title: Reproductive neuronal circuitry in adaptive changes of energy balance

abstract:
The crosstalk between metabolism and reproduction is essential for species survival. When dysfunctional, this interaction may decrease reproductive efficiency, but in physiological conditions of high energy demands, e.g., pregnancy and lactation, it is highly beneficial. Females display adaptive responses that assure offspring survival and health, including increased food intake and suppression of the reproductive function. Some of these physiological responses are modulated by leptin actions in neuronal pathways that are still unclear. The hypothalamic ventral premammillary nucleus (PMv) is a key integrative node of metabolic cues and reproductive status, comprised of either leptin-depolarized or -hyperpolarized neurons. Here, we show that the subset of leptin-hyperpolarized neurons coexpresses dopamine transporter (DAT) and prolactin receptor. DAT expression is higher in prepubertal conditions, when reproductive function is suppressed. These neurons innervate AgRP presynaptic terminals and may potentiate their inhibitory actions on reproduction. We further applied a mathematical model to reconcile our new findings with the current literature and to verify if those neurons are putative components of the metabolic control of reproduction. In our model, leptin-depolarized PMv neurons project to and directly stimulate kisspeptin and gonadotropin releasing hormone (GnRH) neurons. Leptin-hyperpolarized PMv DAT neurons are directly stimulated by prolactin and project to inhibitory control sites. During conditions of high prolactin levels, i.e., late pregnancy and lactation, this pathway may overcome the former, facilitating AgRP actions in the suppression of the reproductive function. Our model also predicts that overstimulation of this pathway may underlie earlier puberty and reproductive deficits observed in conditions of metabolic dysfunction.

Significance StatementWomen with excess or low energy stores (e.g., obesity or anorexia) have reproductive deficits, including altered puberty onset, disruption of reproductive cycles and decreased fertility. If able to conceive, they show higher risks of miscarriages and preterm birth. The hypothalamic circuitry controlling the interplay between metabolism and reproduction is undefined. Neurons in the ventral premammillary nucleus express leptin receptor and project to reproductive control sites. Those neurons are essentially glutamatergic, but functionally and phenotypically heterogeneous. They either depolarize or hyperpolarize in response to leptin. We show that leptin-hyperpolarized neurons coexpress dopamine transporter and prolactin receptor, and project to AgRP inhibitory output. Computational modeling was applied to build a neuronal network integrating metabolism and reproduction in typical and dysfunctional physiology.


title: Laminar microcircuitry of visual cortex producing attention-associated electric fields

abstract: Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the component neural circuitry giving rise to these signals remains unknown. Specifically, the functional architecture of cortical columns which results in attention-associated electric fields has not been explored. Here we detail the laminar cortical circuitry underlying an attention-associated electric field often measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Lastly, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field capable of being measured extracranially and the relative contribution of each column depends upon the underlying functional architecture.

category: neuroscience


title: Clonal evolution and specificity of the human T follicular helper cell response to Plasmodium falciparum circumsporozoite protein

abstract: T follicular helper (TFH) cells play a crucial role in the development of long-lived, quality-improved B cell responses after infection and vaccination. However, little is known about their clonal evolution. Here we assessed the cell phenotype, clonal dynamics, and TCR specificity of human circulating TFH (cTFH) cells at monoclonal level during successive malaria immunizations with radiation-attenuated Plasmodium falciparum (Pf) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cTFH response with high frequency of cells specific to the Pf circumsporozoite protein (PfCSP), the main surface protein of sporozoites and a validated vaccine target. Repeated immunizations were required to induce detectable PfCSP-reactive cTFH cell responses to a small number of epitopes. HLA-restrictions and differences in TCR generation probability explain the high targeting frequency of the polymorphic Th2R/T* region over the conserved T1 epitope. The vast majority of anti-Th2R/T* TCRs failed to tolerate natural polymorphisms in their target peptide sequence suggesting that parasite diversity limits natural boosting of the cTFH cell response in endemic areas and protection from non-vaccine strains. Among convergent anti-Th2R/T* TCRs with high sequence similarity, subtle differences in CDR3 composition discriminated cross-reactive from non-cross-reactive cTFH cells. Thus, our study provides deep molecular and cellular insights into the kinetics, fine specificity and HLA-restrictions of the anti-cTFH cell response that are of direct relevance for the design of PfCSP-based malaria vaccines by guiding the selection of PfCSP peptides that induce optimal B cell help.

category: immunology


title: Induction of transposable element expression is central to innate sensing

abstract: Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.


title: The Application of The Skin Virome for Human Identification

abstract:
The use of skin virome for human identification purposes offers a unique approach to instances where a viable and statistically relevant human DNA profile is unavailable. The human skin virome may act as an alternative DNA profile and/or an additional form of probative genetic material. To date, no study has attempted to investigate the human virome over a time series across various physical locations of the body to identify its potential as a tool for human identification. For this study, we set out to evaluate the stability, diversity, and individualization of the human skin virome. An additional goal was to identify viral signatures that can be used in conjunction with traditional forensic STR loci. In order to accomplish this, human virome metagenomes were collected and sequenced from 42 individuals at three anatomical locations (left hand, right hand, and scalp) across multiple collections periods over a 6-month window of time. Assembly dependent and independent bioinformatic approaches were employed, along with a database-based assessment, which resulted in three sets of stable putative viral markers. In total, with the three sets combined, 59 viral species and uncharacterized viral genome assemblies were identified as being significantly stable (P=5.3x10-15). Viral diversity, based on presence or absence, is significantly different across subjects (P<0.001). Here we demonstrate that not only is the human virome applicable to be used for human identification, but we have identified many viral signatures that can be used for forensic applications, thus providing a foundation to the novel field of forensic virology.

HighlightsO_LIHere we provide the largest human skin virome study, to date. Our study revealed novel diversity findings of high abundance for certain viral taxa, for example, the Cress-like DNA phages, that have not previously been characterized in human skin viral ecology studies.
C_LIO_LIThere were 59 putative human skin viral biomarkers suitable for human identification from the core stable human skin virome of 42 subjects.
C_LIO_LIThe putative markers we identified were significantly stable over a 6-month period of time within individuals and across three autosomal locations of left hand, right hand, and scalp.
C_LIO_LIDiversity of profiles, based on the presence and absence of our putative marker data set, were significantly different across test subjects.
C_LI

category: microbiology


title: Passive plasma membrane transporters play a critical role in perception of carbon availability in yeast

abstract: Recently, our lab found that the canonical glucose/galactose regulation pathway in yeast makes the decision to metabolize galactose based on the ratio of glucose to galactose concentrations in the external medium. This led to the question of where and how the ratio-sensing is achieved. Here, we consider the possibilities of an intracellular, extracellular, or membrane bound ratio sensing mechanisms. We show that hexose transporters in the plasma membrane are mainly responsible for glucose/galactose ratio-sensing in yeast. Further, while the glucose sensors Gpr1, Snf3, and Rgt2 are not required for ratio sensing, they help modulate the ratio sensing phenotype by regulating the expression of individual transporters in different environments. Our study provides an example of an unexpected, but potentially widespread, mechanism for making essential decisions.

category: cell biology


title: Environmental stress determines the colonization and impact of an endophytic fungus on invasive knotweed

abstract:
O_LIThere is increasing evidence that microbes play a key role in some plant invasions. A diverse and widespread but little understood group of plant-associated microbes are the fungal root endophytes of the order Sebacinales. They are associated with exotic populations of invasive knotweed (Reynoutria ssp.) in Europe, but their effects on the invaders are unknown.
C_LIO_LIWe used the recently isolated Sebacinales root endophyte Serendipita herbamans to experimentally inoculate invasive knotweed and study root colonisation and effects on knotweed growth under different environmental conditions. We verified the inoculation success and fungal colonisation through immunofluorescence microscopy and qPCR.
C_LIO_LIWe found that S. herbamans strongly colonized invasive knotweed in low-nutrient and shade environments, but much less under drought or benign conditions. At low nutrients, the endophyte had a positive effect on plant growth, whereas the opposite was true under shaded conditions.
C_LIO_LISynthesis. Our study demonstrates that the root endophyte S. herbamans has the potential to colonize invasive knotweed fine roots and impact its growth, and it could thus also play a role in natural populations. Our results also show that effects of fungal endophytes on plants can be strongly environment-dependent, and may only be visible under stressful environmental conditions.
C_LI

category: ecology


title: Reproductive strategies in vent shrimps shaped by feeding ecology with intriguing seasonality unlinked to surface productivity

abstract: Variations in offspring production according to feeding strategies or food supply have been recognized in many animals from various ecosystems. Despite an unusual trophic structure based on non-photosynthetic primary production, these relationships remain largely under-studied in chemosynthetic ecosystems. Here, we use Rimicaris shrimps from deep-sea hydrothermal vents as a study case to explore relations between reproduction, diets and food supply in these environments. For that, we compared reproductive outputs of three congeneric shrimps differing by their diets. They inhabit vents located under oligotrophic waters of tropical gyres with opposed latitudes, allowing us to also examine the prevalence of phylogenetic vs environmental drivers in their reproductive rhythms. For this we used both our original data and a compilation of published observations on the presence of ovigerous females covering various seasons over the past 35 years. We report distinct egg production trends between Rimicaris species relying solely on chemosymbiosis - R. exoculata and R. kairei - and those relying on mixotrophy - R. chacei - where R. chacei produces broods with higher numbers of smaller eggs. Besides, our data and historical records suggest a reproductive period with substantial proportions of brooding females mostly between January and early April for all examined species whatever the region. Intriguingly, this periodicity does not correspond to seasonal variations in surface production with presence of brooding females during either boreal winter or austral summer. These observations contrast with the long-standing paradigm in deep-sea species for which periodic reproductive patterns have always been attributed to seasonal variations of photosynthetic production sinking from surface. Our results suggest the presence of intrinsic basis for biological rhythms in the deep sea, and bring to light the importance of having year-round observations in order to understand life history of vent animals.


