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.

Microbial colonization induces histone acetylation critical for inherited gut-germline-neural signaling.

The gut-neural axis plays a critical role in the control of several physiological processes, including the communication of signals from the microbiome to the nervous system, which affects learning, memory, and behavior. However, the pathways involved in gut-neural signaling of gut-governed behaviors remain unclear. We found that the intestinal distension caused by the bacterium Pseudomonas aeruginosa induces histone H4 Lys8 acetylation (H4K8ac) in the germline of Caenorhabditis elegans, which is required for both a bacterial aversion behavior and its transmission to the next generation. We show that induction of H4K8ac in the germline is essential for bacterial aversion and that a 14-3-3 chaperone protein family member, PAR-5, is required for H4K8ac. Our findings highlight a role for H4K8ac in the germline not only in the intergenerational transmission of pathogen avoidance but also in the transmission of pathogenic cues that travel through the gut-neural axis to control the aversive behavior.

A developmental perspective on the evolution of the nervous system.

The evolution of nervous systems in animals has always fascinated biologists, and thus multiple evolutionary scenarios have been proposed to explain the appearance of neurons and complex neuronal centers. However, the absence of a robust phylogenetic framework for animal interrelationships, the lack of a mechanistic understanding of development, and a recapitulative view of animal ontogeny have traditionally limited these scenarios. Only recently, the integration of advanced molecular and morphological studies in a broad range of animals has allowed to trace the evolution of developmental and neuronal characters on a better-resolved animal phylogeny. This has falsified most traditional scenarios for nervous system evolution, paving the way for the emergence of new testable hypotheses. Here we summarize recent progress in studies of nervous system development in major animal lineages and formulate some of the arising questions. In particular, we focus on how lineage analyses of nervous system development and a comparative study of the expression of neural-related genes has influenced our understanding of the evolution of an elaborated central nervous system in Bilateria. We argue that a phylogeny-guided study of neural development combining thorough descriptive and functional analyses is key to establish more robust scenarios for the origin and evolution of animal nervous systems.

Transgenic models for investigating the nervous system: Currently available neurofluorescent reporters and potential neuronal markers.

Recombinant DNA technologies have enabled the development of transgenic animal models for use in studying a myriad of diseases and biological states. By placing fluorescent reporters under the direct regulation of the promoter region of specific marker proteins, these models can localize and characterize very specific cell types. One important application of transgenic species is the study of the cytoarchitecture of the nervous system. Neurofluorescent reporters can be used to study the structural patterns of nerves in the central or peripheral nervous system in vivo, as well as phenomena involving embryologic or adult neurogenesis, injury, degeneration, and recovery. Furthermore, crucial molecular factors can also be screened via the transgenic approach, which may eventually play a major role in the development of therapeutic strategies against diseases like Alzheimer's or Parkinson's. This review describes currently available reporters and their uses in the literature as well as potential neural markers that can be leveraged to create additional, robust transgenic models for future studies.

Fast-diffusing p75NTR monomers support apoptosis and growth cone collapse by neurotrophin ligands.

The p75 neurotrophin (NT) receptor (p75NTR) plays a crucial role in balancing survival-versus-death decisions in the nervous system. Yet, despite 2 decades of structural and biochemical studies, a comprehensive, accepted model for p75NTR activation by NT ligands is still missing. Here, we present a single-molecule study of membrane p75NTR in living cells, demonstrating that the vast majority of receptors are monomers before and after NT activation. Interestingly, the stoichiometry and diffusion properties of the wild-type (wt) p75NTR are almost identical to those of a receptor mutant lacking residues previously believed to induce oligomerization. The wt p75NTR and mutated (mut) p75NTR differ in their partitioning in cholesterol-rich membrane regions upon nerve growth factor (NGF) stimulation: We argue that this is the origin of the ability of wt p75NTR , but not of mut p75NTR, to mediate immature NT (proNT)-induced apoptosis. Both p75NTR forms support proNT-induced growth cone retraction: We show that receptor surface accumulation is the driving force for cone collapse. Overall, our data unveil the multifaceted activity of the p75NTR monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature.

