Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism.

PubMed

Dhamne, Sameer C; Silverman, Jill L; Super, Chloe E; Lammers, Stephen H T; Hameed, Mustafa Q; Modi, Meera E; Copping, Nycole A; Pride, Michael C; Smith, Daniel G; Rotenberg, Alexander; Crawley, Jacqueline N; Sahin, Mustafa

2017-01-01

Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant ( Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery.

Demographic and phenotypic responses of juvenile steelhead trout to spatial predictability of food resources

Treesearch

Matthew R. Sloat; Gordon H. Reeves

2014-01-01

We manipulated food inputs among patches within experimental streams to determine how variation in foraging behavior influenced demographic and phenotypic responses of juvenile steelhead trout (Oncorhynchus mykiss) to the spatial predictability of food resources. Demographic responses included compensatory adjustments in fish abundance, mean fish...

Endocrinology of human female sexuality, mating, and reproductive behavior.

PubMed

Motta-Mena, Natalie V; Puts, David A

2017-05-01

Hormones orchestrate and coordinate human female sexual development, sexuality, and reproduction in relation to three types of phenotypic changes: life history transitions such as puberty and childbirth, responses to contextual factors such as caloric intake and stress, and cyclical patterns such as the ovulatory cycle. Here, we review the endocrinology underlying women's reproductive phenotypes, including sexual orientation and gender identity, mate preferences, competition for mates, sex drive, and maternal behavior. We highlight distinctive aspects of women's sexuality such as the possession of sexual ornaments, relatively cryptic fertile windows, extended sexual behavior across the ovulatory cycle, and a period of midlife reproductive senescence-and we focus on how hormonal mechanisms were shaped by selection to produce adaptive outcomes. We conclude with suggestions for future research to elucidate how hormonal mechanisms subserve women's reproductive phenotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks.

PubMed

Spanagel, Rainer

2013-01-01

Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. "from phenotype to genotype". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. "from genotype to phenotype". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior.

Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice.

PubMed

Sidorov, M S; Krueger, D D; Taylor, M; Gisin, E; Osterweil, E K; Bear, M F

2014-06-01

Fragile X (FX) is the most common genetic cause of intellectual disability and autism. Previous studies have shown that partial inhibition of metabotropic glutamate receptor signaling is sufficient to correct behavioral phenotypes in a mouse model of FX, including audiogenic seizures, open-field hyperactivity and social behavior. These phenotypes model well the epilepsy (15%), hyperactivity (20%) and autism (30%) that are comorbid with FX in human patients. Identifying reliable and robust mouse phenotypes to model cognitive impairments is critical considering the 90% comorbidity of FX and intellectual disability. Recent work characterized a five-choice visuospatial discrimination assay testing cognitive flexibility, in which FX model mice show impairments associated with decreases in synaptic proteins in prefrontal cortex (PFC). In this study, we sought to determine whether instrumental extinction, another process requiring PFC, is altered in FX model mice, and whether downregulation of metabotropic glutamate receptor signaling pathways is sufficient to correct both visuospatial discrimination and extinction phenotypes. We report that instrumental extinction is consistently exaggerated in FX model mice. However, neither the extinction phenotype nor the visuospatial discrimination phenotype is corrected by approaches targeting metabotropic glutamate receptor signaling. This work describes a novel behavioral extinction assay to model impaired cognition in mouse models of neurodevelopmental disorders, provides evidence that extinction is exaggerated in the FX mouse model and suggests possible limitations of metabotropic glutamate receptor-based pharmacotherapy. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Trans-generational Effects of Early Life Stress: The Role of Maternal Behavior

PubMed Central

Schmauss, Claudia; Lee-McDermott, Zoe; Medina, Liorimar Ramos

2014-01-01

Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations. These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex. These behavioral and epigenetic phenotypes are transmitted to the first progeny of IMS Balb/c mothers, but not fathers, and cross-fostering experiments revealed that this transmission is triggered by maternal behavior and modulated by the genetic background of the pups. In the continued absence of the original stressor, this transmission fades in later progenies. An adolescent treatment that lowers the levels of acH4K12 in IMS Balb/c mice augments their emotional abnormality but abolishes their cognitive deficits. Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits. Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented. PMID:24786242

Development, maternal effects, and behavioral plasticity.

PubMed

Mateo, Jill M

2014-11-01

Behavioral, hormonal, and genetic processes interact reciprocally, and differentially affect behavior depending on ecological and social contexts. When individual differences are favored either between or within environments, developmental plasticity would be expected. Parental effects provide a rich source for phenotypic plasticity, including anatomical, physiological, and behavioral traits, because parents respond to dynamic cues in their environment and can, in turn, influence offspring accordingly. Because these inter-generational changes are plastic, parents can respond rapidly to changing environments and produce offspring whose phenotypes are well suited for current conditions more quickly than occurs with changes based on evolution through natural selection. I review studies on developmental plasticity and resulting phenotypes in Belding's ground squirrels (Urocitellus beldingi), an ideal species, given the competing demands to avoid predation while gaining sufficient weight to survive an upcoming hibernation, and the need for young to learn their survival behaviors. I will show how local environments and perceived risk of predation influence not only foraging, vigilance, and anti-predator behaviors, but also adrenal functioning, which may be especially important for obligate hibernators that face competing demands on the storage and mobilization of glucose. Mammalian behavioral development is sensitive to the social and physical environments provided by mothers during gestation and lactation. Therefore, maternal effects on offspring's phenotypes, both positive and negative, can be particularly strong. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Neuropathology and Animal Models of Autism: Genetic and Environmental Factors

PubMed Central

Gadad, Bharathi S.; Young, Keith A.; German, Dwight C.

2013-01-01

Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology. PMID:24151553

Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study

PubMed Central

Mandillo, Silvia; Tucci, Valter; Hölter, Sabine M.; Meziane, Hamid; Banchaabouchi, Mumna Al; Kallnik, Magdalena; Lad, Heena V.; Nolan, Patrick M.; Ouagazzal, Abdel-Mouttalib; Coghill, Emma L.; Gale, Karin; Golini, Elisabetta; Jacquot, Sylvie; Krezel, Wojtek; Parker, Andy; Riet, Fabrice; Schneider, Ilka; Marazziti, Daniela; Auwerx, Johan; Brown, Steve D. M.; Chambon, Pierre; Rosenthal, Nadia; Tocchini-Valentini, Glauco; Wurst, Wolfgang

2008-01-01

Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and laboratories. For this reason, we devised and tested a set of SOPs to investigate mouse behavior. Five research centers were involved across France, Germany, Italy, and the UK in this study, as part of the EUMORPHIA program. All the procedures underwent a cross-validation experimental study to investigate the robustness of the designed protocols. Four inbred reference strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ, 129S2/SvPas), reflecting their use as common background strains in mutagenesis programs, were analyzed to validate these tests. We demonstrate that the operating procedures employed, which includes open field, SHIRPA, grip-strength, rotarod, Y-maze, prepulse inhibition of acoustic startle response, and tail flick tests, generated reproducible results between laboratories for a number of the test output parameters. However, we also identified several uncontrolled variables that constitute confounding factors in behavioral phenotyping. The EUMORPHIA SOPs described here are an important start-point for the ongoing development of increasingly robust phenotyping platforms and their application in large-scale, multicentre mouse phenotyping programs. PMID:18505770

Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay.

PubMed

Burnside, Rachel D; Pasion, Romela; Mikhail, Fady M; Carroll, Andrew J; Robin, Nathaniel H; Youngs, Erin L; Gadi, Inder K; Keitges, Elizabeth; Jaswaney, Vikram L; Papenhausen, Peter R; Potluri, Venkateswara R; Risheg, Hiba; Rush, Brooke; Smith, Janice L; Schwartz, Stuart; Tepperberg, James H; Butler, Merlin G

2011-10-01

The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1-BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2-BP3) or uniparental disomy 15. The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.

CKD Self-management: Phenotypes and Associations With Clinical Outcomes.

PubMed

Schrauben, Sarah J; Hsu, Jesse Y; Rosas, Sylvia E; Jaar, Bernard G; Zhang, Xiaoming; Deo, Rajat; Saab, Georges; Chen, Jing; Lederer, Swati; Kanthety, Radhika; Hamm, L Lee; Ricardo, Ana C; Lash, James P; Feldman, Harold I; Anderson, Amanda H

2018-03-24

To slow chronic kidney disease (CKD) progression and its complications, patients need to engage in self-management behaviors. The objective of this study was to classify CKD self-management behaviors into phenotypes and assess the association of these phenotypes with clinical outcomes. Prospective cohort study. Adults with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. 3,939 participants in the CRIC Study recruited between 2003 and 2008 served as the derivation cohort and 1,560 participants recruited between 2013 and 2015 served as the validation cohort. CKD self-management behavior phenotypes. CKD progression, atherosclerotic events, heart failure events, death from any cause. Latent class analysis stratified by diabetes was used to identify CKD self-management phenotypes based on measures of body mass index, diet, physical activity, blood pressure, smoking status, and hemoglobin A 1c concentration (if diabetic); Cox proportional hazards models. 3 identified phenotypes varied according to the extent of implementation of recommended CKD self-management behaviors: phenotype I characterized study participants with the most recommended behaviors; phenotype II, participants with a mixture of recommended and not recommended behaviors; and phenotype III, participants with minimal recommended behaviors. In multivariable-adjusted models for those with and without diabetes, phenotype III was strongly associated with CKD progression (HRs of 1.82 and 1.49), death (HRs of 1.95 and 4.14), and atherosclerotic events (HRs of 2.54 and 1.90; each P < 0.05). Phenotype II was associated with atherosclerotic events and death among those with and without diabetes. No consensus definition of CKD self-management; limited to baseline behavior data. There are potentially 3 CKD self-management behavior phenotypes that distinguish risk for clinical outcomes. These phenotypes may inform the development of studies and guidelines regarding optimal self-management. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Tracking footprints of artificial selection in the dog genome.

PubMed

Akey, Joshua M; Ruhe, Alison L; Akey, Dayna T; Wong, Aaron K; Connelly, Caitlin F; Madeoy, Jennifer; Nicholas, Thomas J; Neff, Mark W

2010-01-19

The size, shape, and behavior of the modern domesticated dog has been sculpted by artificial selection for at least 14,000 years. The genetic substrates of selective breeding, however, remain largely unknown. Here, we describe a genome-wide scan for selection in 275 dogs from 10 phenotypically diverse breeds that were genotyped for over 21,000 autosomal SNPs. We identified 155 genomic regions that possess strong signatures of recent selection and contain candidate genes for phenotypes that vary most conspicuously among breeds, including size, coat color and texture, behavior, skeletal morphology, and physiology. In addition, we demonstrate a significant association between HAS2 and skin wrinkling in the Shar-Pei, and provide evidence that regulatory evolution has played a prominent role in the phenotypic diversification of modern dog breeds. Our results provide a first-generation map of selection in the dog, illustrate how such maps can rapidly inform the genetic basis of canine phenotypic variation, and provide a framework for delineating the mechanistic basis of how artificial selection promotes rapid and pronounced phenotypic evolution.

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST).

PubMed

Sakic, Boris; Cooper, Marcella P A; Taylor, Sarah E; Stojanovic, Milica; Zagorac, Bosa; Kapadia, Minesh

2015-04-23

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of chronic CNS disorders, there is an increasing demand for murine models with high validity at the behavioral level. However, multiple pathogenic mechanisms and complex functional deficits often impose challenges to reliably measure and interpret behavior of chronically sick mice. Therefore, the assessment of peripheral pathology and a behavioral profile at several time points using a battery of tests are required. Video-tracking, behavioral spectroscopy, and remote acquisition of physiological measures are emerging technologies that allow for comprehensive, accurate, and unbiased behavioral analysis in a home-base-like setting. This report describes a refined phenotyping protocol, which includes a custom-made monitoring apparatus (Integrated Behavioral Station, INBEST) that focuses on prolonged measurements of basic functional outputs, such as spontaneous activity, food/water intake and motivated behavior in a relatively stress-free environment. Technical and conceptual improvements in INBEST design may further promote reproducibility and standardization of behavioral studies.

Identifying eating behavior phenotypes and their correlates: a novel direction toward improving weight management interventions

PubMed Central

Bouhlal, Sofia; McBride, Colleen M.; Trivedi, Niraj S.; Agurs-Collins, Tanya; Persky, Susan

2017-01-01

Common reports of over-response to food cues, difficulties with calorie restriction, and difficulty adhering to dietary guidelines suggest that eating behaviors could be interrelated in ways that influence weight management efforts. The feasibility of identifying robust eating phenotypes (showing face, content, and criterion validity) was explored based on well-validated individual eating behavior assessments. Adults (n=260; mean age 34 years) completed online questionnaires with measurements of nine eating behaviors including: appetite for palatable foods, binge eating, bitter taste sensitivity, disinhibition, food neophobia, pickiness and satiety responsiveness. Discovery-based visualization procedures that have the combined strengths of heatmaps and hierarchical clustering were used to investigate: 1) how eating behaviors cluster, 2) how participants can be grouped within eating behavior clusters, and 3) whether group clustering is associated with body mass index (BMI) and dietary self-efficacy levels. Two distinct eating behavior clusters and participant groups that aligned within these clusters were identified: one with higher drive to eat and another with food avoidance behaviors. Participants’ BMI (p=.0002) and dietary self-efficacy (p<.0001) were associated with cluster membership. Eating behavior clusters showed content and criterion validity based on their association with BMI (associated, but not entirely overlapping) and dietary self-efficacy. Identifying eating behavior phenotypes appears viable. These efforts could be expanded and ultimately inform tailored weight management interventions. PMID:28043857

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.

PubMed

Chaudhry, A; Noor, A; Degagne, B; Baker, K; Bok, L A; Brady, A F; Chitayat, D; Chung, B H; Cytrynbaum, C; Dyment, D; Filges, I; Helm, B; Hutchison, H T; Jeng, L J B; Laumonnier, F; Marshall, C R; Menzel, M; Parkash, S; Parker, M J; Raymond, L F; Rideout, A L; Roberts, W; Rupps, R; Schanze, I; Schrander-Stumpel, C T R M; Speevak, M D; Stavropoulos, D J; Stevens, S J C; Thomas, E R A; Toutain, A; Vergano, S; Weksberg, R; Scherer, S W; Vincent, J B; Carter, M T

2015-09-01

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty.

PubMed

Fountain, M D; Tao, H; Chen, C-A; Yin, J; Schaaf, C P

2017-07-01

MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome (PWS)-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wild-type (WT) allele and a paternally inherited Magel2-lacZ knock-in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader-Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity and reduced fertility. An extensive assessment for autism-like behaviors in this mouse model was warranted, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT littermates were assayed via open field, elevated plus maze, tube, three-chamber and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in-depth investigation of behavioral profiles caused by Magel2 loss-of-function helps to elucidate the etiology of behavioral phenotypes both for SHFYNG and PWS in general. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Deletion of Fmr1 results in sex-specific changes in behavior.

PubMed

Nolan, Suzanne O; Reynolds, Conner D; Smith, Gregory D; Holley, Andrew J; Escobar, Brianna; Chandler, Matthew A; Volquardsen, Megan; Jefferson, Taylor; Pandian, Ashvini; Smith, Tileena; Huebschman, Jessica; Lugo, Joaquin N

2017-10-01

In this study, we used a systemic Fmr1 knockout in order to investigate both genotype- and sex-specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear-related learning and memory. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes. Using wild-type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose-poke assay, accelerating rotarod, social partition task, three-chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects. Our results indicate several sex-specific changes in Fmr1 knockout mice, including male-specific increases in activity levels, and female-specific increases in repetitive behaviors on both the nose-poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks. These findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex-specific therapeutics.

Visual and acoustic components of courtship in the bird-of-paradise genus Astrapia (Aves: Paradisaeidae)

PubMed Central

Gillis, Julia M.; Laman, Timothy G.

2017-01-01

The distinctive and divergent courtship phenotypes of the birds-of-paradise make them an important group for gaining insights into the evolution of sexually selected phenotypic evolution. The genus Astrapia includes five long-tailed species that inhabit New Guinea’s montane forests. The visual and acoustic components of courtship among Astrapia species are very poorly known. In this study, we use audiovisual data from a natural history collection of animal behavior to fill gaps in knowledge about the visual and acoustic components of Astrapia courtship. We report seven distinct male behaviors and two female specific behaviors along with distinct vocalizations and wing-produced sonations for all five species. These results provide the most complete assessment of courtship in the genus Astrapia to date and provide a valuable baseline for future research, including comparative and evolutionary studies among these and other bird-of-paradise species. PMID:29134145

Mapping pathological phenotypes in a mouse model of CDKL5 disorder.

PubMed

Amendola, Elena; Zhan, Yang; Mattucci, Camilla; Castroflorio, Enrico; Calcagno, Eleonora; Fuchs, Claudia; Lonetti, Giuseppina; Silingardi, Davide; Vyssotski, Alexei L; Farley, Dominika; Ciani, Elisabetta; Pizzorusso, Tommaso; Giustetto, Maurizio; Gross, Cornelius T

2014-01-01

Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.

The Nutritional Phenotype in the Age of Metabolomics

PubMed Central

Zeisel, S. H.; Freake, H. C.; Bauman, D. E.; Bier, D. M.; Burrin, D. G.; German, J. B.; Klein, S.; Marquis, G. S.; Milner, J. A.; Pelto, G. H.; Rasmussen, K. M.

2008-01-01

The concept of the nutritional phenotype is proposed as a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status. The nutritional phenotype integrates the effects of diet on disease/wellness and is the quantitative indication of the paths by which genes and environment exert their effects on health. Advances in technology and in fundamental biological knowledge make it possible to define and measure the nutritional phenotype accurately in a cross section of individuals with various states of health and disease. This growing base of data and knowledge could serve as a resource for all scientific disciplines involved in human health. Nutritional sciences should be a prime mover in making key decisions that include: what environmental inputs (in addition to diet) are needed; what genes/proteins/metabolites should be measured; what end-point phenotypes should be included; and what informatics tools are available to ask nutritionally relevant questions. Nutrition should be the major discipline establishing how the elements of the nutritional phenotype vary as a function of diet. Nutritional sciences should also be instrumental in linking the elements that are responsive to diet with the functional outcomes in organisms that derive from them. As the first step in this initiative, a prioritized list of genomic, proteomic, and metabolomic as well as functional and behavioral measures that defines a practically useful subset of the nutritional phenotype for use in clinical and epidemiological investigations must be developed. From this list, analytic platforms must then be identified that are capable of delivering highly quantitative data on these endpoints. This conceptualization of a nutritional phenotype provides a concrete form and substance to the recognized future of nutritional sciences as a field addressing diet, integrated metabolism, and health. PMID:15987837

Animal biometrics: quantifying and detecting phenotypic appearance.

PubMed

Kühl, Hjalmar S; Burghardt, Tilo

2013-07-01

Animal biometrics is an emerging field that develops quantified approaches for representing and detecting the phenotypic appearance of species, individuals, behaviors, and morphological traits. It operates at the intersection between pattern recognition, ecology, and information sciences, producing computerized systems for phenotypic measurement and interpretation. Animal biometrics can benefit a wide range of disciplines, including biogeography, population ecology, and behavioral research. Currently, real-world applications are gaining momentum, augmenting the quantity and quality of ecological data collection and processing. However, to advance animal biometrics will require integration of methodologies among the scientific disciplines involved. Such efforts will be worthwhile because the great potential of this approach rests with the formal abstraction of phenomics, to create tractable interfaces between different organizational levels of life. Copyright © 2013 Elsevier Ltd. All rights reserved.