title: Reproduction in deep-sea vent shrimps is shaped by diet and phylogeny, with rhythms unlinked to surface production


title: Extending the CWM approach to intraspecific trait variation: how to deal with overly optimistic standard tests?

abstract: Community weighted means (CWMs) are widely used to study the relationship between community-level functional traits and environment variation. When relationships between CWM traits and environmental variables are directly assessed using linear regression or ANOVA and tested by standard parametric tests, results are prone to inflated Type I error rates, thus producing overly optimistic results. Previous research has found that this problem can be solved by permutation tests (i.e. the max test). A recent extension of this CWM approach, that allows the inclusion of intraspecific trait variation (ITV) by partitioning information in fixed, site-specific and intraspecific CWMs, has proven popular. However, this raises the question whether the same kind of Type I error rate inflation also exists for site-specific CWM or intraspecific CWM-environment relationships. Using simulated community datasets and a real-world dataset from a subtropical montane cloud forest in Taiwan, we show that site-specific CWM-environment relationships also suffer from Type I error rate inflation, and that the severity of this inflation is negatively related to the relative ITV magnitude. In contrast, for intraspecific CWM-environment relationships, standard parametric tests have the correct Type I error rate, while being somewhat conservative, with reduced statistical power. We introduce an ITV-extended version of the max test for the ITV-extended CWM approach, which can solve the inflation problem for site-specific CWM-environment relationships, and which, without considering ITV, becomes equivalent to the "original" max test used for the CWM approach. On both simulated and real-world data, we show that this new ITV-extended max test works well across the full possible magnitude of ITV. We also provide guidelines and R codes of max test solutions for each CWM type and situation. Finally, we suggest recommendations on how to handle the results of previously published studies using the CWM approach without controlling for Type I error rate inflation.


title: Social hosts evade predation but have deadlier parasites

abstract:
Parasites exploit hosts to replicate and transmit, but overexploitation kills host and parasite (1): predators may shift this cost-benefit balance by consuming hosts (2-4) or changing host behavior, but the strength of these effects remains unclear. Modeling both, we find a primary, strong effect: hosts group to defend against predators (5), increasing parasite transmission, thus multiple infections, and therefore favoring more exploitative, virulent, parasites (6). Indeed, among 18 Trinidadian Gyrodactyus spp. parasite lines, those collected from high predation guppy populations were more virulent in common garden than those from low predation populations. Our model accurately predicted this result when parametrized with our experimentally demonstrated virulence-transmission trade-off, implicating the behavioral effects of predation. Broadly, our results indicate that reduced social contact selects against parasite virulence.

One-Sentence SummaryOur theory and data show predators cause increased host social grouping; the resulting transmission favors parasite virulence.


title: Optimal strategies to protect a sub-population at risk due to an established epidemic

abstract: Epidemics can particularly threaten certain sub-populations. For example, for SARS-CoV-2, the elderly are often preferentially protected. For diseases of plants and animals, certain sub-populations can drive mitigation because they are intrinsically more valuable for ecological, economic, socio-cultural or political reasons. Here we use optimal control theory to identify strategies to optimally protect a "high value" sub-population when there is a limited budget and epidemiological uncertainty. We use protection of the Redwood National Park in California in the face of the large ongoing state-wide epidemic of sudden oak death (caused by Phytophthora ramorum) as a case study. We concentrate on whether control should be focused entirely within the National Park itself, or whether treatment of the growing epidemic in the surrounding "buffer region" can instead be more profitable. We find that, depending on rates of infection and the size of the ongoing epidemic, focusing control on the high value region is often optimal. However, priority should sometimes switch from the buffer region to the high value region only as the local outbreak grows. We characterise how the timing of any switch depends on epidemiological and logistic parameters, and test robustness to systematic misspecification of these factors due to imperfect prior knowledge.


title: Biogeographical patterns and diversity in the diet of the culpeo (Lycalopex culpaeus) in South America

abstract:
Here we describe the dietary patterns of the culpeo (or Andean fox) at a biogeographical scale. We also analyze the influence of exotic lagomorphs on its diet and explore differences between culpeo subspecies. We selected 17 mutually comparable diet studies, which include 19 independent diet assessments. Then, we extracted and standardized the values of the different diet components from these studies and calculated the relative frequency of occurrence (RF) of the ten main trophic groups that we found. Further, we calculated the Shannon-Wienner H trophic diversity index.

The results showed that small mammals (41%), lagomorphs (21%), invertebrates (12.4%) and large herbivores (7.3%) were the most consumed groups. A factorial analysis of all trophic groups rendered four orthogonal factors that were used as response variables in relation to a set of environmental predictors. Altitude correlated with most factors (i.e. trophic groups). Exotic lagomorphs were consumed in lowlands, in higher latitudes and in regions showing high values of the human footprint index, replacing in these areas native fauna as the main prey. There were no differences in diet between the two main culpeo subspecies analysed, L.c. culpaeus and L.c. andinus.

Finally, the best explanatory models (GLM) of trophic diversity selected, using the Akaikes information criterion (AIC), showed that the most diverse diets were those composed of large herbivores, edentates, carnivorous species, birds and herptiles (i.e. amphibians and reptils), in areas of high rainfall located in protected areas. Neither latitude nor altitude seemed to have an effect on the trophic diversity of the culpeos, as they were not retained by the final models.


title: Cold shock induces a terminal investment reproductive response in C. elegans

abstract: Challenges from environmental stressors have a profound impact on many life-history traits of an organism, including reproductive strategy. Examples across multiple taxa have demonstrated that maternal reproductive investment resulting from stress can improve offspring survival; a form of matricidal provisioning when death appears imminent is known as terminal investment. Here we report a reproductive response in the nematode Caenorhabditis elegans upon exposure to acute cold shock at 2{degrees}C, whereby vitellogenic lipid movement from the soma to the germline appears to be massively upregulated at the expense of parental survival. This response is dependent on functional TAX-2;TAX-4 cGMP-gated channels that are part of canonical thermosensory mechanisms in worms and can be prevented in the presence of activated SKN-1/Nrf2, the master stress regulator. Increased maternal provisioning promotes improved embryonic cold shock survival, which is notably suppressed in animals with impaired vitellogenesis. These findings suggest that cold shock in C. elegans triggers terminal investment to promote progeny fitness at the expense of parental survival and may serve as a tractable model for future studies of stress-induced progeny plasticity.

category: genetics


title: Long-term effects of wildfire smoke exposure during early-life on the nasal epigenome in rhesus macaques

abstract:
BackgroundWildfire smoke is responsible for around 20% of all particulate emissions in the U.S. and affects millions of people worldwide. Children are especially vulnerable, as ambient air pollution exposure during early childhood is associated with reduced lung function. Most studies, however, have focused on the short-term impacts of wildfire smoke exposures. We aimed to identify long-term baseline epigenetic changes associated with early-life exposure to wildfire smoke. We collected nasal epithelium samples for whole genome bisulfite sequencing (WGBS) from two groups of adult female rhesus macaques: one group born just before the 2008 California wildfire season and exposed to wildfire smoke during early-life (n = 8), and the other group born in 2009 with no wildfire smoke exposure during early-life (n = 14). RNA-sequencing was also performed on a subset of these samples.

ResultsWe identified 3370 differentially methylated regions (DMRs) (difference in methylation [≥] 5% empirical p < 0.05) and 1 differentially expressed gene (FLOT2) (FDR< 0.05, fold of change [≥] 1.2). The DMRs were annotated to genes significantly enriched for synaptogenesis signaling, protein kinase A signaling, and a variety of immune processes, and some DMRs significantly correlated with gene expression differences. DMRs were also significantly enriched within regions of bivalent chromatin (top odds ratio = 1.46, q-value < 3 x 10-6) that often silence key developmental genes while keeping them poised for activation in pluripotent cells.

