Early experiences mediate distinct adult gene expression and reproductive programs in Caenorhabditis elegans.

Environmental stress during early development in animals can have profound effects on adult phenotypes via programmed changes in gene expression. Using the nematode C. elegans, we demonstrated previously that adults retain a cellular memory of their developmental experience that is manifested by differences in gene expression and life history traits; however, the sophistication of this system in response to different environmental stresses, and how it dictates phenotypic plasticity in adults that contribute to increased fitness in response to distinct environmental challenges, was unknown. Using transcriptional profiling, we show here that C. elegans adults indeed retain distinct cellular memories of different environmental conditions. We identified approximately 500 genes in adults that entered dauer due to starvation that exhibit significant opposite ("seesaw") transcriptional phenotypes compared to adults that entered dauer due to crowding, and are distinct from animals that bypassed dauer. Moreover, we show that two-thirds of the genes in the genome experience a 2-fold or greater seesaw trend in gene expression, and based upon the direction of change, are enriched in large, tightly linked regions on different chromosomes. Importantly, these transcriptional programs correspond to significant changes in brood size depending on the experienced stress. In addition, we demonstrate that while the observed seesaw gene expression changes occur in both somatic and germline tissue, only starvation-induced changes require a functional GLP-4 protein necessary for germline development, and both programs require the Argonaute CSR-1. Thus, our results suggest that signaling between the soma and the germ line can generate phenotypic plasticity as a result of early environmental experience, and likely contribute to increased fitness in adverse conditions and the evolution of the C. elegans genome.

Linking the environment, DAF-7/TGFß signaling and LAG-2/DSL ligand expression in the germline stem cell niche.

The developmental accumulation of proliferative germ cells in the C. elegans hermaphrodite is sensitive to the organismal environment. Previously, we found that the TGFß signaling pathway links the environment and proliferative germ cell accumulation. Neuronal DAF-7/TGFß causes a DAF-1/TGFßR signaling cascade in the gonadal distal tip cell (DTC), the germline stem cell niche, where it negatively regulates a DAF-3 SMAD and DAF-5 Sno-Ski. LAG-2, a founding DSL ligand family member, is produced in the DTC and activates the GLP-1/Notch receptor on adjacent germ cells to maintain germline stem cell fate. Here, we show that DAF-7/TGFß signaling promotes expression of lag-2 in the DTC in a daf-3-dependent manner. Using ChIP and one-hybrid assays, we find evidence for direct interaction between DAF-3 and the lag-2 promoter. We further identify a 25 bp DAF-3 binding element required for the DTC lag-2 reporter response to the environment and to DAF-7/TGFß signaling. Our results implicate DAF-3 repressor complex activity as a key molecular mechanism whereby the environment influences DSL ligand expression in the niche to modulate developmental expansion of the germline stem cell pool.

The Role of Emotional Intelligence in Community Integration and Return to Work After Acquired Brain Injury.

OBJECTIVE: To investigate whether emotional intelligence (EI) skills measured via the Perceiving, Understanding, and Managing Emotions branches of the Mayer-Salovey-Caruso Emotional Intelligence Test V2.0 are associated with community integration (CI) and return to work (RTW) after moderate-to-severe acquired brain injury (ABI), after accounting for other established predictors. DESIGN: Retrospective cohort study. SETTING: Outpatient follow-up services within 2 specialist ABI rehabilitation centers in Melbourne, Australia. PARTICIPANTS: Individuals (N=82) with moderate-to-severe ABI discharged from inpatient rehabilitation and living in the community (2mo to 7y postinjury). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Community Integration Questionnaire scores for the total sample (N=82; age range 18-80) and RTW status (employed vs not employed) for the subset of participants employed prior to ABI (n=71; age range 19-66). RESULTS: Hierarchical logistic and multiple regression analyses were used to examine the unique contribution of Perceiving, Understanding, and Managing Emotions scores to RTW and CI, after controlling for demographic, injury-related, psychological, and cognitive predictors. As a set, the 3 EI variables did not explain incremental variance in outcomes. However, individually, Understanding Emotions predicted RTW (adjusted odds ratio=3.10, P=.03), χ2 (12)=35.52, P<.001, and Managing Emotions predicted CI (ß=0.23, P=.036), F12,69=5.14, P<.001. CONCLUSION: Although the EI constructs in combination did not improve prediction beyond the effects of established variables, individual components of strategic EI may be important for specific participation outcomes after ABI.

