could be achieved by reinforcement learning with a penalty on high complexity policies, realized through modulation of dopaminergic learning signals. In support of this hypothesis, we find that policy complexity suppresses midbrain dopamine responses to reward outcomes. Furthermore, neural and behavioral reward sensitivity were positively correlated across sessions. Our results suggest that policy compression shapes basic mechanisms of reinforcement learning in the brain.Significance statement Decision making relies on memory to store information about which actions to produce in which situations. This memory has limited capacity, which means that some information will be lost. The signatures of this information loss can be found in patterns of behavioral bias and randomness. However, relatively little is known about the neural mechanisms which ensure that actions achieve the highest possible reward given the limited capacity of decision memory. In this paper, we show that the neuromodulator dopamine is sensitive to the costs of memory, as predicted by a computational model of capacity-limited learning.
Reward Bases: A simple mechanism for adaptive acquisition of multiple reward types.
Animals can adapt their preferences for different types of reward according to physiological state, such as hunger or thirst. To explain this ability, we employ a simple multi-objective reinforcement learning model that learns multiple values according to different reward dimensions such as food or water. We show that by weighting these learned values according to the current needs, behaviour may be flexibly adapted to present preferences. This model predicts that individual dopamine neurons should encode the errors associated with some reward dimensions more than with others. To provide a preliminary test of this prediction, we reanalysed a small dataset obtained from a single primate in an experiment which to our knowledge is the only published study where the responses of dopamine neurons to stimuli predicting distinct types of rewards were recorded. We observed that in addition to subjective economic value, dopamine neurons encode a gradient of reward dimensions; some neurons respond most to stimuli predicting food rewards while the others respond more to stimuli predicting fluids. We also proposed a possible implementation of the model in the basal ganglia network, and demonstrated how the striatal system can learn values in multiple dimensions, even when dopamine neurons encode mixtures of prediction error from different dimensions. Additionally, the model reproduces the instant generalisation to new physiological states seen in dopamine responses and in behaviour. Our results demonstrate how a simple neural circuit can flexibly guide behaviour according to animals' needs.
Midbrain encodes sound detection behavior without auditory cortex
Hearing involves analyzing the physical attributes of sounds and integrating the results of this analysis with other sensory, cognitive, and motor variables in order to guide adaptive behavior. The auditory cortex is considered crucial for the integration of acoustic and contextual information and is thought to share the resulting representations with subcortical auditory structures via its vast descending projections. By imaging cellular activity in the corticorecipient shell of the inferior colliculus of mice engaged in a sound detection task, we show that the majority of neurons encode information beyond the physical attributes of the stimulus and that the animals’ behavior can be decoded from the activity of those neurons with a high degree of accuracy. Surprisingly, this was also the case in mice in which auditory cortical input to the midbrain had been removed by bilateral cortical lesions. This illustrates that subcortical auditory structures have access to a wealth of non-acoustic information and can, independently of the auditory cortex, carry much richer neural representations than previously thought.
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.