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Fleischmann, R.

Publications and source records attributed to Fleischmann, R..

2 recordsLinked to original sources

Arousal-related mediation of perceptual belief updating across auditory domains

Belief updating refers to the integration of prior beliefs with incoming evidence and guides decision-making under uncertainty. In response to surprising events, this process is thought to be modulated by the locus-coeruleus-noradrenaline (LC-NA) arousal system, observable via pupil dilations (PDs). Pertinent literature has mostly focused on conscious, high-level decision-making and estimation processes, while assuming that the same principles apply to low-level sensory perceptual decision-making and generalize across tasks, domains and modalities. To address some of these assumptions, we devised a novel perceptual discrimination paradigm, investigating behavior and PDs across auditory domains. Participants were presented with auditory sequences of randomized length at a rapid pace, changing intermittently between two latent states: acceleration vs. deceleration (temporal group, N = 25) and clockwise vs. counterclockwise movement (spatial group, N = 22). Under high uncertainty, participants continuously inferred latent states to report the final state per sequence. To extract per-stimulus estimates of PDs during sequences, we fitted a deconvolution-based general linear model to the continuous pupil traces with a free amplitude parameter reflecting ongoing PDs. A Bayesian observer model was fitted to participants responses and used to estimate information gain and surprisal for every stimulus. Participants performance and PDs showed strong sensitivity to the occurrence of change-points. Both computational variables significantly predicted PDs in both domains, with information gain outperforming surprisal in a model comparison. Further model comparison revealed significant preference for models excluding possible domain-specific effects over models including them, pointing towards a constant effect over domains. We conclude that behavior and associated PDs observed in our purely perceptual auditory task align with Bayesian principles of belief updating. The observed lack of domain specificity supports the assumed generalizability of belief updating.

neuroscience↗

Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a+ macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND.

cell biology↗