The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour.

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

Expanding the Toolbox of Upconversion Nanoparticles for In Vivo Optogenetics and Neuromodulation.

Optogenetics is an optical technique that exploits visible light for selective neuromodulation with spatio-temporal precision. Despite enormous effort, the effective stimulation of targeted neurons, which are located in deeper structures of the nervous system, by visible light, remains a technical challenge. Compared to visible light, near-infrared illumination offers a higher depth of tissue penetration owing to a lower degree of light attenuation. Herein, an overview of advances in developing new modalities for neural circuitry modulation utilizing upconversion-nanoparticle-mediated optogenetics is presented. These developments have led to minimally invasive optical stimulation and inhibition of neurons with substantially improved selectivity, sensitivity, and spatial resolution. The focus is to provide a comprehensive review of the mechanistic basis for evaluating upconversion parameters, which will be useful in designing, executing, and reporting optogenetic experiments.

Recent Advances in the Genetic Dissection of Neural Circuits in Drosophila.

Nervous systems endow animals with cognition and behavior. To understand how nervous systems control behavior, neural circuits mediating distinct functions need to be identified and characterized. With superior genetic manipulability, Drosophila is a model organism at the leading edge of neural circuit analysis. We briefly introduce the state-of-the-art genetic tools that permit precise labeling of neurons and their interconnectivity and investigating what is happening in the brain of a behaving animal and manipulating neurons to determine how behaviors are affected. Brain-wide wiring diagrams, created by light and electron microscopy, bring neural circuit analysis to a new level and scale. Studies enabled by these tools advances our understanding of the nervous system in relation to cognition and behavior.

The role of intraspecies variation in fish neurobehavioral and neuropharmacological phenotypes in aquatic models.

Intraspecies variation is common in both clinical and animal research of various brain disorders. Relatively well-studied in mammals, intraspecies variation in aquatic fish models and its role in their behavioral and pharmacological responses remain poorly understood. Like humans and mammals, fishes show high variance of behavioral and drug-evoked responses, modulated both genetically and environmentally. The zebrafish (Danio rerio) has emerged as a particularly useful model organism tool to access neurobehavioral and drug-evoked responses. Here, we discuss recent findings and the role of the intraspecies variance in neurobehavioral, pharmacological and toxicological studies utilizing zebrafish and other fish models. We also critically evaluate common sources of intraspecies variation and outline potential strategies to improve data reproducibility and translatability.

The role of nervous system in adaptive response of bone to mechanical loading.

Bone tissue is remodeled through the catabolic function of the osteoclasts and the anabolic function of the osteoblasts. The process of bone homeostasis and metabolism has been identified to be co-ordinated with several local and systemic factors, of which mechanical stimulation acts as an important regulator. Very recent studies have shown a mutual effect between bone and other organs, which means bone influences the activity of other organs and is also influenced by other organs and systems of the body, especially the nervous system. With the discovery of neuropeptide (calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y) and neurotransmitter in bone and the adrenergic receptor observed in osteoclasts and osteoblasts, the function of peripheral nervous system including sympathetic and sensor nerves in bone resorption and its reaction to on osteoclasts and osteoblasts under mechanical stimulus cannot be ignored. Taken together, bone tissue is not only the mechanical transmitter, but as well the receptor of neural system under mechanical loading. This review aims to summarize the relationship among bone, nervous system, and mechanotransduction.

Paleo-oscillomics: inferring aspects of Neanderthal language abilities from gene regulation of neural oscillations.