ConclusionsThese data suggest that early-life exposure to wildfire smoke leads to long-term changes in the methylome over genes impacting the nervous and immune systems, but follow-up studies will be required to test whether these changes influence transcription following an immune/respiratory challenge.

category: genomics


title: Long-term balancing selection in highly dynamic mating loci generates trans-species polymorphisms in fungi

abstract:
Balancing selection, an evolutionary force that retains genetic diversity, has been detected in multiple genes and organisms, such as the sexual mating loci in fungi. However, to quantify the strength of balancing selection and define the mating-related genes require a large number of specimens. In tetrapolar basidiomycete fungi, sexual type is determined by two unlinked loci, MATA and MATB. Genes in both loci defines mating type identity, control successful mating and completion of the life cycle. These loci are usually highly diverse. Previous studies have speculated, based on culture crosses, that species of the non-model genus Trichaptum (Hymenochaetales, Basidiomycota) possess a tetrapolar mating system, with multiple alleles. Here, we sequenced a hundred and eighty specimens of three Trichaptum species. We characterized the chromosomal location of MATA and MATB, the molecular structure of MAT regions and their allelic richness. Our sequencing effort was sufficient to molecularly characterize multiple MAT alleles segregating before the speciation event of Trichaptum species. Our analyses suggested that long-term balancing selection has generated trans-species polymorphisms. Mating sequences were classified in different allelic classes based on an amino acid identity (AAI) threshold supported by phylogenetics. The inferred allelic information mirrored the outcome of in vitro crosses, thus allowing us to support the degree of allelic divergence needed for successful mating. Even with the high amount of divergence, key amino acids in functional domains are conserved. The observed allelic classes could potentially generate 14,560 different mating types. We conclude that the genetic diversity of mating in Trichaptum loci is due to long-term balancing selection, with limited recombination and duplication activity. Our large number of sequenced specimens highlighted the importance of sequencing multiple individuals from different species to detect the mating-related genes, the mechanisms generating diversity and the evolutionary forces maintaining them.

Author summaryFungi have complex mating systems, and basidiomycete fungi can encode thousands of mating types. Individuals with the same mating type cannot mate. This sexual system has evolved to facilitate sexual mating, increasing the chances to recombine into advantageous allelic combination and prune deleterious alleles. We explored the genomes of hundred and eighty specimens, combined with experimental mating studies of selected specimens, from a non-model organism (Trichaptum). We characterized the genomic regions controlling sex. The mating ability of the specimens confirmed the role of the mating alleles observed in the genomic data. The detailed analyses of many specimens allowed us to observe gene duplication and rearrangements within the mating loci, increasing the diversity within these loci. We supported previous suggestions of balancing selection in this region, an evolutionary force that maintains genomic diversity. These results supports that our fungal specimens are prone to outcross, which might facilitate the adaptation to new conditions.


title: Molecular diversity maintained by long-term balancing selection in mating loci defines multiple mating types in fungi


title: Population genomics indicate three different modes of divergence and speciation with gene flow in the green-winged teal duck complex

abstract:
The processes leading to divergence and speciation can differ broadly among taxa with different life histories. We examine these processes in a small clade of ducks with historically uncertain relationships and species limits. The green-winged teal (Anas crecca) complex is a Holarctic species of dabbling duck currently categorized as three subspecies (Anas crecca crecca, A. c. nimia, and A. c. carolinensis) with a close relative, the yellow-billed teal (Anas flavirostris) from South America. We examined divergence and speciation patterns in this group, determining their phylogenetic relationships and the presence and levels of gene flow among lineages using both mitochondrial and genome-wide nuclear DNA obtained from 1,393 ultraconserved element (UCE) loci. Phylogenetic relationships using nuclear DNA among these taxa showed A. c. crecca, A. c. nimia, and A. c. carolinensis clustering together to form one polytomous clade, with A.flavirostris sister to this clade. This relationship can be summarized as (crecca, nimia, carolinensis)(flavirostris). However, whole mitogenomes revealed a different phylogeny: (crecca, nimia)(carolinensis, flavirostris). The best demographic model for key pairwise comparisons supported divergence with gene flow as the probable speciation mechanism in all three contrasts (crecca-nimia, crecca-carolinensis, and carolinensis-flavirostris). Given prior work, gene flow was expected among the Holarctic taxa, but gene flow between North American carolinensis and South American flavirostris (M [~]0.1 - 0.4 individuals/generation), albeit low, was not expected. Three geographically oriented modes of divergence are likely involved in the diversification of this complex: heteropatric (crecca-nimia), parapatric (crecca-carolinensis), and (mostly) allopatric (carolinensis-flavirostris). Ultraconserved elements are a powerful tool for simultaneously studying systematics and population genomics in systems like this.

Graphical Abstract

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title: Quantitative analysis of the orientation of white stork nestlings' parents from video monitoring

abstract: Video-monitoring has become in the last decades common practice for animal observation and conservation purposes. In Ornithology, it is mostly used for tracking predators and nest surveillance, but, with the rapid development and spreading of webcams on nests for educational purposes, new opportunities arise for behavioral investigation, through citizen science for instance. In this article, we use video-monitoring from a public webcam on a White stork (Ciconia ciconia) nest and perform systematic image analysis to record the positioning and orientation of the guarding parent on the nest, during the nestling period over 60 days. From this data of 450 orientation samples, correlations with weather parameters are drawn. Our results suggest that the sun is responsible for most of the orientation with an hourly dependence, while the wind has prevalence during rainy days. A change in the parent behavior is also observed around the time the nestlings are known to attain their maximal weight. These preliminary findings provide new insights on weather influence on parental care behavior likely linked with the parents sensing. The versatility of the proposed method allows for behavioral studies on a wide variety of species.

category: animal behavior and cognition


title: Making Plants Smell Like Moths: Nicotiana benthamiana release moth pheromone alcohol, aldehyde and acetate upon transient expression of biosynthetic genes of different origin

abstract: Using genetically modified plants as natural dispensers of insect pheromones may eventually become part of a novel strategy for integrated pest management. In the present study, we first characterized essential functional genes for sex pheromone biosynthesis in the rice stem borer Chilo suppressalis (Walker) by heterologous expression in Saccharomyces cerevisiae and Nicotiana benthamiana, including two desaturase genes CsupYPAQ and CsupKPSE, and a reductase gene CsupFAR2. Subsequently, we co-expressed CsupYPAQ and CsupFAR2 together with the previously characterized moth desaturase Atr{Delta}11 in N. benthamiana. This resulted in the production of (Z)-11-hexadecenol together with (Z)-11-hexadecenal, the major pheromone component of C. suppressalis. Both compounds were collected from the transformed N. benthamiana headspace volatiles using solid phase microextraction. We finally added the expression of a yeast acetyltransferase gene ATF1 and could then confirm also (Z)-11-hexadecenyl acetate release from the plant. Our results pave the way for stable transformation of plants to be used as biological pheromone sources in different pest control strategies.

category: bioengineering


title: Modelling neural entrainment and its persistence: influence of frequency of stimulation and phase at the stimulus offset

abstract:
The entrainment (synchronization) of brain oscillations to the frequency of sensory stimuli is a key mechanism that shapes perceptual and cognitive processes, such that atypical neural entrainment leads to neuro-psychological deficits.

ObjectiveWe investigated the dynamic of neural entrainment. Particular attention was paid to the oscillatory behavior that succeed the end of the stimulation, since the persistence (reverberation) of neural entrainment may condition future sensory representations based on predictions about stimulus rhythmicity.

ApproachA modified Jansen-Rit neural mass model of coupled cortical columns generated a time series whose frequency spectrum resembled that of the electroencephalogram. We evaluated spectro-temporal features of entrainment, during and after rhythmic stimulation of different frequencies, as a function of the resonance frequency of the neural population and the coupling strength between cortical columns. We tested if the duration of the entrainment persistence depended on the state of the neural network at the time the stimulus ends.

Main ResultsThe entrainment of the column that received the stimulation was maximum when the frequency of the entrainer was within a narrow range around the resonance frequency of the column. When this occurred, entrainment persisted for several cycles after the stimulus terminated, and the propagation of the entrainment to other columns was facilitated. Propagation depended on the resonance frequency of the second column, and the coupling strength between columns. The duration of the persistence of the entrainment depended on the phase of the neural oscillation at the time the entrainer terminated, such that falling phases (from{pi} /2 to 3{pi}/2 in a sine function) led to longer persistence than rising phases (from 0 to{pi} /2 and 3{pi}/2 to 2{pi}).

