It has been postulated that synaptic potentiation during waking is offset by a homoeostatic reduction in net synaptic strength during sleep. However, molecular mechanisms to support such a process ...are lacking. Here we demonstrate that deficiencies in the RNA-editing gene Adar increase sleep due to synaptic dysfunction in glutamatergic neurons in Drosophila. Specifically, the vesicular glutamate transporter is upregulated, leading to over-activation of NMDA receptors, and the reserve pool of glutamatergic synaptic vesicles is selectively expanded in Adar mutants. Collectively these changes lead to sustained neurotransmitter release under conditions that would otherwise result in synaptic depression. We propose that a shift in the balance from synaptic depression towards synaptic potentiation in sleep-promoting neurons underlies the increased sleep pressure of Adar-deficient animals. Our findings provide a plausible molecular mechanism linking sleep and synaptic plasticity.
Many types of synapses have highly characteristic shapes and tightly regulated distributions of active zones, parameters that are important to the function of neuronal circuits. The development of ...terminal arborizations must therefore include mechanisms to regulate the spacing of terminals, the frequency of branching, and the distribution and density of release sites. At present, however, the mechanisms that control these features remain obscure. Here, we report the development of supernumerary or “satellite” boutons in a variety of endocytic mutants at the
Drosophila neuromuscular junction. Mutants in
endophilin,
synaptojanin,
dynamin,
AP180, and
synaptotagmin all show increases in supernumerary bouton structures. These satellite boutons contain releasable vesicles and normal complements of synaptic proteins that are correctly localized within terminals. Interestingly, however,
synaptojanin terminals have more active zones per unit of surface area and more dense bodies (T-bars) within these active zones, which may in part compensate for reduced transmission per active zone. The altered structural development of the synapse is selectively encountered in endocytosis mutants and is not observed when synaptic transmission is reduced by mutations in glutamate receptors or when synaptic transmission is blocked by tetanus toxin. We propose that endocytosis plays a critical role in sculpting the structure of synapses, perhaps through the endocytosis of unknown regulatory signals that organize morphogenesis at synaptic terminals.
The molecular mechanisms underlying the homeostatic modulation of presynaptic neurotransmitter release are largely unknown. We have previously used an electrophysiology-based forward genetic screen ...to assess the function of >400 neuronally expressed genes for a role in the homeostatic control of synaptic transmission at the neuromuscular junction of Drosophila melanogaster. This screen identified a critical function for dysbindin, a gene linked to schizophrenia in humans (Dickman and Davis, 2009). Biochemical studies in other systems have shown that Snapin interacts with Dysbindin, prompting us to test whether Snapin might be involved in the mechanisms of synaptic homeostasis. Here, we demonstrate that loss of snapin blocks the homeostatic modulation of presynaptic vesicle release following inhibition of postsynaptic glutamate receptors. This is true for both the rapid induction of synaptic homeostasis induced by pharmacological inhibition of postsynaptic glutamate receptors, and the long-term expression of synaptic homeostasis induced by the genetic deletion of the muscle-specific GluRIIA glutamate receptor subunit. Loss of snapin does not alter baseline synaptic transmission, synapse morphology, synapse growth, or the number or density of active zones, indicating that the block of synaptic homeostasis is not a secondary consequence of impaired synapse development. Additional genetic evidence suggests that snapin functions in concert with dysbindin to modulate vesicle release and possibly homeostatic plasticity. Finally, we provide genetic evidence that the interaction of Snapin with SNAP25, a component of the SNARE complex, is also involved in synaptic homeostasis.
The extent to which a “kiss-and-run” mode of endocytosis contributes to synaptic-vesicle recycling remains controversial. The only genetic evidence for kiss-and-run at the synapse comes from ...mutations in the genes encoding synaptojanin and endophilin, proteins that together function to uncoat vesicles in classical clathrin-mediated endocytosis. Here we have characterized the endocytosis that persists in null alleles of
Drosophila synaptojanin and
endophilin. In response to high-frequency stimulation, the synaptic-vesicle pool can be reversibly depleted in these mutants. Recovery from this depletion is slow and indicates the persistence of an impaired form of classical endocytosis. Steady-state exocytosis rates reveal that endocytosis saturates in mutant neuromuscular terminals at ∼80 vesicles/s, 10%–20% of the wild-type rate. Analyses of quantal size, FM1-43 loading, and dynamin function further demonstrate that, even in the absence of synaptojanin or endophilin, vesicles undergo full fusion and re-formation. Therefore, no genetic evidence remains to indicate that synaptic vesicles undergo kiss-and-run.
Abstract
Introduction
Insufficient sleep, circadian misalignment, and altered eating patterns are linked to depression. Despite the temporal association between the sleep/wake and feed/fast cycles, ...it is unclear how depression severity influences this relationship.