Language seemingly evolved from changes in brain anatomy and wiring. We argue that language evolution can be better understood if particular changes in phasal and cross-frequency coupling properties of neural oscillations, resulting in core features of language, are considered. Because we cannot track the oscillatory activity of the brain from extinct hominins, we used our current understanding of the language oscillogenome (that is, the set of genes responsible for basic aspects of the oscillatory activity relevant for language) to infer some properties of the Neanderthal oscillome. We have found that several candidates for the language oscillogenome show differences in their methylation patterns between Neanderthals and humans. We argue that differences in their expression levels could be informative of differences in cognitive functions important for language.

Nervous System Development: Flies and Worms Converging on Neuron Identity Control.

Distinct neuronal cell types display phenotypic similarities such as their neurotransmitter identity. Studies in worms and flies have revealed that this phenotypic convergence can be brought about by distinct transcription factors regulating the same effector genes in different neuron types.

The CeNGEN Project: The Complete Gene Expression Map of an Entire Nervous System.

Differential gene expression defines individual neuron types and determines how each contributes to circuit physiology and responds to injury and disease. The C. elegans Neuronal Gene Expression Map & Network (CeNGEN) will establish a comprehensive gene expression atlas of an entire nervous system at single-neuron resolution.

Morphology and Physiology of the Ascidian Nervous Systems and the Effectors.

Neurobiology in ascidians has made many advances. Ascidians have offered natural advantages to researchers, including fecundity, structural simplicity, invariant morphology, and fast and stereotyped developmental processes. The researchers have also accumulated on this animal a great deal of knowledge, genomic resources, and modern genetic techniques. A recent connectomic analysis has shown an ultimately resolved image of the larval nervous system, whereas recent applications of live imaging and optogenetics have clarified the functional organization of the juvenile nervous system. Progress in resources and techniques have provided convincing ways to deepen what we have wanted to know about the nervous systems of ascidians. Here, the research history and the current views regarding ascidian nervous systems are summarized.

Neural cognitive control moderates the association between insular risk processing and risk-taking behaviors via perceived stress in adolescents.

Adolescence is a critical period for the initiation of risk-taking behaviors. We examined the longitudinal interplay between neural correlates of risk processing and cognitive control in predicting risk-taking behaviors via stress. The sample consisted of 167 adolescents (53% males) who were assessed twice (MAgeTime1 = 14.13, MAgeTime2 = 15.05). Neural risk processing was operationalized as blood-oxygen-level-dependent (BOLD) responses in the anterior insula during a lottery choice task and neural cognitive control as BOLD responses during an inhibitory control task. Adolescents reported on perceived stress and risk-taking behaviors. Structural equation modeling analyses indicated that low insular risk processing predicted increases in perceived stress, while perceived stress did not predict changes in insular risk processing across one year. Moreover, significant moderation by neural cognitive control indicated that low insular risk processing predicted increases in risk-taking behaviors via increases in perceived stress among adolescents with poor neural cognitive control, but not among adolescents with good neural cognitive control. The results suggest that risk processing in the anterior insular cortex plays an important role in stress experience and risk-taking behaviors particularly for vulnerable adolescents with poor neural cognitive control.

Affected pathways and transcriptional regulators in gene expression response to an ultra-marathon trail: Global and independent activity approaches.

Gene expression (GE) analyses on blood samples from marathon and half-marathon runners have reported significant impacts on the immune and inflammatory systems. An ultra-marathon trail (UMT) represents a greater effort due to its more testing conditions. For the first time, we report the genome-wide GE profiling in a group of 16 runners participating in an 82 km UMT competition. We quantified their differential GE profile before and after the race using HuGene2.0st microarrays (Affymetrix Inc., California, US). The results obtained were decomposed by means of an independent component analysis (ICA) targeting independent expression modes. We observed significant differences in the expression levels of 5,084 protein coding genes resulting in an overrepresentation of 14% of the human biological pathways from the Kyoto Encyclopedia of Genes and Genomes database. These were mainly clustered on terms related with protein synthesis repression, altered immune system and infectious diseases related mechanisms. In a second analysis, 27 out of the 196 transcriptional regulators (TRs) included in the Open Regulatory Annotation database were overrepresented. Among these TRs, we identified transcription factors from the hypoxia-inducible factors (HIF) family EPAS1 (p< 0.01) and HIF1A (p<0.001), and others jointly described in the gluconeogenesis program such as HNF4 (p< 0.001), EGR1 (p<0.001), CEBPA (p< 0.001) and a highly specific TR, YY1 (p<0.01). The five independent components, obtained from ICA, further revealed a down-regulation of 10 genes distributed in the complex I, III and V from the electron transport chain. This mitochondrial activity reduction is compatible with HIF-1 system activation. The vascular endothelial growth factor (VEGF) pathway, known to be regulated by HIF, also emerged (p<0.05). Additionally, and related to the brain rewarding circuit, the endocannabinoid signalling pathway was overrepresented (p<0.05).

