PLoS Biology最新文献

Learning and decision-making undergo substantial developmental changes, with adolescence being a particular vulnerable window of opportunity. In adolescents, developmental changes in specific choice behaviors have been observed (e.g., goal-directed behavior, motivational influences over choice). Elevated levels of decision noise, i.e., choosing suboptimal options, were reported consistently in adolescents. However, it remains unknown whether these observations, the development of specific and more sophisticated choice processes and higher decision noise, are independent or related. It is conceivable, but has not yet been investigated, that the development of specific choice processes might be impacted by age-dependent changes in decision noise. To answer this, we examined 93 participants (12 to 42 years) who completed 3 reinforcement learning (RL) tasks: a motivational Go/NoGo task assessing motivational influences over choices, a reversal learning task capturing adaptive decision-making in response to environmental changes, and a sequential choice task measuring goal-directed behavior. This allowed testing of (1) cross-task generalization of computational parameters focusing on decision noise; and (2) assessment of mediation effects of noise on specific choice behaviors. Firstly, we found only noise levels to be strongly correlated across RL tasks. Second, and critically, noise levels mediated age-dependent increases in more sophisticated choice behaviors and performance gain. Our findings provide novel insights into the computational processes underlying developmental changes in decision-making: namely a vital role of seemingly unspecific changes in noise in the specific development of more complex choice components. Studying the neurocomputational mechanisms of how varying levels of noise impact distinct aspects of learning and decision processes may also be key to better understand the developmental onset of psychiatric diseases.

Pain is not a mere reflection of noxious input. Rather, it is constructed through the dynamic integration of current predictions with incoming sensory input. However, the temporal dynamics of the behavioral and neural processes underpinning this integration remain elusive. In the current study involving 59 human participants, we identified a series of brain mediators that integrated cue-induced expectations with noxious inputs into ongoing pain predictions using a semicircular scale designed to capture rating trajectories. Temporal mediation analysis revealed that during the early-to-mid stages of integration, the frontoparietal and dorsal attention network regions, such as the lateral prefrontal, premotor, and parietal cortex, mediated the cue effects. Conversely, during the mid-to-late stages of integration, the somatomotor network regions mediated the effects of stimulus intensity, suggesting that the integration occurs along the cortical hierarchy from the association to sensorimotor brain systems. Our findings advance the understanding of how the brain integrates contextual and sensory information into pain experience over time.

Impaired nutrient cycling under thermal stress foregoes coral bleaching, the loss of symbiotic algae. A new study in PLOS Biology sheds light on how coral larvae avoid bleaching through nitrogen sequestration to uphold glucose translocation from their algal symbionts.

Rising sea surface temperatures are increasingly causing breakdown in the nutritional relationship between corals and algal endosymbionts (Symbiodiniaceae), threatening the basis of coral reef ecosystems and highlighting the critical role of coral reproduction in reef maintenance. The effects of thermal stress on metabolic exchange (i.e., transfer of fixed carbon photosynthates from symbiont to host) during sensitive early life stages, however, remains understudied. We exposed symbiotic Montipora capitata coral larvae in Hawai'i to high temperature (+2.5°C for 3 days), assessed rates of photosynthesis and respiration, and used stable isotope tracing (4 mM 13C sodium bicarbonate; 4.5 h) to quantify metabolite exchange. While larvae did not show any signs of bleaching and did not experience declines in survival and settlement, metabolic depression was significant under high temperature, indicated by a 19% reduction in respiration rates, but with no change in photosynthesis. Larvae exposed to high temperature showed evidence for maintained translocation of a major photosynthate, glucose, from the symbiont, but there was reduced metabolism of glucose through central carbon metabolism (i.e., glycolysis). The larval host invested in nitrogen cycling by increasing ammonium assimilation, urea metabolism, and sequestration of nitrogen into dipeptides, a mechanism that may support the maintenance of glucose translocation under thermal stress. Host nitrogen assimilation via dipeptide synthesis appears to be used for nitrogen limitation to the Symbiodiniaceae, and we hypothesize that nitrogen limitation contributes to retention of fixed carbon by favoring photosynthate translocation to the host. Collectively, our findings indicate that although these larvae are susceptible to metabolic stress under high temperature, diverting energy to nitrogen assimilation to maintain symbiont population density, photosynthesis, and carbon translocation may allow larvae to avoid bleaching and highlights potential life stage specific metabolic responses to stress.

The sensation of gravity anchors our perception of the environment and is important for navigation. However, the neural circuits that transform gravity into commands for navigation are undefined. We first determined that larval zebrafish (Danio rerio) navigate vertically by maintaining a consistent heading across a series of upward climb or downward dive bouts. Gravity-blind mutant fish swim with more variable heading and excessive veering, leading to less effective vertical navigation. After targeted photoablation of ascending vestibular neurons and spinal projecting midbrain neurons, but not vestibulospinal neurons, vertical navigation was impaired. These data define a sensorimotor circuit that uses evolutionarily conserved brainstem architecture to transform gravitational signals into persistent heading for vertical navigation. The work lays a foundation to understand how vestibular inputs allow animals to move effectively through their environment.