Methods
Sixty-eight participants ages 18-65 years across the depression continuum wore an Actiwatch for 5-17 nights and reported daily meal times (730 nights total). Multilevel models tested previous night’s sleep timing and duration as predictors of the length of the next day’s eating window. Within-person sleep duration and timing were entered as Level 1 predictors to account for nightly variation in sleep. Between-person sleep duration and timing were entered as Level 2 predictors. A three-way interaction between depression severity and Level 2 sleep duration/timing was entered. Covariates included age, gender, and day (weeknight/weekend).
Results
Across participants, average later sleep timing predicted a longer eating window (Β= -.222; p =.005). Earlier sleep timing (Β= -.186; p < .001) and shorter sleep duration(Β= -.103; p < .001) relative to a person’s average each predicted a longer next-day eating window. A three-way interaction was found between sleep duration, timing, and depression (Β= -.159; p = .002). At shorter sleep durations, individuals with higher depression severity had a positive relationship between sleep timing and eating window length, and individuals with low depression had a negative relationship between sleep timing and eating window length.
Conclusion
At shorter sleep durations (< 6.5 hr), individuals with high depression and later sleep timing or low depression and early sleep timing had the longest eating windows, which have been linked to adverse metabolic health. Future experiments should test short sleep duration, sleep timing, and depression as potential causes of lengthened eating windows to determine if targeting sleep duration and timing could improve adverse metabolic markers in depression.
Support
NIMH K.A.R. MH103303
The multidomain proteoglycan agrin is a critical organizer of postsynaptic differentiation at the skeletal neuromuscular junction. Agrin is also abundant in the brain, but its roles there are ...unknown. As a step toward understanding these roles, we mapped sites responsible for interactions of neurons with agrin. First, we used a series of recombinant agrin fragments to show that at least four sites on agrin interact with chick ciliary neurons. Use of blocking antibodies and peptides indicated that neurons adhere to a site in the second of three G domains by means of αVβ1 integrin, and to a site in the last of four epidermal growth factor (EGF) repeats via a distinct β1 integrin. A third, integrin‐independent adhesion site is near to but distinct from the site that induces postsynaptic differentiation in muscles. These domains are insufficient, however, to account for neurite outgrowth‐inhibiting properties of full‐length agrin, which are mediated by the N‐terminal half of the molecule. We then used a second set of agrin mutants to demonstrate and map a transmembrane domain in the amino‐terminus of the SN‐isoform of agrin. The extracellular matrix‐bound form of agrin, called LN, bears an amino‐terminus required for secretion and binding to laminin. The SN form, which is selectively expressed by neurons, bears a variant amino terminus that converts agrin from a secreted, matrix‐associated protein to a type‐II transmembrane protein, providing a mechanism for presenting agrin in central, as opposed to neuromuscular, synaptic clefts. The SN‐amino terminus can mediate externalization and membrane anchoring of heterologous proteins, but is insufficient to target them to the synapse. Together, these studies define sites that contribute to the subcellular localization of and signaling by neuronal agrin.
Carnivore predation on livestock often leads people to retaliate. Persecution by humans has contributed strongly to global endangerment of carnivores. Preventing livestock losses would help to ...achieve three goals common to many human societies: preserve nature, protect animal welfare, and safeguard human livelihoods. Between 2016 and 2018, four independent reviews evaluated >40 years of research on lethal and nonlethal interventions for reducing predation on livestock. From 114 studies, we find a striking conclusion: scarce quantitative comparisons of interventions and scarce comparisons against experimental controls preclude strong inference about the effectiveness of methods. For wise investment of public resources in protecting livestock and carnivores, evidence of effectiveness should be a prerequisite to policy making or large-scale funding of any method or, at a minimum, should be measured during implementation. An appropriate evidence base is needed, and we recommend a coalition of scientists and managers be formed to establish and encourage use of consistent standards in future experimental evaluations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although functional gastrointestinal disorders (FGIDs), now called disorders of gut-brain interaction, have major economic effects on health care systems and adversely affect quality of life, little ...is known about their global prevalence and distribution. We investigated the prevalence of and factors associated with 22 FGIDs, in 33 countries on 6 continents.
Data were collected via the Internet in 24 countries, personal interviews in 7 countries, and both in 2 countries, using the Rome IV diagnostic questionnaire, Rome III irritable bowel syndrome questions, and 80 items to identify variables associated with FGIDs. Data collection methods differed for Internet and household groups, so data analyses were conducted and reported separately.
Among the 73,076 adult respondents (49.5% women), diagnostic criteria were met for at least 1 FGID by 40.3% persons who completed the Internet surveys (95% confidence interval CI, 39.9–40.7) and 20.7% of persons who completed the household surveys (95% CI, 20.2–21.3). FGIDs were more prevalent among women than men, based on responses to the Internet survey (odds ratio, 1.7; 95% CI, 1.6–1.7) and household survey (odds ratio, 1.3; 95% CI, 1.3–1.4). FGIDs were associated with lower quality of life and more frequent doctor visits. Proportions of subjects with irritable bowel syndrome were lower when the Rome IV criteria were used, compared with the Rome III criteria, in the Internet survey (4.1% vs 10.1%) and household survey (1.5% vs 3.5%).
