Biology subjects

Kaiser, J.

Publications and source records attributed to Kaiser, J..

34 records · Page 2Linked to original sources

bioRxiv2022

Molecular specification of cortico-brainstem versus corticospinal projection neurons in development

Skilled motor control requires precise connections between subcerebral projection neurons (SCPN) in the cerebral cortex and their appropriate subcerebral targets in the brainstem or spinal cord. The brainstem is an important motor control center and cortical projections to the brainstem serve distinct motor control functions than corticospinal projections. However, mechanisms controlling cortico-brainstem versus corticospinal projections during development remain unknown. Here, we show that the transition between the brainstem and cervical cord distinguishes cortico-brainstem from corticospinal neurons from the earliest stages of SCPN axon extension in white matter. We used high throughput single-cell RNA sequencing of FACS-purified SCPN, retrogradely labeled from either the cerebral peduncle (labeling both cortico-brainstem and corticospinal neurons) or the cervical cord (labeling corticospinal neurons only) at critical times of axon extension. We identify that cortico-brainstem and corticospinal neurons are molecularly distinct: We establish Neuropeptide Y (Npy) as specifically enriched in cortico-brainstem neurons in lateral cortex, while CART prepropeptide (Cartpt) delineates cervical-projecting corticospinal neurons. Our results highlight molecular specification of cortico-brainstem vs. corticospinal projections well before these axons reach their appropriate segmental target and suggest a broad molecular program over SCPN axon targeting to distinct subcerebral targets early in development. These findings are likely to inform future investigations of motor circuit development, as well as approaches aimed at enhancing motor recovery after central nervous system damage. HighlightsO_LICortico-brainstem neurons (CBN) limit their axon extension to supraspinal levels from the earliest time points of white matter axon extension in development. C_LIO_LICBN can be molecularly delineated from corticospinal neurons (CSN) even at these initial time points. C_LIO_LIMolecular diversification of developing subcerebral projection neurons occurs across at least two axes: cortical location (medial vs. lateral) and projection targeting specificity (brainstem vs. spinal) C_LIO_LIWithin lateral cortex, Neuropeptide Y (Npy) is expressed by CBN, while CART prepropeptide (Cartpt) expression delineates cervical-projecting CSN. C_LI O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/494253v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@48776corg.highwire.dtl.DTLVardef@1987eaeorg.highwire.dtl.DTLVardef@a50390org.highwire.dtl.DTLVardef@18d1588_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Long-distance axon growth ability of corticospinal neurons is lost in a segmentally-distinct manner.

Established experimental lesions in the developing central nervous system (CNS) disrupt microenvironments critical for long-distance axon growth and guidance. Therefore, the precise developmental time at which the CNS ceases its capacity to support long-distance axon growth remains unknown. Accordingly, we established a new microsurgical approach to axotomize developing corticospinal tract (CST) axons in the neonatal spinal cord while leaving their local microenvironments relatively intact. This enables unambiguous investigation of long-distance CST growth ability in the CNS. Surprisingly, we find that CST axons lose their capacity for long-distance growth even during the developmental period of CST extension. While this ability remains intact in spinal locations where normal CST extension is occurring, it is completely abolished at sites distant from these locations. Further, the developmental time window for which this ability is maintained is much shorter than for other forms of axon growth such as sprouting. Long-distance CST growth ability does not correlate with astrocytic or microglial activation, nor with myelination levels. These results indicate that long-distance CST growth is controlled by mechanisms that operate early in development in a time- and region-specific manner.

neuroscience↗

bioRxiv2022

High resolution micro-CT imaging in mice stroke models: from 3D detailed infarct characterization to automatic area segmentation

