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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

Small RNA library cloning procedure for deep sequencing of specific endogenous siRNA classes in Caenorhabditis elegans.

In recent years, distinct classes of small RNAs ranging in size from ~21 to 26 nucleotides have been discovered and shown to play important roles in a wide array of cellular functions. Because of the abundance of these small RNAs, library preparation from an RNA sample followed by deep sequencing provides the identity and quantity of a particular class of small RNAs. In this chapter we describe a detailed protocol for preparing small RNA libraries for deep sequencing on the Illumina platform from the nematode C. elegans.

Effect of signaled reinforcer magnitude on delayed matching-to-sample performance in individuals with intellectual disabilities.

The present study investigated effects of signaled reinforcer magnitude in a delayed identity matching-to-sample procedure. Four individuals with intellectual disabilities were trained on conditional discrimination with three geometric stimuli as sample and comparison stimuli. Retention intervals ranged from 0.1 to 16s. The magnitude of the reinforcer (different durations of access to a video game) was signaled by the background color of the screen. Matching accuracy was overall higher when the larger reinforcer was signaled, independently of retention intervals.

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.

Complementary and alternative treatment use for autism spectrum disorders.

Autism spectrum disorders (ASD) have rapidly become one of the more frequent reasons for seeking diagnosis and treatment. Depending on health care services available, the standard treatment options are often limited; many parents turn to complementary and alternative medicine (CAM) approaches. CAM treatments and some of the factors that may contribute to parents' decisions to use CAM treatments were examined using a web-based survey. Four general factors emerges as influencing the decision-making processes of parents/caregivers - severity, child acceptance of the treatment, marital status, and educational level. Notably, research support did not emerge as contributing to variance for CAM use.

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.

Developmental changes in anger expression and attention focus: learning to wait.

Being able to wait is an essential part of self-regulation. In the present study, the authors examined the developmental course of changes in the latency to and duration of target-waiting behaviors by following 65 boys and 55 girls from rural and semirural economically strained homes from ages 18 months to 48 months. Age-related changes in latency to and duration of children's anger expressions and attention focus (e.g., self-initiated distraction) during an 8-min wait for a gift were found. On average, at 18 and 24 months of age, children were quick to react angrily and slower to shift attention away from the desired object than they were at later ages. Over time, children were quicker to distract themselves. By 36 months, distractions occurred before children expressed anger, and anger expressions were briefer. At 48 months, children typically made a quick bid to their mothers about having to wait before distracting themselves; on average, they did not appear angry until the latter half of the wait. Unexpectedly, children bid to their mothers as much at age 48 months as they had at 18 months; however, bids became less angry as children got older. Developmental changes in distraction and bidding predicted age-related changes in the latency to anger. Findings are discussed in terms of the neurocognitive control of attention around age 30 months, the limitations of children's self-regulatory efforts at age 48 months, and the importance of fostering children's ability to forestall, as well as modulate, anger.