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Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
Species diversity promotes the delivery of multiple ecosystem functions (multifunctionality). However, the relative functional importance of rare and common species in driving the biodiversity multifunctionality relationship remains unknown. We studied the relationship between the diversity of rare and common species (according to their local abundances and across nine different trophic groups), and multifunctionality indices derived from 14 ecosystem functions on 150 grasslands across a land use intensity (LUI) gradient. The diversity of above- and below-ground rare species had opposite effects, with rare above-ground species being associated with high levels of multifunctionality, probably because their effects on different functions did not trade off against each other. Conversely, common species were only related to average, not high, levels of multifunctionality, and their functional effects declined with LUI. Apart from the community level effects of diversity, we found significant positive associations between the abundance of individual species and multifunctionality in 6% of the species tested. Species specific functional effects were best predicted by their response to LUI: species that declined in abundance with land use intensification were those associated with higher levels of multifunctionality. Our results highlight the importance of rare species for ecosystem multifunctionality and help guiding future conservation priorities.
Long and short-term climatic variation affect the ability of plants to simultaneously cope with increasing abiotic stress and biotic interactions. Specifically, ecotypes adapted to different climatic conditions (i.e., long-term legacy) may have to adjust their allocation to chemical defenses against enemies under acute drought (i.e., short-term response). Although several studies have addressed drought effects on chemical defense production, little is known about their intraspecific variation along resource gradients. Studying intraspecific variation is important for understanding how different environments select for defense strategies and how these may be affected directly and indirectly by changing climatic conditions. We conducted greenhouse experiments with the annual Biscutella didyma (Brassicaceae) to test the effects of long-term climatic legacy versus short-term drought stress on the concentrations of defense compounds (glucosinolates). To this aim, four ecotypes originating from a steep aridity gradient were exposed to contrasting water treatments. Concentrations of chemical defenses were measured separately in leaves of young (8 weeks) and old (14 weeks) plants, respectively. For young plants, ecotypes from the wettest climate (long-term legacy) as well as plants receiving high water treatments (short-term response) were better defended. A marginally significant interaction suggested that wetter ecotypes experienced a larger shift in defense production across water treatments. Older plants contained much lower glucosinolate concentrations and showed no differences between ecotypes and water treatments. Our results indicate that younger plants invest more resources into chemical defenses, possibly due to higher vulnerability to tissue loss compared to older plants. We propose that the strong response of wet ecotypes to water availability may be explained by a less pronounced adaptation to drought.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
We selected the immunogenic cell wall beta-(1,3)-glucosyltransferase Bgl2p from Candida albicans as a target protein for the production of antibodies. We identified a unique peptide sequence in the protein and generated monoclonal anti- C. albicans Bgl2p antibodies, which bound in particular to whole C. albicans cells.
Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions.
Global change has complex eco-evolutionary consequences for organisms and ecosystems, but related concepts (e.g., novel ecosystems) do not cover their full range. Here we propose an umbrella concept of "ecological novelty" comprising (1) a site-specific and (2) an organism-centered, eco-evolutionary perspective. Under this umbrella, complementary options for studying and communicating effects of global change on organisms, ecosystems, and landscapes can be included in a toolbox. This allows researchers to address ecological novelty from different perspectives, e.g., by defining it based on (a) categorical or continuous measures, (b) reference conditions related to sites or organisms, and (c) types of human activities. We suggest striving for a descriptive, non-normative usage of the term "ecological novelty" in science. Normative evaluations and decisions about conservation policies or management are important, but require additional societal processes and engagement with multiple stakeholders.