Publications by authors named "Anders Nelson"

13 Publications

  • Page 1 of 1

Corticospinal populations broadcast complex motor signals to coordinated spinal and striatal circuits.

Nat Neurosci 2021 Nov 4. Epub 2021 Nov 4.

Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.

Many models of motor control emphasize the role of sensorimotor cortex in movement, principally through the projections that corticospinal neurons (CSNs) make to the spinal cord. Additionally, CSNs possess expansive supraspinal axon collaterals, the functional organization of which is largely unknown. Using anatomical and electrophysiological circuit-mapping techniques in the mouse, we reveal dorsolateral striatum as the preeminent target of CSN collateral innervation. We found that this innervation is biased so that CSNs targeting different striatal pathways show biased targeting of spinal cord circuits. Contrary to more conventional perspectives, CSNs encode not only individual movements, but also information related to the onset and offset of motor sequences. Furthermore, similar activity patterns are broadcast by CSN populations targeting different striatal circuits. Our results reveal a logic of coordinated connectivity between forebrain and spinal circuits, where separate CSN modules broadcast similarly complex information to downstream circuits, suggesting that differences in postsynaptic connectivity dictate motor specificity.
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http://dx.doi.org/10.1038/s41593-021-00939-wDOI Listing
November 2021

The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation.

J Am Heart Assoc 2021 07 22;10(13):e019904. Epub 2021 Jun 22.

Cardiovascular Research Center School of Medicine University of Virginia Charlottesville VA.

Background A hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase-like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.
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http://dx.doi.org/10.1161/JAHA.120.019904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403294PMC
July 2021

Network model-based screen for FDA-approved drugs affecting cardiac fibrosis.

CPT Pharmacometrics Syst Pharmacol 2021 04 27;10(4):377-388. Epub 2021 Feb 27.

Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.

Cardiac fibrosis is a significant component of pathological heart remodeling, yet it is not directly targeted by existing drugs. Systems pharmacology approaches have the potential to provide mechanistic frameworks with which to predict and understand how drugs modulate biological systems. Here, we combine network modeling of the fibroblast signaling network with 36 unique drug-target interactions from DrugBank to predict drugs that modulate fibroblast phenotype and fibrosis. Galunisertib was predicted to decrease collagen and α-SMA expression, which we validated in human cardiac fibroblasts. In vivo fibrosis data from the literature validated predictions for 10 drugs. Further, the model was used to identify network mechanisms by which these drugs work. Arsenic trioxide was predicted to induce fibrosis by AP1-driven TGFβ expression and MMP2-driven TGFβ activation. Entresto (valsartan/sacubitril) was predicted to suppress fibrosis by valsartan suppression of ERK signaling and sacubitril enhancement of PKG activity, both of which decreased Smad3 activity. Overall, this study provides a framework for integrating drug-target mechanisms with logic-based network models, which can drive further studies both in cardiac fibrosis and other conditions.
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http://dx.doi.org/10.1002/psp4.12599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099443PMC
April 2021

Network Analysis Reveals a Distinct Axis of Macrophage Activation in Response to Conflicting Inflammatory Cues.

J Immunol 2021 02 6;206(4):883-891. Epub 2021 Jan 6.

Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908; and

Macrophages are subject to a wide range of cytokine and pathogen signals in vivo, which contribute to differential activation and modulation of inflammation. Understanding the response to multiple, often-conflicting cues that macrophages experience requires a network perspective. In this study, we integrate data from literature curation and mRNA expression profiles obtained from wild type C57/BL6J mice macrophages to develop a large-scale computational model of the macrophage signaling network. In response to stimulation across all pairs of nine cytokine inputs, the model predicted activation along the classic M1-M2 polarization axis but also a second axis of macrophage activation that distinguishes unstimulated macrophages from a mixed phenotype induced by conflicting cues. Along this second axis, combinations of conflicting stimuli, IL-4 with LPS, IFN-γ, IFN-β, or TNF-α, produced mutual inhibition of several signaling pathways, e.g., NF-κB and STAT6, but also mutual activation of the PI3K signaling module. In response to combined IFN-γ and IL-4, the model predicted genes whose expression was mutually inhibited, e.g., or and , or mutually enhanced, e.g., and , validated by independent experimental data. Knockdown simulations further predicted network mechanisms underlying functional cross-talk, such as mutual STAT3/STAT6-mediated enhancement of Il4rα expression. In summary, the computational model predicts that network cross-talk mediates a broadened spectrum of macrophage activation in response to mixed pro- and anti-inflammatory cytokine cues, making it useful for modeling in vivo scenarios.
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http://dx.doi.org/10.4049/jimmunol.1901444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854506PMC
February 2021

Computational model predicts paracrine and intracellular drivers of fibroblast phenotype after myocardial infarction.

Matrix Biol 2020 09 21;91-92:136-151. Epub 2020 Mar 21.