Characterization of brain infarct lesion in rodent models of stroke is crucial to assess the outcome of stroke therapies and to study the disease pathophysiology. However, so far it has been mostly performed by: 1) histological methods, a time-consuming process that lead to significant flaws and tissue distortion; or 2) via MRI imaging, which is faster, yielding 3D information but at high costs. High-resolution micro-CT imaging became, in the last decade, a simple, fast, and cheaper solution, allowing 3D analysis of samples. Here, we describe that high-resolution micro-CT, either using iodine/OsO4 as contrast agents, can be successfully applied for fine quantification and localization of lesion size and edema volume in preclinical stroke models. We successfully correlated this new approach with the standard histological method TTC. In transient MCAO mouse stroke model, we were able to identify/quantify large lesioned areas (segmented in core and penumbra), up to degenerated finer striatal myelinated fibers in a transient ischemic attack (TIA) mouse model, at different timepoints post-ischemia, through manual and automatic segmentation approaches (deep learning). Furthermore, 3D reconstructions of the whole brain allow for brain atlas co-registration of the specific affected brain areas. Hence, the presented methodology, through iodine/OsO4 micro-CT imaging, constitutes a valuable advance in tools for precise and detailed assessment of stroke outcomes in preclinical animal studies.

neuroscience↗

bioRxiv2021

Deep learning based behavioral profiling of rodent stroke recovery

Stroke research heavily relies on rodent behavior when assessing underlying disease mechanisms and treatment efficacy. Although functional motor recovery is considered the primary targeted outcome, tests in rodents are still poorly reproducible, and often unsuitable for unraveling the complex behavior after injury. Here, we provide a comprehensive 3D gait analysis of mice after focal cerebral ischemia based on the new deep learning-based software (DeepLabCut, DLC) that only requires basic behavioral equipment. We demonstrate a high precision 3D tracking of 10 body parts (including all relevant joints and reference landmarks) in several mouse strains with an accuracy of 99.4%. Building on this rigor motion tracking, a comprehensive post-analysis (with >100 parameters) unveils biologically relevant differences in locomotor profiles after a stroke over a time course of three weeks. We further refine the widely used ladder rung test using deep learning and compare its performance to human annotators. The generated DLC-assisted tests were then benchmarked to five widely used conventional behavioral set-ups (neurological scoring, rotarod, ladder rung walk, cylinder test, and single-pellet grasping) regarding sensitivity, accuracy, time use and costs. We conclude that deep learning-based motion tracking with comprehensive post-analysis provides accurate and sensitive data to describe the complex recovery of rodents following a stroke. The experimental set-up and analysis can also benefit a range of other neurological injuries that affect locomotion.

neuroscience↗

bioRxiv2021

Bleeding in patients and mice with Alagille syndrome: sex differences and risk factors

Spontaneous lethal bleeds are major cause of death in the pediatric liver disease Alagille syndrome (ALGS), yet risk factors and screening methods have not been established. We performed a systematic review and identified significantly more female than male patients with idiopathic intracranial hemorrhage (10:1). We investigated bleeding and vasculature in patients and a mouse model for ALGS (Jag1Ndr/Ndr mice) and asked whether phenotypes identified in mice could be detected in patients non-invasively. Jag1Ndr/Ndr mice bled spontaneously, exhibiting a thin skull and vascular defects including artery-vein crossings, tortuous vessels, capillary breakdown and CADASIL-like sparse vascular smooth muscle cell coverage which was aggravated by hypertension. Retinographs from patients confirmed tortuous blood vessels and artery-vein crossings in ALGS. In conclusion, Jag1Ndr/Ndr mice could be used to develop interventions for vascular defects in ALGS, and retinography could provide a non-invasive method for vascular analysis in these pediatric patients.

developmental biology↗

bioRxiv2021

Financial incentives facilitate the neural computation of prosocial decisions stronger in low empathic individuals