Advances in understanding behavioral phenotypes in neurogenetic syndromes.

PubMed

Harris, James C

2010-11-15

Syndrome-specific behavior was proposed by Langdon Down in his first clinical descriptions. Research interest followed but waned during the eugenics era when antisocial behavior was attributed to people with intellectual disability (ID) and the US Supreme Court legalized involuntary sterilization. When these claims were refuted and behavioral treatments introduced, their focus on environmental determination minimized the importance of biological research. The modern era began with the recognition that patterned behavior, for example, self-injury in Lesch-Nyhan syndrome and hyperphagia in PWS, was syndrome-specific, and when parent support groups pointed out syndrome-specific behavioral similarities in their children. Syndrome-specific rating scales and methodologies followed to allow behavioral comparisons between syndromes. The focus initially was on specific behaviors but with refinements in neuropsychological tests has expanded to include neurocognitive profiles. Greater clarification in genetic diagnoses has led to mutant mouse behavioral models and neurophysiologic and neuroimaging strategies have made possible the study of brain circuits. There is growing interest in investigating the developmental trajectory of behaviors from infancy to adulthood and old age. Because anxiety, mood disturbance, repetitive behaviors, and social deficits commonly occur in people with severe ID, those affected are often given multiple psychiatric diagnoses. This has led to considerable confusion in the literature. It is critical to focus on specific behaviors and cognitive patterns in research and not confuse psychiatric symptoms that lack precise definitions and involve multiple genes, the so-called psychiatric phenotype, with the more specific behavioral phenotype. New treatments based on knowledge of underlying neurobiology call for more fine-grained definition of behavior. © 2010 Wiley-Liss, Inc.

Collective Motion in Bacterial Populations with Mixed Phenotypic Behaviors

NASA Astrophysics Data System (ADS)

Hoeger, Kentaro; Strickland, Ben; Shoup, Daniel; Ursell, Tristan

The motion of large, densely packed groups of organisms is often qualitatively distinct from the motion of individuals, yet hinges on individual properties and behaviors. Collective motion of bacteria depends strongly on the phenotypic behaviors of individual cells, the physical interactions between cells, and the geometry of their environment, often with multiple phenotypes coexisting in a population. Thus, to characterize how these selectively important interactions affect group traits, such as cell dispersal, spatial segregation of phenotypes, and material transport in groups, we use a library of Bacillus subtilis mutants that modulate chemotaxis, motility, and biofilm formation. By mixing phenotypes and observing bacterial behaviors and motion at single cell resolution, we probe collective motion as a function of phenotypic mixture and environmental geometry. Our work demonstrates that collective microbial motion exhibits a transition, from `turbulence' to semiballistic burrowing, as phenotypic composition varies. This work illuminates the role that individual cell behaviors play in the emergence of collective motion, and may signal qualitatively distinct regimes of material transport in bacterial populations. University of Oregon.

Neuroendocrine-Immune Circuits, Phenotypes, and Interactions

PubMed Central

Ashley, Noah T.; Demas, Gregory E.

2016-01-01

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions. PMID:27765499

Neuroendocrine-immune circuits, phenotypes, and interactions.

PubMed

Ashley, Noah T; Demas, Gregory E

2017-01-01

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions. Copyright © 2016 Elsevier Inc. All rights reserved.

Identifying eating behavior phenotypes and their correlates: A novel direction toward improving weight management interventions.

PubMed

Bouhlal, Sofia; McBride, Colleen M; Trivedi, Niraj S; Agurs-Collins, Tanya; Persky, Susan

2017-04-01

Common reports of over-response to food cues, difficulties with calorie restriction, and difficulty adhering to dietary guidelines suggest that eating behaviors could be interrelated in ways that influence weight management efforts. The feasibility of identifying robust eating phenotypes (showing face, content, and criterion validity) was explored based on well-validated individual eating behavior assessments. Adults (n = 260; mean age 34 years) completed online questionnaires with measurements of nine eating behaviors including: appetite for palatable foods, binge eating, bitter taste sensitivity, disinhibition, food neophobia, pickiness and satiety responsiveness. Discovery-based visualization procedures that have the combined strengths of heatmaps and hierarchical clustering were used to investigate: 1) how eating behaviors cluster, 2) how participants can be grouped within eating behavior clusters, and 3) whether group clustering is associated with body mass index (BMI) and dietary self-efficacy levels. Two distinct eating behavior clusters and participant groups that aligned within these clusters were identified: one with higher drive to eat and another with food avoidance behaviors. Participants' BMI (p = 0.0002) and dietary self-efficacy (p < 0.0001) were associated with cluster membership. Eating behavior clusters showed content and criterion validity based on their association with BMI (associated, but not entirely overlapping) and dietary self-efficacy. Identifying eating behavior phenotypes appears viable. These efforts could be expanded and ultimately inform tailored weight management interventions. Published by Elsevier Ltd.

Behavioral Phenotyping Assays for Genetic Mouse Models of Neurodevelopmental, Neurodegenerative, and Psychiatric Disorders.

PubMed

Sukoff Rizzo, Stacey J; Crawley, Jacqueline N

2017-02-08

Animal models offer heuristic research tools to understand the causes of human diseases and to identify potential treatments. With rapidly evolving genetic engineering technologies, mutations identified in a human disorder can be generated in the mouse genome. Phenotypic outcomes of the mutation are then explicated to confirm hypotheses about causes and to discover effective therapeutics. Most neurodevelopmental, neurodegenerative, and psychiatric disorders are diagnosed primarily by their prominent behavioral symptoms. Mouse behavioral assays analogous to the human symptoms have been developed to analyze the consequences of mutations and to evaluate proposed therapeutics preclinically. Here we describe the range of mouse behavioral tests available in the established behavioral neuroscience literature, along with examples of their translational applications. Concepts presented have been successfully used in other species, including flies, worms, fish, rats, pigs, and nonhuman primates. Identical strategies can be employed to test hypotheses about environmental causes and gene × environment interactions.

Identifying Novel Phenotypes of Vulnerability and Resistance to Activity-Based Anorexia in Adolescent Female Rats

PubMed Central

Barbarich-Marsteller, Nicole C.; Underwood, Mark D.; Foltin, Richard W.; Myers, Michael M.; Walsh, B. Timothy; Barrett, Jeffrey S.; Marsteller, Douglas A.

2018-01-01

Objective Activity-based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self-starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats. Method Sprague-Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30–35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes. Results Objective criteria were identified for distinguishing novel phenotypes of activity-based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit. Discussion The identification of objective criteria for defining vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self-starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa. PMID:23853140

Identifying novel phenotypes of vulnerability and resistance to activity-based anorexia in adolescent female rats.

PubMed

Barbarich-Marsteller, Nicole C; Underwood, Mark D; Foltin, Richard W; Myers, Michael M; Walsh, B Timothy; Barrett, Jeffrey S; Marsteller, Douglas A

2013-11-01

Activity-based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self-starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats. Sprague-Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30-35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes. Objective criteria were identified for distinguishing novel phenotypes of activity-based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit. The identification of objective criteria for defining vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self-starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa. Copyright © 2013 Wiley Periodicals, Inc.

Have studies of the developmental regulation of behavioral phenotypes revealed the mechanisms of gene-environment interactions?

PubMed Central

Hall, F. Scott; Perona, Maria T. G.

2012-01-01

This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) is to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that are determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. PMID:22643448

Behavioral and physiological consequences of enrichment loss in rats

PubMed Central

Smith, Brittany L.; Lyons, Carey E; Correa, Fernanda Guilhaume; Benoit, Stephen C.; Myers, Brent; Solomon, Matia B.; Herman, James P.

2017-01-01

Significant loss produces the highest degree of stress and compromised well-being in humans. Current rodent models of stress involve the application of physically or psychologically aversive stimuli, but do not address the concept of loss. We developed a rodent model for significant loss, involving removal of long-term access to a rewarding enriched environment. Our results indicate that removal from environmental enrichment produces a profound behavioral and physiological phenotype with depression-like qualities, including helplessness behavior, hypothalamo-pituitary-adrenocortical axis dysregulation and overeating. Importantly, this enrichment removal phenotype was prevented by antidepressant treatment. Furthermore, the effects of enrichment removal do not occur following relief from chronic stress and are not duplicated by loss of exercise or social contact. PMID:28012292

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice.

PubMed

Alfieri, Julio A; Silva, Pablo R; Igaz, Lionel M

2016-01-01

Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). To investigate in depth the behavioral phenotype associated with this proteinopathy, we used as a model transgenic (Tg) mice conditionally overexpressing human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons. We previously characterized these mice at the neuropathological level and found progressive neurodegeneration and other features that evoke human TDP-43 proteinopathies of the FTD/ALS spectrum. In the present study we analyzed the behavior of mice at multiple domains, including motor, social and cognitive performance. Our results indicate that young hTDP-43-WT Tg mice (1 month after post-weaning transgene induction) present a normal motor phenotype compared to control littermates, as assessed by accelerated rotarod performance, spontaneous locomotor activity in the open field test and a mild degree of spasticity shown by a clasping phenotype. Analysis of social and cognitive behavior showed a rapid installment of deficits in social interaction, working memory (Y-maze test) and recognition memory (novel object recognition test) in the absence of overt motor abnormalities. To investigate if the motor phenotype worsen with age, we analyzed the behavior of mice after long-term (up to 12 months) transgene induction. Our results reveal a decreased performance on the rotarod test and in the hanging wire test, indicating a motor phenotype that was absent in younger mice. In addition, long-term hTDP-43-WT expression led to hyperlocomotion in the open field test. In sum, these results demonstrate a time-dependent emergence of a motor phenotype in older hTDP-43-WT Tg mice, recapitulating aspects of clinical FTD presentations with motor involvement in human patients, and providing a complementary animal model for studying TDP-43 proteinopathies.

Social Approach and Autistic Behavior in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Jane E.; Weisenfeld, Leigh Anne H.; Hatton, Deborah D.; Heath, Morgan; Kaufmann, Walter E.

2007-01-01

Social avoidance is a core phenotypic characteristic of fragile X syndrome (FXS) that has critical cognitive and social consequences. However, no study has examined modulation of multiple social avoidant behaviors in children with FXS. In the current study, we introduce the "Social Approach Scale" (SAS), an observation scale that includes physical…

Behavior of 10 patients with FG Syndrome (Opitz-Kaveggia Syndrome) and the p.R961W Mutation in the MED12 Gene

PubMed Central

Graham, John M; Visootsak, Jeannie; Dykens, Elisabeth; Huddleston, Lillie; Clark, Robin D; Jones, Kenneth L; Moeschler, John B; Opitz, John M; Morford, Jackie; Simensen, Richard; Rogers, R. Curtis; Schwartz, Charles E; Friez, Michael J; Stevenson, Roger E

2011-01-01

Opitz and Kaveggia [1974] reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus and hypotonia. Risheg et al. [2007] identified an identical mutation (p.R961W) in MED12 in six families with Opitz-Kaveggia syndrome, including a surviving affected man from the family reported in 1974. The previously defined behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with this mutation, along with socially oriented, attention-seeking behaviors. We present case studies of two older males with FG syndrome and the p.R961W mutation to illustrate how their behavior changes with age. We also characterize the behavior of eight additional individuals with FG syndrome and this recurrent mutation in MED12 using the Vineland Adaptive Behavior Scales 2nd ed., the Reiss Profile of Fundamental Goals and Motivation Sensitivities, and the Achenbach Child Behavior Checklist. Males with this MED12 mutation had deficits in communication skills compared to their socialization and daily living skills. In addition, they were at increased risk for maladaptive behavior, with a propensity towards aggression, anxiety, and inattention. Based on the behavior phenotype in 10 males with this recurrent MED12 mutation, we offer specific recommendations and interventional strategies. Our findings reinforce the importance of testing for the p.R961W MED12 mutation in males who are suspected of having developmental and behavioral problems with a clinical phenotype that is consistent with FG syndrome. PMID:18973276

Genetic association of impulsivity in young adults: a multivariate study

PubMed Central

Khadka, S; Narayanan, B; Meda, S A; Gelernter, J; Han, S; Sawyer, B; Aslanzadeh, F; Stevens, M C; Hawkins, K A; Anticevic, A; Potenza, M N; Pearlson, G D

2014-01-01

Impulsivity is a heritable, multifaceted construct with clinically relevant links to multiple psychopathologies. We assessed impulsivity in young adult (N~2100) participants in a longitudinal study, using self-report questionnaires and computer-based behavioral tasks. Analysis was restricted to the subset (N=426) who underwent genotyping. Multivariate association between impulsivity measures and single-nucleotide polymorphism data was implemented using parallel independent component analysis (Para-ICA). Pathways associated with multiple genes in components that correlated significantly with impulsivity phenotypes were then identified using a pathway enrichment analysis. Para-ICA revealed two significantly correlated genotype–phenotype component pairs. One impulsivity component included the reward responsiveness subscale and behavioral inhibition scale of the Behavioral-Inhibition System/Behavioral-Activation System scale, and the second impulsivity component included the non-planning subscale of the Barratt Impulsiveness Scale and the Experiential Discounting Task. Pathway analysis identified processes related to neurogenesis, nervous system signal generation/amplification, neurotransmission and immune response. We identified various genes and gene regulatory pathways associated with empirically derived impulsivity components. Our study suggests that gene networks implicated previously in brain development, neurotransmission and immune response are related to impulsive tendencies and behaviors. PMID:25268255

Redefining Aging in HIV Infection Using Phenotypes.

PubMed

Stoff, David M; Goodkin, Karl; Jeste, Dilip; Marquine, Maria

2017-10-01

This article critically reviews the utility of "phenotypes" as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging. The main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited. Three paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths.

The Effect of Otolith Malformation on Behavior and Cortisol Levels in Juvenile Red Drum Fish (Sciaenops ocellatus)

PubMed Central

Browning, Zoe S; Wilkes, Allison A; Moore, Erica J; Lancon, Trevor W; Clubb, Fred J

2012-01-01

Captive-raised red drum fish were observed with phenotypic abnormalities, including deformities of the spine, jaw, and cephalic region, that were consistent with vitamin C deficiency during the larval stage. In light of their visible exterior skeletal abnormalities, we suspected that the affected fish would also have abnormal otoliths. Otoliths are dense calcareous structures that function in fish hearing. We hypothesized that abnormal fish would have irregular otoliths that would alter behavior and cortisol levels as compared with those of phenotypically normal fish. The normal and abnormal fish had statistically significant differences in behavior, cortisol levels, and otolith volume and density. MicroCT assessment of abnormal fish revealed operculum abnormalities, malocclusions, and several types of otolith malformations. Therefore, the affected fish had not only an abnormal skeletal appearance but also significantly abnormal behavior and cortisol responses. PMID:23043776

Cross-fostering: Elucidating the effects of gene×environment interactions on phenotypic development.

PubMed

McCarty, Richard

2017-02-01

Cross-fostering of litters from soon after birth until weaning is a valuable tool to study the ways in which gene×environment interactions program the development of neural, physiological and behavioral characteristics of mammalian species. In laboratory mice and rats, the primary focus of this review, cross-fostering of litters between mothers of different strains or treatment groups (intraspecific) or between mothers of different species (interspecific) has been conducted over the past 9 decades. Areas of particular interest have included maternal effects on emotionality, social preferences, responses to stressful stimulation, nutrition and growth, blood pressure regulation, and epigenetic effects on brain development and behavior. Results from these areas of research highlight the critical role of the postnatal maternal environment in programming the development of offspring phenotypic characteristics. In addition, experimental paradigms that have included cross-fostering have permitted investigators to tease apart prenatal versus postnatal effects of various treatments on offspring development and behavior. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mapping Pathological Phenotypes in a Mouse Model of CDKL5 Disorder

PubMed Central

Amendola, Elena; Zhan, Yang; Mattucci, Camilla; Castroflorio, Enrico; Calcagno, Eleonora; Fuchs, Claudia; Lonetti, Giuseppina; Silingardi, Davide; Vyssotski, Alexei L.; Farley, Dominika; Ciani, Elisabetta; Pizzorusso, Tommaso; Giustetto, Maurizio; Gross, Cornelius T.

2014-01-01

Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder. PMID:24838000

Neurobehavioral phenotype in Prader-Willi syndrome.

PubMed

Whittington, Joyce; Holland, Anthony

2010-11-15

The focus of this article is on the lifetime development of people with Prader-Willi syndrome (PWS) and specifically on the neurobehavioral phenotype. We consider studies of this aspect of the phenotype (the "behavioral phenotype" of the syndrome) that have confirmed that there are specific behaviors and psychiatric disorders, the propensities to which are increased in those with PWS, and cannot be accounted for by other variables such as IQ or adaptive behavior. Beginning with a description of what is observed in people with PWS, we review the evolving PWS phenotype and consider how some aspects of the phenotype might be best explained, and how this complex phenotype may relate to the equally complex genotype. We then consider in more detail some of the neurobehavioral aspects of the phenotype listed above that raise the greatest management problems for parents and carers. © 2010 Wiley-Liss, Inc.

Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome1,2,3

PubMed Central

Dinday, Matthew T.

2015-01-01

Abstract Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy. PMID:26465006

Gene Mutations and Genomic Rearrangements in the Mouse as a Result of Transposon Mobilization from Chromosomal Concatemers

PubMed Central

Geurts, Aron M; Collier, Lara S; Geurts, Jennifer L; Oseth, Leann L; Bell, Matthew L; Mu, David; Lucito, Robert; Godbout, Susan A; Green, Laura E; Lowe, Scott W; Hirsch, Betsy A; Leinwand, Leslie A; Largaespada, David A

2006-01-01

Previous studies of the Sleeping Beauty (SB) transposon system, as an insertional mutagen in the germline of mice, have used reverse genetic approaches. These studies have led to its proposed use for regional saturation mutagenesis by taking a forward-genetic approach. Thus, we used the SB system to mutate a region of mouse Chromosome 11 in a forward-genetic screen for recessive lethal and viable phenotypes. This work represents the first reported use of an insertional mutagen in a phenotype-driven approach. The phenotype-driven approach was successful in both recovering visible and behavioral mutants, including dominant limb and recessive behavioral phenotypes, and allowing for the rapid identification of candidate gene disruptions. In addition, a high frequency of recessive lethal mutations arose as a result of genomic rearrangements near the site of transposition, resulting from transposon mobilization. The results suggest that the SB system could be used in a forward-genetic approach to recover interesting phenotypes, but that local chromosomal rearrangements should be anticipated in conjunction with single-copy, local transposon insertions in chromosomes. Additionally, these mice may serve as a model for chromosome rearrangements caused by transposable elements during the evolution of vertebrate genomes. PMID:17009875

Repetitive Self-Grooming Behavior in the BTBR Mouse Model of Autism is Blocked by the mGluR5 Antagonist MPEP

PubMed Central

Silverman, Jill L; Tolu, Seda S; Barkan, Charlotte L; Crawley, Jacqueline N

2010-01-01

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated deficits in reciprocal social interactions and social approach, unusual patterns of ultrasonic vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays for translational investigations of pharmacological compounds. Two suggested treatments for autism were evaluated in the BTBR mouse model. Methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, blocks aberrant phenotypes in the Fmr1 mouse model of Fragile X, a comorbid neurodevelopmental disorder with autistic features. Risperidone has been approved by the United States Food and Drug Administration for the treatment of irritability, tantrums, and self-injurious behavior in autistic individuals. We evaluated the actions of MPEP and risperidone on two BTBR phenotypes, low sociability and high repetitive self-grooming. Open field activity served as an independent control for non-social exploratory activity and motor functions. C57BL/6J (B6), an inbred strain with high sociability and low self-grooming, served as the strain control. MPEP significantly reduced repetitive self-grooming in BTBR, at doses that had no sedating effects on open field activity. Risperidone reduced repetitive self-grooming in BTBR, but only at doses that induced sedation in both strains. No overall improvements in sociability were detected in BTBR after treatment with either MPEP or risperidone. Our findings suggest that antagonists of mGluR5 receptors may have selective therapeutic efficacy in treating repetitive behaviors in autism. PMID:20032969

Using Machine Learning to Discover Latent Social Phenotypes in Free-Ranging Macaques

PubMed Central

Madlon-Kay, Seth; Brent, Lauren J. N.; Heller, Katherine A.; Platt, Michael L.