RNAi pathways contribute to developmental history-dependent phenotypic plasticity in C. elegans.

Early environmental experiences profoundly influence adult phenotypes through complex mechanisms that are poorly understood. We previously showed that adult Caenorhabditis elegans that transiently passed through the stress-induced dauer larval stage (post-dauer adults) exhibit significant changes in gene expression profiles, chromatin states, and life history traits when compared with adults that bypassed the dauer stage (control adults). These wild-type, isogenic animals of equivalent developmental stages exhibit different signatures of molecular marks that reflect their distinct developmental trajectories. To gain insight into the mechanisms that contribute to these developmental history-dependent phenotypes, we profiled small RNAs from post-dauer and control adults by deep sequencing. RNA interference (RNAi) pathways are known to regulate genome-wide gene expression both at the chromatin and post-transcriptional level. By quantifying changes in endogenous small interfering RNA (endo-siRNA) levels in post-dauer as compared with control animals, our analyses identified a subset of genes that are likely targets of developmental history-dependent reprogramming through a complex RNAi-mediated mechanism. Mutations in specific endo-siRNA pathways affect expected gene expression and chromatin state changes for a subset of genes in post-dauer animals, as well as disrupt their increased brood size phenotype. We also find that both chromatin state and endo-siRNA distribution in dauers are unique, and suggest that remodeling in dauers provides a template for the subsequent establishment of adult post-dauer profiles. Our results indicate a role for endo-siRNA pathways as a contributing mechanism to early experience-dependent phenotypic plasticity in adults, and describe how developmental history can program adult physiology and behavior via epigenetic mechanisms.

RNAi-dependent expression of sperm genes in ADL chemosensory neurons is required for olfactory responses in Caenorhabditis elegans.

Environmental conditions experienced early in the life of an animal can result in gene expression changes later in its life history. We have previously shown that C. elegans animals that experienced the developmentally arrested and stress resistant dauer stage (postdauers) retain a cellular memory of early-life stress that manifests during adulthood as genome-wide changes in gene expression, chromatin states, and altered life history traits. One consequence of developmental reprogramming in C. elegans postdauer adults is the downregulation of osm-9 TRPV channel gene expression in the ADL chemosensory neurons resulting in reduced avoidance to a pheromone component, ascr#3. This altered response to ascr#3 requires the principal effector of the somatic nuclear RNAi pathway, the Argonaute (AGO) NRDE-3. To investigate the role of the somatic nuclear RNAi pathway in regulating the developmental reprogramming of ADL due to early-life stress, we profiled the mRNA transcriptome of control and postdauer ADL in wild-type and nrde-3 mutant adults. We found 711 differentially expressed (DE) genes between control and postdauer ADL neurons, 90% of which are dependent upon NRDE-3. Additionally, we identified a conserved sequence that is enriched in the upstream regulatory sequences of the NRDE-3-dependent differentially expressed genes. Surprisingly, 214 of the ADL DE genes are considered "germline-expressed", including 21 genes encoding the Major Sperm Proteins and two genes encoding the sperm-specific PP1 phosphatases, GSP-3 and GSP-4. Loss of function mutations in gsp-3 resulted in both aberrant avoidance and attraction behaviors. We also show that an AGO pseudogene, Y49F6A.1 (wago-11), is expressed in ADL and is required for ascr#3 avoidance. Overall, our results suggest that small RNAs and reproductive genes program the ADL mRNA transcriptome during their developmental history and highlight a nexus between neuronal and reproductive networks in calibrating animal neuroplasticity.

Inheritance of Stress Responses via Small Non-Coding RNAs in Invertebrates and Mammals.

While reports on the generational inheritance of a parental response to stress have been widely reported in animals, the molecular mechanisms behind this phenomenon have only recently emerged. The booming interest in epigenetic inheritance has been facilitated in part by the discovery that small non-coding RNAs are one of its principal conduits. Discovered 30 years ago in the Caenorhabditis elegans nematode, these small molecules have since cemented their critical roles in regulating virtually all aspects of eukaryotic development. Here, we provide an overview on the current understanding of epigenetic inheritance in animals, including mice and C. elegans, as it pertains to stresses such as temperature, nutritional, and pathogenic encounters. We focus on C. elegans to address the mechanistic complexity of how small RNAs target their cohort mRNAs to effect gene expression and how they govern the propagation or termination of generational perdurance in epigenetic inheritance. Presently, while a great amount has been learned regarding the heritability of gene expression states, many more questions remain unanswered and warrant further investigation.