Financial incentives are commonly used to motivate behaviours. There is also evidence that incentives can decline the behaviour they are supposed to foster, for example, documented by a decrease in blood donations if a financial incentive is offered. Based on these findings, previous studies assumed that prosocial motivation is shaped by incentives. However, so far, there is no direct evidence showing an interaction between financial incentives and a specific prosocial motive. Combining drift-diffusion modelling and fMRI, we investigated the effect of financial incentives on empathy, i.e., one of the key motives driving prosocial decisions. In the empathy-alone condition, participants made prosocial decisions based on empathy, in the empathy-bonus condition, they were offered a financial bonus for prosocial decisions, in addition to empathy induction. On average, the bonus enhanced the information accumulation in empathy-based decision. On the neural level, this enhancement was related to the anterior insula, the same region that also correlated with empathy ratings. Moreover, the effect of the financial incentive on anterior insula activation was stronger the lower a person scored on empathy. These findings show that financial incentives enhance prosocial motivation in the absence of empathy but have little effect on high empathic individuals.

neuroscience↗

bioRxiv2021

Multichromatic Near-Infrared Imaging to Assess Interstitial Lymphatic and Venous Uptake In Vivo

SignificanceChanges in interstitial fluid clearance are implicated in many diseases. Using NIR imaging with properly sized tracers could enhance our understanding of how venous and lymphatic drainage are involved in disease progression or enhance drug delivery strategies. AimWe investigated multichromatic NIR imaging with multiple tracers to assess in vivo microvascular clearance kinetics and pathways in different tissue spaces. ApproachWe used a chemically inert IR Dye 800CW (free dye) to target venous capillaries and a purified conjugate of IR Dye 680RD with a 40 kDa PEG (PEG) to target lymphatic capillaries in vivo. Optical imaging settings were validated and tuned in vitro using tissue phantoms. We investigated multichromatic NIR imagings utility in two in vivo tissue beds - the mouse tail and rat knee joint. We then tested the ability of the approach to detect interstitial fluid perturbations due to exercise. ResultsIn an in vitro simulated tissue environment, free dye and PEG mixture allowed for simultaneous detection without interference. Co-injected NIR tracers cleared from the interstitial space via distinct routes allowed assessment lymphatic and venous uptake in the mouse tail. We determined that exercise after injection transiently increased lymphatic drainage as measured by lower normalized intensity immediately after exercise, while exercise pre-injection exhibited a transient delay in clearance from the joint ConclusionsNIR imaging enables of simultaneous imaging of lymphatic and venous-mediated fluid clearance with great sensitivity and can be used to measure transient changes in clearance rates and pathways.

bioengineering↗

bioRxiv2020

Effects of osteogenic ambulatory mechanical stimulation on early stages of BMP-2mediated bone repair

Mechanical loading of bone defects through rehabilitation is a promising therapeutic approach to stimulate repair and reduce the risk of non-union; however, little is known about how therapeutic mechanical stimuli modulate early stages of repair before mineralized bone formation. In a previous study, we established an osteogenic mechanical loading protocol using early ambulatory rehabilitation and a compliant, load-sharing fixator in a rat model of BMP-2 mediated bone defect repair. The objective of this study was to investigate the early effects of osteogenic loading on cytokine expression, tissue composition, and angiogenesis during the first 3 weeks of repair in this model. Using a wireless implantable strain sensor for local measurements of mechanical boundary conditions, finite element simulations showed that osteogenic mechanical loading increased mean compressive strain in defect soft tissue during rehabilitative ambulation at 1 week (load-sharing: -1.54 {+/-} 0.17% vs. load-shielded: -0.76 {+/-} 0.06%), and that strain was amplified in remaining soft tissue regions at 3 weeks as mineralization progressed (load-sharing: -1.89 {+/-} 0.35% vs. load-shielded: -1.38 {+/-} 0.35%). Multivariate analysis of multiplex cytokine arrays revealed that loading significantly altered cytokine expression profiles in the defect tissue at 2 weeks compared to load-shielded defects. Specifically, loading reduced VEGF and increased CXCL5 (LIX) levels. Subsequently, vascular volume in loaded defects was reduced relative to load-shielded defects but similar to intact bone at 3 weeks. Endochondral bone repair was also observed histologically in loaded defects only at 3 weeks. Together, these results demonstrate that moderate ambulatory strains previously shown to stimulate functional bone regeneration significantly alter early angiogenic and cytokine signaling and may promote endochondral ossification in large segmental bone defects. Authors ContributionsB.S.K., N.J.W., and R.E.G. designed the research and performed surgeries; B.S.K., C.E.V., and J.K. performed experiments; B.S.K., C.E.V., J.K., and L.B.W., analyzed data; B.S.K., C.E.V., N.J.W., and R.E.G. wrote the manuscript; All authors interpreted data, critically edited, and have read and approved the final manuscript.