2017-01-01

Investigating the biological bases of social phenotypes is challenging because social behavior is both high-dimensional and richly structured, and biological factors are more likely to influence complex patterns of behavior rather than any single behavior in isolation. The space of all possible patterns of interactions among behaviors is too large to investigate using conventional statistical methods. In order to quantitatively define social phenotypes from natural behavior, we developed a machine learning model to identify and measure patterns of behavior in naturalistic observational data, as well as their relationships to biological, environmental, and demographic sources of variation. We applied this model to extensive observations of natural behavior in free-ranging rhesus macaques, and identified behavioral states that appeared to capture periods of social isolation, competition over food, conflicts among groups, and affiliative coexistence. Phenotypes, represented as the rate of being in each state for a particular animal, were strongly and broadly influenced by dominance rank, sex, and social group membership. We also identified two states for which variation in rates had a substantial genetic component. We discuss how this model can be extended to identify the contributions to social phenotypes of particular genetic pathways. PMID:28754001

Heterozygous Ambra1 Deficiency in Mice: A Genetic Trait with Autism-Like Behavior Restricted to the Female Gender

PubMed Central

Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

2014-01-01

Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1+/− females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1+/− mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1+/− females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation. PMID:24904333

Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.

PubMed

Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

2014-01-01

Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

Deletion 1q43 encompassing only CHRM3 in a patient with autistic disorder.

PubMed

Petersen, Andrea Klunder; Ahmad, Ausaf; Shafiq, Mustafa; Brown-Kipphut, Brigette; Fong, Chin-To; Anwar Iqbal, M

2013-02-01

Deletions on the distal portion of the long arm of chromosome 1 result in complex and highly variable clinical phenotypes which include intellectual disability, autism, seizures, microcephaly/craniofacial dysmorphology, corpus callosal agenesis/hypogenesis, cardiac and genital anomalies, hand and foot abnormalities and short stature. Genotype-phenotype correlation reported a minimum region of 2 Mb at 1q43-q44. We report on a 3 ½ year old male patient diagnosed with autistic disorder who has social withdrawal, eating problems, repetitive stereotypic behaviors including self-injurious head banging and hair pulling, and no seizures, anxiety, or mood swings. Array comparative genomic hybridization (aCGH) showed an interstitial deletion of 473 kb at 1q43 region (239,412,391-239,885,394; NCBI build37/hg19) harboring only CHRM3 (Acetylcholine Receptor, Muscarinic, 3; OMIM: 118494). Recently, another case with a de novo interstitial deletion of 911 kb at 1q43 encompassing three genes including CHRM3 was reported. The M3 muscarinic receptor influences a multitude of central and peripheral nervous system processes via its interaction with acetylcholine and may be an important modulator of behavior, learning and memory. We propose CHRM3 as a candidate gene responsible for our patient's specific phenotype as well as the overlapping phenotypic features of other patients with 1q43 or 1q43-q44 deletions. Copyright © 2013. Published by Elsevier Masson SAS.

A dictionary of behavioral motifs reveals clusters of genes affecting Caenorhabditis elegans locomotion.

PubMed

Brown, André E X; Yemini, Eviatar I; Grundy, Laura J; Jucikas, Tadas; Schafer, William R

2013-01-08

Visible phenotypes based on locomotion and posture have played a critical role in understanding the molecular basis of behavior and development in Caenorhabditis elegans and other model organisms. However, it is not known whether these human-defined features capture the most important aspects of behavior for phenotypic comparison or whether they are sufficient to discover new behaviors. Here we show that four basic shapes, or eigenworms, previously described for wild-type worms, also capture mutant shapes, and that this representation can be used to build a dictionary of repetitive behavioral motifs in an unbiased way. By measuring the distance between each individual's behavior and the elements in the motif dictionary, we create a fingerprint that can be used to compare mutants to wild type and to each other. This analysis has revealed phenotypes not previously detected by real-time observation and has allowed clustering of mutants into related groups. Behavioral motifs provide a compact and intuitive representation of behavioral phenotypes.

Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model.

PubMed

Zeidler, Shimriet; Pop, Andreea S; Jaafar, Israa A; de Boer, Helen; Buijsen, Ronald A M; de Esch, Celine E F; Nieuwenhuizen-Bakker, Ingeborg; Hukema, Renate K; Willemsen, Rob

2018-06-01

Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABA B agonists. As FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABA B agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three-chamber sociability test. Unexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild-type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice. Altogether, the disappointing results of recent clinical trials with the R-baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Emergent cell and tissue dynamics from subcellular modeling of active biomechanical processes

NASA Astrophysics Data System (ADS)

Sandersius, S. A.; Weijer, C. J.; Newman, T. J.

2011-08-01

Cells and the tissues they form are not passive material bodies. Cells change their behavior in response to external biochemical and biomechanical cues. Behavioral changes, such as morphological deformation, proliferation and migration, are striking in many multicellular processes such as morphogenesis, wound healing and cancer progression. Cell-based modeling of these phenomena requires algorithms that can capture active cell behavior and their emergent tissue-level phenotypes. In this paper, we report on extensions of the subcellular element model to model active biomechanical subcellular processes. These processes lead to emergent cell and tissue level phenotypes at larger scales, including (i) adaptive shape deformations in cells responding to slow stretching, (ii) viscous flow of embryonic tissues, and (iii) streaming patterns of chemotactic cells in epithelial-like sheets. In each case, we connect our simulation results to recent experiments.

Putting prey back together again: integrating predator-induced behavior, morphology, and life history.

PubMed

Hoverman, Jason T; Auld, Josh R; Relyea, Rick A

2005-07-01

The last decade has seen an explosion in the number of studies exploring predator-induced plasticity. Recently, there has been a call for more comprehensive approaches that can identify functional relationships between traits, constraints on phenotypic responses, and the cost and benefits of alternative phenotypes. In this study, we exposed Helisoma trivolvis, a freshwater snail, to a factorial combination of three resource levels and five predator environments (no predator, one or two water bugs, and one or two crayfish) and examined ten traits including behavior, morphology, and life history. Each predator induced a unique suite of behavioral and morphological responses. Snails increased near-surface habitat use with crayfish but not with water bugs. Further, crayfish induced narrow and high shells whereas water bugs induced wide shells and wide apertures. In terms of life history, both predators induced delayed reproduction and greater mass at reproduction. However, crayfish induced a greater delay in reproduction that resulted in reduced fecundity whereas water bugs did not induce differences in fecundity. Resource levels impacted the morphology of H. trivolvis; snails reared with greater resource levels produced higher shells, narrower shells, and wider apertures. Resource levels also impacted snail life history; lower resources caused longer times to reproduction and reduced fecundity. Based on an analysis of phenotypic correlations, the morphological responses to each predator most likely represent phenotypic trade-offs. Snails could either produce invasion-resistant shells for defense against water bugs or crush-resistant shells for defense against crayfish, but not both. Our use of a comprehensive approach to examine the responses of H. trivolvis has provided important information regarding the complexity of phenotypic responses to different environments, the patterns of phenotypic integration across environments, and the potential costs and benefits associated with plastic traits.

Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.

PubMed

Kalueff, A V; Fox, M A; Gallagher, P S; Murphy, D L

2007-06-01

Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.

Targeting Neural Endophenotypes of Eating Disorders with Non-invasive Brain Stimulation

PubMed Central

Dunlop, Katharine A.; Woodside, Blake; Downar, Jonathan

2016-01-01

The term “eating disorders” (ED) encompasses a wide variety of disordered eating and compensatory behaviors, and so the term is associated with considerable clinical and phenotypic heterogeneity. This heterogeneity makes optimizing treatment techniques difficult. One class of treatments is non-invasive brain stimulation (NIBS). NIBS, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), are accessible forms of neuromodulation that alter the cortical excitability of a target brain region. It is crucial for NIBS to be successful that the target is well selected for the patient population in question. Targets may best be selected by stepping back from conventional DSM-5 diagnostic criteria to identify neural substrates of more basic phenotypes, including behavior related to rewards and punishment, cognitive control, and social processes. These phenotypic dimensions have been recently laid out by the Research Domain Criteria (RDoC) initiative. Consequently, this review is intended to identify potential dimensions as outlined by the RDoC and the underlying behavioral and neurobiological targets associated with ED. This review will also identify candidate targets for NIBS based on these dimensions and review the available literature on rTMS and tDCS in ED. This review systematically reviews abnormal neural circuitry in ED within the RDoC framework, and also systematically reviews the available literature investigating NIBS as a treatment for ED. PMID:26909013

Genetic Variability of Smoking Persistence in African Americans

PubMed Central

Hamidovic, A; Kasberger, J; Young, T; Goodloe, R; Redline, S; Buxbaum, S; Benowitz, N; Bergen, A; Butler, K; Franceschini, N; Gharib, S; Hitsman, B; Levy, D; Meng, Y; Papanicolaou, G; Preiss, S; Spring, B; Styn, M; Tong, E; White, W; Wiggins, K; Jorgenson, E

2011-01-01

To date, most genetic association analyses of smoking behaviors have been conducted in populations of European ancestry and many of these studies focused on the phenotype that measures smoking quantity, i.e. cigarettes per day. Additional association studies in diverse populations with different linkage disequilibrium (LD) patterns and an alternate phenotype, such as total tobacco exposure which accounts for intermittent periods of smoking cessation within a larger smoking period as measured in large cardiovascular risk studies, can aid the search for variants relevant to smoking behavior. For these reasons, we undertook an association analysis using a genotyping array that includes 2100 genes to analyze smoking persistence in unrelated African-American participants from The Atherosclerosis Risk in Communities (ARIC) study. A locus located ~ 4 Kb downstream from the 3’ UTR of the Brain-Derived Neurotrophic Factor (BDNF) significantly influenced smoking persistence. In addition, independent variants rs12915366 and rs12914385 in the cluster of genes encoding nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4) on 15q25.1 were also associated with the phenotype in this sample of African American subjects. To our knowledge, this is the first study to more extensively evaluate the genome in the African American population as a limited number of previous studies of smoking behavior in this population included evaluations of only single genomic regions. PMID:21436384

Deconstructing Memory in Drosophila

PubMed Central

Margulies, Carla; Tully, Tim; Dubnau, Josh

2011-01-01

Unlike most organ systems, which have evolved to maintain homeostasis, the brain has been selected to sense and adapt to environmental stimuli by constantly altering interactions in a gene network that functions within a larger neural network. This unique feature of the central nervous system provides a remarkable plasticity of behavior, but also makes experimental investigations challenging. Each experimental intervention ramifies through both gene and neural networks, resulting in unpredicted and sometimes confusing phenotypic adaptations. Experimental dissection of mechanisms underlying behavioral plasticity ultimately must accomplish an integration across many levels of biological organization, including genetic pathways acting within individual neurons, neural network interactions which feed back to gene function, and phenotypic observations at the behavioral level. This dissection will be more easily accomplished for model systems such as Drosophila, which, compared with mammals, have relatively simple and manipulable nervous systems and genomes. The evolutionary conservation of behavioral phenotype and the underlying gene function ensures that much of what we learn in such model systems will be relevant to human cognition. In this essay, we have not attempted to review the entire Drosophila memory field. Instead, we have tried to discuss particular findings that provide some level of intellectual synthesis across three levels of biological organization: behavior, neural circuitry and biochemical pathways. We have attempted to use this integrative approach to evaluate distinct mechanistic hypotheses, and to propose critical experiments that will advance this field. PMID:16139203

GAL3 receptor KO mice exhibit an anxiety-like phenotype

PubMed Central

Brunner, Susanne M.; Farzi, Aitak; Locker, Felix; Holub, Barbara S.; Drexel, Meinrad; Reichmann, Florian; Lang, Andreas A.; Mayr, Johannes A.; Vilches, Jorge J.; Navarro, Xavier; Lang, Roland; Sperk, Günther; Holzer, Peter; Kofler, Barbara

2014-01-01

The neuropeptide galanin (GAL) is widely distributed in the central and peripheral nervous systems. It is a modulator of various physiological and pathological processes, and it mediates its effects via three G protein-coupled receptors (GAL1–3 receptors). A role for GAL as a modulator of mood and anxiety was suggested, because GAL and its receptors are highly expressed in limbic brain structures of rodents. In recent years, numerous studies of animal models have suggested an involvement of GAL and GAL1 and GAL2 receptors in anxiety- and depression-related behavior. However, to date, there is sparse literature implicating GAL3 receptors in behavioral functions. Therefore, we studied the behavior of GAL3 receptor-deficient (GAL3-KO) mice to elucidate whether GAL3 receptors are involved in mediating behavior-associated actions of GAL. The GAL3-KO mouse line exhibited normal breeding and physical development. In addition to behavioral tests, phenotypic characterization included analysis of hematology, amino acid profiles, metabolism, and sudomotor function. In contrast to WT littermates, male GAL3-KO mice exhibited an anxiety-like phenotype in the elevated plus maze, open field, and light/dark box tests, and they were less socially affiliated than WT animals to a stranger mouse in a social interaction test. In conclusion, our data suggest involvement of GAL3 receptors in GAL-mediated effects on mood, anxiety, and behavior, making it a possible target for alternative treatment strategies for mood disorders. PMID:24782539

Analyzing gene expression data in mice with the Neuro Behavior Ontology.

PubMed

Hoehndorf, Robert; Hancock, John M; Hardy, Nigel W; Mallon, Ann-Marie; Schofield, Paul N; Gkoutos, Georgios V

2014-02-01

We have applied the Neuro Behavior Ontology (NBO), an ontology for the annotation of behavioral gene functions and behavioral phenotypes, to the annotation of more than 1,000 genes in the mouse that are known to play a role in behavior. These annotations can be explored by researchers interested in genes involved in particular behaviors and used computationally to provide insights into the behavioral phenotypes resulting from differences in gene expression. We developed the OntoFUNC tool and have applied it to enrichment analyses over the NBO to provide high-level behavioral interpretations of gene expression datasets. The resulting increase in the number of gene annotations facilitates the identification of behavioral or neurologic processes by assisting the formulation of hypotheses about the relationships between gene, processes, and phenotypic manifestations resulting from behavioral observations.

Behavioral Genetic Toolkits: Toward the Evolutionary Origins of Complex Phenotypes.

PubMed

Rittschof, C C; Robinson, G E

2016-01-01

The discovery of toolkit genes, which are highly conserved genes that consistently regulate the development of similar morphological phenotypes across diverse species, is one of the most well-known observations in the field of evolutionary developmental biology. Surprisingly, this phenomenon is also relevant for a wide array of behavioral phenotypes, despite the fact that these phenotypes are highly complex and regulated by many genes operating in diverse tissues. In this chapter, we review the use of the toolkit concept in the context of behavior, noting the challenges of comparing behaviors and genes across diverse species, but emphasizing the successes in identifying genetic toolkits for behavior; these successes are largely attributable to the creative research approaches fueled by advances in behavioral genomics. We have two general goals: (1) to acknowledge the groundbreaking progress in this field, which offers new approaches to the difficult but exciting challenge of understanding the evolutionary genetic basis of behaviors, some of the most complex phenotypes known, and (2) to provide a theoretical framework that encompasses the scope of behavioral genetic toolkit studies in order to clearly articulate the research questions relevant to the toolkit concept. We emphasize areas for growth and highlight the emerging approaches that are being used to drive the field forward. Behavioral genetic toolkit research has elevated the use of integrative and comparative approaches in the study of behavior, with potentially broad implications for evolutionary biologists and behavioral ecologists alike. © 2016 Elsevier Inc. All rights reserved.

Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants.

PubMed

Diaz, Silvina Laura; Narboux-Nême, Nicolas; Boutourlinsky, Katia; Doly, Stéphane; Maroteaux, Luc

2016-02-01

Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr(2B)(-/-)), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr(2B)(-/-) mice. We find, here, that Htr(2B)(-/-) mice display an antidepressant-like phenotype, which includes reduced latency to feed in the novelty suppressed feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr(2B)(+/+)) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr(2B)(-/-) mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr(2B)(-/-) mice and similarly no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model displaying panoply of conditions among which behavioral, neurotrophic and plastic causative factors can be analyzed. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

The effects of disturbance threat on leaf-cutting ant colonies: a laboratory study.

PubMed

Norman, V C; Pamminger, T; Hughes, W O H

2017-01-01

The flexibility of organisms to respond plastically to their environment is fundamental to their fitness and evolutionary success. Social insects provide some of the most impressive examples of plasticity, with individuals exhibiting behavioral and sometimes morphological adaptations for their specific roles in the colony, such as large soldiers for nest defense. However, with the exception of the honey bee model organism, there has been little investigation of the nature and effects of environmental stimuli thought to instigate alternative phenotypes in social insects. Here, we investigate the effect of repeated threat disturbance over a prolonged (17 month) period on both behavioral and morphological phenotypes, using phenotypically plastic leaf-cutting ants ( Atta colombica ) as a model system. We found a rapid impact of threat disturbance on the behavioral phenotype of individuals within threat-disturbed colonies becoming more aggressive, threat responsive, and phototactic within as little as 2 weeks. We found no effect of threat disturbance on morphological phenotypes, potentially, because constraints such as resource limitation outweighed the benefit for colonies of producing larger individuals. The results suggest that plasticity in behavioral phenotypes can enable insect societies to respond to threats even when constraints prevent alteration of morphological phenotypes.

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

PubMed Central

Sauer, Aisha V.; Hernandez, Raisa Jofra; Fumagalli, Francesca; Bianchi, Veronica; Poliani, Pietro L.; Dallatomasina, Chiara; Riboni, Elisa; Politi, Letterio S.; Tabucchi, Antonella; Carlucci, Filippo; Casiraghi, Miriam; Carriglio, Nicola; Cominelli, Manuela; Forcellini, Carlo Alberto; Barzaghi, Federica; Ferrua, Francesca; Minicucci, Fabio; Medaglini, Stefania; Leocani, Letizia; la Marca, Giancarlo; Notarangelo, Lucia D.; Azzari, Chiara; Comi, Giancarlo; Baldoli, Cristina; Canale, Sabrina; Sessa, Maria; D’Adamo, Patrizia; Aiuti, Alessandro

2017-01-01

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency. PMID:28074903

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

PubMed

Sauer, Aisha V; Hernandez, Raisa Jofra; Fumagalli, Francesca; Bianchi, Veronica; Poliani, Pietro L; Dallatomasina, Chiara; Riboni, Elisa; Politi, Letterio S; Tabucchi, Antonella; Carlucci, Filippo; Casiraghi, Miriam; Carriglio, Nicola; Cominelli, Manuela; Forcellini, Carlo Alberto; Barzaghi, Federica; Ferrua, Francesca; Minicucci, Fabio; Medaglini, Stefania; Leocani, Letizia; la Marca, Giancarlo; Notarangelo, Lucia D; Azzari, Chiara; Comi, Giancarlo; Baldoli, Cristina; Canale, Sabrina; Sessa, Maria; D'Adamo, Patrizia; Aiuti, Alessandro

2017-01-11

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.