A crossmodal crossover: opposite effects of visual and auditory perceptual load on steady-state evoked potentials to irrelevant visual stimuli.

Mechanisms of attention are required to prioritise goal-relevant sensory events under conditions of stimulus competition. According to the perceptual load model of attention, the extent to which task-irrelevant inputs are processed is determined by the relative demands of discriminating the target: the more perceptually demanding the target task, the less unattended stimuli will be processed. Although much evidence supports the perceptual load model for competing stimuli within a single sensory modality, the effects of perceptual load in one modality on distractor processing in another is less clear. Here we used steady-state evoked potentials (SSEPs) to measure neural responses to irrelevant visual checkerboard stimuli while participants performed either a visual or auditory task that varied in perceptual load. Consistent with perceptual load theory, increasing visual task load suppressed SSEPs to the ignored visual checkerboards. In contrast, increasing auditory task load enhanced SSEPs to the ignored visual checkerboards. This enhanced neural response to irrelevant visual stimuli under auditory load suggests that exhausting capacity within one modality selectively compromises inhibitory processes required for filtering stimuli in another.

Epigenetic regulation of nervous system development and function.

Building a brain is complicated but maintaining one may be an even greater challenge. Epigenetic mechanisms, including DNA methylation, histone and chromatin modifications, and the actions of non-coding RNAs, play an indispensable role in both. They orchestrate long-term changes in gene expression that underpin establishment of cellular identity as well as the distinct functionality of each cell type, while providing the needed plasticity for the brain to respond to a changing environment. The rapid expansion of studies on these epigenetic mechanisms over the last few decades has brought an evolving definition of the term epigenetics, including in the specialized context of the nervous system. The goal of this special issue is thus not only to bring a greater understanding of the myriad ways in which epigenetic mechanisms regulate nervous system development and function, but also to provide a platform for discussion of what is and what is not epigenetics. To this end, the editors have compiled a collection of review articles highlighting some of the remarkable breadth of epigenetic mechanisms that act at all stages of neuronal development and function, spanning from neurodevelopment, through learning and memory, and neurodegeneration.

piRNAs and endo-siRNAs: Small molecules with large roles in the nervous system.

Since their discovery, small non-coding RNAs have emerged as powerhouses in the regulation of numerous cellular processes. In addition to guarding the integrity of the reproductive system, small non-coding RNAs play critical roles in the maintenance of the soma. Accumulating evidence indicates that small non-coding RNAs perform vital functions in the animal nervous system such as restricting the activity of deleterious transposable elements, regulating nerve regeneration, and mediating learning and memory. In this review, we provide an overview of the current understanding of the contribution of two major classes of small non-coding RNAs, piRNAs and endo-siRNAs, to the nervous system development and function, and present highlights on how the dysregulation of small non-coding RNA pathways can assist in understanding the neuropathology of human neurological disorders.

Somatic aging pathways regulate reproductive plasticity in Caenorhabditis elegans.

In animals, early-life stress can result in programmed changes in gene expression that can affect their adult phenotype. In C. elegans nematodes, starvation during the first larval stage promotes entry into a stress-resistant dauer stage until environmental conditions improve. Adults that have experienced dauer (postdauers) retain a memory of early-life starvation that results in gene expression changes and reduced fecundity. Here, we show that the endocrine pathways attributed to the regulation of somatic aging in C. elegans adults lacking a functional germline also regulate the reproductive phenotypes of postdauer adults that experienced early-life starvation. We demonstrate that postdauer adults reallocate fat to benefit progeny at the expense of the parental somatic fat reservoir and exhibit increased longevity compared to controls. Our results also show that the modification of somatic fat stores due to parental starvation memory is inherited in the F1 generation and may be the result of crosstalk between somatic and reproductive tissues mediated by the germline nuclear RNAi pathway.

Assessment of emotion processing skills in acquired brain injury using an ability-based test of emotional intelligence.