bioengineering↗

bioRxiv2020

Local retinoic acid directs emergence of the extraocular muscle functional unit

Coordinated development of muscles, tendons, and their attachment sites ensures emergence of functional musculoskeletal units that are adapted to diverse anatomical demands among different species. How these different tissues are patterned and functionally assembled during embryogenesis is poorly understood. Here, we investigated the morphogenesis of extraocular muscles (EOMs), an evolutionary conserved cranial muscle group that is crucial for the coordinated movement of the eyeballs and for visual acuity. By means of lineage analysis, we redefined the cellular origins of periocular connective tissues interacting with the EOMs, which do not arise exclusively from neural crest mesenchyme as previously thought. Using 3D imaging approaches, we established an integrative blueprint for the EOM functional unit. By doing so, we identified a developmental time window where individual EOMs emerge from a unique muscle anlage and establish insertions in the sclera, which sets these muscles apart from classical muscle-to-bone type of insertions. Further, we demonstrate that the eyeballs are a source of diffusible retinoic acid that allow their targeting by the EOMs in a temporal and dose dependent manner. Using genetically modified mice and inhibitor treatments, we find that endogenous local variations in the concentration of retinoids contribute to the establishment of tendon condensations and attachment sites that precede the initiation of muscle patterning. Collectively, our results highlight how global and site-specific programs are deployed for the assembly of muscle functional units with precise definition of muscle shapes and topographical wiring of their tendon attachments.

developmental biology↗

bioRxiv2019

The neural computation of human goal-directed behavior in complex motivational states

Motives motivate human behavior. Most behaviors are driven by more than one motive, yet it is unclear how different motives interact and how such motive combinations affect the neural computation of the behaviors they drive. To answer this question, we induced two prosocial motives simultaneously (multi-motive condition) and separately (single motive conditions). After the different motive inductions, participants performed the same choice task in which they allocated points in favor of the other person (prosocial choice) or in favor of themselves (egoistic choice). We used fMRI to assess prosocial choice-related brain responses and drift diffusion modelling to specify how motive combinations affect individual components of the choice process. Our results showed that the combination of the two motives in the multi-motive condition increased participants choice biases prior to the behavior itself. On the neural level, these changes in initial prosocial bias were associated with neural responses in the bilateral dorsal striatum. In contrast, the efficiency of the prosocial decision process was comparable between the multi-motive and the single-motive conditions. These findings provide insights into the computation of prosocial choices in complex motivational states, the motivational setting that drives most human behaviors. HighlightsO_LIActivating different social motives simultaneously can enhance prosocial choices C_LIO_LIMulti-motive combinations change initial prosocial biases C_LIO_LIDorso-striatal activation increases with larger increase of prosocial bias C_LIO_LIMulti-motive combinations modulate relative response caution C_LI

neuroscience↗

bioRxiv2019

DoUble resin Casting micro computed Tomography (DUCT) reveals biliary and vascular pathology in a mouse model of Alagille syndrome