SignificanceThe study bridges between models of neural oscillations and empirical electrophysiology, and provides insights to the use of rhythmic sensory stimulation for neuroenhancement.


title: A model-guided pipeline for drug cardiotoxicity screening with human stem-cell derived cardiomyocytes

abstract: New therapeutic compounds go through a preclinical drug cardiotoxicity screening process that is overly conservative and provides limited mechanistic insight, leading to the misclassification of potentially beneficial drugs as proarrhythmic. There is a need to develop a screening paradigm that maintains this high sensitivity, while ensuring non-cardiotoxic compounds pass this phase of the drug approval process. In this study, we develop an in vitro-in silico pipeline using human induced stem-cell derived cardiomyocytes (iPSC-CMs) to address this problem. The pipeline includes a model-guided optimization that produces a voltage-clamp (VC) protocol to determine drug block of seven cardiac ion channels. Such VC data, along with action potential (AP) recordings, were acquired from iPSC-CMs before and after treatment with a control solution or a low-, intermediate-, or high-risk drug. We identified significant AP prolongation (a proarrhythmia indicator) in two high-risk drugs and, from the VC data, determined strong ion channel blocks that led to the AP changes. The VC data also uncovered an undocumented funny current (If) block by quinine, which we confirmed with experiments using a HEK-293 expression line. We present a new approach to cardiotoxicity screening that simultaneously evaluates proarrhythmia risk (e.g. AP prolongation) and mechanism (e.g. channel block) from iPSC-CMs.


title: MetaCoAG: Binning Metagenomic Contigs via Composition, Coverage and Assembly Graphs

abstract: Metagenomics binning has allowed us to study and characterize various genetic material of different species and gain insights into microbial communities. While existing binning tools bin metagenomics de novo assemblies, they do not make use of the assembly graphs that produce such assemblies. Here we propose MetaCoAG, a tool that utilizes assembly graphs with the composition and coverage information to bin metagenomic contigs. MetaCoAG uses single-copy marker genes to estimate the number of initial bins, assigns contigs into bins iteratively and adjusts the number of bins dynamically throughout the binning process. Experimental results on simulated and real datasets demonstrate that MetaCoAG significantly outperforms state-of-the-art binning tools, producing more high-quality bins than the second-best tool, with an average median F1-score of 88.40%. To the best of our knowledge, MetaCoAG is the first stand-alone binning tool to make direct use of the assembly graph information. MetaCoAG is available at https://github.com/Vini2/MetaCoAG.

category: bioinformatics


title: An integrated view of baseline protein expression in human tissues

abstract:
The availability of proteomics datasets in the public domain, and in the PRIDE database in particular, has increased dramatically in recent years. This unprecedented large-scale availability of data provides an opportunity for combined analyses of datasets to get organism-wide protein expression data in a consistent manner. We have reanalysed 24 public proteomics datasets from healthy human individuals, to assess baseline protein abundance in 31 organs. We defined tissue as a distinct functional or structural region within an organ. Overall, the aggregated dataset contains 67 healthy tissues, corresponding to 3,119 mass spectrometry runs covering 498 samples, coming from 489 individuals.

We compared protein expression between the different organs and studied the distribution of proteins across organs. We also compared the results with data generated in analogous studies. We also performed gene ontology and pathway enrichment analyses to identify organ-specific enriched biological processes and pathways. As a key point, we have integrated the protein expression results into the resource Expression Atlas, where it can be accessed and visualised either individually or together with gene expression data coming from transcriptomics datasets. We believe this is a good mechanism to make proteomics data more accessible for scientists, especially those non-experts in proteomics.


title: Using BERT to identify drug-target interactions from whole PubMed

abstract:
BackgroundDrug-target interactions (DTIs) are critical for drug repurposing and elucidation of drug mechanisms, and they are collected in large databases, such as ChEMBL, BindingDB, DrugBank and DrugTargetCommons. However, the number of studies providing this data (~0.1 million) likely constitutes only a fraction of all studies on PubMed that contain experimental DTI data. Finding such studies and extracting the experimental information is a challenging task, and there is a pressing need for machine learning for the extraction and curation of DTIs. To this end, we developed new text mining document classifiers based on the Bidirectional Encoder Representations from Transformers (BERT) algorithm. Because DTI data intimately depends on the type of assays used to generate it, we also aimed to incorporate functions to predict the assay format.

ResultsOur novel method identified and extracted DTIs from 2.1 million studies not previously included in public DTI databases. Using 10-fold cross-validation, we obtained ~99% accuracy for identifying studies containing drug-target pairs. The accuracy for the prediction of assay format is ~90%, which leaves room for improvement in future studies.

ConclusionThe BERT model in this study is robust and the proposed pipeline can be used to identify new and previously overlooked studies containing DTIs and automatically extract the DTI data points. The tabular output facilitates validation of the extracted data and assay format information. Overall, our method provides a significant advancement in machine-assisted DTI extraction and curation. We expect it to be a useful addition to drug mechanism discovery and repurposing.


title: How biological cells including platelets and megakaryocytes decide complex problems fast but risky

abstract:
Short AbstractMathematical decision processes are accurate but sometimes take very long time or simply do not happen. Decisions in biology happen fast and driven by evolution, optimizing survival chances. This results in stochastic decisions with on average good adaptation to the environment but an inherent risk of individual errors e.g. developing cancer during cell regeneration. We calculate and show in platelets and megakaryocytes how cellular decision processes increases risk for errors and inflammation. Short cut solutions adapted from nature improve computer strategies for protein folding and network decision processes. Complex problems are not always solved in foreseeable time, instead the fast solutions in biology speed up errors everywhere including biochemical aging of blood vessels, misfolded proteins, mis-programmed cells, cancer and heart failure.

One sentence abstractWe investigate in biological networks how complex decision problems are mastered not by an accurate but unforeseeable long mathematical search but rather pragmatic and fast, with an inherent risk of error, a basis for inflammation and cancer.


title: clipplotr - a comparative visualisation and analysis tool for CLIP data

abstract: CLIP technologies are now widely used to study RNA-protein interactions and many datasets are now publicly available. An important first step in CLIP data exploration is the visual inspection and assessment of processed genomic data on selected genes or regions and performing comparisons: either across conditions within a particular project, or incorporating publicly available data. However, the output files produced by data processing pipelines or preprocessed files available to download from data repositories are often not suitable for direct comparison and usually need further processing. Furthermore, to derive biological insight it is usually necessary to visualise CLIP signal alongside other data such as annotations, or orthogonal functional genomic data (e.g. RNA-seq). We have developed a simple, but powerful, command-line tool: clipplotr, which facilitates these visual comparative and integrative analyses with normalisation and smoothing options for CLIP data and the ability to show these alongside reference annotation tracks and functional genomic data. These data can be supplied as input to clipplotr in a range of file formats, which will output a publication quality figure. It is written in R and can both run on a laptop computer independently, or be integrated into computational workflows on a high-performance cluster. Releases, source code and documentation are freely available at: https://github.com/ulelab/clipplotr.


title: Reconstruction of the binding pathway of an anti-HIV drug, Indinavir, in complex with the HTLV-1 protease by Unaggregated Unbiased Molecular Dynamics simulation

abstract: Retroviruses are a growing concern for the health of human beings, and one of the dangerous members of this family is the Human T-cell Leukemia Virus 1 (HTLV-1) virus. It has affected more than 20 million people so far, and since there are no registered treatments against it yet, urgent treatment solutions are needed. One of the most promising drug targets to fight this virus is the protease enzyme of the viruss protein machinery. In this study, by utilizing a computational method called Unaggregated Unbiased Molecular Dynamics (UUMD), we reconstructed the binding pathway of a HTLV-1 protease inhibitor, Indinavir, to find the details of the binding pathway, the influential residues, and also the stable states of the binding pathway. We achieved the native conformation of the inhibitor in 6 rounds, 360 replicas by performing over 4 micro-seconds of UMD simulations. We found 3 Intermediate states between the solvated state and the native conformation state in the binding pathway. We also discovered that aromatic residues such as Trp98 and Trp98', catalytic residues Asp32 and Asp32', and the flap regions residues have the most influential roles in the binding pathway and also have the most contribution to the total interaction energies. We believe that the details found in this study would be a great guide for developing new treatment solutions against the HTLV-1 virus by inhibiting the HTLV-1 protease.


title: Gilda: biomedical entity text normalization with machine-learned disambiguation as a service

abstract:
SummaryGilda is a software tool and web service which implements a scored string matching algorithm for names and synonyms across entries in biomedical ontologies covering genes, proteins (and their families and complexes), small molecules, biological processes and diseases. Gilda integrates machine-learned disambiguation models to choose between ambiguous strings given relevant surrounding text as context, and supports species-prioritization in case of ambiguity.

AvailabilityThe Gilda web service is available at http://grounding.indra.bio with source code, documentation and tutorials are available via https://github.com/indralab/gilda.

Contactbenjamin_gyori@hms.harvard.edu


title: iCn3D: from Web-based 3D Viewer to Structure Analysis Tool in Batch Mode

abstract: iCn3D was initially developed as a web-based 3D molecular viewer. It then evolved from visualization into a full-featured interactive structural analysis software. It became a collaborative research instrument through the sharing of permanent, shortened URLs that encapsulate not only annotated visual molecular scenes, but also all underlying data and analysis scripts in a FAIR manner. More recently, with the growth of structural databases, the need to analyze large structural datasets systematically led us to use Python scripts and convert the code to be used in Node.js scripts. We showed a few examples of Python scripts at https://github.com/ncbi/icn3d/tree/master/icn3dpython to export secondary structures or PNG images from iCn3D. Users just need to replace the URL in the Python scripts to export other annotations from iCn3D. Furthermore, any interactive iCn3D feature can be converted into a Node.js script to be run in batch mode, enabling an interactive analysis performed on one or a handful of protein complexes to be scaled up to analysis features of large ensembles of structures. Currently available Node.js analysis scripts examples are available at https://github.com/ncbi/icn3d/tree/master/icn3dnode. This development will enable ensemble analyses on growing structural databases such as AlphaFold or RoseTTAFold on one hand and Electron Microscopy on the other. In this paper, we also review new features such as DelPhi electrostatic potential, 3D view of mutations, alignment of multiple chains, assembly of multiple structures by realignment, dynamic symmetry calculation, 2D cartoons at different levels, interactive contact maps, and use of iCn3D in Jupyter Notebook as described at https://pypi.org/project/icn3dpy.


title: iCn3D: From Web-based 3D Viewer to Structure Analysis Tool in Batch Mode


title: Streamlined use of protein structures in variant analysis

abstract:
MotivationVariant analysis is a core task in bioinformatics that requires integrating data from many sources. This process can be helped by using 3D structures of proteins, which can provide a spatial context that can provide insight into how variants affect function. Many available tools can help with mapping variants onto structures; but each has specific restrictions, with the result that many researchers fail to benefit from valuable insights that could be gained from structural data.