Social and emotional problems are commonly reported after moderate to severe acquired brain injury (ABI) and pose a significant barrier to rehabilitation. However, progress in assessment of emotional skills has been limited by a lack of validated measurement approaches. This study represents the first formal psychometric evaluation of the use of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) V2.0 as a tool for assessing skills in perceiving, using, understanding and managing emotions following ABI. The sample consisted of 82 participants aged 18-80 years in the postacute phase of recovery (2 months-7 years) after moderate to severe ABI. Participants completed the MSCEIT V2.0 and measures of cognition and mood. Sociodemographic and clinical variables were collated from participant interview and medical files. Results revealed deficits across all MSCEIT subscales (approximately 1 SD below the normative mean). Internal consistency was adequate at overall, area, and branch levels, and MSCEIT scores correlated in expected ways with key demographic, clinical, cognitive, and mood variables. MSCEIT performance was related to injury severity and clinician-rated functioning after ABI. Confirmatory factor analysis favored a 3-factor model of EI due to statistical redundancy of the Using Emotions branch. Overall, these findings suggest that the MSCEIT V2.0 is sensitive to emotion processing deficits after moderate to severe ABI, and can yield valid and reliable scores in an ABI sample. In terms of theoretical contributions, our findings support a domain-based, 3-factor approach for characterizing emotion-related abilities in brain-injured individuals. (PsycINFO Database Record

Metabolic redesign of vitamin E biosynthesis in plants for tocotrienol production and increased antioxidant content.

Tocotrienols are the primary form of vitamin E in seeds of most monocot plants, including cereals such as rice and wheat. As potent antioxidants, tocotrienols contribute to the nutritive value of cereal grains in human and livestock diets. cDNAs encoding homogentisic acid geranylgeranyl transferase (HGGT), which catalyzes the committed step of tocotrienol biosynthesis, were isolated from barley, wheat and rice seeds. Transgenic expression of the barley HGGT in Arabidopsis thaliana leaves resulted in accumulation of tocotrienols, which were absent from leaves of nontransformed plants, and a 10- to 15-fold increase in total vitamin E antioxidants (tocotrienols plus tocopherols). Overexpression of the barley HGGT in corn seeds resulted in an increase in tocotrienol and tocopherol content of as much as six-fold. These results provide insight into the genetic basis for tocotrienol biosynthesis in plants and demonstrate the ability to enhance the antioxidant content of crops by introduction of an enzyme that redirects metabolic flux.

Endogenous RNAi Pathways Are Required in Neurons for Dauer Formation in Caenorhabditis elegans.

Animals can adapt to unfavorable environments through changes in physiology or behavior. In the nematode, Caenorhabditis elegans, environmental conditions perceived early in development determine whether the animal enters either the reproductive cycle, or enters into an alternative diapause stage named dauer. Here, we show that endogenous RNAi pathways play a role in dauer formation in crowding (high pheromone), starvation, and high temperature conditions. Disruption of the Mutator proteins or the nuclear Argonaute CSR-1 result in differential dauer-deficient phenotypes that are dependent upon the experienced environmental stress. We provide evidence that the RNAi pathways function in chemosensory neurons for dauer formation, upstream of the TGF-ß and insulin signaling pathways. In addition, we show that Mutator MUT-16 expression in a subset of individual pheromone-sensing neurons is sufficient for dauer formation in high pheromone conditions, but not in starvation or high temperature conditions. Furthermore, we also show that MUT-16 and CSR-1 are required for expression of a subset of G proteins with functions in the detection of pheromone components. Together, our data suggest a model where Mutator-amplified siRNAs that associate with the CSR-1 pathway promote expression of genes required for the detection and signaling of environmental conditions to regulate development and behavior in C. elegans This study highlights a mechanism whereby RNAi pathways mediate the link between environmental stress and adaptive phenotypic plasticity in animals.

Early Pheromone Experience Modifies a Synaptic Activity to Influence Adult Pheromone Responses of C. elegans.

Experiences during early development can influence neuronal functions and modulate adult behaviors [1, 2]. However, the molecular mechanisms underlying the long-term behavioral effects of these early experiences are not fully understood. The C. elegans ascr#3 (asc-ΔC9; C9) pheromone triggers avoidance behavior in adult hermaphrodites [3-7]. Here, we show that hermaphrodites that are briefly exposed to ascr#3 immediately after birth exhibit increased ascr#3-specific avoidance as adults, indicating that ascr#3-experienced animals form a long-lasting memory or imprint of this early ascr#3 exposure [8]. ascr#3 imprinting is mediated by increased synaptic activity between the ascr#3-sensing ADL neurons and their post-synaptic SMB motor neuron partners via increased expression of the odr-2 glycosylated phosphatidylinositol (GPI)-linked signaling gene in the SMB neurons. Our study suggests that the memory for early ascr#3 experience is imprinted via alteration of activity of a single synaptic connection, which in turn shapes experience-dependent plasticity in adult ascr#3 responses.