Department of Biomedical Engineering, University of Virginia, PO Box 800759, Charlottesville, VA 22908-0759, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA. Electronic address:

The fibroblast is a key mediator of wound healing in the heart and other organs, yet how it integrates multiple time-dependent paracrine signals to control extracellular matrix synthesis has been difficult to study in vivo. Here, we extended a computational model to simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction (MI) in response to time-dependent data for nine paracrine stimuli. This computational model was validated against dynamic collagen expression and collagen area fraction data from post-infarction rat hearts. The model predicted that while many features of the fibroblast phenotype at inflammatory or maturation phases of healing could be recapitulated by single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking the reparative phase required paired stimuli (e.g. TGFβ and endothelin-1). Virtual overexpression screens simulated with either static cytokine pairs or post-MI paracrine dynamic predicted phase-specific regulators of collagen expression. Several regulators increased (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the reparative phase. NADPH oxidase (NOX) overexpression sustained collagen expression from reparative to maturation phases, driven by TGFβ and endothelin positive feedback loops. Interleukin-1 overexpression had mixed effects, both enhancing collagen via the TGFβ positive feedback loop and suppressing collagen via NFκB and BAMBI (BMP and activin membrane-bound inhibitor) incoherent feed-forward loops. These model-based predictions reveal network mechanisms by which the dynamics of paracrine stimuli and interacting signaling pathways drive the progression of fibroblast phenotypes and fibrosis after myocardial infarction.
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http://dx.doi.org/10.1016/j.matbio.2020.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434705PMC
September 2020

Multiscale Coupling of an Agent-Based Model of Tissue Fibrosis and a Logic-Based Model of Intracellular Signaling.

Front Physiol 2019 17;10:1481. Epub 2019 Dec 17.

Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States.

Wound healing and fibrosis following myocardial infarction (MI) is a dynamic process involving many cell types, extracellular matrix (ECM), and inflammatory cues. As both incidence and survival rates for MI increase, management of post-MI recovery and associated complications are an increasingly important focus. Complexity of the wound healing process and the need for improved therapeutics necessitate a better understanding of the biochemical cues that drive fibrosis. To study the progression of cardiac fibrosis across spatial and temporal scales, we developed a novel hybrid multiscale model that couples a logic-based differential equation (LDE) model of the fibroblast intracellular signaling network with an agent-based model (ABM) of multi-cellular tissue remodeling. The ABM computes information about cytokine and growth factor levels in the environment including TGFβ, TNFα, IL-1β, and IL-6, which are passed as inputs to the LDE model. The LDE model then computes the network signaling state of individual cardiac fibroblasts within the ABM. Based on the current network state, fibroblasts make decisions regarding cytokine secretion and deposition and degradation of collagen. Simulated fibroblasts respond dynamically to rapidly changing extracellular environments and contribute to spatial heterogeneity in model predicted fibrosis, which is governed by many parameters including cell density, cell migration speeds, and cytokine levels. Verification tests confirmed that predictions of the coupled model and network model alone were consistent in response to constant cytokine inputs and furthermore, a subset of coupled model predictions were validated with experiments with human cardiac fibroblasts. This multiscale framework for cardiac fibrosis will allow for systematic screening of the effects of molecular perturbations in fibroblast signaling on tissue-scale extracellular matrix composition and organization.
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http://dx.doi.org/10.3389/fphys.2019.01481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928129PMC
December 2019

Contactless Transport and Mixing of Liquids on Self-Sustained Sublimating Coatings.

Langmuir 2017 02 13;33(8):1799-1809. Epub 2017 Feb 13.

Laboratory of Thermodynamics in Emerging Technologies, Institute of Energy Technology, Department of Mechanical and Process Engineering, ETH Zürich , 8092 Zürich, Switzerland.

Controlled handling of liquids and colloidal suspensions as they interact with surfaces, targeting a broad palette of related functionalities, is of great importance in science, technology, and nature. When small liquid volumes (drops on the order of microliters or nanoliters) need to be processed in microfluidic devices, contamination on the solid/liquid interface and loss of liquid due to adhesion on the transport channels are two very common problems that can significantly alter the process outcome, for example, the chemical reaction efficiency or the purity and the final concentration of a suspension. It is, therefore, no surprise that both levitation and minimal contact transport methods-including nonwetting surfaces-have been developed to minimize the interactions between liquids and surfaces. Here, we demonstrate contactless surface levitation and transport of liquid drops, realized by harnessing and sustaining the natural sublimation of a solid-carbon-dioxide-coated substrate to generate a continuous supporting vapor layer. The capability and limitations of this technique in handling liquids of extreme surface tension and kinematic viscosity values are investigated both experimentally and theoretically. The sublimating coating is capable of repelling many viscous and low-surface-tension liquids, colloidal suspensions, and non-Newtonian fluids as well, displaying outstanding omniphobic properties. Finally, we demonstrate how sublimation can be used for liquid transport, mixing, and drop coalescence, with a sublimating layer coated on an underlying substrate with prefabricated channels, conferring omniphobicity using a simple physical approach (i.e., phase change) rather than a chemical one. The independence of the surface levitation principle from material properties, such as electromagnetic, thermal or optical, surface energy, adhesion, or mechanical properties, renders this method attractive for a wide range of potential applications.
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http://dx.doi.org/10.1021/acs.langmuir.6b04377DOI Listing
February 2017

The Basal Forebrain and Motor Cortex Provide Convergent yet Distinct Movement-Related Inputs to the Auditory Cortex.