ResultsTo address this, we have created a streamlined system for incorporating 3D structures into variant analysis. Variants can be easily specified via URLs that are easily readable and writable, and use the notation recommended by the Human Genome Variation Society (HGVS). For example,  https://aquaria.app/SARS-CoV-2/S/?N501Y specifies the N501Y variant of SARS-CoV-2 S protein. In addition to mapping variants onto structures, our system provides summary information from multiple external resources, including COSMIC, CATH-FunVar, and PredictProtein. Furthermore, our system identifies and summarizes structures containing the variant, as well as the variant-position. Our system supports essentially any mutation for any well-studied protein, and uses all available structural data -- including models inferred via very remote homology -- integrated into a system that is fast and simple to use. By giving researchers easy, streamlined access to a wealth of structural information during variant analysis, our system will help in revealing novel insights into the molecular mechanisms underlying protein function in health and disease.

AvailabilityOur resource is freely available at the project home page (https://aquaria.app). After peer review, the code will be openly available via a GPL version 2 license at https://github.com/ODonoghueLab/Aquaria. PSSH2, the database of sequence-to-structure alignments, is also freely available for download at https://zenodo.org/record/4279164.

Contactsean@odonoghuelab.org

Supplementary informationNone.


title: Benchmarking feature quality assurance strategies for non-targeted metabolomics

abstract: Automated data pre-processing (DPP) forms the basis of any liquid chromatography-high resolution mass spectrometry-driven non-targeted metabolomics experiment. However, current strategies for quality control of this important step have rarely been investigated or even discussed. We exemplified how reliable benchmark peak lists could be generated for eleven publicly available datasets acquired across different instrumental platforms. Moreover, we demonstrated how these benchmarks can be utilized to derive performance metrics for DPP and tested whether these metrics can be generalized for entire datasets. Relying on this principle, we cross-validated different strategies for quality assurance of DPP, including manual parameter adjustment, variance of replicate injection-based metrics, unsupervised clustering performance, automated parameter optimization, and deep learning-based classification of chromatographic peaks. Overall, we want to highlight the importance of assessing DPP performance on a regular basis.


title: CuBi-MeAn Customized Pipeline for Metagenomic Data Analysis

abstract:
1.Whole genome shotgun sequencing is a powerful to study microbial community is a given environment. Metagenomic binning offers a genome centric approach to study microbiomes. There are several tools available to process metagenomic data from raw reads to the interpretation there is still lack of standard approach that can be used to process the metagenomic data step by step. In this study CuBi-MeAn (Customizable Binning and Metagenomic Analysis) create a customizable and flexible processing pipeline, to process the metagenomic data and generate results for further interpretation.

This study aims to perform metagenomic binning to enhance taxonomical classification, functional potentials, and interactions among microbial populations in environmental systems. This customized pipeline which is comprised of a series of genomic/metagenomic tools designed to recover better quality results and reliable interpretation of the system dynamics for the given systems. For this reason, a metagenomic data processing pipeline is developed to evaluate metagenomic data from three environmental engineering projects.

The use of our pipeline was demonstrated and compared on three different datasets that were of different sizes, from different sequencing platforms, and generated from three different environmental sources. By designing and developing a flexible and customized pipeline, this study has showed how to process large metagenomic data sets with limited resources. This result not only would help to uncover new information from environmental samples, but also, could be applicable to any other metagenomic studies across various disciplines.


title: Characterization of the secretome, transcriptome and proteome of human β cell line EndoC-βH1

abstract:
Early diabetes research is hampered by limited availability, variable quality and instability of human pancreatic islets in culture. Little is known about the human {beta} cell secretome, and recent studies question translatability of rodent {beta} cell secretory profiles. Here, we verify representativeness of EndoC-{beta}H1, one of the most widely used human {beta} cell lines, as a translational human {beta} cell model based on omics and characterize the EndoC-{beta}H1 secretome. We profiled EndoC-{beta}H1 cells using RNA-seq, Data Independent Acquisition (DIA) and Tandem Mass Tag proteomics of cell lysate. Omics profiles of EndoC-{beta}H1 cells were compared to human {beta} cells and insulinomas. Secretome composition was assessed by DIA proteomics. Agreement between EndoC-{beta}H1 cells and primary adult human {beta} cells was ~90% for global omics profiles as well as for {beta} cell markers, transcription factors and enzymes. Discrepancies in expression were due to elevated proliferation rate of EndoC-{beta}H1 cells compared to adult {beta} cells. Consistently, similarity was slightly higher with benign non-metastatic insulinomas. EndoC-{beta}H1 secreted 671 proteins in untreated baseline state and 3,278 proteins when stressed with non-targeting control siRNA, including known {beta} cell hormones INS, IAPP, and IGF2. Further, EndoC-{beta}H1 secreted proteins known to generate bioactive peptides such as granins and enzymes required for production of bioactive peptides. Unexpectedly, exosomes appeared to be a major mode of secretion in EndoC-{beta}H1 cells. We believe that secretion of exosomes and bioactive peptides warrant further investigation with specialized proteomics workflows in future studies.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/459582v1_ufig1.gif" ALT="Figure 1">
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C_LIO_LIWe present the first unbiased proteomics composition of human {beta} cell line secretome.
C_LIO_LIThe secretome of human {beta} cells is more extensive than previously thought.
C_LIO_LIUntreated cells secreted 671 proteins and stressed cells secreted 3,278 proteins.
C_LIO_LISecretion of exosomes and bioactive peptides constitute directions of future research.
C_LI


title: Identification of hub genes and pathways in nonalcoholic steatohepatitis by integrated bioinformatics analysis

abstract:
BackgroundCurrently, non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world. Forecasting the short-term, up to 2025, NASH due to fibrosis is one of the leading causes of liver transplantation. Cohort studies revealed that non-alcoholic steatohepatitis (NASH) has a higher risk of fibrosis progression among NAFLD patients. Identifying differentially expressed genes helps to determine NASH pathogenic pathways, make more accurate diagnoses, and prescribe appropriate treatment.

Methods and ResultsIn this study, we found 11 NASH datasets by searching in the Gene Expression Omnibus (GEO) database. Subsequently, NASH datasets with low-quality control scores were excluded. Four datasets were analyzed with packages of R/Bioconductor. Then, all integrated genes were Imported into Cytoscape to illustrate the protein-protein interactions network. All hubs and nodes degree has been calculated to determine the hub genes with critical roles in networks.Possible correlations between expression profiles of mutual DEGs were identified employing Principal Component Analysis (PCA). Primary analyzed data were filtered based on gene expression (logFC > 1, logFC < -1) and adj-P-value (<0.05). Ultimately, among 379 DEGs, we selected the top 10 genes (MYC, JUN, EGR1, FOS, CCL2, IL1B, CXCL8, PTGS2, IL6, SERPINE1) as candidates among up and down regulated genes, and critical pathways such as IL-6, IL-17, TGF {beta}, and TNF were identified.

