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Piilgaard, L.

Publications and source records attributed to Piilgaard, L..

2 recordsLinked to original sources

Lack of Consensus for Manual Mouse Sleep Scoring Limits Implementation of Automatic Deep Learning Models

Scientists have for decades attempted to automate the manual sleep staging problem not only for human polysomnography data but also for rodent data. No model has, however, succeeded in fully replacing the manual procedure across clinics and laboratories. We hypothesize that this is due to the models limited ability to generalize to data from unseen laboratories. Our findings show that despite the high performance of four state-of-the-art models reported in initial publications, the published models struggle to generalize to other laboratories. We further show a significant improvement in model performance across labs by re-training them on a diverse dataset from five different sites. To assess the contribution of variability in manual scoring, ten experts from five laboratories all labelled the same nine mouse sleep recordings. The result revealed substantial scoring variability, particularly for rapid eye movement (REM) sleep, both within and between labs. In conclusion our study demonstrates that key challenges in the generalizability of state-of-the-art sleep scoring models are signal variability and label noise. Our study highlights the need for a standardized set of mouse sleep scoring guidelines to enable consistency and collaboration across the field. Until such a consensus is reached, we present four sufficiently robust models trained on diverse datasets that can serve as standardized tools across labs.

neuroscience↗

Generation of human appetite-regulating neurons and tanycytes from stem cells

The balance between energy intake and expenditure is controlled by the hypothalamus, a small brain region characterised by high neuronal diversity. Specifically, the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are key hypothalamic nuclei controlling appetite through behavioural response to circulating humoral signals. Yet, despite their physiological importance, the cellular and functional characteristics of this highly specialised neural region has been studied mainly in animals due to a lack of human models. Here, we fine-tuned the differentiation of human pluripotent stem cells toward the ARC and VMH hypothalamic nuclei and identified key subtype-specific progenitor markers of these subregions. We demonstrate that the timing for initiation and termination of bone morphogenetic protein (BMP) signalling is essential for controlling subregional specification of tuberal hypothalamic progenitors along the anterior-posterior axis, balancing VMH versus ARC fates. A particular population of SHH-/NKX2.1+/FGF10high/RAXhigh/TBX3high posterior tuberal progenitors was identified as the source for generation of ARC-associated agouti-related peptide (AGRP) neurons and tanycytes whilst anterior tuberal SHH+/NKX2.1+/FGF10low/RAXlow/TBX3low progenitors generated VMH phenotypes including NR5A1 neurons. Upon maturation in vitro and in xenografts, ARC-patterned progenitors gave rise to key appetite-regulating cell types including those producing AGRP, prepronociceptin (PNOC), growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH) and pro-opiomelanocortin (POMC), as well as tanycyte glial cells. Differentiated ARC cultures showed high transcriptomic similarity to the human ARC and displayed evidence of functionality by AGRP secretion and responsiveness to leptin and fibroblast growth factor 1 (FGF1). In summary, our work provides insights into the developmental lineages underlying hypothalamic subregional specification and enables access to highly characterised human ARC and VMH cultures, which will provide novel opportunities for investigating the cellular and molecular pathways triggered by obesity-associated genetic variants and weight-regulating stimuli.

neuroscience↗