The rapidly evolving field of plant centromeres.

Meiotic and mitotic chromosome segregation are highly conserved in eukaryotic organisms, yet centromeres--the chromosomal sites that mediate segregation--evolve extremely rapidly. Plant centromeres have DNA elements that are shared across species, yet they diverge rapidly through large- and small-scale changes. Over evolutionary time-scales, centromeres migrate to non-centromeric regions and, in plants, heterochromatic knobs can acquire centromere activity. Discerning the functional significance of these changes will require comparative analyses of closely related species. Combined with functional assays, continued efforts in plant genomics will uncover key DNA elements that allow centromeres to retain their role in chromosome segregation while allowing rapid evolution.

Differential rates of local and global homogenization in centromere satellites from Arabidopsis relatives.

Higher eukaryotic centromeres contain thousands of satellite repeats organized into tandem arrays. As species diverge, new satellite variants are homogenized within and between chromosomes, yet the processes by which particular sequences are dispersed are poorly understood. Here, we isolated and analyzed centromere satellites in plants separated from Arabidopsis thaliana by 5-20 million years, uncovering more rapid satellite divergence compared to primate alpha-satellite repeats. We also found that satellites derived from the same genomic locus were more similar to each other than satellites derived from disparate genomic regions, indicating that new sequence alterations were homogenized more efficiently at a local, rather than global, level. Nonetheless, the presence of higher-order satellite arrays, similar to those identified in human centromeres, indicated limits to local homogenization and suggested that sequence polymorphisms may play important functional roles. In two species, we defined more extensive polymorphisms, identifying physically separated and highly distinct satellite types. Taken together, these data show that there is a balance between plant satellite homogenization and the persistence of satellite variants. This balance could ultimately generate sufficient sequence divergence to cause mating incompatibilities between plant species, while maintaining adequate conservation within a species for centromere activity.

The Role of Trait and State Absorption in the Enjoyment of Music.

Little is known about the role of state versus trait characteristics on our enjoyment of music. The aim of this study was to investigate the influence of state and trait absorption upon preference for music, particularly preference for music that evokes negative emotions. The sample consisted of 128 participants who were asked to listen to two pieces of self-selected music and rate the music on variables including preference and felt and expressed emotions. Participants completed a brief measure of state absorption after listening to each piece, and a trait absorption inventory. State absorption was strongly positively correlated with music preference, whereas trait absorption was not. Trait absorption was related to preference for negative emotions in music, with chi-square analyses demonstrating greater enjoyment of negative emotions in music among individuals with high trait absorption. This is the first study to show that state and trait absorption have separable and distinct effects on a listener's music experience, with state characteristics impacting music enjoyment in the moment, and trait characteristics influencing music preference based on its emotional content.

Developmental programming modulates olfactory behavior in C. elegans via endogenous RNAi pathways.

Environmental stress during early development can impact adult phenotypes via programmed changes in gene expression. C. elegans larvae respond to environmental stress by entering the stress-resistant dauer diapause pathway and resume development once conditions improve (postdauers). Here we show that the osm-9 TRPV channel gene is a target of developmental programming and is down-regulated specifically in the ADL chemosensory neurons of postdauer adults, resulting in a corresponding altered olfactory behavior that is mediated by ADL in an OSM-9-dependent manner. We identify a cis-acting motif bound by the DAF-3 SMAD and ZFP-1 (AF10) proteins that is necessary for the differential regulation of osm-9, and demonstrate that both chromatin remodeling and endo-siRNA pathways are major contributors to the transcriptional silencing of the osm-9 locus. This work describes an elegant mechanism by which developmental experience influences adult phenotypes by establishing and maintaining transcriptional changes via RNAi and chromatin remodeling pathways.

A Method for Obtaining Large Populations of Synchronized Caenorhabditis elegans Dauer Larvae.

The C. elegans dauer is an attractive model with which to investigate fundamental biological questions, such as how environmental cues are sensed and are translated into developmental decisions through a series of signaling cascades that ultimately result in a transformed animal. Here we describe a simple method of using egg white plates to obtain highly synchronized purified dauers that can be used in downstream applications requiring large quantities of dauers or postdauer animals.