BACKGROUND AND AIMSAlagille syndrome, like several other liver diseases, is characterized by malformation of lumenized structures, such as the circulatory or biliary systems. Liver architecture has typically been studied through 2D sections and, more recently, using thick tissue sections combined with immunofluorescence. We aimed to develop a robust method to image, digitalize and quantify 3D architecture of the biliary and vascular systems in tandem. METHODSThe biliary and portal vein trees of the mouse liver were injected with Microfil resin, followed by microCT scanning. Tomographic data was segmented and analyzed using a MATLAB script we wrote to investigate length, volume, tortuosity, branching, and the relation between the vascular and biliary systems. Double resin casting micro computed tomography (DUCT) was applied to a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice), in which the biliary system is absent at postnatal stages, but regenerates by adulthood. Phenotypes discovered using DUCT were validated with cumbersome consecutive liver sections from mouse and human liver including patients with Alagille syndrome. RESULTSDUCT revealed tortuous bile ducts either placed further from portal veins, or ectopically traversing the parenchyma and connecting two portal areas, in Jag1Ndr/Ndr mice. Furthermore, bile ducts either ended abruptly, or branched independently of portal vein branching, with bifurcations placed hilar or peripheral to portal vein branches. The branching defects, parenchymal bile ducts, and blunt endings were confirmed in patient samples. CONCLUSIONDUCT is a powerful technique, which provides computerized 3D reconstruction of casted networks. It exposes and quantifies previously unknown vascular and biliary phenotypes in mouse models, revealing new phenotypes in patients. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/848481v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1565121org.highwire.dtl.DTLVardef@1e86cfcorg.highwire.dtl.DTLVardef@4b4cc3org.highwire.dtl.DTLVardef@19cb20e_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2019

Context information supports serial dependence of multiple visual objects across memory episodes

Visual perception operates in an object-based manner, by integrating associated features via attention. Working memory allows a flexible access to a limited number of currently relevant objects, even when they are occluded or physically no longer present. Recently, it has been shown that we compensate for small changes of an objects feature over memory episodes, which can support its perceptual stability. This phenomenon was termed serial dependence and has mostly been studied in situations that comprised only a single relevant object. However, since we are typically confronted with situations where several objects have to be perceived and held in working memory, the central question of how we selectively create temporal stability of several objects has remained unsolved. As different objects can be distinguished by their accompanying context features, like their color or temporal position, we tested whether serial dependence is supported by the congruence of context features across memory episodes. Specifically, we asked participants to remember the motion directions of two sequentially presented colored dot fields per trial. At the end of a trial one motion direction was cued for continuous report either by its color (Experiment 1) or serial position (Experiment 2). We observed serial dependence, i.e., an attractive bias of currently toward previously memorized objects, between current and past motion directions that was clearly enhanced when items had the same color or serial position across trials. This bias was particularly pronounced for the context feature that was used for cueing and for the target of the previous trial. Together, these findings demonstrate that coding of current object representations depends on previous representations, especially when they share similar content and context features. Apparently the binding of content and context features is not completely erased after a memory episode, but it is carried over to subsequent episodes. As this reflects temporal dependencies in natural settings, the present findings reveal a mechanism that integrates corresponding bundles of content and context features to support stable representations of individualized objects over time.

neuroscience↗

bioRxiv2019

Real-time monitoring of mechanical cues in the regenerative niche reveal dynamic strain magnitudes that enhance bone repair

Mechanical loads exerted on the skeleton during activities such as walking are important regulators of bone repair, but dynamic biomechanical signals are difficult to measure inside the body. The inability to measure the mechanical environment in injured tissues is a significant barrier to developing integrative regenerative and rehabilitative strategies that can accelerate recovery from fracture, segmental bone loss, and spinal fusion. Here we engineered an implantable strain sensor platform and measured strain across a bone defect in real-time throughout rehabilitation. We used the sensor to longitudinally quantify mechanical cues imparted by a load-sharing fixation plate that significantly enhanced bone regeneration in rats. We found that sensor readings correlated with the status of healing, suggesting a potential role for strain sensing as an X-ray-free healing assessment platform. This study demonstrates a promising approach to quantitatively develop and exploit mechanical rehabilitation strategies that enhance bone repair.