Effect of phenotype on health care costs in Crohn's disease: A European study using the Montreal classification.

PubMed

Odes, Selwyn; Vardi, Hillel; Friger, Michael; Wolters, Frank; Hoie, Ole; Moum, Bjørn; Bernklev, Tomm; Yona, Hagit; Russel, Maurice; Munkholm, Pia; Langholz, Ebbe; Riis, Lene; Politi, Patrizia; Bondini, Paolo; Tsianos, Epameinondas; Katsanos, Kostas; Clofent, Juan; Vermeire, Severine; Freitas, João; Mouzas, Iannis; Limonard, Charles; O'Morain, Colm; Monteiro, Estela; Fornaciari, Giovanni; Vatn, Morten; Stockbrugger, Reinhold

2007-12-01

Crohn's disease (CD) is a chronic inflammation of the gastrointestinal tract associated with life-long high health care costs. We aimed to determine the effect of disease phenotype on cost. Clinical and economic data of a community-based CD cohort with 10-year follow-up were analyzed retrospectively in relation to Montreal classification phenotypes. In 418 patients, mean total costs of health care for the behavior phenotypes were: nonstricturing-nonpenetrating 1690, stricturing 2081, penetrating 3133 and penetrating-with-perianal-fistula 3356 €/patient-phenotype-year (P<0.001), and mean costs of surgical hospitalization 215, 751, 1293 and 1275 €/patient-phenotype-year respectively (P<0.001). Penetrating-with-perianal-fistula patients incurred significantly greater expenses than penetrating patients for total care, diagnosis and drugs, but not surgical hospitalization. Total costs were similar in the location phenotypes: ileum 1893, colon 1748, ileo-colonic 2010 and upper gastrointestinal tract 1758 €/patient-phenotype-year, but surgical hospitalization costs differed significantly, 558, 209, 492 and 542 €/patient-phenotype-year respectively (P<0.001). By multivariate analysis, the behavior phenotype significantly impacted total, medical and surgical hospitalization costs, whereas the location phenotype affected only surgical costs. Younger age at diagnosis predicted greater surgical expenses. Behavior is the dominant phenotype driving health care cost. Use of the Montreal classification permits detection of cost differences caused by perianal fistula.

Behavior in Prader-Willi syndrome: relationship to genetic subtypes and age.

PubMed

Dykens, Elisabeth M; Roof, Elizabeth

2008-09-01

Some behavioral features of Prader-Willi syndrome (PWS) are associated with the major genetic subtypes of this disorder. While most agree that those with maternal uniparental disomy (UPD) have a distinctive cognitive and psychiatric profile, findings are more controversial regarding possible differences among persons who vary in paternal deletion size. Caregivers of 88 persons with PWS aged 5 to 51 years (M = 22 years) were administered measures of problem behavior, compulsivity, hyperphagia, and adaptive skills. The sample was well characterized as having relatively large, Type I (n = 26) or smaller, Type II (n = 29) deletions, or UPD (n = 33). No significant behavioral differences were found between the Type I versus Type II deletion groups. Within each genetic subtype, however, differences emerged in how advancing age related to behavior. Although age did not emerge as a significant correlate of behavior in the Type II or UPD groups, in the Type I group age was consistently associated with lower problem behaviors, adaptive skills, and externalizing symptoms. Although differences between deletion subtypes were not found, significant within-subtype differences emerged in relationships between age and behavior. Negative associations between age and behavior in the Type I group only may relate to non-imprinted genes that are deleted in Type I but not Type II cases, including CYFIP1. Altered expression of CYFIP1 is seen in other developmental disabilities, including 15q disorders, and haploinsufficiency of CYFIP1 in Type I PWS cases may be associated with age-related phenotypic effects. Findings underscore the importance of a life-span perspective in phenotypic research.

Repint of "Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity".

PubMed

Tordjman, S; Cohen, D; Anderson, G M; Botbol, M; Canitano, R; Coulon, N; Roubertoux, P L

2018-06-01

Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism. Copyright © 2018. Published by Elsevier Ltd.

Appetitive behavior, compulsivity, and neurochemistry in Prader-Willi syndrome.

PubMed

Dimitropoulos, A; Feurer, I D; Roof, E; Stone, W; Butler, M G; Sutcliffe, J; Thompson, T

2000-01-01

Advances in genetic research have led to an increased understanding of genotype-phenotype relationships. Excessive eating and weight gain characteristic of Prader-Willi syndrome (PWS) have been the understandable focus of much of the research. The intense preoccupation with food, lack of satiation, and incessant food seeking are among the most striking features of PWS. It has become increasingly clear that the behavioral phenotype of PWS also includes symptoms similar to obsessive compulsive disorder, which in all probability interact with the incessant hunger and lack of satiation to engender the intense preoccupation and food seeking behavior that is characteristic of this disorder. Several lines of evidence suggest that genetic material on chromosome 15 may alter synthesis, release, metabolism, binding, intrinsic activity, or reuptake of specific neurotransmitters, or alter the receptor numbers and/or distribution involved in modulating feeding. Among the likely candidates are GABAnergic, serotonergic, and neuropeptidergic mechanisms. This review summarizes what is known about the appetitive behavior and compulsivity in PWS and discusses the possible mechanisms underlying these behaviors. MRDD Research Reviews 2000;6:125-130. Copyright 2000 Wiley-Liss, Inc.

Behavior change is not one size fits all: psychosocial phenotypes of childhood obesity prevention intervention participants.

PubMed

Burgermaster, Marissa; Contento, Isobel; Koch, Pamela; Mamykina, Lena

2018-01-17

Variability in individuals' responses to interventions may contribute to small average treatment effects of childhood obesity prevention interventions. But, neither the causes of this individual variability nor the mechanism by which it influences behavior are clear. We used qualitative methods to characterize variability in students' responses to participating in a childhood obesity prevention intervention and psychosocial characteristics related to the behavior change process. We interviewed 18 students participating in a school-based curriculum and policy behavior change intervention. Descriptive coding, summary, and case-ordered descriptive meta-matrices were used to group participants by their psychosocial responses to the intervention and associated behavior changes. Four psychosocial phenotypes of responses emerged: (a) Activated-successful behavior-changers with strong internal supports; (b) Inspired-motivated, but not fully successful behavior-changers with some internal supports, whose taste preferences and food environment overwhelmed their motivation; (c) Reinforced-already practiced target behaviors, were motivated, and had strong family support; and (d) Indifferent-uninterested in behavior change and only did target behaviors if family insisted. Our findings contribute to the field of behavioral medicine by suggesting the presence of specific subgroups of participants who respond differently to behavior change interventions and salient psychosocial characteristics that differentiate among these phenotypes. Future research should examine the utility of prospectively identifying psychosocial phenotypes for improving the tailoring of nutrition behavior change interventions. © Society of Behavioral Medicine 2018.

Effects of behavioral and morphological plasticity on risk of predation in a Neotropical tadpole

USGS Publications Warehouse

McIntyre, P.B.; Baldwin, S.; Flecker, A.S.

2004-01-01

Predator-induced phenotypic plasticity is widespread among aquatic animals, however the relative contributions of behavioral and morphological shifts to reducing risk of predation remain uncertain. We tested the phenotypic plasticity of a Neotropical tadpole (Rana palmipes) in response to chemical cues from predatory Belostoma water bugs, and how phenotype affects risk of predation. Behavior, morphology, and pigmentation all were plastic, resulting in a predator-induced phenotype with lower activity, deeper tail fin and muscle, and darker pigmentation. Tadpoles in the predator cue treatment also grew more rapidly, possibly as a result of the nutrient subsidy from feeding the caged predator. For comparison to phenotypes induced in the experiment, we quantified the phenotype of tadpoles from a natural pool. Wildcaught tadpoles did not match either experimentally induced phenotype; their morphology was more similar to that produced in the control treatment, but their low swimming activity was similar to that induced by predator cues. Exposure of tadpoles from both experimental treatments and the natural pool to a free-ranging predator confirmed that predator-induced phenotypic plasticity reduces risk of predation. Risk of predation was comparable among wild-caught and predator-induced tadpoles, indicating that behavioral shifts can substantially alleviate risk in tadpoles that lack the typical suite of predator-induced morphological traits. The morphology observed in wild-caught tadpoles is associated with rapid growth and high competition in other tadpole species, suggesting that tadpoles may profitably combine a morphology suited to competition for food with behaviors that minimize risk of predation. ?? Springer-Verlag 2004.

A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD-associated cognitive phenotypes.

PubMed

Zhu, Jinmin; Fan, Fangfang; McCarthy, Deirdre M; Zhang, Lin; Cannon, Elisa N; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

2017-05-01

Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Real-Time Assessment of Wellness and Disease in Daily Life.

PubMed

Ausiello, Dennis; Lipnick, Scott

2015-09-01

The next frontier in medicine involves better quantifying human traits, known as "phenotypes." Biological markers have been directly associated with disease risks, but poor measurement of behaviors such as diet and exercise limits our understanding of preventive measures. By joining together an uncommonly wide range of disciplines and expertise, the Kavli HUMAN Project will advance measurement of behavioral phenotypes, as well as environmental factors that impact behavior. By following the same individuals over time, KHP will liberate new understanding of dynamic links between behavioral phenotypes, disease, and the broader environment. As KHP advances understanding of the bio-behavioral complex, it will seed new approaches to the diagnosis, prevention, and treatment of human disease.

Biological Risk for the Development of Problem Behavior in Adolescence: Integrating Insights from Behavioral Genetics and Neuroscience.

PubMed

Harden, K Paige; Mann, Frank D

2015-12-01

Adolescence is a time of increasing engagement in a variety of problem behaviors, including substance use and delinquency. Genetic risk for problem behavior increases over adolescence, is mediated partially by individual differences in sensation seeking, and is exacerbated by involvement with deviant peers. In this article, we describe how findings from behavioral genetic research on problem behavior intersect with research from developmental neuroscience. In particular, the incentive-processing system, including the ventral striatum, responds increasingly to rewards in adolescence, particularly in peer contexts. This developmental shift may be influenced by hormonal changes at puberty. Individual differences in the structure and function of reward-responsive brain regions may be intermediary phenotypes that mediate adolescents' genetic risk for problem behavior. The study of problem behavior can be enriched by interdisciplinary research that integrates measures of brain structure and function into genetically informed studies.

Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis

PubMed Central

Kozol, Robert A.; Cukier, Holly N.; Zou, Bing; Mayo, Vera; De Rubeis, Silvia; Cai, Guiqing; Griswold, Anthony J.; Whitehead, Patrice L.; Haines, Jonathan L.; Gilbert, John R.; Cuccaro, Michael L.; Martin, Eden R.; Baker, James D.; Buxbaum, Joseph D.; Pericak-Vance, Margaret A.; Dallman, Julia E.

2015-01-01

Despite significant progress in the genetics of autism spectrum disorder (ASD), how genetic mutations translate to the behavioral changes characteristic of ASD remains largely unknown. ASD affects 1–2% of children and adults, and is characterized by deficits in verbal and non-verbal communication, and social interactions, as well as the presence of repetitive behaviors and/or stereotyped interests. ASD is clinically and etiologically heterogeneous, with a strong genetic component. Here, we present functional data from syngap1 and shank3 zebrafish loss-of-function models of ASD. SYNGAP1, a synaptic Ras GTPase activating protein, and SHANK3, a synaptic scaffolding protein, were chosen because of mounting evidence that haploinsufficiency in these genes is highly penetrant for ASD and intellectual disability (ID). Orthologs of both SYNGAP1 and SHANK3 are duplicated in the zebrafish genome and we find that all four transcripts (syngap1a, syngap1b, shank3a and shank3b) are expressed at the earliest stages of nervous system development with pronounced expression in the larval brain. Consistent with early expression of these genes, knockdown of syngap1b or shank3a cause common embryonic phenotypes including delayed mid- and hindbrain development, disruptions in motor behaviors that manifest as unproductive swim attempts, and spontaneous, seizure-like behaviors. Our findings indicate that both syngap1b and shank3a play novel roles in morphogenesis resulting in common brain and behavioral phenotypes. PMID:25882707

Frontotemporal Dementia

PubMed Central

Olney, Nicholas T.; Spina, Salvatore; Miller, Bruce L.

2017-01-01

Frontotemporal Dementia (FTD) is a heterogeneous disorder with distinct clinical phenotypes associated with multiple neuropathologic entities. Presently, the term FTD encompasses clinical disorders that include changes in behavior, language, executive control and often motor symptoms. The core FTD spectrum disorders include: behavioral variant FTD (bvFTD), nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). Related FTD disorders include frontotemporal dementia with motor neuron disease (FTD-MND), progressive supranuclear palsy syndrome (PSP-S) and corticobasal syndrome (CBS). In this chapter we will discuss the clinic presentation, diagnostic criteria, neuropathology, genetics and treatments of these disorders. PMID:28410663

The neurobehavior ontology: an ontology for annotation and integration of behavior and behavioral phenotypes.

PubMed

Gkoutos, Georgios V; Schofield, Paul N; Hoehndorf, Robert

2012-01-01

In recent years, considerable advances have been made toward our understanding of the genetic architecture of behavior and the physical, mental, and environmental influences that underpin behavioral processes. The provision of a method for recording behavior-related phenomena is necessary to enable integrative and comparative analyses of data and knowledge about behavior. The neurobehavior ontology facilitates the systematic representation of behavior and behavioral phenotypes, thereby improving the unification and integration behavioral data in neuroscience research. Copyright © 2012 Elsevier Inc. All rights reserved.

Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia

PubMed Central

Huang, Ching-Hsun; Pei, Ju-Chun; Luo, Da-Zhong; Chen, Ching; Chen, Yi-Wen; Lai, Wen-Sung

2015-01-01

Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1+/−, Nrg1+/−, and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1+/− and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1+/− mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. PMID:25688191

Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia.

PubMed

Huang, Ching-Hsun; Pei, Ju-Chun; Luo, Da-Zhong; Chen, Ching; Chen, Yi-Wen; Lai, Wen-Sung

2014-01-01

Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1 (+/-), Nrg1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.

A new case of interstitial 6q16.2 deletion in a patient with Prader-Willi-like phenotype and investigation of SIM1 gene deletion in 87 patients with syndromic obesity.

PubMed

Varela, Monica C; Simões-Sato, Alex Y; Kim, Chong A; Bertola, Débora R; De Castro, Claudia I E; Koiffmann, Celia P

2006-01-01

The association of obesity, phenotypic abnormalities and mental retardation characterizes syndromic obesity. Its most common form is the Prader-Willi syndrome (PWS-- neonatal hypotonia, poor sucking, delayed psychomotor development, hyperphagia, severe obesity, short stature, small hands and feet, hypogonadism, mild to moderate mental retardation and behavioral disorders). A PWS-like phenotype has been described in patients with chromosome abnormalities involving the chromosome region 6q16.2 that includes the SIM1 gene. Herein we report cytogenetic and gene studies including a screening for the SIM1 gene deletion, performed on 87 patients with PWS-like phenotype, and describe the fifth case of syndromic obesity with an interstitial deletion of the chromosome segment 6q16-q21 and suggest that mutational analysis and further studies of the parental origin of chromosome alterations of 6q16.2 in patients with and without PWS-like phenotype are needed to evaluate possible imprinting effects of SIM1 gene and establish the contribution that alterations in this gene makes to the etiology of syndromic and non-syndromic obesity.

The neurotropic parasite Toxoplasma gondii increases dopamine metabolism

USDA-ARS?s Scientific Manuscript database

The common parasite Toxoplasma gondii induces behavioral alterations in its hosts including phenotypes increasing the likelihood of its transmission in rodents and reports of psychobehavioral alterations in humans. We have found that elevated levels of dopamine are associated with the encysted stage...

Genotyping-by-sequencing of glossy mutants

USDA-ARS?s Scientific Manuscript database

Glossy mutants are a common occurrence in Brassica oleracea L. and they have been documented in most crop varieties of the species including cabbage, kale, broccoli, and collard. Glossy phenotypes have been of particular interest to researchers due to observations that they influence insect behavior...

Bio-chemo-mechanics of thoracic aortic aneurysms.

PubMed

Wagenseil, Jessica E

2018-03-01

Most thoracic aortic aneurysms (TAAs) occur in the ascending aorta. This review focuses on the unique bio-chemo-mechanical environment that makes the ascending aorta susceptible to TAA. The environment includes solid mechanics, fluid mechanics, cell phenotype, and extracellular matrix composition. Advances in solid mechanics include quantification of biaxial deformation and complex failure behavior of the TAA wall. Advances in fluid mechanics include imaging and modeling of hemodynamics that may lead to TAA formation. For cell phenotype, studies demonstrate changes in cell contractility that may serve to sense mechanical changes and transduce chemical signals. Studies on matrix defects highlight the multi-factorial nature of the disease. We conclude that future work should integrate the effects of bio-chemo-mechanical factors for improved TAA treatment.

Male and Female Mice Lacking Neuroligin-3 Modify the Behavior of Their Wild-Type Littermates.

PubMed

Kalbassi, Shireene; Bachmann, Sven O; Cross, Ellen; Roberton, Victoria H; Baudouin, Stéphane J

2017-01-01

In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion of Nlgn3 , a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other's behavior. We have found that, when raised together, male Nlgn3 knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult male Nlgn3 knockout mice correlated with an increase in their anxiety. Re-expression of Nlgn3 in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior of Nlgn3 knockout mice has a direct and measurable impact on wild-type animals' behavior. Finally, we showed that, unlike male mice, female mice lacking Nlgn3 were insensitive to their peers' behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lacking Nlgn3 , being more influential in males than females.

Male and Female Mice Lacking Neuroligin-3 Modify the Behavior of Their Wild-Type Littermates

PubMed Central

Kalbassi, Shireene; Cross, Ellen

2017-01-01

Abstract In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion of Nlgn3, a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other’s behavior. We have found that, when raised together, male Nlgn3 knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult male Nlgn3 knockout mice correlated with an increase in their anxiety. Re-expression of Nlgn3 in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior of Nlgn3 knockout mice has a direct and measurable impact on wild-type animals’ behavior. Finally, we showed that, unlike male mice, female mice lacking Nlgn3 were insensitive to their peers’ behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lacking Nlgn3, being more influential in males than females. PMID:28795135

Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior.

PubMed

Hall, Joseph M; Savage, Lisa M

2016-04-01

Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time points: 24-h or 2-weeks post-exercise. It was found that only after the 2-week adaption period did exercise lead to an interrelated sequence of events in PTD rats that included: (1) restored spatial working memory; (2) rescued behaviorally-stimulated hippocampal acetylcholine efflux; and (3) within the medial septum/diagonal band, the re-emergence of the cholinergic (choline acetyltransferase [ChAT+]) phenotype, with the greatest change occurring in the ChAT+/nestin+ neurons. Furthermore, in control rats, exercise followed by a 2-week adaption period improved hippocampal acetylcholine efflux and increased the number of neurons co-expressing the ChAT and nestin phenotype. These findings demonstrate a novel mechanism by which exercise can modulate the mature cholinergic/nestin neuronal phenotype leading to improved neurotransmitter function as well as enhanced learning and memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Autistic disorder in patients with Williams-Beuren syndrome: a reconsideration of the Williams-Beuren syndrome phenotype.

PubMed

Tordjman, Sylvie; Anderson, George M; Botbol, Michel; Toutain, Annick; Sarda, Pierre; Carlier, Michèle; Saugier-Veber, Pascale; Baumann, Clarisse; Cohen, David; Lagneaux, Céline; Tabet, Anne-Claude; Verloes, Alain

2012-01-01

Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder. The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH. FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time. The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism.

