TGFß-mediated inhibition of hypodermal adipocyte progenitor differentiation promotes wound-induced skin fibrosis.

Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4+Ly6A+THY1+ hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFß pathway signature. TGFß was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFß receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFß pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFß-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases.

The role of intraspecies variation in fish neurobehavioral and neuropharmacological phenotypes in aquatic models.

Intraspecies variation is common in both clinical and animal research of various brain disorders. Relatively well-studied in mammals, intraspecies variation in aquatic fish models and its role in their behavioral and pharmacological responses remain poorly understood. Like humans and mammals, fishes show high variance of behavioral and drug-evoked responses, modulated both genetically and environmentally. The zebrafish (Danio rerio) has emerged as a particularly useful model organism tool to access neurobehavioral and drug-evoked responses. Here, we discuss recent findings and the role of the intraspecies variance in neurobehavioral, pharmacological and toxicological studies utilizing zebrafish and other fish models. We also critically evaluate common sources of intraspecies variation and outline potential strategies to improve data reproducibility and translatability.

DARK Classics in Chemical Neuroscience: Arecoline.

Arecoline is a naturally occurring psychoactive alkaloid from areca (betel) nuts of the areca palm ( Areca catechu) endemic to South and Southeast Asia. A partial agonist of nicotinic and muscarinic acetylcholine receptors, arecoline evokes multiple effects on the central nervous system (CNS), including stimulation, alertness, elation, and anxiolysis. Like nicotine, arecoline also evokes addiction and withdrawal symptoms (upon discontinuation). The abuse of areca nuts is widespread, with over 600 million users globally. The importance of arecoline is further supported by its being the world's fourth most commonly used human psychoactive substance (after alcohol, nicotine, and caffeine). Here, we discuss neuropharmacology, pharmacokinetics, and metabolism of arecoline, as well as social and historical aspects of its use and abuse. Paralleling clinical findings, we also evaluate its effects in animal models and outline future clinical and preclinical CNS research in this field.

Zebrafish models of diabetes-related CNS pathogenesis.

Diabetes mellitus (DM) is a common metabolic disorder that affects multiple organ systems. DM also affects brain processes, contributing to various CNS disorders, including depression, anxiety and Alzheimer's disease. Despite active research in humans, rodent models and in-vitro systems, the pathogenetic link between DM and brain disorders remains poorly understood. Novel translational models and new model organisms are therefore essential to more fully study the impact of DM on CNS. The zebrafish (Danio rerio) is a powerful novel model species to study metabolic and CNS disorders. Here, we discuss how DM alters brain functions and behavior in zebrafish, and summarize their translational relevance to studying DM-related CNS pathogenesis in humans. We recognize the growing utility of zebrafish models in translational DM research, as they continue to improve our understanding of different brain pathologies associated with DM, and may foster the discovery of drugs that prevent or treat these diseases.