bioengineering↗

bioRxiv2018

Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues

In vertebrates, head and trunk muscles develop from different mesodermal populations and are regulated by distinct genetic networks. Neck muscles at the head-trunk interface remain poorly defined due to their complex morphogenesis and dual mesodermal origins. Here, we use genetically modified mice to establish a 3D model that integrates regulatory genes, cell populations and morphogenetic events that define this transition zone. We show that the evolutionary conserved cucullaris-derived muscles originate from posterior cardiopharyngeal mesoderm, not lateral plate mesoderm, and we define new boundaries for neural crest and mesodermal contributions to neck connective tissue. Furthermore, lineage studies and functional analysis of Tbx1- and Pax3-null mice reveal a unique genetic program for somitic neck muscles that is distinct from that of somitic trunk muscles. Our findings unveil the embryological and developmental requirements underlying tetrapod neck myogenesis and provide a blueprint to investigate how muscle subsets are selectively affected in some human myopathies.

developmental biology↗

bioRxiv2018

Attention samples objects held in working memory at a theta rhythm

Attention selects relevant information regardless of whether it is physically present or internally stored in working memory. Perceptual research has shown that attentional selection of external information is better conceived as rhythmic prioritization than as stable allocation. Here we tested this principle using information processing of internal representations held in working memory. Participants memorized four spatial positions that formed the endpoints of two objects. One of the positions was cued for a delayed match-non-match test. When uncued positions were probed, participants responded faster to uncued positions located on the same object as the cued position than to those located on the other object, revealing object-based attention in working memory. Manipulating the interval between cue and probe at a high temporal resolution revealed that reaction times oscillated at a theta rhythm of 6 Hz. Moreover, oscillations showed an anti-phase relationship between memorized but uncued positions on the same versus other object as the cued position, suggesting that attentional prioritization fluctuated rhythmically in an object-based manner. Our results demonstrate the highly rhythmic nature of attentional selection in working memory. Moreover, the striking similarity between rhythmic attentional selection of mental representations and perceptual information suggests that attentional oscillations are a general mechanism of information processing in human cognition. These findings have important implications for current, attention-based models of working memory.

neuroscience↗

bioRxiv2017

Predictive coding over the lifespan: Increased reliance on perceptual priors in older adults -- a magnetoencephalography and dynamic causal modelling study

Aging is accompanied by unisensory decline; but to compensate for this, two complementary strategies are potentially relied upon increasingly: first, older adults integrate more information from different sensory organs. Second, according to predictive coding (PC) we form templates (internal models or priors) of the environment through our experiences. It is through increased life experience that older adults may rely more on these templates compared to younger adults. Multisensory integration and predictive coding would be effective strategies for the perception of near-threshold stimuli, but they come at the cost of integrating irrelevant information. Their role can be studied in multisensory illusions because these require the integration of different sensory information, as well as an internal model of the world that can take precedence over sensory input. Here, we elicited a classic multisensory illusion, the sound-induced flash illusion, in younger (mean: 27 yrs) and older (mean: 67 yrs) adult participants while recording the magnetoencephalogram. Older adults perceived more illusions than younger adults. Older adults had increased pre-stimulus beta({beta})-band activity compared to younger adults as predicted by microcircuit theories of predictive coding, which suggest priors and predictions are linked to {beta}-band activity. In line with our hypothesis, transfer entropy analysis and dynamic causal models of pre-stimulus MEG data revealed a stronger illusion-related modulation of cross-modal connectivity from auditory to visual cortices in older compared to younger adults. We interpret this as the neural correlate of increased reliance on a cross-modal predictive template in older adults that is leading to the illusory percept.

neuroscience↗