The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses.

PubMed

Buxbaum, Joseph D; Bolshakova, Nadia; Brownfeld, Jessica M; Anney, Richard Jl; Bender, Patrick; Bernier, Raphael; Cook, Edwin H; Coon, Hilary; Cuccaro, Michael; Freitag, Christine M; Hallmayer, Joachim; Geschwind, Daniel; Klauck, Sabine M; Nurnberger, John I; Oliveira, Guiomar; Pinto, Dalila; Poustka, Fritz; Scherer, Stephen W; Shih, Andy; Sutcliffe, James S; Szatmari, Peter; Vicente, Astrid M; Vieland, Veronica; Gallagher, Louise

2014-01-01

There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.

5p13 microduplication syndrome: a new case and better clinical definition of the syndrome.

PubMed

Novara, Francesca; Alfei, Enrico; D'Arrigo, Stefano; Pantaleoni, Chiara; Beri, Silvana; Achille, Valentina; Sciacca, Francesca L; Giorda, Roberto; Zuffardi, Orsetta; Ciccone, Roberto

2013-01-01

Chromosome 5p13 duplication syndrome (OMIM #613174), a contiguous gene syndrome involving duplication of several genes on chromosome 5p13 including NIPBL (OMIM 608667), has been described in rare patients with developmental delay and learning disability, behavioral problems and peculiar facial dysmorphisms. 5p13 duplications described so far present with variable sizes, from 0.25 to 13.6 Mb, and contain a variable number of genes. Here we report another patient with 5p13 duplication syndrome including NIPBL gene only. Proband's phenotype overlapped that reported in patients with 5p13 microduplication syndrome and especially that of subjects with smaller duplications. Moreover, we better define genotype-phenotype relationship associated with this duplication and confirmed that NIPBL was likely the major dosage sensitive gene for the 5p13 microduplication phenotype. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder.

PubMed

Tilot, Amanda K; Frazier, Thomas W; Eng, Charis

2015-07-01

Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

Structure and composition of the courtship phenotype in the bird of paradise Parotia lawesii (Aves: Paradisaeidae).

PubMed

Scholes, Edwin

2008-01-01

Ethology is rooted in the idea that behavior is composed of discrete units and sub-units that can be compared among taxa in a phylogenetic framework. This means that behavior, like morphology and genes, is inherently modular. Yet, the concept of modularity is not well integrated into how we envision the behavioral components of phenotype. Understanding ethological modularity, and its implications for animal phenotype organization and evolution, requires that we construct interpretive schemes that permit us to examine it. In this study, I describe the structure and composition of a complex part of the behavioral phenotype of Parotia lawesii Ramsay, 1885--a bird of paradise (Aves: Paradisaeidae) from the forests of eastern New Guinea. I use archived voucher video clips, photographic ethograms, and phenotype ontology diagrams to describe the modular units comprising courtship at various levels of integration. Results show P. lawesii to have 15 courtship and mating behaviors (11 males, 4 females) hierarchically arranged within a complex seven-level structure. At the finest level examined, male displays are comprised of 49 modular sub-units (elements) differentially employed to form more complex modular units (phases and versions) at higher-levels of integration. With its emphasis on hierarchical modularity, this study provides an important conceptual framework for understanding courtship-related phenotypic complexity and provides a solid basis for comparative study of the genus Parotia.

The BTBR mouse model of idiopathic autism – current view on mechanisms

PubMed Central

Meyza, K. Z.; Blanchard, D. C.

2017-01-01

Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder, with current estimates of more than 1% of affected children across nations. The patients form a highly heterogeneous group with only the behavioral phenotype in common. The genetic heterogeneity is reflected in a plethora of animal models representing multiple mutations found in families of affected children. Despite many years of scientific effort, for the majority of cases the genetic cause remains elusive. It is therefore crucial to include well-validated models of idiopathic autism in studies searching for potential therapeutic agents. One of these models is the BTBR T+Itpr3tf/J mouse. The current review summarizes data gathered in recent research on potential molecular mechanisms responsible for the autism-like behavioral phenotype of this strain. PMID:28167097

The down syndrome behavioral phenotype: implications for practice and research in occupational therapy.

PubMed

Daunhauer, Lisa A; Fidler, Deborah J

2011-01-01

ABSTRACT Down syndrome (DS) is the most common chromosomal cause of intellectual disability. The genetic causes of DS are associated with characteristic outcomes, such as relative strengths in visual-spatial skills and relative challenges in motor planning. This profile of outcomes, called the DS behavioral phenotype, may be a critical tool for intervention planning and research in this population. In this article, aspects of the DS behavioral phenotype potentially relevant to occupational therapy practice are reviewed. Implications and challenges for etiology-informed research and practice are discussed.

Behavior-specific changes in transcriptional modules lead to distinct and predictable neurogenomic states

PubMed Central

Chandrasekaran, Sriram; Ament, Seth A.; Eddy, James A.; Rodriguez-Zas, Sandra L.; Schatz, Bruce R.; Price, Nathan D.; Robinson, Gene E.

2011-01-01

Using brain transcriptomic profiles from 853 individual honey bees exhibiting 48 distinct behavioral phenotypes in naturalistic contexts, we report that behavior-specific neurogenomic states can be inferred from the coordinated action of transcription factors (TFs) and their predicted target genes. Unsupervised hierarchical clustering of these transcriptomic profiles showed three clusters that correspond to three ecologically important behavioral categories: aggression, maturation, and foraging. To explore the genetic influences potentially regulating these behavior-specific neurogenomic states, we reconstructed a brain transcriptional regulatory network (TRN) model. This brain TRN quantitatively predicts with high accuracy gene expression changes of more than 2,000 genes involved in behavior, even for behavioral phenotypes on which it was not trained, suggesting that there is a core set of TFs that regulates behavior-specific gene expression in the bee brain, and other TFs more specific to particular categories. TFs playing key roles in the TRN include well-known regulators of neural and behavioral plasticity, e.g., Creb, as well as TFs better known in other biological contexts, e.g., NF-κB (immunity). Our results reveal three insights concerning the relationship between genes and behavior. First, distinct behaviors are subserved by distinct neurogenomic states in the brain. Second, the neurogenomic states underlying different behaviors rely upon both shared and distinct transcriptional modules. Third, despite the complexity of the brain, simple linear relationships between TFs and their putative target genes are a surprisingly prominent feature of the networks underlying behavior. PMID:21960440

Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities

PubMed Central

Hodge, Jennelle C.; Mitchell, Elyse; Pillalamarri, Vamsee; Toler, Tomi L.; Bartel, Frank; Kearney, Hutton M.; Zou, Ying S.; Tan, Wen-Hann; Hanscom, Carrie; Kirmani, Salman; Hanson, Rae R.; Skinner, Steven A.; Rogers, Curtis; Everman, David B.; Boyd, Ellen; Mullegama, Sureni V.; Keelean-Fuller, Debra; Powell, Cynthia M.; Elsea, Sarah H.; Morton, Cynthia C.; Gusella, James F.; DuPont, Barbara; Chaubey, Alka; Lin, Angela E.; Talkowski, Michael E.

2016-01-01

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 contribute to a spectrum of neurodevelopmental phenotypes, however the impact of this locus in human psychopathology has not been described. To characterize the structural variation landscape of MBD5 disruptions and the associated psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation, and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5′UTR, confirming the critical impact of non-coding sequence at this locus. We found heterogeneous, multi-system pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, which includes sensory integration disorder, anxiety, self-hugging, bipolar disorder and others. Importantly, unique features of the oldest assessed patient were early-onset dementia and behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study indicates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology, and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also suggests that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression and early-onset dementia. PMID:23587880

Movement ecology: size-specific behavioral response of an invasive snail to food availability.

PubMed

Snider, Sunny B; Gilliam, James F

2008-07-01

Immigration, emigration, migration, and redistribution describe processes that involve movement of individuals. These movements are an essential part of contemporary ecological models, and understanding how movement is affected by biotic and abiotic factors is important for effectively modeling ecological processes that depend on movement. We asked how phenotypic heterogeneity (body size) and environmental heterogeneity (food resource level) affect the movement behavior of an aquatic snail (Tarebia granifera), and whether including these phenotypic and environmental effects improves advection-diffusion models of movement. We postulated various elaborations of the basic advection diffusion model as a priori working hypotheses. To test our hypotheses we measured individual snail movements in experimental streams at high- and low-food resource treatments. Using these experimental movement data, we examined the dependency of model selection on resource level and body size using Akaike's Information Criterion (AIC). At low resources, large individuals moved faster than small individuals, producing a platykurtic movement distribution; including size dependency in the model improved model performance. In stark contrast, at high resources, individuals moved upstream together as a wave, and body size differences largely disappeared. The model selection exercise indicated that population heterogeneity is best described by the advection component of movement for this species, because the top-ranked model included size dependency in advection, but not diffusion. Also, all probable models included resource dependency. Thus population and environmental heterogeneities both influence individual movement behaviors and the population-level distribution kernels, and their interaction may drive variation in movement behaviors in terms of both advection rates and diffusion rates. A behaviorally informed modeling framework will integrate the sentient response of individuals in terms of movement and enhance our ability to accurately model ecological processes that depend on animal movement.

Phenotypic and genetic relationships of feeding behavior with feed intake, growth performance, feed efficiency, and carcass merit traits in Angus and Charolais steers.

PubMed

Chen, L; Mao, F; Crews, D H; Vinsky, M; Li, C

2014-03-01

Feeding behavior traits including daily feeding duration (FD), daily feeding head down time (HD), average feeding duration per feeding event (FD_AVE), average feeding head down time per feeding event (HD_AVE), feeding frequency (FF), and meal eating rate (ER) were analyzed to estimate their phenotypic and genetic correlations with feed intake, growth performance, residual feed intake (RFI), ultrasound, and carcass merit traits in Angus and Charolais finishing steers. Heritability estimates for FD, HD, FD_AVE, HD_AVE, FF, and ER were 0.27 ± 0.09 (SE), 0.25 ± 0.09, 0.19 ± 0.06, 0.11 ± 0.05, 0.24 ± 0.08, and 0.38 ± 0.10, respectively, in the Angus population and 0.49 ± 0.12, 0.38 ± 0.11, 0.31 ± 0.09, 0.29 ± 0.10, 0.43 ± 0.11, and 0.56 ± 0.13, respectively, in the Charolais population. In both the Angus and Charolais steer populations, FD and HD had relatively stronger phenotypic (0.17 ± 0.06 to 0.32 ± 0.04) and genetic (0.29 ± 0.17 to 0.54 ± 0.18) correlations with RFI in comparison to other feeding behavior traits investigated, suggesting the potential of FD and HD as indicators in assessing variation of RFI. In general, feeding behavior traits had weak phenotypic correlations with most of the ultrasound and carcass merit traits; however, estimated genetic correlations of the feeding behavior traits with some fat deposition related traits were moderate to moderately strong but differed in magnitude or sign between the Angus and Charolais steer populations, likely reflecting their different biological types. Genetic parameter estimation studies involving feeding behavior traits in beef cattle are lacking and more research is needed to better characterize the relationships between feeding behavior and feed intake, growth, feed utilization, and carcass merit traits, in particular with respect to different biological types of cattle.

Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.

PubMed

Moy, Sheryl S; Riddick, Natallia V; Nikolova, Viktoriya D; Teng, Brian L; Agster, Kara L; Nonneman, Randal J; Young, Nancy B; Baker, Lorinda K; Nadler, Jessica J; Bodfish, James W

2014-02-01

Restricted repetitive behaviors are core symptoms of autism spectrum disorders (ASDs). The range of symptoms encompassed by the repetitive behavior domain includes lower-order stereotypy and self-injury, and higher-order indices of circumscribed interests and cognitive rigidity. Heterogeneity in clinical ASD profiles suggests that specific manifestations of repetitive behavior reflect differential neuropathology. The present studies utilized a set of phenotyping tasks to determine a repetitive behavior profile for the C58/J mouse strain, a model of ASD core symptoms. In an observational screen, C58/J demonstrated overt motor stereotypy, but not over-grooming, a commonly-used measure for mouse repetitive behavior. Amphetamine did not exacerbate motor stereotypy, but had enhanced stimulant effects on locomotion and rearing in C58/J, compared to C57BL/6J. Both C58/J and Grin1 knockdown mice, another model of ASD-like behavior, had marked deficits in marble-burying. In a nose poke task for higher-order repetitive behavior, C58/J had reduced holeboard exploration and preference for non-social, versus social, olfactory stimuli, but did not demonstrate cognitive rigidity following familiarization to an appetitive stimulus. Analysis of available high-density genotype data indicated specific regions of divergence between C58/J and two highly-sociable strains with common genetic lineage. Strain genome comparisons identified autism candidate genes, including Cntnap2 and Slc6a4, located within regions divergent in C58/J. However, Grin1, Nlgn1, Sapap3, and Slitrk5, genes linked to repetitive over-grooming, were not in regions of divergence. These studies suggest that specific repetitive phenotypes can be used to distinguish ASD mouse models, with implications for divergent underlying mechanisms for different repetitive behavior profiles. Copyright © 2013 Elsevier B.V. All rights reserved.

Specific Medical Conditions Are Associated with Unique Behavioral Profiles in Autism Spectrum Disorders.

PubMed

Zachor, Ditza A; Ben-Itzchak, Esther

2016-01-01

Autism spectrum disorder (ASD) is a heterogeneous group of disorders which occurs with numerous medical conditions. In previous research, subtyping in ASD has been based mostly on cognitive ability and ASD symptom severity. The aim of the current study was to investigate whether specific medical conditions in ASD are associated with unique behavioral profiles. The medical conditions included in the study were macrocephaly, microcephaly, developmental regression, food selectivity, and sleep problems. The behavioral profile was composed of cognitive ability, adaptive skills, and autism severity, and was examined in each of the aforementioned medical conditions. The study population included 1224 participants, 1043 males and 181 females (M:F ratio = 5.8:1) with a mean age of 49.9 m (SD = 29.4) diagnosed with ASD using standardized tests. Groups with and without the specific medical conditions were compared on the behavioral measures. Developmental regression was present in 19% of the population and showed a more severe clinical presentation, with lower cognitive abilities, more severe ASD symptoms, and more impaired adaptive functioning. Microcephaly was observed in 6.3% of the population and was characterized by a lower cognitive ability and more impaired adaptive functioning in comparison to the normative head circumference (HC) group. Severe food selectivity was found in 9.8% and severe sleep problems in 5.1% of the ASD population. The food selectivity and sleep problem subgroups, both showed more severe autism symptoms only as described by the parents, but not per the professional assessment, and more impaired adaptive skills. Macrocephaly was observed in 7.9% of the ASD population and did not differ from the normative HC group in any of the examined behavioral measures. Based on these findings, two unique medical-behavioral subtypes in ASD that affect inherited traits of cognition and/or autism severity were suggested. The microcephaly phenotype occurred with more impaired cognition and the developmental regression phenotype with widespread, more severe impairments in cognition and autism severity. In contrast, severe food selectivity and sleep problems represent only comorbidities to ASD that affect functioning. Defining specific subgroups in ASD with a unique biological signature and specific behavioral phenotypes may help future genetic and neuroscience research.

Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.

PubMed

Aziz, Nadine M; Guedj, Faycal; Pennings, Jeroen L A; Olmos-Serrano, Jose Luis; Siegel, Ashley; Haydar, Tarik F; Bianchi, Diana W

2018-06-12

Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits, and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here, we directly compared brain histogenesis, gene expression and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared with Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Neurogenetic and Neurodevelopmental Pathways to Learning Disabilities.

ERIC Educational Resources Information Center

Mazzocco, Michele M. M.; And Others

1997-01-01

This paper reviews ongoing research designed to specify the cognitive, behavioral, and neuroanatomical phenotypes of specific genetic etiologies of learning disability. The genetic disorders at the focus of the research include reading disability, neurofibromatosis type 1, Tourette syndrome, and fragile X syndrome. Implications for identifying…

Accelerated bang recovery in Drosophila genderblind mutants.

PubMed

Featherstone, David E; Yanoga, Fatoumata; Grosjean, Yael

2008-07-01

Cystine-glutamate transporters import cystine into cells for glutathione synthesis and protection from oxidative stress, but also export significant amounts of glutamate. Increasing evidence suggests that 'ambient extracellular glutamate' secreted by cystine-glutamate transporters in the nervous system modulates glutamatergic synapse strength and behavior. To date, the only cystine-glutamate transporter mutants examined behaviorally are Drosophila genderblind mutants. These animals contain loss-of-function mutations in the 'genderblind' gene, which encodes an xCT subunit essential for cystine-glutamate transporter function. Genderblind was named based on a mutant courtship phenotype: male genderblind mutants are attracted to normally aversive male pheromones and thus court and attempt to copulate with both male and female partners equally. However, genderblind protein is expressed in many parts of the fly brain and thus might be expected to also regulate other behaviors, including behaviors not related to male courtship or chemosensation. Here, we show that genderblind mutants display faster recovery and increased negative geotaxis after strong mechanical stimuli (e.g., they climb faster and farther after vial banging). This phenotype is displayed by both males and females, consistent with strong genderblind expression in both sexes.

Human Facial Expressions as Adaptations:Evolutionary Questions in Facial Expression Research

PubMed Central

SCHMIDT, KAREN L.; COHN, JEFFREY F.

2007-01-01

The importance of the face in social interaction and social intelligence is widely recognized in anthropology. Yet the adaptive functions of human facial expression remain largely unknown. An evolutionary model of human facial expression as behavioral adaptation can be constructed, given the current knowledge of the phenotypic variation, ecological contexts, and fitness consequences of facial behavior. Studies of facial expression are available, but results are not typically framed in an evolutionary perspective. This review identifies the relevant physical phenomena of facial expression and integrates the study of this behavior with the anthropological study of communication and sociality in general. Anthropological issues with relevance to the evolutionary study of facial expression include: facial expressions as coordinated, stereotyped behavioral phenotypes, the unique contexts and functions of different facial expressions, the relationship of facial expression to speech, the value of facial expressions as signals, and the relationship of facial expression to social intelligence in humans and in nonhuman primates. Human smiling is used as an example of adaptation, and testable hypotheses concerning the human smile, as well as other expressions, are proposed. PMID:11786989

An animated landscape representation of CD4+ T-cell differentiation, variability, and plasticity: Insights into the behavior of populations versus cells

PubMed Central

Rebhahn, Jonathan A; Deng, Nan; Sharma, Gaurav; Livingstone, Alexandra M; Huang, Sui; Mosmann, Tim R

2014-01-01

Recent advances in understanding CD4+ T-cell differentiation suggest that previous models of a few distinct, stable effector phenotypes were too simplistic. Although several well-characterized phenotypes are still recognized, some states display plasticity, and intermediate phenotypes exist. As a framework for reexamining these concepts, we use Waddington's landscape paradigm, augmented with explicit consideration of stochastic variations. Our animation program “LAVA” visualizes T-cell differentiation as cells moving across a landscape of hills and valleys, leading to attractor basins representing stable or semistable differentiation states. The model illustrates several principles, including: (i) cell populations may behave more predictably than individual cells; (ii) analogous to reticulate evolution, differentiation may proceed through a network of interconnected states, rather than a single well-defined pathway; (iii) relatively minor changes in the barriers between attractor basins can change the stability or plasticity of a population; (iv) intrapopulation variability of gene expression may be an important regulator of differentiation, rather than inconsequential noise; (v) the behavior of some populations may be defined mainly by the behavior of outlier cells. While not a quantitative representation of actual differentiation, our model is intended to provoke discussion of T-cell differentiation pathways, particularly highlighting a probabilistic view of transitions between states. PMID:24945794

High-throughput behavioral phenotyping of drug and alcohol susceptibility traits in the expanded panel of BXD recombinant inbred strains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Philip, Vivek M; Ansah, T; Blaha, C,

Genetic reference populations, particularly the BXD recombinant inbred strains, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and co- ariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic co-regulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium havemore » obtained behavioral phenotype data from 260 measures related to multiple behavioral assays across several domains: self-administration, response to, and withdrawal from cocaine, MDMA, morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity; and sleep/wake cycles. All traits have been measured in both sexes and the recently expanded panel of 69 additional BXD recombinant inbred strains (N=69). Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent BXD RI lines was performed. Primary data is publicly available for heritability, sex difference and genetic analyses using www.GeneNetwork.org. These analyses include QTL detection and genetic analysis of gene expression. Stored results from these analyses are available at http://ontologicaldiscovery.org for comparison to other genomic analysis results. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.« less

Autism-like behavioral phenotypes in BTBR T+tf/J mice.