ConclusionThe present study suggests an important DEGs, biological processes, and critical pathways involved in the pathogenesis of NASH disease. Further investigations are needed to clarify the exact mechanisms underlying the development and progression of NASH disease.


title: LongPhase: an ultra-fast chromosome-scale phasing algorithm for small and large variants

abstract: Long-read phasing has been used for reconstructing diploid genomes, improving variant calling, and resolving microbial strains in metagenomics. However, the phasing blocks of existing methods are broken by large Structural Variations (SVs), and the efficiency is unsatisfactory for population-scale phasing. This paper presents an ultra-fast algorithm, LongPhase, which can simultaneously phase single nucleotide polymorphisms (SNPs) and SVs of a human genome in [~]10-20 minutes, 10x faster than the state-of-the-art WhatsHap and Margin. In particular, LongPhase produces much larger phased blocks at almost chromosome level with only long reads (N50=26Mbp). We demonstrate that LongPhase combined with Nanopore is a cost-effective approach for providing chromosome-scale phasing without the need for additional trios, chromosome-conformation, and single-cell strand-seq data.


title: A-Prot: Protein structure modeling using MSA transformer

abstract: In this study, we propose a new protein 3D structure modeling method, A-Prot, using MSA Transformer, one of the state-of-the-art protein language models. For a given MSA, an MSA feature tensor and row attention maps are extracted and converted into 2D residue-residue distance and dihedral angle predictions. We demonstrated that A-Prot predicts long-range contacts better than the existing methods. Additionally, we modeled the 3D structures of the free modeling and hard template-based modeling targets of CASP14. The assessment shows that the A-Prot models are more accurate than most top server groups of CASP14. These results imply that A-Prot captures evolutionary and structural information of proteins accurately with relatively low computational cost. Thus, A-Prot can provide a clue for the development of other protein property prediction methods.


title: Orientations of Mistaken Point fronds indicate morphology impacted ability to survive turbulence

abstract: The Ediacaran organisms of the Mistaken Point E surface have provided crucial insight into early animal communities, including how they reproduced, the importance of Ediacaran height and what the most important factors were to their community dynamics. Here, we use this iconic community to investigate how morphological variation between eight taxa affected their ability to withstand different flow conditions. For each of Beothukis, Bradgatia, Charniodiscus procerus, Charniodiscus spinosus, Plumeropriscum, Primocandelabrum and Fractofusus we measured the orientation and length of their stems (if present) and their fronds. We statistically tested each taxons stem and frond orientation distributions to see whether they displayed a uniform or multimodal distribution. Where multimodal distributions were identified, the stem/frond length of each cohort was tested to identify if there were differences in size between different orientation groups. We find that Bradgatia and Thectardis show a bimodal felling direction, and infer that they were felled by the turbulent head of the felling flow. In contrast, the frondose rangeomorphs including Beothukis, Plumeropriscum, Primocandelabrum, and the arboreomorphs were felled in a single direction, indicating that they were upright in the water column, and were likely felled by the laminar tail of the felling flow. These differences in directionality suggests that an elongate habit, and particularly possession of a stem, lent greater resilience to frondose taxa against turbulent flows, suggesting that such taxa would have had improved survivability in conditions with higher background turbulence than taxa like Bradgatia and Thectardis, which lacked a stem and which had a higher centre of mass, which may have fared better in quieter water conditions.

category: paleontology


title: Quercetin prevents insulin dysfunction in hypertensive animals

abstract: Angiotensin II induced increase in hypertension enhances oxidative stress and compromises insulin action and pancreatic function. Quercetin-rich foods are beneficial for hypertensive and diabetic animals owing to their antioxidant function. The aim of this study was to evaluate the antioxidant effects of quercetin in hypertensive rats on insulin action, signaling, and secretion. Wistar rats were randomly divided into three groups: sham, hypertensive rats (H), and hypertensive rats supplemented with quercetin (HQ). After three months of initial hypertension, quercetin was administered at 50 mg/kg/day for 30 days. Our results indicate that hypertension and serum lipid peroxidation levels were reduced by quercetin supplementation. We observed increased insulin sensitivity in adipose tissue, corroborating the insulin tolerance test, HOMA index, and improvements in lipid profile. Despite normal insulin secretion at 2.8 and 20 mM of glucose, animals treated with quercetin exhibited increased number of islets per section; increased protein expression of muscarinic receptor type 3, VEGF, and catalase in islets; and hepatic mRNA levels of Ide were normalized. In conclusion, supplementation with quercetin improved insulin action and prevented pancreatic and metabolic dysfunction.

category: physiology


title: STAYGREEN-mediated chlorophyll a catabolism is critical for photosystem stability upon heat stress in ryegrass

abstract: Chlorophyll (Chl) loss is one of the most visible symptoms of heat-induced leaf senescence, especially for cool-season grass species. Suppression of the Chl a Me-dechelatase gene, SGR (also named as nye1), blocked the degradation of Chl a and resulted in the  stay-green trait during leaf senescence. However, effect of Chl a catabolism on plant tolerance to long-term moderate heat stress (35-40{degrees}C) remains unclear. In this study, we suppressed the expression of Chl a catabolic gene, LpSGR, in both constitutive and inducible manners in perennial ryegrass. Constitutive suppression of LpSGR aggravated heat stress-induced chloroplast structure and photosystem damages, disrupted energy utilization/dissipation during photosynthesis, activated ROS generation with weakened ROS-scavenging enzyme activities. Transcriptome comparison among wildtype (WT) and transgenic RNAi plants under either the optimum or high temperature conditions also emphasized the effect of Chl a catabolism on expression of genes encoding photosynthesis system, ROS-generation and scavenging system, and heat shock transcription factors. Furthermore, making use of a modified ethanol-inducible system, we generated stable transgenic perennial ryegrass to suppress LpSGR in an inducible manner. Without ethanol induction, these transgenic lines exhibited the same growth and heat tolerance traits to WT, while under the induction of ethanol spray, the transgenic lines also showed compromised heat tolerance. Taken together, our data suggest that Chl a catabolism is critical for energy dissipation and electron transfer in photosynthesis, ROS-balancing and chloroplast membrane system stability upon long-term moderate heat stress.

category: plant biology


title: Dormancy Breaking Treatments in Northern Wild Rice (Zizania palustris L.) Seed Suggest a Physiological Source of Dormancy

abstract: Dormancy is a limiting factor for breeding in northern wild rice (NWR; Zizania palustris L). This study developed a dormancy curve and tested a combination of scarification and hormone treatments, across three timepoints, for their ability to break dormancy in NWR and produce viable seedlings and plants. A dormancy curve was established across 9 months post-harvest, which showed maximum germination (95%) by 17 weeks post-harvest and high germination ([≥]81 %) through the rest of the testing period. Next, dormancy breaking treatments were tested. At 1 week post-harvest, few seeds germinated ([≤] 15 %) across all treatment combinations. However, sulfuric acid increased germination shortly after harvest (5.8 %), compared to water (0.5 %) and NaClO (0 %) but resulted in stunted seedlings, all but one of which died shortly thereafter. At 7 weeks, sulfuric acid treated seeds did not result in significantly higher germination than water and maximum germination was still below 15%. By 11 weeks post-harvest, the water treatments had the highest germination and resulted in the most viable plants, indicating that dormancy had begun to break naturally and exceeded the effect of the other scarification treatments. Hormonal treatments had no significant effect on germination or seed viability and no strong conclusions could be drawn about their effect on seedling or plant health. Due to the inability of early germinated seed to consistently produce viable plants and the increase in germination following sufficient cold storage, it is likely that NWR seed has intermediate or deep physiological dormancy.


title: BaRTv2: A highly resolved barley reference transcriptome for accurate transcript-specific RNA-seq quantification

abstract: Accurate characterization of splice junctions as well as transcription start and end sites in reference transcriptomes allows precise quantification of transcripts from RNA-seq data and enable detailed investigations of transcriptional and post-transcriptional regulation. Using novel computational methods and a combination of PacBio Iso-seq and Illumina short read sequences from 20 diverse tissues and conditions, we generated a comprehensive and highly resolved barley reference transcript dataset (RTD) from the European 2-row spring barley cultivar Barke (BaRTv2.18). Stringent and thorough filtering was carried out to maintain the quality and accuracy of the splice junctions and transcript start and end sites. BaRTv2.18 shows increased transcript diversity and completeness compared to an earlier version, BaRTv1.0. The accuracy of transcript level quantification, splice junctions and transcript start and end sites has been validated extensively using parallel technologies and analysis, including high resolution RT PCR and 5 RACE. BaRTv2.18 contains 39,434 genes and 148,260 transcripts, representing the most comprehensive and resolved reference transcriptome in barley to date. It provides an important and high-quality resource for advanced transcriptomic analyses, including both transcriptional and post-transcriptional regulation, with exceptional resolution and precision.


title: Effectors from a Bacterial Vector-Borne Pathogen Exhibit Diverse Subcellular Localization, Expression Profiles and Manipulation of Plant Defense

abstract: Climate change is predicted to increase the prevalence of vector borne disease due to expansion of insect populations. Candidatus Liberibacter solanacearum (CLso) is a phloem-limited pathogen associated with multiple economically important diseases in Solanaceous crops. Little is known about the strategies and pathogenicity factors CLso uses to colonize vector and host. We determined the CLso effector repertoire by predicting SEC secreted proteins across four different CLso haplotypes, investigated effector localization in planta, and profiled effector expression in vector and host. The localization of CLso effectors in Nicotiana revealed diverse eukaryotic subcellular targets. The majority of tested effectors were unable to suppress plant immune responses, indicating they possess unique activities. Expression profiling in tomato and the psyllid Bactericera cockerelli indicated CLso differentially interacts with its host and vector and can switch effector expression in response to the environment. This study reveals CLso effectors possess complex expression patterns, target diverse host organelles and the majority are unable to suppress host immune responses. A mechanistic understanding of Lso effector function will reveal novel targets and provide insight into phloem biology.