In a large-scale multinational study, we found that more than 40% of persons worldwide have FGIDs, which affect quality of life and health care use. Although the absolute prevalence was higher among Internet respondents, similar trends and relative distributions were found in people who completed Internet vs personal interviews.
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Non-structural carbohydrates (NSC) in plant tissue are frequently quantified to make inferences about plant responses to environmental conditions. Laboratories publishing estimates of NSC of woody ...plants use many different methods to evaluate NSC. We asked whether NSC estimates in the recent literature could be quantitatively compared among studies. We also asked whether any differences among laboratories were related to the extraction and quantification methods used to determine starch and sugar concentrations. These questions were addressed by sending sub-samples collected from five woody plant tissues, which varied in NSC content and chemical composition, to 29 laboratories. Each laboratory analyzed the samples with their laboratory-specific protocols, based on recent publications, to determine concentrations of soluble sugars, starch and their sum, total NSC. Laboratory estimates differed substantially for all samples. For example, estimates for Eucalyptus globulus leaves (EGL) varied from 23 to 116 (mean = 56) mg g(-1) for soluble sugars, 6-533 (mean = 94) mg g(-1) for starch and 53-649 (mean = 153) mg g(-1) for total NSC. Mixed model analysis of variance showed that much of the variability among laboratories was unrelated to the categories we used for extraction and quantification methods (method category R(2) = 0.05-0.12 for soluble sugars, 0.10-0.33 for starch and 0.01-0.09 for total NSC). For EGL, the difference between the highest and lowest least squares means for categories in the mixed model analysis was 33 mg g(-1) for total NSC, compared with the range of laboratory estimates of 596 mg g(-1). Laboratories were reasonably consistent in their ranks of estimates among tissues for starch (r = 0.41-0.91), but less so for total NSC (r = 0.45-0.84) and soluble sugars (r = 0.11-0.83). Our results show that NSC estimates for woody plant tissues cannot be compared among laboratories. The relative changes in NSC between treatments measured within a laboratory may be comparable within and between laboratories, especially for starch. To obtain comparable NSC estimates, we suggest that users can either adopt the reference method given in this publication, or report estimates for a portion of samples using the reference method, and report estimates for a standard reference material. Researchers interested in NSC estimates should work to identify and adopt standard methods.
Feral cats (Felis catus) have devastated wildlife globally. In Australia, feral cats are implicated in most recent mammal extinctions and continue to threaten native species. Cat control is a ...high-profile priority for Australian policy, research and management. To develop the evidence-base to support this priority, we first review information on cat presence/absence on Australian islands and mainland cat-proof exclosures, finding that cats occur across >99.8% of Australia's land area. Next, we collate 91 site-based feral cat density estimates in Australia and examine the influence of environmental and geographic influences on density. We extrapolate from this analysis to estimate that the feral cat population in natural environments fluctuates between 1.4 million (95% confidence interval: 1.0–2.3 million) after continent-wide droughts, to 5.6 million (95% CI: 2.5–11 million) after extensive wet periods. We estimate another 0.7 million feral cats occur in Australia's highly modified environments (urban areas, rubbish dumps, intensive farms). Feral cat densities are higher on small islands than the mainland, but similar inside and outside conservation land. Mainland cats reach highest densities in arid/semi-arid areas after wet periods. Regional variation in cat densities corresponds closely with attrition rates for native mammal fauna. The overall population estimate for Australia's feral cats (in natural and highly modified environments), fluctuating between 2.1 and 6.3 million, is lower than previous estimates, and Australian feral cat densities are lower than reported for North America and Europe. Nevertheless, cats inflict severe impacts on Australian fauna, reflecting the sensitivity of Australia's native species to cats and reinforcing that policy, research and management to reduce their impacts is critical.
•A collation of 91 studies was used to estimate Australia's feral cat population.•Feral cats are present on >>99.8% of Australia's land area.•Feral cat numbers in Australia fluctuate (2.1–6.3 million) with antecedent rainfall.•Feral cat density is higher on small islands, and in arid/semi-arid areas after rain.•Feral cat impacts on Australian biodiversity have been particularly severe.
The population size of feral cats in natural environments in Australia fluctuates between 1.4 and 5.6 million, depending on rainfall. An additional 0.7 million feral cats live in heavily modified environments like towns and intensive farms. The maps show the model predictions for cat density in natural environments across Australia during dry-average rainfall conditions (on the left) and after extensive rainfall events (on the right). They show that cat density is fairly uniform across the continent during average-dry conditions, but extensive rainfall events cause an increase in feral cat density in the inland of Australia. As predictors, the regression model includes mean annual rainfall, mean annual temperature, tree cover, ruggedness and fox presence/absence. For islands smaller than Tasmania, island area was also included as a predictor of density (small islands have higher cat densities). The dashed lines indicate the Tropic of Capricorn. Display omitted
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