Ulbrich, P. | Search bioRxiv

bioRxiv2023

Vascular and neural transcriptomics reveal stage-dependent pathways to inflammation and cognitive dysfunction in a rat model of hypertension

Chronic arterial hypertension causes cerebral microvascular dysfunction and doubles dementia risk in aging. However, cognitive health preservation by therapeutic blood pressure lowering alone is limited and depends on disease duration, the degree of irreversible tissue damage and whether microvascular function can be restored. This study aimed to understand molecular and cellular temporo-spatial pathomechanisms in the course of hypertension. We investigated the effects of initial, early chronic and late chronic hypertension in the frontal brain of rats by applying behavioral tests, histopathology, immunofluorescence, FACS, microvascular/neural tissue RNA sequencing as well as 18F-FDG PET imaging. Chronic hypertension caused frontal brain-specific behavioral deficits. Our results highlight stage-dependent responses to continuous microvascular stress and wounding by hypertension. Early responses included a fast recruitment of activated microglia to the blood vessels, immigration of peripheral immune cells, blood-brain-barrier leakage and an energy-demanding hypermetabolic state. Vascular adaptation mechanisms were observed in later stages and included angiogenesis and vessel wall strengthening by upregulation of cellular adhesion molecules and extracellular matrix. Additionally, we identified late chronic accumulation of Igfbp-5 in the brains of hypertensive rats, which is also a signature of Alzheimers dementia and attenuates protective Igf-1 signaling. Our study advances the knowledge of involved pathomechanisms and highlights the stage-dependent nature of hypertensive pathobiology. This groundwork might be helpful for basic and clinical research to identify stage-dependent markers in the human disease course, investigate stage-dependent interventions besides blood pressure lowering and better understand the relationship between poor vascular health and neurodegenerative diseases.

neuroscience↗

bioRxiv2020

The Cone Method: Inferring Decision Times from Single-Trial 3D Movement Trajectories in Choice Behavior

Ongoing goal-directed movements can be rapidly adjusted following new environmental information, e.g. when chasing pray or foraging. This makes movement trajectories in go-before-you-know decision-making a suitable behavioral readout of the ongoing decision process. Yet, existing methods of movement analysis are often based on statistically comparing two groups of trial-averaged trajectories and are not easily applied to three-dimensional data, preventing them from being applicable to natural free behavior. We developed and tested the cone method to estimate the point of overt commitment (POC) along a single two- or three-dimensional trajectory, i.e. the position where movement is adjusted towards a newly selected spatial target. In Experiment 1, we established a "ground truth" data set in which the cone method successfully identified the experimentally constrained POCs across a wide range of all but the shallowest adjustment angles. In Experiment 2, we demonstrate the power of the method in a typical decision-making task with expected decision time differences known from previous findings. The POCs identified by cone method matched these expected effects. In both experiments, we compared the cone methods single trial performance with a trial-averaging method and obtained comparable results. We discuss the advantages of the single-trajectory cone method over trial-averaging methods and possible applications beyond the examples presented in this study. The cone method provides a distinct addition to existing tools used to study decisions during ongoing movement behavior, which we consider particularly promising towards studies of non-repetitive free behavior.

neuroscience↗