Biology subjects

Koehling, R.

Publications and source records attributed to Koehling, R..

6 recordsLinked to original sources

bioRxiv2024

Utilising activity patterns of a complex biophysical network model to optimise intra-striatal deep brain stimulation

AO_SCPLOWBSTRACTC_SCPLOWIn this study, we develop a large-scale biophysical network model for the isolated striatal body to optimise potential intrastriatal deep brain stimulation applied in, e.g. obsessive-compulsive disorder by using spatiotemporal patterns produced by the network. The model uses modified Hodgkin-Huxley models on small-world connectivity, while the spatial information, i.e. the positions of neurons, is obtained from a detailed human atlas. The model produces neuronal activity patterns segregating healthy from pathological conditions. Three indices were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the mean activity of the ventral striatal area (emerging as a defined community using modularity detection algorithms), and the frequency spectrum of the entire network activity. By minimising the deviation of the aforementioned indices from the normal state, we guide the optimisation of deep brain stimulation parameters regarding position, amplitude and frequency.

neuroscience↗

bioRxiv2020

Collective migration of human osteoblasts in direct current electric field

Under both physiological (development, regeneration) and pathological conditions (cancer metastasis), cells migrate while sensing environmental cues in the form of mechanical, chemical or electrical stimuli. Although it is known that osteoblasts respond to exogenous electric fields, the underlying mechanism of electrotactic collective movement of human osteoblasts is unclear. Theoretical approaches to study electrotactic cell migration until now mainly used reaction-diffusion models, and did not consider the effect of electric field on single-cell motility, or incorporate spatially dependent cell-to-cell interactions. Here, we present a computational model that takes into account cell interactions and describes cell migration in direct current electric field. We compare this model with in vitro experiments in which human primary osteoblasts are exposed to direct current electric field of varying field strength. Our results show that cell-cell interactions and fluctuations in the migration direction together lead to anode-directed collective migration of osteoblasts. Author summaryElectrotactic migration of cells involves directed movement of a large number of single cells under the influence of external electric field. Influencing the migration behaviour of osteoblasts by external direct current electric field offers a promising approach towards building highly effective implants for bone regeneration. We present a computational model for electrotactic migration of osteoblasts subject to external direct current electric field. Our model considers individual cells that interact with each other and the external electric field, and, replicates the experimental observations, based on single-cell analysis, of the response of osteoblasts to electrical stimulation of varying strengths for 7 hours. Our results suggest that tracking trajectories of individual cells provide a way of determining the role of various interactions of a cell in collective migration. Our model provides a framework that links single cell response to the large scale collective dynamics.

biophysics↗

bioRxiv2020

Pallidal deep brain stimulation alters cortico-striatal synaptic communication in dystonic hamsters

BackgroundDeep brain stimulation (DBS) of the globus pallidus internus (GPi) is considered to be the most relevant therapeutic option for patients with severe dystonias, which are thought to arise from a disturbance in striatal control of the GPi, possibly resulting in thalamic disinhibition. The mechanisms of GPi-DBS are far from understood. Hypotheses range from an overall silencing of target nuclei (due to e.g. depolarisation block), via differential alterations in thalamic firing, to disruption of oscillatory activity in the {beta}-range. Although a disturbance of striatal function is thought to play a key role in dystonia, the effects of DBS on cortico-striatal function are unknown. ObjectiveWe hypothesised that DBS, via axonal backfiring, or indirectly via thalamic and cortical coupling, alters striatal network function. We aimed to test this hypothesis in the dtsz-hamster, an animal model of inherited generalised, paroxysmal dystonia. MethodsHamsters (dtsz-dystonic and non-dystonic controls) were bilaterally implanted with stimulation electrodes targeting the entopeduncular nucleus (EPN, equivalent of human GPi). DBS (130 Hz), and sham DBS, were performed in unanaesthetised animals for 3 hours. Synaptic cortico-striatal field potential responses, as well as miniature excitatory postsynaptic currents (mEPSC) and firing properties of medium spiny striatal neurons were subsequently recorded in brain slice preparations obtained from these animals immediately after EPN-DBS, to gauge synaptic responsiveness of cortico-striatal projections, their inhibitory control, and striatal neuronal excitability. ResultsDBS increased cortico-striatal responses in slices from control, but not dystonic animals. Inhibitory control of these responses, in turn, was differentially affected: DBS increased inhibitory control in dystonic, and decreased it in healthy tissue. A modulation of presynaptic mechanisms is likely involved, as mEPSC frequency was reduced strongly in dystonic, and less prominently in healthy tissues, while cellular properties of medium-spiny neurons remained unchanged. ConclusionDBS leads to dampening of cortico-striatal communication with restored inhibitory tone.

neuroscience↗

bioRxiv2018

Maternally inherited differences within mitochondrial Complex I control murine healthspan.

Mitochondrial complex I, the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery, has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA-encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C>A in mt-Nd2 lived significantly shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA-encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.

genetics↗

bioRxiv2018

Healthspan pathway maps in C. elegans and humans highlight transcription, prolifera-tion/biosynthesis and lipids

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. However, a precise definition of health and healthspan is not straightforward, and the causal molecular basis of health \"per se\" is largely unknown. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans, featuring the themes transcription initiation, proliferation and cholesterol/lipid processing, and for C. elegans, featuring the themes immune response, mitochondrion and biosynthesis based on genetic and compound intervention data, and lipids, biosynthesis and transcription based on WormBase compound intervention data. Overlaying healthspan-related gene expression data (describing effects of metabolic intervention associated with improvements in health) onto the aforementioned healthspan pathway maps, we observe the downregulation of Notch signalling in humans and of proliferation/cell-cycle in C. elegans. The former reflects the proinflammatory role of the Notch pathway. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, is available as a reference for future investigations, at http://www.h2020awe.eu/index.php/pathways/.

bioinformatics↗

bioRxiv2017

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e. the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally-arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of a AKR/J mouse strain (B6-mtAKR) together with a C57BL/6J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to wild-type C57BL/6J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair metabolic health and lifespan in mice.\n\nHighlightsO_LIWe identify heteroplasmy of the adenine-repeat variation (9 to 13A) in nt5172 in the origin of light-strand DNA replication (OriL) in inbred mice.\nC_LIO_LIB6-mtAKR mice carry >20% 12A heteroplasmy in the OriL, while B6 mice carry only [~] 10% heteroplasmy.\nC_LIO_LIThe level of 12A heteroplasmy correlates to mtDNA copy number, glucose metabolism, and lifespan in mice.\nC_LIO_LIGiven the established role of mtDNA heteroplasmy in regards to endurance exercise performance in athletes, these findings may impact our understanding of metabolism and aging in humans.\nC_LI

genetics↗