Biology subjects

Pakkenberg, B.

Publications and source records attributed to Pakkenberg, B..

5 recordsLinked to original sources

bioRxiv2025

Schistosoma mansoni-induced host immunopathology is gut microbiota dependent

Despite progress in schistosomiasis control during recent decades in endemic areas, this parasitic blood-fluke infection continues to pose a substantial public health burden. In depth understanding of the mechanisms behind the complex immunopathology and drivers of morbidity in schistosomiasis is urgently needed. Chronic infection with the parasitic blood fluke Schistosoma mansoni manifests the most severe pathology in relation to egg-induced host immune responses and fibrosis development. Host immune homeostasis is influenced by the commensal gut microbiota, which may therefore also affect systemic immunopathology induced by S. mansoni. Both humans and experimental animal models show metabolomic changes related to gut microbial and liver metabolism during S. mansoni infection, further supporting a link between gut microbiota and regulation of S. mansoni pathology. To investigate whether a radically changed gut microbiota composition would result in changed S. mansoni egg-induced pathology, a mouse model combining antibiotic treatment and infection was established. In the model, the commensal gut microbial composition of female C57BL/6-NTac mice was altered by oral administration of a broad-spectrum ampicillin-vancomycin cocktail prior to infection with S. mansoni and throughout the experiment. An ecosystem view of the host immune milieu was collated by measuring a wide range of parameters: gut microbiome characterisation, immune profiling on the transcriptional level (ileum and liver) supported by flow cytometry of cells (spleen and mesenteric lymph nodes) and bead-based measurements of immune parameters in sera, short-chain fatty acid measurements in sera and caecal content, intestinal permeability assessment, liver enzyme levels in sera, and histology and stereology to characterise immunopathology (ileum and liver). The application of stereological principles to address the non-spherical nature of egg-induced liver granulomas and ileum inflammation supported by liver enzyme levels, collagen deposition, and immune parameters, enabled demonstration of significantly less granuloma formation in livers from antibiotics treated mice compared to controls. The observed difference in the degree of egg-induced inflammatory response in livers from infected mice mediated by antibiotics treatment, was not observed in ileum tissue and could not be explained by infection burden. Our mouse model results demonstrate a role for the gut microbiota and intestinal immune milieu in regulation of systemic S. mansoni infection-driven liver pathology and, hence, potential morbidity. In translational context, these findings warrant that drivers of gut microbial changes and intestinal immune milieu must be considered when pursuing novel holistic interventions for treatment or alleviation of persistent schistosomiasis.

immunology↗

bioRxiv2021

Profiling the transcallosal response of rat motor cortex evoked by contralateral optogenetic stimulation of glutamatergic cortical neurons

BackgroundEfficient interhemispheric integration of neural activity between left and right primary motor cortex (M1) is critical for inter-limb motor control. ObjectiveWe employed optogenetic stimulation to establish a framework for probing transcallosal M1-M1 interactions in rats. MethodsIn male rats, we optogenetically stimulated glutamatergic neurons in right M1 and recorded the transcallosally evoked potential with chronically implanted electrodes in contralateral left M1 during dexmedetomidine anesthesia. We systematically varied the stimulation intensity and duration to characterize the relationship between stimulation parameters in right M1 and the characteristics of the evoked intracortical potentials in left M1. ResultsOptogenetic stimulation of right M1 consistently evoked a transcallosal response in left M1 with a consistent negative peak (N1) that sometimes was preceded by a smaller positive peak (P1). Higher stimulation intensity or longer stimulation duration gradually increased N1 amplitude and reduced N1 variability across trials. Median N1 latencies remained stable, once stimulation elicited a reliable N1 peak and did not display a systematic shortening with increasing stimulation intensity or duration. ConclusionsOptogenetically stimulated glutamatergic neurons in M1 can reliably evoke a transcallosal response in anesthetized rats and can be used to characterize the relationship between "stimulation dose" and "response magnitude" (i.e., the gain function) of transcallosal M1-to-M1 glutamatergic connections. Detailed knowledge of the stimulus-response relationship is needed to optimize the efficacy of optogenetic stimulation. Since transcallosal M1-M1 interactions can also be probed non-invasively with transcranial magnetic stimulation in humans, our optogenetic stimulation approach bears translational potential for studying how unilateral M1 stimulation can induce interhemispheric plasticity.

neuroscience↗

bioRxiv2020

Axon morphology is modulated by the local environment and impacts the non-invasive investigation of its structure-function relationship

Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Non-invasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires 3D validation. Here, high resolution, 3D synchrotron X-ray Nano-Holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variance in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure-function relationship.

neuroscience↗

bioRxiv2018

Striking reduction in neurons and glial cells in anterior thalamic nuclei of older patients with Down’s syndrome

The anterior thalamic nuclei are important for spatial and episodic memory; however, there is surprisingly little information about how these nuclei are affected in many conditions that present with memory impairments, including Downs syndrome. To assess the status of the anterior thalamic nuclei in Downs syndrome we quantified neurons and glial cells in the brains from four older patients with this condition. There was a striking reduction in the volume of the anterior thalamic nuclei and this appeared to reflect the loss of approximately 70% of neurons. The number of glial cells was also reduced but to a lesser degree than neurons. The anterior thalamic nuclei appear to be particularly sensitive to effects of aging in Downs syndrome and the pathology in this region likely contributes to the memory impairments observed. These findings re-affirm the importance of assessing the status of the anterior thalamic nuclei in conditions where memory impairments have been principally assigned to pathology in the medial temporal lobe.

neuroscience↗

bioRxiv2018

The behavioral and neurobiological effects of reduced Brd1 expression in mice are sex-biased and implicate gender dependent dysregulation of nuclear receptor mediated signaling in mental disorders

The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/- mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/- mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/- mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/- mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.

neuroscience↗