Global S&T Development Trend Analysis Platform of Resources and Environment
Since its introduction, the reward prediction error theory of dopamine has explained a wealth of empirical phenomena, providing a unifying framework for understanding the representation of reward and value in the brain(1-3). According to the now canonical theory, reward predictions are represented as a single scalar quantity, which supports learning about the expectation, or mean, of stochastic outcomes. Here we propose an account of dopamine-based reinforcement learning inspired by recent artificial intelligence research on distributional reinforcement learning(4-6). We hypothesized that the brain represents possible future rewards not as a single mean, but instead as a probability distribution, effectively representing multiple future outcomes simultaneously and in parallel. This idea implies a set of empirical predictions, which we tested using single-unit recordings from mouse ventral tegmental area. Our findings provide strong evidence for a neural realization of distributional reinforcement learning.
Analyses of single-cell recordings from mouse ventral tegmental area are consistent with a model of reinforcement learning in which the brain represents possible future rewards not as a single mean of stochastic outcomes, as in the canonical model, but instead as a probability distribution.
Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders(1). Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility(2-5), but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.
In a mouse model, aryl hydrocarbon receptor signalling in enteric neurons is revealed as a mechanism that helps to maintain gut homeostasis by integrating the luminal environment with the physiology of intestinal neural circuits.
Inhibitor pairs that suppress the crystallization of haematin, which is a part of malaria parasites'
Ubiquitous processes in nature and the industry exploit crystallization from multicomponent environments(1-5)
PLXND1 is a mechanosensor that is required for endothelial cells to respond to shear stress both in vitro and in vivo by regulating the site-specific distribution of atherosclerotic lesions.
Shear stress on arteries produced by blood flow is important for vascular development and homeostasis but can also initiate atherosclerosis(1). Endothelial cells that line the vasculature use molecular mechanosensors to directly detect shear stress profiles that will ultimately lead to atheroprotective or atherogenic responses(2). Plexins are key cell-surface receptors of the semaphorin family of cell-guidance signalling proteins and can regulate cellular patterning by modulating the cytoskeleton and focal adhesion structures(3-5). However, a role for plexin proteins in mechanotransduction has not been examined. Here we show that plexin D1 (PLXND1) has a role in mechanosensation and mechanically induced disease pathogenesis. PLXND1 is required for the response of endothelial cells to shear stress in vitro and in vivo and regulates the site-specific distribution of atherosclerotic lesions. In endothelial cells, PLXND1 is a direct force sensor and forms a mechanocomplex with neuropilin-1 and VEGFR2 that is necessary and sufficient for conferring mechanosensitivity upstream of the junctional complex and integrins. PLXND1 achieves its binary functions as either a ligand or a force receptor by adopting two distinct molecular conformations. Our results establish a previously undescribed mechanosensor in endothelial cells that regulates cardiovascular pathophysiology, and provide a mechanism by which a single receptor can exhibit a binary biochemical nature.