Biology subjects

Witte, O. W.

Publications and source records attributed to Witte, O. W..

10 recordsLinked to original sources

bioRxiv2024

Harnessing early multimodal motor training to drive motor recovery and brain-wide structural reorganization after stroke

Stroke survivors often suffer from severe motor impairments, highlighting the critical need for effective rehabilitation strategies. In experimental models, extensive task-specific motor training within the first few weeks post-stroke significantly mitigates motor deficits. However, whether more multimodal motor training approaches after stroke can restore task-specific performance in non-trained motor tasks remains largely unknown. Additionally, while stroke itself triggers structural brain reorganization, the influence of early multimodal motor training on this process remains unclear. Here, we employed T2-weighted MRI to investigate brain region-specific volumetric changes over eight weeks in rats subjected to stroke and subsequent early multimodal motor training. We found that this combination not only facilitated task-specific motor function recovery, but also induced dramatic, multi-region, brain-wide volumetric changes. Specifically, over 80 locations within 50 distinct brain regions across both hemispheres exhibited substantial volumetric alterations in a predominantly bilateral symmetric pattern. In contrast, stroke or training alone resulted in changes in 8-15 locations within 7-13 brain regions, with stroke alone primarily affecting the infarcted hemisphere. Analysis of temporal volume changes revealed two distinct trajectories in post-stroke trained rats: one of initial swelling followed by shrinkage, and another of initial shrinkage followed by swelling, suggesting an early and delayed motor learning period. Overall, our findings demonstrate that multimodal motor training early after stroke effectively restores task-specific motor function and profoundly reshapes brain structure on a brain-wide scale, offering vital insights for developing optimized rehabilitation protocols to maximize recovery in stroke patients.

neuroscience↗

bioRxiv2024

Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

Aging is the predominant cause of morbidity and mortality in industrialized countries. The specific molecular mechanisms that drive aging are poorly understood, especially the contribution of the microbiota in these processes. Here, we combined multi-omics with metabolic modeling in mice to comprehensively characterize host-microbiome interactions and how they are affected by aging. Our findings reveal a complex dependency of host metabolism on microbial functions, including previously known as well as novel interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome, which we attribute to reduced beneficial interactions in the microbial community and a reduction in its metabolic output. These microbial changes coincided with a corresponding downregulation of key host pathways predicted by our model to be dependent on the microbiome that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based therapies against aging. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/587009v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a8e7faorg.highwire.dtl.DTLVardef@115f35aorg.highwire.dtl.DTLVardef@1bbf32org.highwire.dtl.DTLVardef@1a58c7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2022

Generation of adult hippocampal neural stem cells occurs in the early postnatal dentate gyrus and depends on cyclin D2

In the hippocampus, lifelong neurogenesis is maintained by a pool of multipotent adult neural stem cells (aNSCs) residing in the subgranular zone of the dentate gyrus (DG). Yet, the mechanisms guiding the transition of NSCs from developmental to adult remain unclear. By using nestin-reporter mice deficient for D2, a cyclin expressed mainly postnatally, we show that the aNSC pool is established through D2-dependent proliferation during the first two weeks of life. The absence of D2 allows the normal development of the DG until birth but prevents the postnatal formation of radial glia-like aNSCs. Additionally, retroviral fate mapping demonstrates that aNSCs are born on-site from precursors located in the DG shortly after birth. Altogether, our data suggest that aNSCs are a population distinct from developmental NSCs and thus imply that adult hippocampal neurogenesis is not a mere continuation of development.

neuroscience↗

bioRxiv2022

A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration

Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems might combine such information. Here in mice we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a subarea of primary visual cortex (VISp) whose visual space covers the whisker search space. This is mediated by local fast spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 of the primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.

neuroscience↗

bioRxiv2022

Overcoming the Reproducibility Crisis - Results of the first Community Survey of the German National Research Data Infrastructure for Neuroscience.

