Alcohol consumption is a widespread phenomenon throughout the world. However, how recreational alcohol use evolves into alcohol use disorder (AUD) remains poorly understood. The Smpd3 gene and its coded protein neutral sphingomyelinase (NSM) are associated with alcohol consumption in humans and alcohol-related behaviors in mice, suggesting a potential role in this transition. Using multiparametric magnetic resonance imaging, we characterized the role of NSM in acute and chronic effects of alcohol on brain anatomy and function in female mice. Chronic voluntary alcohol consumption (16 vol% for at least 6 days) affected brain anatomy in WT mice, reducing regional structure volume predominantly in cortical regions. Attenuated NSM activity prevented these anatomical changes. Functional MRI linked these anatomical adaptations to functional changes: Chronic alcohol consumption in mice significantly modulated resting state functional connectivity (RS FC) in response to an acute ethanol challenge (i.p. bolus of 2 g kg-1) in heterozygous NSM knockout (Fro), but not in WT mice. Acute ethanol administration in alcohol-naïve WT mice significantly decreased RS FC in cortical and brainstem regions, a key finding that was amplified in Fro mice. Regarding direct pharmacological effects, acute ethanol administration increased the regional cerebral blood volume (rCBV) in many brain areas. Here, chronic alcohol consumption otherwise attenuated the acute rCBV response in WT mice but enhanced it in Fro mice. Altogether, these findings suggest a differential role for NSM in acute and chronic functional brain responses to alcohol. Therefore, targeting NSM may be useful in the prevention or treatment of AUD.
Freshwater ecosystems are highly biodiverse1 and important for livelihoods and economic development2, but are under substantial stress3. To date, comprehensive global assessments of extinction risk have not included any speciose groups primarily living in freshwaters. Consequently, data from predominantly terrestrial tetrapods4,5 are used to guide environmental policy6 and conservation prioritization7, whereas recent proposals for target setting in freshwaters use abiotic factors8-13. However, there is evidence14-17 that such data are insufficient to represent the needs of freshwater species and achieve biodiversity goals18,19. Here we present the results of a multi-taxon global freshwater fauna assessment for The IUCN Red List of Threatened Species covering 23,496 decapod crustaceans, fishes and odonates, finding that one-quarter are threatened with extinction. Prevalent threats include pollution, dams and water extraction, agriculture and invasive species, with overharvesting also driving extinctions. We also examined the degree of surrogacy of both threatened tetrapods and freshwater abiotic factors (water stress and nitrogen) for threatened freshwater species. Threatened tetrapods are good surrogates when prioritizing sites to maximize rarity-weighted richness, but poorer when prioritizing based on the most range-restricted species. However, they are much better surrogates than abiotic factors, which perform worse than random. Thus, although global priority regions identified for tetrapod conservation are broadly reflective of those for freshwater faunas, given differences in key threats and habitats, meeting the needs of tetrapods cannot be assumed sufficient to conserve freshwater species at local scales.