H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here, we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine virus, and we show that a mutation present in some recent H5 HAs causes a large antigenic change. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.

Establishment of the 3 primordial germ layers (ectoderm, endoderm, and mesoderm) during early animal development represents an essential prerequisite for the emergence of properly patterned embryos. β-catenin is an ancient protein that is known to play essential roles in this process. However, these roles have chiefly been established through inhibition of β-catenin translation or function at the time of fertilization. Comprehensive analyses reporting the totality of functions played by nuclear β-catenin, during the early embryogenesis of a given animal, i.e., at different developmental stages and in different germ layers, are thus still lacking. In this study, we used an inducible, conditional knockdown system in the sea urchin to characterize all possible requirements of β-catenin for germ layer establishment and patterning. By blocking β-catenin protein production starting at 7 different time points of early development, between fertilization and 12 h post fertilization, we established a clear correlation between the position of a germ layer along the primary embryonic axis (the animal-vegetal axis) and its dependence on nuclear β-catenin activity. For example, in the vegetal hemisphere, we determined that the 3 germ layers (skeletogenic mesoderm, non-skeletogenic mesoderm, and endoderm) require distinct and highly specific durations of β-catenin production for their respective specification, with the most vegetal germ layer, the skeletogenic mesoderm, requiring the shortest duration. Likewise, for the 2 animal territories (ectoderm and anterior neuroectoderm), we established that their restriction, along the animal-vegetal axis, relies on different durations of β-catenin production, and that the longest duration is for the most animal territory, the anterior neuroectoderm. Moreover, we found that 2 of the vegetal germ layers, the non-skeletogenic mesoderm and the endoderm, further require a prolonged period of nuclear β-catenin activity, after their specification, to maintain their respective germ layer identities through time. Finally, we determined that restriction of the anterior neuroectoderm territory depends on at least 2 nuclear β-catenin-dependent inputs and a nuclear β-catenin-independent mechanism. Taken together, this work is the first to comprehensively define the spatiotemporal requirements of β-catenin during the early embryogenesis of a single animal, the sea urchin Paracentrotus lividus, thereby providing new experimental evidence for a better understanding of the roles played by this evolutionary conserved protein during animal development.

Bacteria sense population density via the cell-cell communication system called quorum sensing (QS). The evolution of QS and its maintenance or loss in mixed bacterial communities is highly relevant to understanding how cell-cell signaling impacts bacterial fitness and competition, particularly under varying environmental conditions such as nutrient availability. We uncovered a phenomenon in which Vibrio cells grown in minimal medium optimize expression of the methionine and tetrahydrofolate (THF) synthesis genes via QS. Strains that are genetically "locked" at high cell density grow slowly in minimal glucose media and suppressor mutants accumulate via inactivating-mutations in metF (methylenetetrahydrofolate reductase) and luxR (the master QS transcriptional regulator). In mixed cultures, QS mutant strains initially coexist with wild type, but as glucose is depleted, wild type outcompetes the QS mutants. Thus, QS regulation of methionine/THF synthesis is a fitness benefit that links nutrient availability and cell density, preventing accumulation of QS-defective mutants.

Mitochondria regulate several physiological functions through mitochondrial Ca2+ dynamics. However, role of mitochondrial Ca2+ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+ uptake. In vitro gain and loss of function studies demonstrate that mitochondrial Ca2+ uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, MCU+/- and MCUb-/- mice models show that MCU complex drives pigmentation in vivo. Mechanistically, MCU silencing activates transcription factor NFAT2 to induce expression of keratin (5, 7, and 8) filaments. Interestingly, keratin5 in turn augments mitochondrial Ca2+ uptake and potentiates melanogenesis by regulating melanosome biogenesis and maturation. Hence this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ signaling and pigmentation. Notably, mitoxantrone, an FDA approved drug that inhibits MCU, reduces pigmentation thereby highlighting therapeutic potential of targeting mitochondrial Ca2+ uptake for clinical management of pigmentary disorders. Taken together, we reveal an MCU-NFAT2-Keratin5 driven signaling axis that acts as a critical determinant of mitochondrial Ca2+ uptake and pigmentation. Given the vital role of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop could be operational in a variety of other patho-physiological processes.

Perception is shaped by both incoming sensory input and expectations derived from our prior knowledge. Numerous studies have shown stronger neural activity for surprising inputs, suggestive of predictive processing. However, it is largely unclear what predictions are made across the cortical hierarchy, and therefore what kind of surprise drives this up-regulation of activity. Here, we leveraged fMRI in human volunteers and deep neural network (DNN) models to arbitrate between 2 hypotheses: prediction errors may signal a local mismatch between input and expectation at each level of the cortical hierarchy, or prediction errors may be computed at higher levels and the resulting surprise signal is broadcast to earlier areas in the cortical hierarchy. Our results align with the latter hypothesis. Prediction errors in both low- and high-level visual cortex responded to high-level, but not low-level, visual surprise. This scaling with high-level surprise in early visual cortex strongly diverged from feedforward tuning. Combined, our results suggest that high-level predictions constrain sensory processing in earlier areas, thereby aiding perceptual inference.