Neuron 2016 05 21;90(3):635-48. Epub 2016 Apr 21.

Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA. Electronic address:

Cholinergic inputs to the auditory cortex from the basal forebrain (BF) are important to auditory processing and plasticity, but little is known about the organization of these synapses onto different auditory cortical neuron types, how they influence auditory responsiveness, and their activity patterns during various behaviors. Using intersectional tracing, optogenetic circuit mapping, and in vivo calcium imaging, we found that cholinergic axons arising from the caudal BF target major excitatory and inhibitory auditory cortical cell types, rapidly modulate auditory cortical tuning, and display fast movement-related activity. Furthermore, the BF and the motor cortex-another source of movement-related activity-provide convergent input onto some of the same auditory cortical neurons. Cholinergic and motor cortical afferents to the auditory cortex display distinct activity patterns and presynaptic partners, indicating that the auditory cortex integrates bottom-up cholinergic signals related to ongoing movements and arousal with top-down information concerning impending movements and motor planning.
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http://dx.doi.org/10.1016/j.neuron.2016.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866808PMC
May 2016

A synaptic and circuit basis for corollary discharge in the auditory cortex.

Nature 2014 Sep 27;513(7517):189-94. Epub 2014 Aug 27.

Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.

Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.
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http://dx.doi.org/10.1038/nature13724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248668PMC
September 2014

A circuit for motor cortical modulation of auditory cortical activity.

J Neurosci 2013 Sep;33(36):14342-53

Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity.
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http://dx.doi.org/10.1523/JNEUROSCI.2275-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761045PMC
September 2013

New modules are added to vibrissal premotor circuitry with the emergence of exploratory whisking.

Neuron 2013 Jan;77(2):346-60

Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.

Rodents begin to use bilaterally coordinated, rhythmic sweeping of their vibrissae ("whisking") for environmental exploration around 2 weeks after birth. Whether (and how) the vibrissal control circuitry changes after birth is unknown, and the relevant premotor circuitry remains poorly characterized. Using a modified rabies virus transsynaptic tracing strategy, we labeled neurons synapsing directly onto vibrissa facial motor neurons (vFMNs). Sources of potential excitatory, inhibitory, and modulatory vFMN premotor neurons, and differences between the premotor circuitry for vFMNs innervating intrinsic versus extrinsic vibrissal muscles were systematically characterized. The emergence of whisking is accompanied by the addition of new sets of bilateral excitatory inputs to vFMNs from neurons in the lateral paragigantocellularis (LPGi). Furthermore, descending axons from the motor cortex directly innervate LPGi premotor neurons. Thus, neural modules that are well suited to facilitate the bilateral coordination and cortical control of whisking are added to the premotor circuitry in parallel with the emergence of this exploratory behavior.
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http://dx.doi.org/10.1016/j.neuron.2012.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559006PMC
January 2013

Characterizing biobank organizations in the U.S.: results from a national survey.

Genome Med 2013 25;5(1). Epub 2013 Jan 25.

Department of Health Policy and Management, CB 7411, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7411, USA.

Background: Effective translational biomedical research hinges on the operation of 'biobanks,' repositories that assemble, store, and manage collections of human specimens and related data. Some are established intentionally to address particular research needs; many, however, have arisen opportunistically, in a variety of settings and with a variety of expectations regarding their functions and longevity. Despite their rising prominence, little is known about how biobanks are organized and function beyond simple classification systems (government, academia, industry).

Methods: In 2012, we conducted the first national survey of biobanks in the U.S., collecting information on their origins, specimen collections, organizational structures, and market contexts and sustainability. From a list of 636 biobanks assembled through a multi-faceted search strategy, representatives from 456 U.S. biobanks were successfully recruited for a 30-minute online survey (72% response rate). Both closed and open-ended responses were analyzed using descriptive statistics.

Results: While nearly two-thirds of biobanks were established within the last decade, 17% have been in existence for over 20 years. Fifty-three percent listed research on a particular disease as the most important reason for establishment; 29% listed research generally. Other reasons included response to a grant or gift, and intent to centralize, integrate, or harmonize existing research structures. Biobank collections are extraordinarily diverse in number and types of specimens and in sources (often multiple) from which they are obtained, including from individuals, clinics or hospitals, public health programs, and research studies. Forty-four percent of biobanks store pediatric specimens, and 36% include postmortem specimens. Most biobanks are affiliated in one or multiple ways with other entities: 88% are part of at least one or more larger organizations (67% of these are academic, 23% hospitals, 13% research institutes). The majority of biobanks seem to fill a particular 'niche' within a larger organization or research area; a minority are concerned about competition for services, although many are worried about underutilization of specimens and long-term funding.

Conclusions: Effective utilization of biobank collections and effective policies to govern their use will require understanding of the immense diversity found in organizational features, including the very different history and primary goals that many biobanks have.
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http://dx.doi.org/10.1186/gm407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706795PMC
May 2014
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