PubMed

McFarlane, H G; Kusek, G K; Yang, M; Phoenix, J L; Bolivar, V J; Crawley, J N

2008-03-01

Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.

Cognitive, Linguistic, and Motor Abilities in a Multigenerational Family with Childhood Apraxia of Speech.

PubMed

Carrigg, Bronwyn; Parry, Louise; Baker, Elise; Shriberg, Lawrence D; Ballard, Kirrie J

2016-10-05

This study describes the phenotype in a large family with a strong, multigenerational history of severe speech sound disorder (SSD) persisting into adolescence and adulthood in approximately half the cases. Aims were to determine whether a core phenotype, broader than speech, separated persistent from resolved SSD cases; and to ascertain the uniqueness of the phenotype relative to published cases. Eleven members of the PM family (9-55 years) were assessed across cognitive, language, literacy, speech, phonological processing, numeracy, and motor domains. Between group comparisons were made using the Mann-Whitney U-test (p < 0.01). Participant performances were compared to normative data using standardized tests and to the limited published data on persistent SSD phenotypes. Significant group differences were evident on multiple speech, language, literacy, phonological processing, and verbal intellect measures without any overlapping scores. Persistent cases performed within the impaired range on multiple measures. Phonological memory impairment and subtle literacy weakness were present in resolved SSD cases. A core phenotype distinguished persistent from resolved SSD cases that was characterized by a multiple verbal trait disorder, including Childhood Apraxia of Speech. Several phenotypic differences differentiated the persistent SSD phenotype in the PM family from the few previously reported studies of large families with SSD, including the absence of comorbid dysarthria and marked orofacial apraxia. This study highlights how comprehensive phenotyping can advance the behavioral study of disorders, in addition to forming a solid basis for future genetic and neural studies. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Behavioral science and the study of gene-nutrition and gene-physical activity interactions in obesity research.

PubMed

Faith, Myles S

2008-12-01

This report summarizes emerging opportunities for behavioral science to help advance the field of gene-environment and gene-behavior interactions, based on presentations at The National Cancer Institute (NCI) Workshop, "Gene-Nutrition and Gene-Physical Activity Interactions in the Etiology of Obesity." Three opportunities are highlighted: (i) designing potent behavioral "challenges" in experiments, (ii) determining viable behavioral phenotypes for genetics studies, and (iii) identifying specific measures of the environment or environmental exposures. Additional points are underscored, including the need to incorporate novel findings from neuroimaging studies regarding motivation and drive for eating and physical activity. Advances in behavioral science theory and methods can play an important role in advancing understanding of gene-brain-behavior relationships in obesity onset.

Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brunner, H.G.; Nelen, M.; Ropers, H.H.

1993-10-22

Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated completemore » MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.« less

Phenotypic divergence despite low genetic differentiation in house sparrow populations.

PubMed

Ben Cohen, Shachar; Dor, Roi

2018-01-10

Studying patterns of phenotypic variation among populations can shed light on the drivers of evolutionary processes. The house sparrow (Passer domesticus) is one of the world's most ubiquitous bird species, as well as a successful invader. We investigated phenotypic variation in house sparrow populations across a climatic gradient and in relation to a possible scenario of an invasion. We measured variation in morphological, coloration, and behavioral traits (exploratory behavior and neophobia) and compared it to the neutral genetic variation. We found that sparrows were larger and darker in northern latitudes, in accordance with Bergmann's and Gloger's biogeographic rules. Morphology and behavior mostly differed between the southernmost populations and the other regions, supporting the possibility of an invasion. Genetic differentiation was low and diversity levels were similar across populations, indicating high gene flow. Nevertheless, the southernmost and northern populations differed genetically to some extent. Furthermore, genetic differentiation (F ST ) was lower in comparison to phenotypic variation (P ST ), indicating that the phenotypic variation is shaped by directional selection or by phenotypic plasticity. This study expands our knowledge on evolutionary mechanisms and biological invasions.

Behavior and neuropsychiatric manifestations in Angelman syndrome

PubMed Central

Pelc, Karine; Cheron, Guy; Dan, Bernard

2008-01-01

Angelman syndrome has been suggested as a disease model of neurogenetic developmental condition with a specific behavioral phenotype. It is due to lack of expression of the UBE3A gene, an imprinted gene located on chromosome 15q. Here we review the main features of this phenotype, characterized by happy demeanor with prominent smiling, poorly specific laughing and general exuberance, associated with hypermotor behavior, stereotypies, and reduced behavioral adaptive skills despite proactive social contact. All these phenotypic characteristics are currently difficult to quantify and have been subject to some differences in interpretation. For example, prevalence of autistic disorder is still debated. Many of these features may occur in other syndromic or nonsyndromic forms of severe intellectual disability, but their combination, with particularly prominent laughter and smiling may be specific of Angelman syndrome. Management of problematic behaviors is primarily based on behavioral approaches, though psychoactive medication (eg, neuroleptics or antidepressants) may be required. PMID:18830393

Mouse Behavior on ISS: The Emergence of Distinctive, Organized Group Circling Behavior Unique to Spaceflight

NASA Technical Reports Server (NTRS)

Ronca, A. E.; Moyer, E. L.; Talyansky, Y.; Solomides, P.; Choi, S.; Gong, C.; Globus, R. K.

2017-01-01

As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. Only a handful of papers have previously reported behavior of mice and rats in the weightless environment of space (Andreev-Andrievskiy, et al., 2013; Cancedda et al., 2012; Ronca et al., 2008). The Rodent Research Hardware and Operations Validation Mission (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS. Ten adult (16-week-old) female C57BL6J mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in flight. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the RH during this long duration flight. Video was recorded for 34 days on the ISS, permitting daily assessments of overall health and well being of the mice, and providing a valuable repository for detailed behavioral analysis. As compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allogrooming,and social interactions at similar or greater levels of occurrence. Overallactivity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized circling or race-tracking behavior that emerged within thefirst few days of flight following a common developmental sequence, comprising theprimary dark cycle activity of FLT mice. Circling participation by individual micepersisted throughout the mission. Analysis of group behavior over mission days revealed recruitment of mice into the group phenotype, coupled with decreasing numbers of collisions between circling mice. This analysis provides insights into the behavior of mice in microgravity, and clear evidence for the emergence of a distinctive,organized group behavior unique to the weightless space environment.

Song evolution, speciation, and vocal learning in passerine birds.

PubMed

Mason, Nicholas A; Burns, Kevin J; Tobias, Joseph A; Claramunt, Santiago; Seddon, Nathalie; Derryberry, Elizabeth P

2017-03-01

Phenotypic divergence can promote reproductive isolation and speciation, suggesting a possible link between rates of phenotypic evolution and the tempo of speciation at multiple evolutionary scales. To date, most macroevolutionary studies of diversification have focused on morphological traits, whereas behavioral traits─including vocal signals─are rarely considered. Thus, although behavioral traits often mediate mate choice and gene flow, we have a limited understanding of how behavioral evolution contributes to diversification. Furthermore, the developmental mode by which behavioral traits are acquired may affect rates of behavioral evolution, although this hypothesis is seldom tested in a phylogenetic framework. Here, we examine evidence for rate shifts in vocal evolution and speciation across two major radiations of codistributed passerines: one oscine clade with learned songs (Thraupidae) and one suboscine clade with innate songs (Furnariidae). We find that evolutionary bursts in rates of speciation and song evolution are coincident in both thraupids and furnariids. Further, overall rates of vocal evolution are higher among taxa with learned rather than innate songs. Taken together, these findings suggest an association between macroevolutionary bursts in speciation and vocal evolution, and that the tempo of behavioral evolution can be influenced by variation in developmental modes among lineages. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

The Role of the Asn40Asp Polymorphism of the Mu Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

PubMed Central

Ray, Lara A.; Barr, Christina S.; Blendy, Julie A.; Oslin, David; Goldman, David; Anton, Raymond F.

2011-01-01

The endogenous opioid system has been implicated in the pathophysiology of alcoholism as it modulates the neurobehavioral effects of alcohol. A variant in the mu opioid receptor gene (OPRM1), the Asn40Asp polymorphism, has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: (i) genetic association studies; (ii) behavioral studies of alcoholism; (iii) neuroimaging studies; (iv) pharmacogenetic studies and clinical trials; and (v) preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response. PMID:21895723

Effect of Phospholipidosis on the Cellular Pharmacokinetics of ChloroquineS⃞

PubMed Central

Zheng, Nan; Zhang, Xinyuan

2011-01-01

In vivo, the weakly basic, lipophilic drug chloroquine (CQ) accumulates in the kidney to concentrations more than a thousand-fold greater than those in plasma. To study the cellular pharmacokinetics of chloroquine in cells derived from the distal tubule, Madin-Darby canine kidney cells were incubated with CQ under various conditions. CQ progressively accumulated without exhibiting steady-state behavior. Experiments failed to yield evidence that known active transport mechanisms mediated CQ uptake at the plasma membrane. CQ induced a phospholipidosis-like phenotype, characterized by the appearance of numerous multivesicular and multilamellar bodies (MLBs/MVBs) within the lumen of expanded cytoplasmic vesicles. Other induced phenotypic changes including changes in the volume and pH of acidic organelles were measured, and the integrated effects of all these changes were computationally modeled to establish their impact on intracellular CQ mass accumulation. Based on the passive transport behavior of CQ, the measured phenotypic changes fully accounted for the continuous, nonsteady-state CQ accumulation kinetics. Consistent with the simulation results, Raman confocal microscopy of live cells confirmed that CQ became highly concentrated within induced, expanded cytoplasmic vesicles that contained multiple MLBs/MVBs. Progressive CQ accumulation was increased by sucrose, a compound that stimulated the phospholipidosis-like phenotype, and was decreased by bafilomycin A1, a compound that inhibited this phenotype. Thus, phospholipidosis-associated changes in organelle structure and intracellular membrane content can exert a major influence on the local bioaccumulation and biodistribution of drugs. PMID:21156819

Autistic Disorder in Patients with Williams-Beuren Syndrome: A Reconsideration of the Williams-Beuren Syndrome Phenotype

PubMed Central

Tordjman, Sylvie; Anderson, George M.; Botbol, Michel; Toutain, Annick; Sarda, Pierre; Carlier, Michèle; Saugier-Veber, Pascale; Baumann, Clarisse; Cohen, David; Lagneaux, Céline; Tabet, Anne-Claude; Verloes, Alain

2012-01-01

Background Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder. Methodology The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH. Findings FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time. Conclusions The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism. PMID:22412832

Absence of strong strain effects in behavioral analyses of Shank3-deficient mice

PubMed Central

Drapeau, Elodie; Dorr, Nate P.; Elder, Gregory A.; Buxbaum, Joseph D.

2014-01-01

Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid syndrome, symptoms of which can include absent or delayed speech, intellectual disability, neurological changes and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin-repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions, in Shank3 heterozygous mice. Changes in phenotype owing to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype owing to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3 heterozygous, knockout and wild-type mice, using C57BL/6, 129SVE and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain-independent. PMID:24652766

Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

PubMed Central

Mullegama, Sureni V.; Alaimo, Joseph T.; Chen, Li; Elsea, Sarah H.

2015-01-01

Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention. PMID:25853262

Light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats

PubMed Central

Gonzalez, M. M. C.; Aston-Jones, G.

2008-01-01

Light is an important environmental factor for regulation of mood. There is a high frequency of seasonal affective disorder in high latitudes where light exposure is limited, and bright light therapy is a successful antidepressant treatment. We recently showed that rats kept for 6 weeks in constant darkness (DD) have anatomical and behavioral features similar to depressed patients, including dysregulation of circadian sleep–waking rhythms and impairment of the noradrenergic (NA)-locus coeruleus (LC) system. Here, we analyzed the cell viability of neural systems related to the pathophysiology of depression after DD, including NA-LC, serotoninergic-raphe nuclei and dopaminergic-ventral tegmental area neurons, and evaluated the depressive behavioral profile of light-deprived rats. We found increased apoptosis in the three aminergic systems analyzed when compared with animals maintained for 6 weeks in 12:12 light-dark conditions. The most apoptosis was observed in NA-LC neurons, associated with a significant decrease in the number of cortical NA boutons. Behaviorally, DD induced a depression-like condition as measured by increased immobility in a forced swim test (FST). DD did not appear to be stressful (no effect on adrenal or body weights) but may have sensitized responses to subsequent stressors (increased fecal number during the FST). We also found that the antidepressant desipramine decreases these neural and behavioral effects of light deprivation. These findings indicate that DD induces neural damage in monoamine brain systems and this damage is associated with a depressive behavioral phenotype. Our results suggest a mechanism whereby prolonged limited light intensity could negatively impact mood. PMID:18347342

From Research to Practice: Teacher and Pediatrician Awareness of Phenotypic Traits in Neurogenetic Syndromes

ERIC Educational Resources Information Center

Lee, Tammy H.; Blasey, Christine M.; Dyer-Friedman, Jennifer; Glaser, Bronwyn; Reiss, Allan L.; Eliez, Stephan

2005-01-01

Pediatricians' and teachers' knowledge of physical, cognitive, and behavioral features associated with three genetic syndromes were assessed and the effectiveness of information sources about these syndromes evaluated. The surveyed sample included 53 pediatricians and 69 teachers from Northern and Central California. Respondents demonstrated…

Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent.

PubMed

Schmechel, Donald E; Edwards, Christopher L

2012-12-01

Persons with single copies of common alpha-1-antitrypsin polymorphisms such as S and Z are often considered "silent carriers". Published evidence however supports a complex behavioral phenotype or trait - intense creative energy ("ICE")-associated with A1AT polymorphisms. We now confirm that phenotype and present an association of fibromyalgia syndrome (FMS) and A1AT in a consecutive series of neurological patients. This is a retrospective case control series of 3176 consecutive patients presenting to Duke University Memory Clinic (747 patients) and to regional community-based Caldwell Hospital Neurology and Memory center (2429 patients). Work-up included medical history and examination, psychological evaluation, and genetic analysis. Chronic widespread pain (CWP) or FMS were diagnosed according to clinical guidelines, mostly as secondary diagnoses. Neurological patients carrying A1AT polymorphisms were common (ca 16% prevalence) and carriers had significantly higher use of inhaler and anxiolytic medications. Patients with ICE phenotype had a significantly higher proportion of A1AT polymorphisms (42%) compared to non-ICE patients (13%). Presence of CWP or FMS was common (14-22%) with average age at presentation of 56 years old and mostly female gender (82%). Patients with CWP/FMS had again significantly higher proportion of A1AT polymorphisms (38%) compared to other neurological patients (13%). Patients with anxiety disorders, bipolar I or bipolar II disorders or PTSD also had increased proportion of A1AT polymorphisms and significant overlap with ICE and FMS phenotype. Significant reductions in CWP/FMS prevalence are seen in apolipoprotein E4 carriers and methylene tetrahydrofolate reductase (MTHFR) mutation homozygotes. Since ICE phenotype is reported as a lifelong behavioral attribute, the presumption is that A1AT carriers have fundamental differences in brain development and inflammatory response. In support of this concept is finding those persons reporting a diagnosis of juvenile rheumatoid or idiopathic arthritis (JRA, JIA) had a significantly high proportion of A1AT polymorphisms (63%), suggesting a spectrum for JRA to later FMS presentations. Likewise, persons reporting a history of attention deficit disorder (ADD) had an increased proportion of A1AT polymorphisms (26%) compared to non-ADD persons (13%). Toxic environmental exposures are common (23%) and associated with diagnoses of PSP, PPA, FTD, FTD-PD, PD and ADVD. A1AT carriers were increased in cases of toxic exposure and PSP, PPA and FTD-PD. Our findings support the ICE behavioral phenotype for A1AT polymorphism carriers and the reported association with anxiety and bipolar spectrum disorders. We now extend that phenotype to apparent vulnerability to inflammatory muscle disease in a spectrum from JRA to fibromyalgia (FMS) and specific behavioral subsets of ADD, PTSD, and specific late onset neurological syndromes (FTD-PD and PPA). High and low risk FMS subsets can be defined using A1AT, MTHFR and APOE genotyping. Clinical diagnoses associated with A1AT polymorphisms included fibromyalgia, JRA/JIA, bipolar disorder, PTSD, primary progressive aphasia and FTDPD, but not most Alzheimer Disease subtypes. These results support an extended phenotype for A1AT mutation carriers beyond liver and lung vulnerability to selective advantages: ICE phenotype and disadvantages: fibromyalgia, affective disorders, and selected late onset neurological syndromes. Copyright © 2012 Elsevier Inc. All rights reserved.

SEE locomotor behavior test discriminates C57BL/6J and DBA/2J mouse inbred strains across laboratories and protocol conditions.

PubMed

Kafkafi, Neri; Lipkind, Dina; Benjamini, Yoav; Mayo, Cheryl L; Elmer, Gregory I; Golani, Ilan

2003-06-01

Conventional tests of behavioral phenotyping frequently have difficulties differentiating certain genotypes and replicating these differences across laboratories and protocol conditions. This study explores the hypothesis that automated tests can be designed to quantify ethologically relevant behavior patterns that more readily characterize heritable and replicable phenotypes. It used SEE (Strategy for the Exploration of Exploration) to phenotype the locomotor behavior of the C57BL/6 and DBA/2 mouse inbred strains across 3 laboratories. The 2 genotypes differed in 15 different measures of behavior, none of which had a significant genotype-laboratory interaction. Within the same laboratory, most of these differences were replicated in additional experiments despite the test photoperiod phase being changed and saline being injected. Results suggest that well-designed tests may considerably enhance replicability across laboratories.

Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model.

PubMed

Jul, Pia; Volbracht, Christiane; de Jong, Inge E M; Helboe, Lone; Elvang, Anders Brandt; Pedersen, Jan Torleif

2016-01-01

Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.

Olfactory behavior and physiology are disrupted in prion protein knockout mice.

PubMed

Le Pichon, Claire E; Valley, Matthew T; Polymenidou, Magdalini; Chesler, Alexander T; Sagdullaev, Botir T; Aguzzi, Adriano; Firestein, Stuart

2009-01-01

The prion protein PrP(C) is infamous for its role in disease, but its normal physiological function remains unknown. Here we found a previously unknown behavioral phenotype of Prnp(-/-) mice in an odor-guided task. This phenotype was manifest in three Prnp knockout lines on different genetic backgrounds, which provides strong evidence that the phenotype is caused by a lack of PrP(C) rather than by other genetic factors. Prnp(-/-) mice also showed altered behavior in a second olfactory task, suggesting that the phenotype is olfactory specific. Furthermore, PrP(C) deficiency affected oscillatory activity in the deep layers of the main olfactory bulb, as well as dendrodendritic synaptic transmission between olfactory bulb granule and mitral cells. Notably, both the behavioral and electrophysiological alterations found in Prnp(-/-) mice were rescued by transgenic neuronal-specific expression of PrP(C). These data suggest that PrP(C) is important in the normal processing of sensory information by the olfactory system.