The lack of reproducibility of research results is a serious problem - known as "the reproducibility crisis". The German National Research Data Infrastructure (NFDI) initiative implemented by the German Research Foundation (DFG) aims to help overcoming this crisis by developing sustainable solutions for research data management (RDM). NFDI comprises domain specific consortia across all science disciplines. In the field of neuroscience, NFDI Neuroscience (NFDI-Neuro) contributes to the strengthening of systematic and standardized RDM in its research communities. NFDI-Neuro conducted a comprehensive survey amongst the neuroscience community to determine the current needs, challenges, and opinions with respect to RDM. The outcomes of this survey are presented here. The German neuroscience community perceives barriers with respect to RDM and data sharing mainly linked to (1) lack of data and metadata standards, (2) lack of community adopted provenance tracking methods, 3) lack of a privacy preserving research infrastructure for sensitive data (4) lack of RDM literacy and (5) lack of required time and resources for proper RDM. NFDI-Neuro aims to systematically address these barriers by leading and contributing to the development of standards, tools, and infrastructure and by providing training, education, and support, as well as additional resources for RDM to its research community. The RDM work of NFDI-Neuro is conducted in close collaboration with its partner EBRAINS AISBL, the coordinating entity of the EU Flagship Human Brain Project, and its Research Infrastructure (RI) EBRAINS with more than 5000 registered users and developers from more than 70 countries of all continents. While NFDI-Neuro aims to address the German national needs, it closely aligns with the international community and the topics of the Digital Europe Program and EU Data Spaces. Significance StatementA comprehensive survey amongst the neuroscience community in Germany determined the current needs, challenges, and opinions with respect to standardized research data management (RDM) to overcome the reproducibility crisis. Significant deficits were pointed out concerning the perceived lack of standards for data and metadata, lack of provenance tracking and versioning of data, lack of protected digital research infrastructure for sensitive data and the lack of education and resources for proper RDM. Yet, at the same time, an overwhelming majority of community members indicated that they would be willing to share their data with other researchers and are interested to increase their RDM skills. Thus, the survey results suggest that training, the provision of standards, tools, infrastructure and additional resources for RDM holds the potential to significantly facilitate reproducible research in neuroscience.

neuroscience↗

bioRxiv2021

Post-stroke dendritic arbor regrowth - a cortical repair process requiring the actin nucleator Cobl

Ischemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in post-stroke dendritic arbor repair in peri-infarct areas. In Cobl KO mice, the dendritic repair window determined to span day 2-4 post-stroke in WT strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful post-stroke recovery process and identified causal molecular mechanisms critical during post-stroke repair.

neuroscience↗

bioRxiv2021

Network instability dynamics drive a transient bursting period in the developing hippocampus in vivo

Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying network burstiness in the intact developing brain are largely unknown. Here, we use two-photon Ca2+ imaging to comprehensively map the developmental trajectories of spontaneous network activity in hippocampal area CA1 in vivo. We unexpectedly find that network burstiness peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network burstiness reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts (NBs) recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for NB generation. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration.

neuroscience↗

bioRxiv2020

Experience-dependent structural plasticity in the adult brain: How the learning brain grows.

Volumetric magnetic resonance imaging studies have shown that intense learning can be associated with grey matter volume increases in the adult brain. The underlying mechanisms are poorly understood. Here we used monocular deprivation in rats to analyze the mechanisms underlying use-dependent grey matter increases. Optometry for quantification of visual acuity was combined with volumetric magnetic resonance imaging and microscopic techniques in longitudinal and cross-sectional studies. We found an increased spatial vision of the open eye which was associated with a transient increase in the volumes of the contralateral visual and lateral entorhinal cortex. In these brain areas dendrites of neurons elongated, and there was a strong increase in the number of spines, the targets of synapses, which was followed by spine maturation and partial pruning. Astrocytes displayed a transient pronounced swelling and underwent a reorganization of their processes. The use-dependent increase in grey matter corresponded predominantly to the swelling of the astrocytes. Experience-dependent increase in brain grey matter volume indicates a gain of structure plasticity with both synaptic and astrocyte remodeling. HighlightsO_LIPerception learning causes a transient increase in brain grey matter volume detectable by MRI. C_LIO_LIThis learning results in pronounced changes of neuronal dendrites and an increase in the number of dendritic spines. C_LIO_LIStructural neuronal plasticity is associated with a reorganization and transient swelling of astrocytes. C_LIO_LIBrain volume and astrocyte volume return to baseline post-learning, with a persistent increase in the number of mature spines. C_LI

neuroscience↗

bioRxiv2020

Intraneuronal chloride accumulation via NKCC1 is not essential for hippocampal network development in vivo

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in-vitro excitatory GABA actions and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics and behavioral performance are subtle. Our data reveal a neural network function of depolarizing GABA in the hippocampus in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

neuroscience↗

bioRxiv2017

Effects of Prenatal Stress on Structural Brain Development and Aging in Humans

Healthy brain aging is a major determinant of quality of life, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to lifestyle and genetic factors, environmental influences in prenatal life have a major impact on brain aging and age-associated brain disorders. The aim of this review is to summarize the existing literature on the consequences of maternal anxiety, stress, and malnutrition for structural brain aging and predisposition for age-associated brain diseases, focusing on studies with human samples. In conclusion, the results underscore the importance of a healthy mother-child relationship, starting in pregnancy, and the need for early interventions if this relationship is compromised.

neuroscience↗