title: Finding a Balance: Characterizing Teaching and Research Anxieties in Biology Graduate Teaching Assistants (GTAs)

abstract: Graduate students in the United States are reporting increased anxiety, affecting their mental health and attrition in graduate programs. Yet we are only beginning to understand what contributes to graduate student anxiety. Biology Graduate Teaching Assistants (GTAs) have simultaneous roles as teachers, researchers, students, and employees, and factors associated with these tasks may contribute to anxieties in graduate school, particularly in relation to teaching and research responsibilities. To explore factors related to GTA teaching and research anxieties, and guided by social cognitive career theory, we interviewed 23 Biology GTAs at a research-intensive southeastern university. Thematic analysis of interview transcripts revealed five major factors related to GTA anxieties: negative impact on self, negative impact on others, lack of self-efficacy, role tension, and personal anxieties. Lack of self-efficacy was most prevalent for research anxieties, compared to teaching anxieties, where the impact on others (e.g. students) was most prevalent. In research contexts, GTAs with academic career aspirations expressed less anxiety about role tensions compared to GTAs with non-academic career goals. By investigating GTA anxieties, this work can inform professional development or mental health interventions for GTAs and encourage greater awareness and dialogue about mental health issues in academia.

category: scientific communication and education


title: Canonical retinotopic shifts under an inverse force field explain predictive remapping

abstract: Saccadic eye-movements allow us to bring visual objects of interest to high-acuity central vision. Although saccades cause large displacements of retinal images, our percept of the visual world remains stable. Predictive remapping -- the ability of cells in retinotopic brain areas to transiently exhibit spatio-temporal retinotopic shifts beyond the spatial extent of their classical receptive fields -- has been proposed as a primary mechanism that mediates this seamless visual percept. Despite the well documented effects of predictive remapping, no study to date has been able to provide a mechanistic account of the neural computations and architecture that actively mediate this ubiquitous phenomenon. Borne out by the spatio-temporal dynamics of peri-saccadic sensitivity to probe stimuli in human subjects, we propose a novel neurobiologically inspired phenomenological model in which the underlying peri-saccadic attentional and oculomotor signals manifest as three temporally overlapping forces that act on retinotopic brain areas. These three forces - a compressive one toward the center of gaze, a convergent one toward the saccade target and a translational one parallel to the saccade trajectory - act in an inverse force field and specify the spatio-temporal window of predictive remapping of population receptive fields.

category: systems biology


title: Predictors of Taxonomic Inflation and its Role in Primate Conservation

abstract: Species are the main unit used to measure biodiversity, but different preferred diagnostic criteria can lead to very different delineations. For instance, named primate species have more than doubled since 1982. Such increases have been termed "taxonomic inflation" and have been attributed to the widespread adoption of the  phylogenetic species concept (PSC) in preference to the previously popular  biological species concept (BSC). Criticisms of the PSC have suggested taxonomic inflation may be biased toward particular taxa and have unfavourable consequences for conservation. Here, we explore predictors of taxonomic inflation across primate taxa since the initial application of the PSC nearly 40 years ago. We do not find evidence that diversification rate, the rate of lineage formation over evolutionary time, is linked to inflation, contrary to expectations if the PSC identifies incipient species. We also do not find evidence of research effort in fields where work has been suggested to motivate splitting being associated with increases in species numbers among genera. To test the suggestion that splitting groups is likely to increase their perceived risk of extinction, we test whether genera that have undergone more splitting have also observed a greater increase in their proportion of threatened species since the introduction of the PSC. We find no cohesive signal of inflation leading to higher threat probabilities across primate genera. Overall, this analysis sends a positive message that threat statuses of primate species are not being overwhelmingly affected by splitting in line with what has recently been reported for birds. Regardless, we echo warnings that it is unwise for conservation to be reliant on taxonomic stability. Species (however defined) are not independent from one another, thus, monitoring and managing them as such may not meet the overarching goal of conserving biodiversity.

category: zoology


title: Whole brain mapping of glutamate in adult and old primates at 11.7T

abstract:
Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimers and Huntingtons diseases, epilepsy as well as during aging.

Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can map glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field.

In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the glutamate index in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimers disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates.

Graphical abstract

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title: High-fat diet feeding reduces the expression of Rab3a, Rab3gap1, and Rab3Gap2 genes that are pivotal to neuronal exocytosis.

abstract:
The Rab3A and Rab3gaps are essential to the Ca+2-dependent neuronal exocytosis in the hypothalamus. The arcuate nucleus of the hypothalamus (ARC) controls food intake and energy expenditure. We have earlier described that the high-fat diet (HFD) feeding induces an obesity phenotype with high leptin production and alteration of proteins related to endosome sorting, and ubiquitination in the ARC of mice. In this study, real-time PCR data analysis revealed that HFD feeding decreases significantly Rab3a, Rab3gap1, and Rab3gap2 transcript levels in the ARC when compared to the group receiving a control diet. The decrease of Rab3gap1/2 transcript levels in the ARC was strongly associated with an increase in plasma leptin. Altogether, our studies demonstrate that HFD feeding could be altering the general network of endosome compartmentalization in the ARC of mice, contributing to a failure in exocytosis and receptor recycling.

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title: Identifying microstructural changes in diffusion MRI; How to break parameter degeneracy

abstract:
Biophysical models that attempt to infer real-world quantities from data usually have many free parameters. This over-parameterisation can result in degeneracies in model inversion and render parameter estimation ill-posed. However, often, we are not interested in estimating the parameters per se, but rather in identifying changes in parameters between experimental conditions (e.g. patients vs controls). Here we present a Bayesian framework to make inference on changes in the parameters of biophysical models even when model inversion is degenerate, which we refer to as Bayesian EstimatioN of CHange (BENCH).

We infer the parameter changes in two steps; First, we train models that can estimate the pattern of change in the measurements given any hypothetical change in the parameters using simulations. Next, for any pair of real data sets, we use these pre-trained models to estimate the probability that an observed difference in the data can be explained by each model of change.

The approach is general and particularly useful for biophysical models with parameter de-generacies. In this paper, we apply the approach in the context of microstructural modelling of diffusion MRI data, where the models are usually over-parameterised and not invertible without injecting strong assumptions. Using simulations, we show that in the context of the standard model for diffusion our approach is able to identify changes in microstructural parameters from multi-shell diffusion MRI data. We also apply our approach to a subset of subjects from the UK-Biobank Imaging to identify the dominant standard model parameter change in areas of white matter hyperintensities.


title: Dynamic brain activity during associative learning examined with MEG/fMRI co-processing

abstract:
BackgroundDue to limitations of individual neuroimaging methods we examine spatial and temporal contributions to self-generation using multimodality imaging with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) within the Bayesian framework Multiple Sparse Priors (MSP).

New Method24 healthy participants performed an fMRI and MEG paired-associate learning task. FMRI data were processed within Group ICA fMRI Toolbox. Independent components (ICs) were temporally sorted by task time series (|r|>0.30 threshold identified task-related ICs). Task-positive ("generate") ICs were retained as spatial priors for MEG analyses. MEG data were processed by averaging trials to increase the signal-to-noise ratio within subjects and with an event-related theta power approach. MEG source reconstructions were constrained within the task-positive ICs for both analytical approaches.

ResultsFor fMRI, five networks were identified as task-related. Four ICs underlying active generation spanned bilateral parietal, orbitofrontal, medial frontal and superior temporal regions, and occipital lobe. FMRI-constrained MEG source reconstructions yielded early visual cortex activity followed by left inferior frontal gyrus (IFG) and orbito-frontal cortex (OFC) recruitment to coalesce in the left inferior temporal lobe. For the event-related theta approach, reconstructions showed a progression of activity from bilateral temporal areas to left OFC and middle temporal gyrus, followed by right IFG.

Comparison with Existing MethodsMSP analyses informed by fMRI produced more focused regional activity than reconstructions without priors suggesting increased attention and maintenance when selecting relevant semantic information during active generation.

ConclusionsConstraining MEG source reconstruction to fMRI priors during active generation implicates interconnected fronto-temporal and fronto-parietal networks across time.


title: Probing neuropeptide volume transmission in vivo by a novel all-optical approach

abstract: Neuropeptides are essential signaling molecules in the nervous system involved in modulating neural circuits and behavior. Although hypothesized to signal via volume transmission through G-protein coupled receptors (GPCR), remarkably little is known about their extrasynaptic diffusion. Here, we developed an all-optical approach to probe neuropeptide volume transmission in mouse neocortex. To control neuropeptide release, we engineered photosensitive nanovesicles with somatostatin-14 (SST) that is released with near-infrared light stimulation. To detect SST, we created a new cell-based neurotransmitter fluorescent engineered reporter (CNiFER) using the SST2 GPCR. Under two-photon imaging, we determined the time to activate SST2R at defined distances as well as the maximal distance and loss rate for SST volume transmission in neocortex. Importantly, we determined that SST transmission is significantly faster in neocortex with a chemically degraded extracellular matrix, a diseased condition indicated in neuroinflammation and Parkinsons disease. These new neurotechnologies can reveal important biological signaling processes previously not possible, and provide new opportunities to investigate volume transmission in the brain.