Genetic and phenotypic relationships of feeding behavior and temperament with performance, feed efficiency, ultrasound, and carcass merit of beef cattle.

PubMed

Nkrumah, J D; Crews, D H; Basarab, J A; Price, M A; Okine, E K; Wang, Z; Li, C; Moore, S S

2007-10-01

Feeding behavior and temperament may be useful in genetic evaluations either as indicator traits for other economically relevant traits or because the behavior traits may have a direct economic value. We determined the variation in feeding behavior and temperament of beef cattle sired by Angus, Charolais, or Hybrid bulls and evaluated their associations with performance, efficiency, and carcass merit. The behavior traits were daily feeding duration, feeding head down (HD) time, feeding frequency (FF), and flight speed (FS, as a measure of temperament). A pedigree file of 813 animals forming 28 paternal half-sib families with about 20 progeny per sire was used. Performance, feeding behavior, and efficiency records were available on 464 animals of which 381 and 302 had records on carcass merit and flight speed, respectively. Large SE reflect the number of animals used. Direct heritability estimates were 0.28 +/- 0.12 for feeding duration, 0.33 +/- 0.12 for HD, 0.38 +/- 0.13 for FF, and 0.49 +/- 0.18 for FS. Feeding duration had a weak positive genetic (r(g)) correlation with HD (r(g) = 0.25 +/- 0.32) and FS (r(g) = 0.42 +/- 0.26) but a moderate negative genetic correlation with FF (r(g) = -0.40 +/- 0.30). Feeding duration had positive phenotypic (r(p)) and genetic correlations with DMI (r(p) = 0.27; r(g) = 0.56 +/- 0.20) and residual feed intake (RFI; r(p) = 0.49; r(g) = 0.57 +/- 0.28) but was unrelated phenotypically with feed conversion ratio [FCR; which is the reciprocal of the efficiency of growth (G:F)]. Feeding duration was negatively correlated with FCR (r(g) = -0.25 +/- 0.29). Feeding frequency had a moderate to high negative genetic correlation with DMI (r(g) = -0.74 +/- 0.15), FCR (r(g) = -0.52 +/- 0.21), and RFI (r(g) = -0.77 +/- 0.21). Flight speed was negatively correlated phenotypically with DMI (r(p) = -0.35) but was unrelated phenotypically with FCR or RFI. On the other hand, FS had a weak negative genetic correlation with DMI (r(g) = -0.11 +/- 0.26), a moderate genetic correlation with FCR (r(g) = 0.40 +/- 0.26), and a negative genetic correlation with RFI (r(g) = -0.59 +/- 0.45). The results indicate that behavior traits may contribute to the variation in the efficiency of growth of beef cattle, and there are potential correlated responses to selection to improve efficiency. Feeding behavior and temperament may need to be included in the definition of beef cattle breeding goals, and approaches such as the culling of unmanageable cattle and the introduction of correct handling facilities or early life provision of appropriate experiences to improve handling will be useful.

Suggestive Linkage of the Child Behavior Checklist Juvenile Bipolar Disorder Phenotype to 1p21, 6p21, and 8q21

ERIC Educational Resources Information Center

Doyle, Alysa E.; Biederman, Joseph; Ferreira, Manuel A. R.; Wong, Patricia; Smoller, Jordan W.; Faraone, Stephen V.

2010-01-01

Objective: Several studies have documented a profile of elevated scores on the Attention Problems, Aggressive Behavior and Anxious/Depressed scales of the Child Behavior Checklist (CBCL) in youth with bipolar disorder. The sum of these scales, referred to as the CBCL Juvenile Bipolar Disorder (JBD) phenotype, has modest diagnostic utility, and…

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

PubMed Central

Pappas, Andrea L.; Bey, Alexandra L.; Wang, Xiaoming; Rossi, Mark; Kim, Yong Ho; Yan, Haidun; Porkka, Fiona; Duffney, Lara J.; Phillips, Samantha M.; Cao, Xinyu; Ding, Jin-dong; Rodriguiz, Ramona M.; Yin, Henry H.; Wetsel, William C.

2017-01-01

Genetic defects in the synaptic scaffolding protein gene, SHANK2, are linked to a variety of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and bipolar disorder, but the molecular mechanisms underlying the pleotropic effects of SHANK2 mutations are poorly understood. We generated and characterized a line of Shank2 mutant mice by deleting exon 24 (Δe24). Shank2Δe24–/– mice engage in significantly increased locomotor activity, display abnormal reward-seeking behavior, are anhedonic, have perturbations in circadian rhythms, and show deficits in social and cognitive behaviors. While these phenotypes recapitulate the pleotropic behaviors associated with human SHANK2-related disorders, major behavioral features in these mice are reminiscent of bipolar disorder. For instance, their hyperactivity was augmented with amphetamine but was normalized with the mood stabilizers lithium and valproate. Shank2 deficiency limited to the forebrain recapitulated the bipolar mania phenotype. The composition and functions of NMDA and AMPA receptors were altered at Shank2-deficient synapses, hinting toward the mechanism underlying these behavioral abnormalities. Human genetic findings support construct validity, and the behavioral features in Shank2 Δe24 mice support face and predictive validities of this model for bipolar mania. Further genetic studies to understand the contribution of SHANK2 deficiencies in bipolar disorder are warranted. PMID:29046483

Phenotypic plasticity in a population of odonates.

PubMed

Bowman, Randi M; Schmidt, Sharol; Weeks, Chelsea; Clark, Hunter; Brown, Christopher; Latta, Leigh C; Edgehouse, Michael

2018-05-31

The maintenance of phenotypic plasticity within a species ensures survival through environmental flux. Plastic strategies are increasingly important given the number and magnitude of modern anthropogenic threats to the environment. We tested for phenotypic plasticity in the odonate Argia vivida in response to resource limitation. By limiting food availability, effectively inducing hunger, we were able to quantify shifts in agonistic behavior during intraspecific interactions. Scoring behavior in one-on-one combat trials after 1 and 4 days without food revealed phenotypic plasticity. Three classes of genotypes were identified, genotypes exhibiting either increased aggression, decreased aggression, or no phenotypic plasticity, in response to resource limitation. The variable plastic strategies in this population of odonates likely aids in maintaining fitness in fluctuating environments.

Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome.

PubMed

Tordjman, Sylvie; Anderson, George M; Cohen, David; Kermarrec, Solenn; Carlier, Michèle; Touitou, Yvan; Saugier-Veber, Pascale; Lagneaux, Céline; Chevreuil, Claire; Verloes, Alain

2013-08-23

Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized. Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.

The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses

PubMed Central

2014-01-01

Background There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). Conclusions TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples. PMID:25392729

Brain mast cells link the immune system to anxiety-like behavior

PubMed Central

Nautiyal, Katherine M.; Ribeiro, Ana C.; Pfaff, Donald W.; Silver, Rae

2008-01-01

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient KitW−sh/W−sh (sash−/−) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links. PMID:19004805

Brain mast cells link the immune system to anxiety-like behavior.

PubMed

Nautiyal, Katherine M; Ribeiro, Ana C; Pfaff, Donald W; Silver, Rae

2008-11-18

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient Kit(W-sh/W-sh) (sash(-/-)) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

Indirect genetic effect model using feeding behaviour traits to define the degree of interaction between mates: an implementation in pigs growth rate.

PubMed

Ragab, M; Piles, M; Quintanilla, R; Sánchez, J P

2018-06-06

An alternative implementation of the animal model including indirect genetic effect (IGE) is presented considering pair-mate-specific interaction degrees to improve the performance of the model. Data consisted of average daily gain (ADG) records from 663 pigs kept in groups of 10 to 14 mates during the fattening period. Three types of models were used to fit ADG data: (i) animal model (AM); (ii) AM with classical IGE (AM-IGE); and (iii) AM fitting IGE with a specific degree of interaction between each pair of mates (AM-IGEi). Several feeding behavior phenotypes were used to define the pair-mate-specific degree of interaction in AM-IGEi: feeding rate (g/min), feeding frequency (min/day), the time between consecutive visits to the feeder (min/day), occupation time (min/day) and an index considering all these variables. All models included systematic effects batch, initial age (covariate), final age (covariate), number of pigs per pen (covariate), plus the random effect of the pen. Estimated posterior mean (posterior SD) of heritability was 0.47 (0.15) using AM. Including social genetic effects in the model, total heritable variance expressed as a proportion of total phenotypic variance (T 2) was 0.54 (0.29) using AM-IGE, whereas it ranged from 0.51 to 0.55 (0.12 to 0.14) with AM-IGEi, depending on the behavior trait used to define social interactions. These results confirm the contribution of IGEs to the total heritable variation of ADG. Moreover, important differences between models were observed in EBV rankings. The percentage of coincidence of top 10% animals between AM and AM-IGEi ranged from 0.44 to 0.89 and from 0.41to 0.68 between AM-IGE and AM-IGEi. Based on the goodness of fit and predictive ability, social models are preferred for the genetic evaluation of ADG. Among models including IGEs, when the pair-specific degree of interaction was defined using feeding behavior phenotypes we obtained an increase in the accuracy of genetic parameters estimates, the better goodness of fit and higher predictive ability. We conclude that feeding behavior variables can be used to measure the interaction between pen mates and to improve the performance of models including IGEs.

Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice.

PubMed

Ren, Zhen; Sahir, Nadia; Murakami, Shoko; Luellen, Beth A; Earnheart, John C; Lal, Rachnanjali; Kim, Ju Young; Song, Hongjun; Luscher, Bernhard

2015-01-01

Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2(+/-) mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The γ2(+/-) model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2(+/-) mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical γ2(+/-) neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of γ2(+/-) mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of γ2(+/-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

Alcohol-related Genes Show an Enrichment of Associations with a Persistent Externalizing Factor

PubMed Central

Ashenhurst, James R.; Harden, K. Paige; Corbin, William R.; Fromme, Kim

2016-01-01

Research using twins has found that much of the variability in externalizing phenotypes – including alcohol and drug use, impulsive personality traits, risky sex and property crime – is explained by genetic factors. Nevertheless, identification of specific genes and variants associated with these traits has proven to be difficult, likely because individual differences in externalizing are explained by many genes of small individual effect. Moreover, twin research indicates that heritable variance in externalizing behaviors is mostly shared across the externalizing spectrum rather than specific to any behavior. We use a longitudinal, “deep phenotyping” approach to model a general externalizing factor reflecting persistent engagement in a variety of socially problematic behaviors measured at eleven assessment occasions spanning early adulthood (ages 18 to 28). In an ancestrally homogenous sample of non-Hispanic Whites (N = 337), we then tested for enrichment of associations between the persistent externalizing factor and a set of 3,281 polymorphisms within 104 genes that were previously identified as associated with alcohol-use behaviors. Next we tested for enrichment among domain-specific factors (e.g., property crime) composed of residual variance not accounted for by the common factor. Significance was determined relative to bootstrapped empirical thresholds derived from permutations of phenotypic data. Results indicated significant enrichment of genetic associations for persistent externalizing, but not for domain-specific factors. Consistent with twin research findings, these results suggest that genetic variants are broadly associated with externalizing behaviors rather than unique to specific behaviors. General Scientific Summary This study shows that variation in 104 genes is associated with socially problematic “externalizing” behavior, including substance misuse, property crime, risky sex, and aspects of impulsive personality. Importantly, this association was with the common variation across these behaviors rather than with the variation unique to any given behavior. The manuscript demonstrates a potentially advantageous technique for relating sets of hypothesized genes to complex traits or behaviors. PMID:27505405

Applying Quantitative Genetic Methods to Primate Social Behavior

PubMed Central

Brent, Lauren J. N.

2013-01-01

Increasingly, behavioral ecologists have applied quantitative genetic methods to investigate the evolution of behaviors in wild animal populations. The promise of quantitative genetics in unmanaged populations opens the door for simultaneous analysis of inheritance, phenotypic plasticity, and patterns of selection on behavioral phenotypes all within the same study. In this article, we describe how quantitative genetic techniques provide studies of the evolution of behavior with information that is unique and valuable. We outline technical obstacles for applying quantitative genetic techniques that are of particular relevance to studies of behavior in primates, especially those living in noncaptive populations, e.g., the need for pedigree information, non-Gaussian phenotypes, and demonstrate how many of these barriers are now surmountable. We illustrate this by applying recent quantitative genetic methods to spatial proximity data, a simple and widely collected primate social behavior, from adult rhesus macaques on Cayo Santiago. Our analysis shows that proximity measures are consistent across repeated measurements on individuals (repeatable) and that kin have similar mean measurements (heritable). Quantitative genetics may hold lessons of considerable importance for studies of primate behavior, even those without a specific genetic focus. PMID:24659839

Cognitive, emotional and social phenotyping of mice in an observer-independent setting.

PubMed

Dere, Ekrem; Ronnenberg, Anja; Tampe, Björn; Arinrad, Sahab; Schmidt, Manuela; Zeisberg, Elisabeth; Ehrenreich, Hannelore

2018-04-01

Based on the intellicage paradigm, we have developed a novel cognitive, emotional and social phenotyping battery that permits comprehensive standardized behavioral characterization of mice in an experimenter-independent social setting. Evaluation of this battery in a large number of male and female C57BL/6 wildtype mice, tested in >20 independent cohorts, revealed high reproducibility of the behavioral readouts and may serve as future reference tool. We noticed robust sex-specific differences in general activity, cognitive and emotional behavior, but not regarding preference for social pheromones. Specifically, female mice revealed higher activity, decreased sucrose preference, impaired reversal and place-time-reward learning. Furthermore, female mice reacted more sensitively than males to reward-withdrawal showing a negative emotional contrast/Crespi-effect. In a series of validation experiments, we tested mice with different pathologies, including neuroligin-3 deficient mice (male Nlgn3 y/- and female Nlgn3 +/- ) for autistic behavior, oligodendrocyte-specific erythropoietin receptor knockout (oEpoR -/- ) mice for cognitive impairment, as well as mouse models of renal failure (unilateral ureteral obstruction and 5/6 nephrectomy) and of type 2 diabetes (ApoE -/- ) - for delineating potentially confounding effects of motivational factors (thirst, glucose-craving) on learning and memory assessments. As prominent features, we saw in Nlgn3 mutants reduced preference for social pheromones, whereas oEpoR -/- mice showed learning deficits in place or reversal learning tasks. Renal failure led to increased water intake, and diabetic metabolism to enhanced glucose preference, limiting interpretation of hereon based learning and memory performance in these mice. The phenotyping battery presented here may be well-suited as high-throughput multifaceted diagnostic instrument for translational neuropsychiatry and behavioral genetics. Copyright © 2018. Published by Elsevier Inc.

Exposure to dim light at night during early development increases adult anxiety-like responses.

PubMed

Borniger, Jeremy C; McHenry, Zachary D; Abi Salloum, Bachir A; Nelson, Randy J

2014-06-22

Early experiences produce effects that may persist throughout life. Therefore, to understand adult phenotype, it is important to investigate the role of early environmental stimuli in adult behavior and health. Artificial light at night (LAN) is an increasingly common phenomenon throughout the world. However, animals, including humans, evolved under dark night conditions. Many studies have revealed affective, immune, and metabolic alterations provoked by aberrant light exposure and subsequent circadian disruption. Pups are receptive to entraining cues from the mother and then light early during development, raising the possibility that the early life light environment may influence subsequent behavior. Thus, to investigate potential influences of early life exposure to LAN on adult phenotype, we exposed mice to dim (~5 lux; full spectrum white light) or dark (~0 lux) nights pre- and/or postnatally. After weaning at 3 weeks of age, all mice were maintained in dark nights until adulthood (9 weeks of age) when behavior was assessed. Mice exposed to dim light in early life increased anxiety-like behavior and fearful responses on the elevated plus maze and passive avoidance tests. These mice also displayed reduced growth rates, which ultimately normalized during adolescence. mRNA expression of brain derived neurotrophic factor (BDNF), a neurotrophin previously linked to early life environment and adult phenotype, was not altered in the prefrontal cortex or hippocampus by early life LAN exposure. Serum corticosterone concentrations were similar between groups at weaning, suggesting that early life LAN does not elicit a long-term physiologic stress response. Dim light exposure did not influence behavior on the open field, novel object, sucrose anhedonia, or forced swim tests. Our data highlight the potential deleterious consequences of low levels of light during early life to development and subsequent behavior. Whether these changes are due to altered maternal behavior or persistent circadian abnormalities incurred by LAN remains to be determined. Copyright © 2014 Elsevier Inc. All rights reserved.

Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis.

PubMed

Ravits, John; Appel, Stanley; Baloh, Robert H; Barohn, Richard; Brooks, Benjamin Rix; Elman, Lauren; Floeter, Mary Kay; Henderson, Christopher; Lomen-Hoerth, Catherine; Macklis, Jeffrey D; McCluskey, Leo; Mitsumoto, Hiroshi; Przedborski, Serge; Rothstein, Jeffrey; Trojanowski, John Q; van den Berg, Leonard H; Ringel, Steven

2013-05-01

Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable.

Auditory Phenotype of Smith-Magenis Syndrome.

PubMed

Brendal, Megan A; King, Kelly A; Zalewski, Christopher K; Finucane, Brenda M; Introne, Wendy; Brewer, Carmen C; Smith, Ann C M

2017-04-14

The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings. Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11-49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1-10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings. This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care.

A Federated Network for Translational Cancer Research Using Clinical Data and Biospecimens

PubMed Central

Becich, Michael J.; Bollag, Roni J.; Chavan, Girish; Corrigan, Julia; Dhir, Rajiv; Feldman, Michael D.; Gaudioso, Carmelo; Legowski, Elizabeth; Maihle, Nita J.; Mitchell, Kevin; Murphy, Monica; Sakthivel, Mayur; Tseytlin, Eugene; Weaver, JoEllen

2015-01-01

Advances in cancer research and personalized medicine will require significant new bridging infrastructures, including more robust biorepositories that link human tissue to clinical phenotypes and outcomes. In order to meet that challenge, four cancer centers formed the TIES Cancer Research Network, a federated network that facilitates data and biospecimen sharing among member institutions. Member sites can access pathology data that is de-identified and processed with the TIES natural language processing system, which creates a repository of rich phenotype data linked to clinical biospecimens. TIES incorporates multiple security and privacy best practices that, combined with legal agreements, network policies and procedures, enable regulatory compliance. The TIES Cancer Research Network now provides integrated access to investigators at all member institutions, where multiple investigator-driven pilot projects are underway. Examples of federated search across the network illustrate the potential impact on translational research, particularly for studies involving rare cancers, rare phenotypes, and specific biologic behaviors. The network satisfies several key desiderata including local control of data and credentialing, inclusion of rich phenotype information, and applicability to diverse research objectives. The TIES Cancer Research Network presents a model for a national data and biospecimen network. PMID:26670560

Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice.