Acute doses of caffeine shift nervous system cell expression profiles toward promotion of neuronal projection growth.

Caffeine is a widely consumed psychoactive substance, but little is known about the effects of caffeine stimulation on global gene expression changes in neurons. Here, we conducted gene expression profiling of human neuroepithelial stem cell-derived neurons, stimulated with normal consumption levels of caffeine (3 µM and 10 µM), over a period of 9 h. We found dosage-dependent activation of immediate early genes after 1 h. Neuronal projection development processes were up-regulated and negative regulation of axon extension processes were down-regulated at 3 h. In addition, genes involved in extracellular matrix organization, response for wound healing, and regulation of immune system processes were down-regulated by caffeine at 3 h. This study identified novel genes within the neuronal projection guidance pathways that respond to acute caffeine stimulation and suggests potential mechanisms for the effects of caffeine on neuronal cells.

Behavioral Performance and Neural Systems Are Robust to Sensory Injury in Workers of the Ant Pheidole dentata.

Miniaturized nervous systems have been thought to limit behavioral ability, and animals with miniaturized brains may be less flexible when challenged by injuries resulting in sensory deficits that impact the development, maintenance, and plasticity of small-scale neural networks. We experimentally examined how injuries to sensory structures critical for olfactory ability affect behavioral performance in workers of the ant Pheidole dentata, which have minute brains (0.01 mm3) and primarily rely on the perception and processing of chemical signals and cues to direct their social behavior. We employed unilateral antennal denervation to decrease the olfactory perception ability of workers and quantified consequential neuroanatomical and behavioral performance effects. Postablation neuroanatomical metrics revealed a 25% reduction in the volume of the antennal lobe ipsilateral to the antennal lesion relative to the contralateral lobe, indicating atrophy of the input-deprived tissue. However, antennectomy did not affect the volumes of the mushroom body or its subcompartments or the number of mushroom body synaptic complexes (microglomeruli) in either brain hemisphere. Synapsin immunoreactivity, however, was significantly higher in the ipsilateral mushroom body calyces, which could reflect presynaptic potentiation and homeostatic compensation in higher-order olfactory regions. Despite tissue loss caused by antennal lesioning and resulting unilateral sensory deprivation, the ability of workers to perform behaviors that encompass the breadth of their task repertoire and meet demands for colony labor remained largely intact. The few behavioral deficits recorded were restricted to pheromone trail-following ability, a result that was expected due to the need for bilateral olfactory input to process spatial odor information. Our macroscopic and cellular neuroanatomical measurements and assessments of task performance demonstrate that the miniaturized brains of P. dentata workers and their sensorimotor functions are remarkably robust to injury-related size reduction and remain capable of generating behaviors required to respond appropriately to chemical social signals and effectively nurse immatures, as well as participate in coordinated foraging.

Copy-number variation of housekeeping gene rpl13a in rat strains selected for nervous system excitability.

We evaluated copy number variation (CNV) for four genes in rat strains differing in nervous system excitability. rpl13a copy number is significantly reduced in hippocampus and bone marrow in rats with a high excitability threshold and stress. The observed phenomenon may be associated with a role for rpl13a in lipid metabolism.