title: Horizontal connectivity in V1 : Prediction of coherence in contour and motion integration

abstract: This study demonstrates the functional importance of the Surround context relayed laterally in V1 by the horizontal connectivity, in controlling the latency and the gain of the cortical response to the feedforward visual drive. We report here four main findings : 1) a centripetal apparent motion sequence results in a shortening of the spiking latency of V1 cells, when the orientation of the local inducer and the global motion axis are both co-aligned with the RF orientation preference; 2) this contextual effects grows with visual flow speed, peaking at 150-250{degrees}/s when it matches the propagation speed of horizontal connectivity (0.15-0.25 mm/ms); 3) For this speed range, the axial sensitivity of V1 cells is tilted by 90{degrees} to become co-aligned with the orientation preference axis; 4) the strength of modulation by the surround context correlates with the spatiotemporal coherence of the apparent motion flow. Our results suggest an internally-generated binding process, linking local (orientation /position) and global (motion/direction) features as early as V1. This long-range diffusion process constitutes a plausible substrate in V1 of the human psychophysical bias in speed estimation for collinear motion. Since it is demonstrated in the anesthetized cat, this novel form of contextual control of the cortical gain and phase is a built-in property in V1, whose expression does not require behavioral attention and top-down control from higher cortical areas. We propose that horizontal connectivity participates in the propagation of an internal "prediction" wave, shaped by visual experience, which links contour co-alignment and global axial motion at an apparent speed in the range of saccade-like eye-movements.


title: Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

abstract: Inherited retinal diseases (IRDs) are a group of neurodegenerative disorders that lead to photoreceptor cell death and eventually blindness. IRDs are characterised by a high genetic heterogeneity, making it imperative to design mutation-independent therapies. Mutations in a number of IRD disease genes have been associated with a rise of cyclic 3,5-guanosine monophosphate (cGMP) levels in photoreceptors. Accordingly, the cGMP-dependent protein kinase (PKG) has emerged as a new potential target for the mutation-independent treatment of IRDs. However, the substrates of PKG and the downstream degenerative pathways triggered by its activity have yet to be determined. Here, we performed kinome activity profiling of different murine organotypic retinal explant cultures (diseased rd1 and wild-type controls) using multiplex peptide microarrays to identify proteins whose phosphorylation was significantly altered by PKG activity. In addition, we tested the downstream effect of a known PKG inhibitor CN03 in these organotypic retina cultures. Among the PKG substrates were potassium channels belonging to the Kv1 family (KCNA3, KCNA6), Cyclic AMP-responsive element-binding protein 1 (CREB1), DNA topoisomerase 2- (TOP2A), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (F263), and the glutamate ionotropic receptor kainate 2 (GRIK2). The retinal expression of these PKG targets was further confirmed by immunofluorescence and could be assigned to various neuronal cell types, including photoreceptors, horizontal cells, and ganglion cells. Taken together, this study confirmed the key role of PKG in photoreceptor cell death and identified new downstream targets of cGMP/PKG signalling that will improve the understanding of the degenerative mechanisms underlying IRDs.


title: Deficits in decision-making induced by parietal cortex inactivation are compensated at two time scales

abstract: Perceptual decisions arise through the transformation of samples of evidence into a commitment to a proposition or plan of action. Such transformation is thought to involve cortical circuits capable of computation over time scales associated with working memory, attention, and planning. Neurons in the lateral intraparietal area (LIP) are thought to play a role in all of these functions, and much of what is known about the neurobiology of decision making has been influenced by studies of LIP and its network of cortical and subcortical connections. However a causal role of neurons in LIP remains controversial. We used pharmacological and chemogenetic methods to inactivate LIP in one hemisphere of four rhesus monkeys. Inactivation produced clear biases in decisions, but the effects dissipated despite the persistence of neural inactivation, implying compensation by other unaffected areas. Compensation occurs on a rapid times scale, within an experimental session, and more gradually, across sessions. The findings resolve disparate studies and inform interpretation of focal perturbations of brain function.


title: Deep-Learning-Based Accelerated and Noise-Suppressed Estimation (DANSE) of quantitative Gradient Recalled Echo (qGRE) MRI metrics associated with Human Brain Neuronal Structure and Hemodynamic Properties

abstract:
PurposeTo introduce a Deep-Learning-Based Accelerated and Noise-Suppressed Estimation (DANSE) method for reconstructing quantitative maps of biological tissue cellular-specific, R2t* and hemodynamic-specific, R2' from Gradient-Recalled-Echo (GRE) MRI data with multiple gradient-recalled echoes.

MethodsDANSE method adapts supervised learning paradigm to train a convolutional neural network for robust estimation of R2t* and R2' maps free from the adverse effects of macroscopic (B0) magnetic field inhomogeneities directly from the GRE magnitude images without utilizing phase images. The corresponding ground-truth maps were generated by means of a voxel-by-voxel fitting of a previously-developed biophysical quantitative GRE (qGRE) model accounting for tissue, hemodynamic and B0-inhomogeneities contributions to GRE signal with multiple gradient echoes using nonlinear least square (NLLS) algorithm.

ResultsWe show that the DANSE model efficiently estimates the aforementioned brain maps and preserves all features of NLLS approach with significant improvements including noise-suppression and computation speed (from many hours to seconds). The noise-suppression feature of DANSE is especially prominent for data with SNR characteristic for typical GRE data (SNR~50), where DANSE-generated R2t* and R2' maps had three times smaller errors than that of NLLS method.

ConclusionsDANSE method enables fast reconstruction of magnetic-field-inhomogeneity-free and noise-suppressed quantitative qGRE brain maps. DANSE method does not require any information about field inhomogeneities during application. It exploits spatial patterns in the qGRE MRI data and previously-gained knowledge from the biophysical model, thus producing clean brain maps even in the environments with high noise levels. These features along with fast computational speed can lead to broad qGRE clinical and research applications.


title: Corticothalamic Projections Gate Alpha Rhythms in the Pulvinar

abstract: Two types of corticothalamic (CT) terminals reach the pulvinar nucleus of the thalamus, and their distribution varies according to the hierarchical level of the cortical area they originate from. While type 2 terminals are more abundant at lower hierarchical levels, terminals from higher cortical areas mostly exhibit type 1 axons. Such terminals also evoke different excitatory postsynaptic potential dynamic profiles, presenting facilitation for type 1 and depression for type 2. As the pulvinar is involved in the oscillatory regulation between intercortical areas, fundamental questions about the role of these different terminal types in the neuronal communication throughout the cortical hierarchy are yielded. Our theoretical results support that the co-action of the two types of terminals produces different oscillatory rhythms in pulvinar neurons. More precisely, terminal types 1 and 2 produce alpha-band oscillations at a specific range of connectivity weights. Such oscillatory activity is generated by an unstable transition of the balanced state networks properties that it is found between the quiescent state and the stable asynchronous spike response state. While CT projections from areas 17 and 21a are arranged in the model as the empirical proportion of terminals types 1 and 2, the actions of these two cortical connections are antagonistic. As area 17 generates low-band oscillatory activity, cortical area 21a shifts pulvinar responses to stable asynchronous spiking activity and vice-versa when area 17 produces an asynchronous state. To further investigate such oscillatory effects through corticothalamo-cortical projections, the transthalamic pathway, we created a cortical feedforward network of two cortical areas, 17 and 21a, with CT connections to a pulvinar-like network. With this model, the transthalamic pathway propagates alpha waves from the pulvinar to area 21a. This oscillatory transfer ceases when reciprocal connections from area 21a reach the pulvinar, closing the cortico-thalamic loop. Taken together, results of our model suggest that the pulvnar shows a bi-stable spiking activity, oscillatory or regular asynchronous spiking, whose responses are gated by the different activation of cortico-pulvinar projections from lower to higher-order areas such as areas 17 and 21a.


title: Dopamine biases sensitivity to personal goals and social influence in self-control over everyday desires

abstract: People regularly give in to daily temptations in spite of conflict with personal goals. To test hypotheses about neuropharmacological influences on self-control, we used positron emission tomography to measure dopamine D2-like receptors (D2R) and experience sampling surveys to naturalistically track daily desires outside the laboratory in everyday life in a sample of 103 adults. Higher D2R availability in the ventral striatum was associated with increased sensitivity to personal goal conflict but not desire strength in deciding whether to attempt to resist a desire. The influence of D2Rs on sensitivity to personal goal conflict depended on whether desires were experienced in a social context. D2R availability in the midbrain (but not the ventral striatum) influenced whether desires were enacted. These findings provide unique evidence that the dopamine system influences decision making and regulatory behavior and provides new insights into how these mechanisms interact with personal goals and social contexts.


title: Dense cortical input to the rostromedial tegmental nucleus mediates aversive signaling

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. While initial studies describing the RMTg revealed the presence of cortical afferents, the density and distribution of this input has not been explored in detail. In addition, the functional consequences of cortical modulation of RMTg signaling are only just beginning to be investigated. The current study anatomically and functionally characterizes cortical input to the RMTg in rats. Findings from this work reveal dense input spanning the entire medial prefrontal cortex (PFC) as well as the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area which has also been implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V and collateralize extensively throughout the brain. In-situ mRNA hybridization further revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Optogenetic stimulation of dmPFC terminals in the RMTg drives avoidance, and cFos expression is enhanced in this neural circuit during exposure to aversive stimuli. Exposure to such aversive stimuli results in significant physiological and structural plasticity suggestive of a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over the balance between reward and aversion.