PubMed

Williams, Aislinn J; Yee, Patricia; Smith, Mitchell C; Murphy, Geoffrey G; Umemori, Hisashi

2016-07-01

Specific growth factors induce formation and differentiation of excitatory and inhibitory synapses, and are essential for brain development and function. Fibroblast growth factor 22 (FGF22) is important for specifying excitatory synapses during development, including in the hippocampus. Mice with a genetic deletion of FGF22 (FGF22KO) during development subsequently have fewer hippocampal excitatory synapses in adulthood. As a result, FGF22KO mice are resistant to epileptic seizure induction. In addition to playing a key role in learning, the hippocampus is known to mediate mood and anxiety. Here, we explored whether loss of FGF22 alters affective, anxiety or social cognitive behaviors in mice. We found that relative to control mice, FGF22KO mice display longer duration of floating and decreased latency to float in the forced swim test, increased immobility in the tail suspension test, and decreased preference for sucrose in the sucrose preference test, which are all suggestive of a depressive-like phenotype. No differences were observed between control and FGF22KO mice in other behavioral assays, including motor, anxiety, or social cognitive tests. These results suggest a novel role for FGF22 specifically in affective behaviors. Copyright © 2016 Elsevier B.V. All rights reserved.

Distinct behavioral phenotypes in ethanol-induced place preference are associated with different extinction and reinstatement but not behavioral sensitization responses

PubMed Central

Pildervasser, João V. N.; Abrahao, Karina P.; Souza-Formigoni, Maria L. O.

2014-01-01

Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. In outbred strains, individual variability may affect some behavioral measures. However, there are few studies focusing on understanding how different phenotypes of ethanol conditioned behavior may influence its extinction, reinstatement, and behavioral adaptation measures. We used male Swiss Webster mice to study different phenotypes related to ethanol conditioning strength, reinstatement and behavioral sensitization. Mice went through a CPP procedure with ethanol (2.2 g/kg, i.p.). After that, one group of mice was submitted to repeated extinction sessions, while another group remained in their home cages without any drug treatment. Mice went through environmental and ethanol priming (1.0 g/kg, i.p.) reinstatement tests. Ethanol priming test reinstated the conditioned behavior only in the animals kept in the home-cage during the abstinence period. Besides, the ethanol conditioned behavior strength was positively correlated with the time required to be extinguished. In the second set of experiments, some mice went through a CPP protocol followed by behavioral sensitization (five i.p. administrations of ethanol 2.2 g/kg or saline per week, for 3 weeks) and another group of mice went through sensitization followed by CPP. No positive correlation was observed between ethanol CPP strength and the intensity of behavioral sensitization. Considering that different phenotypes observed in CPP strength predicted the variability in other CPP measures, we developed a statistics-based method to classify mice according to CPP strength to be used in the evaluation of ethanol conditioning properties. PMID:25152719

Distinct behavioral phenotypes in ethanol-induced place preference are associated with different extinction and reinstatement but not behavioral sensitization responses.

PubMed

Pildervasser, João V N; Abrahao, Karina P; Souza-Formigoni, Maria L O

2014-01-01

Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. In outbred strains, individual variability may affect some behavioral measures. However, there are few studies focusing on understanding how different phenotypes of ethanol conditioned behavior may influence its extinction, reinstatement, and behavioral adaptation measures. We used male Swiss Webster mice to study different phenotypes related to ethanol conditioning strength, reinstatement and behavioral sensitization. Mice went through a CPP procedure with ethanol (2.2 g/kg, i.p.). After that, one group of mice was submitted to repeated extinction sessions, while another group remained in their home cages without any drug treatment. Mice went through environmental and ethanol priming (1.0 g/kg, i.p.) reinstatement tests. Ethanol priming test reinstated the conditioned behavior only in the animals kept in the home-cage during the abstinence period. Besides, the ethanol conditioned behavior strength was positively correlated with the time required to be extinguished. In the second set of experiments, some mice went through a CPP protocol followed by behavioral sensitization (five i.p. administrations of ethanol 2.2 g/kg or saline per week, for 3 weeks) and another group of mice went through sensitization followed by CPP. No positive correlation was observed between ethanol CPP strength and the intensity of behavioral sensitization. Considering that different phenotypes observed in CPP strength predicted the variability in other CPP measures, we developed a statistics-based method to classify mice according to CPP strength to be used in the evaluation of ethanol conditioning properties.

Brief Report: Impact of Child Problem Behaviors and Parental Broad Autism Phenotype Traits on Substance Use among Parents of Children with ASD

ERIC Educational Resources Information Center

Wade, Jordan L.; Cox, Neill Broderick; Reeve, Ronald E.; Hull, Michael

2014-01-01

Using data from the Simons Simplex Collection, the present study examined the impact of child externalizing behavior and parental broad autism phenotype traits on substance use among parents of children with autism spectrum disorder (n = 2,388). For both fathers and mothers, child externalizing behaviors predicted tobacco use (OR = 1.01 and OR =…

RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex

PubMed Central

Clare, Alison J.; Wicky, Hollie E.; Empson, Ruth M.; Hughes, Stephanie M.

2017-01-01

Forebrain embryonic zinc finger (Fezf2) encodes a transcription factor essential for the specification of layer 5 projection neurons (PNs) in the developing cerebral cortex. As with many developmental transcription factors, Fezf2 continues to be expressed into adulthood, suggesting it remains crucial to the maintenance of neuronal phenotypes. Despite the continued expression, a function has yet to be explored for Fezf2 in the PNs of the developed cortex. Here, we investigated the role of Fezf2 in mature neurons, using lentiviral-mediated delivery of a shRNA to conditionally knockdown the expression of Fezf2 in the mouse primary motor cortex (M1). RNA-sequencing analysis of Fezf2-reduced M1 revealed significant changes to the transcriptome, identifying a regulatory role for Fezf2 in the mature M1. Kyoto Encyclopedia Genes and Genomes (KEGG) pathway analyses of Fezf2-regulated genes indicated a role in neuronal signaling and plasticity, with significant enrichment of neuroactive ligand-receptor interaction, cell adhesion molecules and calcium signaling pathways. Gene Ontology analysis supported a functional role for Fezf2-regulated genes in neuronal transmission and additionally indicated an importance in the regulation of behavior. Using the mammalian phenotype ontology database, we identified a significant overrepresentation of Fezf2-regulated genes associated with specific behavior phenotypes, including associative learning, social interaction, locomotor activation and hyperactivity. These roles were distinct from that of Fezf2-regulated genes identified in development, indicating a dynamic transition in Fezf2 function. Together our findings demonstrate a regulatory role for Fezf2 in the mature brain, with Fezf2-regulated genes having functional roles in sustaining normal neuronal and behavioral phenotypes. These results support the hypothesis that developmental transcription factors are important for maintaining neuron transcriptomes and that disruption of their expression could contribute to the progression of disease phenotypes. PMID:28936162

The insomnia with short sleep duration phenotype: an update on it's importance for health and prevention.

PubMed

Fernandez-Mendoza, Julio

2017-01-01

It was first proposed in the late 1990s that objective markers of sleep disturbance could serve as an index of the biological severity of insomnia. In 2013, a heuristic model of two insomnia phenotypes based on objective sleep duration was proposed. Herein, we review the studies conducted in the past 3 years on the insomnia with short sleep duration phenotype and its implications for a clinical research agenda. Studies have shown that insomnia with objective short sleep duration is associated with physiologic hyperarousal and cardiometabolic and neurocognitive morbidity, whereas insomnia with normal sleep duration is not. Both insomnia phenotypes are associated with psychiatric morbidity albeit through different psychobiological mechanisms. Novel recent studies have included occupational outcomes, developmental approaches, at-home objective sleep testing, diagnostic accuracy measures, and response to cognitive-behavioral treatment. Accumulating evidence in the past years has continued to support that insomnia with short sleep duration is a more severe phenotype of the disorder associated with physiologic changes, significant morbidity and mortality and, potentially, a differential response to treatment.

Behavioral characterization of CD36 knockout mice with SHIRPA primary screen.

PubMed

Zhang, Shuxiao; Wang, Wei; Li, Juan; Cheng, Ke; Zhou, Jingjing; Zhu, Dan; Yang, Deyu; Liang, Zihong; Fang, Liang; Liao, Li; Xie, Peng

2016-02-15

CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36(-/-)) mice. We characterized the behavior of CD36(-/-) mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36(-/-) mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36(-/-) mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36(-/-) mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36(-/-) mice present an anxious phenotype and might be involved in neuropsychiatric disorders. Copyright © 2015. Published by Elsevier B.V.

Mental Health Concerns in Williams Syndrome: Intervention Considerations and Illustrations from Case Examples

ERIC Educational Resources Information Center

Phillips, Kristin D.; Klein-Tasman, Bonita P.

2009-01-01

The refinement of the Williams syndrome phenotype has frequently included the study of behavioral and temperamental features common to individuals with this disorder. Within this line of research, the importance of evaluating incidence of psychopathology has been increasingly recognized, with studies consistently identifying an increased risk for…

Sensitive periods in epigenetics: bringing us closer to complex behavioral phenotypes.

PubMed

Nagy, Corina; Turecki, Gustavo

2012-08-01

Genetic studies have attempted to elucidate causal mechanisms for the development of complex disease, but genome-wide associations have been largely unsuccessful in establishing these links. As an alternative link between genes and disease, recent efforts have focused on mechanisms that alter the function of genes without altering the underlying DNA sequence. Known as epigenetic mechanisms, these include DNA methylation, chromatin conformational changes through histone modifications, ncRNAs and, most recently, 5-hydroxymethylcytosine. Although DNA methylation is involved in normal development, aging and gene regulation, altered methylation patterns have been associated with disease. It is generally believed that early life constitutes a period during which there is increased sensitivity to the regulatory effects of epigenetic mechanisms. The purpose of this review is to outline the contribution of epigenetic mechanisms to genomic function, particularly in the development of complex behavioral phenotypes, focusing on the sensitive periods.

Sensitive Periods in Epigenetics: bringing us closer to complex behavioral phenotypes

PubMed Central

Nagy, Corina; Turecki, Gustavo

2017-01-01

Genetic studies have attempted to elucidate causal mechanisms for the development of complex disease but genome-wide associations have been largely unsuccessful in establishing these links. As an alternative link between genes and disease, recent efforts have focused on mechanisms that alter the function of genes without altering the underlying DNA sequence. Known as epigenetic mechanisms, these include: DNA methylation, chromatin conformational changes through histone modifications, non-coding RNAs, and most recently, 5-hydroxymethylcytosine. Though DNA methylation is involved in normal development, aging and gene regulation, altered methylation patterns have been associated with disease. It is generally believed that early life constitutes a period during which there is increased sensitivity to the regulatory effects of epigenetic mechanisms. The purpose of this review is to outline the contribution of epigenetic mechanisms to genomic function, particularly in the development of complex behavioral phenotypes, focusing on the sensitive periods. PMID:22920183

Complexity in models of cultural niche construction with selection and homophily.

PubMed

Creanza, Nicole; Feldman, Marcus W

2014-07-22

Niche construction is the process by which organisms can alter the ecological environment for themselves, their descendants, and other species. As a result of niche construction, differences in selection pressures may be inherited across generations. Homophily, the tendency of like phenotypes to mate or preferentially associate, influences the evolutionary dynamics of these systems. Here we develop a model that includes selection and homophily as independent culturally transmitted traits that influence the fitness and mate choice determined by another focal cultural trait. We study the joint dynamics of a focal set of beliefs, a behavior that can differentially influence the fitness of those with certain beliefs, and a preference for partnering based on similar beliefs. Cultural transmission, selection, and homophily interact to produce complex evolutionary dynamics, including oscillations, stable polymorphisms of all cultural phenotypes, and simultaneous stability of oscillation and fixation, which have not previously been observed in models of cultural evolution or gene-culture interactions. We discuss applications of this model to the interaction of beliefs and behaviors regarding education, contraception, and animal domestication.

Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems.

PubMed

D'Angelo, Carla S; Da Paz, José A; Kim, Chong A; Bertola, Débora R; Castro, Claudia I E; Varela, Monica C; Koiffmann, Célia P

2006-01-01

Monosomy 1p36 is one of the most commonly observed mental retardation (MR) syndromes that results in a clinically recognizable phenotype including delayed psychomotor development and/or MR, hypotonia, epilepsy, hearing loss, growth delay, microcephaly, deep-set eyes, flat nasal bridge and pointed chin. Besides, a Prader-Willi syndrome (PWS)-like phenotype has been described in patients with 1p36 monosomy. Forty-one patients presenting hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who tested negative for PWS were investigated by FISH and/or microsatellite markers. Twenty-six were analyzed with a 1p-specific subtelomeric probe, and one terminal deletion was identified. Thirty patients (15 of which also studied by FISH) were investigated by microsatellite markers, and no interstitial 1p36 deletion was found. Our patient presenting the 1p36 deletion did not have the striking features of this monosomy, but her clinical and behavioral features were quite similar to those observed in patients with PWS, except for the presence of normal sucking at birth. The extent of the deletion could be limited to the most terminal 2.5 Mb of 1p36, within the chromosomal region 1p36.33-1p36.32, that is smaller than usually seen in monosomy 1p36 patients. Therefore, chromosome 1p36.33 deletion should be investigated in patients with hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who test negative for PWS.

The phenotype of cancer cell invasion controlled by fibril diameter and pore size of 3D collagen networks.

PubMed

Sapudom, Jiranuwat; Rubner, Stefan; Martin, Steve; Kurth, Tony; Riedel, Stefanie; Mierke, Claudia T; Pompe, Tilo

2015-06-01

The behavior of cancer cells is strongly influenced by the properties of extracellular microenvironments, including topology, mechanics and composition. As topological and mechanical properties of the extracellular matrix are hard to access and control for in-depth studies of underlying mechanisms in vivo, defined biomimetic in vitro models are needed. Herein we show, how pore size and fibril diameter of collagen I networks distinctively regulate cancer cell morphology and invasion. Three-dimensional collagen I matrices with a tight control of pore size, fibril diameter and stiffness were reconstituted by adjustment of concentration and pH value during matrix reconstitution. At first, a detailed analysis of topology and mechanics of matrices using confocal laser scanning microscopy, image analysis tools and force spectroscopy indicate pore size and not fibril diameter as the major determinant of matrix elasticity. Secondly, by using two different breast cancer cell lines (MDA-MB-231 and MCF-7), we demonstrate collagen fibril diameter--and not pore size--to primarily regulate cell morphology, cluster formation and invasion. Invasiveness increased and clustering decreased with increasing fibril diameter for both, the highly invasive MDA-MB-231 cells with mesenchymal migratory phenotype and the MCF-7 cells with amoeboid migratory phenotype. As this behavior was independent of overall pore size, matrix elasticity is shown to be not the major determinant of the cell characteristics. Our work emphasizes the complex relationship between structural-mechanical properties of the extracellular matrix and invasive behavior of cancer cells. It suggests a correlation of migratory and invasive phenotype of cancer cells in dependence on topological and mechanical features of the length scale of single fibrils and not on coarse-grained network properties. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors' in Mice

PubMed Central

Vitucci, Daniela; Di Giorgio, Annabella; Napolitano, Francesco; Pelosi, Barbara; Blasi, Giuseppe; Errico, Francesco; Attrotto, Maria Teresa; Gelao, Barbara; Fazio, Leonardo; Taurisano, Paolo; Di Maio, Anna; Marsili, Valentina; Pasqualetti, Massimo; Bertolino, Alessandro; Usiello, Alessandro

2016-01-01

Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia. PMID:26228524

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.

PubMed

Vitucci, Daniela; Di Giorgio, Annabella; Napolitano, Francesco; Pelosi, Barbara; Blasi, Giuseppe; Errico, Francesco; Attrotto, Maria Teresa; Gelao, Barbara; Fazio, Leonardo; Taurisano, Paolo; Di Maio, Anna; Marsili, Valentina; Pasqualetti, Massimo; Bertolino, Alessandro; Usiello, Alessandro

2016-02-01

Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.

Pancreatic Autoantibodies Against CUZD1 and GP2 Are Associated with Distinct Clinical Phenotypes of Crohn's Disease.

PubMed

Michaels, Maike Anna; Jendrek, Sebastian Torben; Korf, Tobias; Nitzsche, Thomas; Teegen, Bianca; Komorowski, Lars; Derer, Stefanie; Schröder, Torsten; Baer, Florian; Lehnert, Henrik; Büning, Jürgen; Fellerman, Klaus; Sina, Christian

2015-12-01

Inflammatory bowel disease (IBD) is characterized by a broad spectrum of clinical phenotypes with different outcomes. In the last decades, several IBD-associated autoantibodies have been identified and investigated for their diagnostic relevance. Autoantibodies against the pancreatic glycoproteins (PAB) CUB and zona pellucida-like domains-containing protein 1 (CUZD1), and glycoprotein 2 (GP2) have been demonstrated to possess high specificity for the diagnosis of IBD. Although several studies have shown significant interrelations of anti-GP2 positivity with disease phenotype, associations of clinical phenotypes with anti-CUZD1 are still unknown. The aim was to identify the association of clinical phenotypes with anti-CUZD1 and anti-GP2 in a well-defined German IBD cohort. Patients with IBD (224 patients with Crohn's disease and 136 patients with ulcerative colitis), who were tested for anti-GP2 and anti-CUZD1 immunoglobulin G and immunoglobulin A by indirect immunofluorescence on transfected cells between 2005 and 2013, were included. Serotype and specified phenotypic data were collected in retrospect and statistically analyzed. Both anti-GP2 (P < 0.001) and anti-CUZD1 (P < 0.001) were significantly more prevalent in patients with Crohn's disease than in ulcerative colitis. PAB positivity was associated with ileocolonic disease (P = 0.002), perianal disease (P = 0.011), immunosuppressive treatment (P = 0.036), and ASCA positivity (P = 0.036). Anti-CUZD1 positivity was associated with ileocolonic (P = 0.016) and perianal disease (P = 0.002), whereas anti-GP2 positivity was positively associated with stricturing behavior (P = 0.016). We found distinct clinical phenotypes to be associated with PAB positivity. Therefore, determination of PABs and their subgroup analysis might identify patients with complicated disease behavior. However, the clinical relevance of our findings should be further evaluated in prospective cohorts.

Genes located in a chromosomal inversion are correlated with territorial song in white-throated sparrows.

PubMed

Zinzow-Kramer, W M; Horton, B M; McKee, C D; Michaud, J M; Tharp, G K; Thomas, J W; Tuttle, E M; Yi, S; Maney, D L

2015-11-01

The genome of the white-throated sparrow (Zonotrichia albicollis) contains an inversion polymorphism on chromosome 2 that is linked to predictable variation in a suite of phenotypic traits including plumage color, aggression and parental behavior. Differences in gene expression between the two color morphs, which represent the two common inversion genotypes (ZAL2/ZAL2 and ZAL2/ZAL2(m) ), may therefore advance our understanding of the molecular underpinnings of these phenotypes. To identify genes that are differentially expressed between the two morphs and correlated with behavior, we quantified gene expression and terrirorial aggression, including song, in a population of free-living white-throated sparrows. We analyzed gene expression in two brain regions, the medial amygdala (MeA) and hypothalamus. Both regions are part of a 'social behavior network', which is rich in steroid hormone receptors and previously linked with territorial behavior. Using weighted gene co-expression network analyses, we identified modules of genes that were correlated with both morph and singing behavior. The majority of these genes were located within the inversion, showing the profound effect of the inversion on the expression of genes captured by the rearrangement. These modules were enriched with genes related to retinoic acid signaling and basic cellular functioning. In the MeA, the most prominent pathways were those related to steroid hormone receptor activity. Within these pathways, the only gene encoding such a receptor was ESR1 (estrogen receptor 1), a gene previously shown to predict song rate in this species. The set of candidate genes we identified may mediate the effects of a chromosomal inversion on territorial behavior. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Investigating host-pathogen behavior and their interaction using genome-scale metabolic network models.

PubMed

Sadhukhan, Priyanka P; Raghunathan, Anu

2014-01-01

Genome Scale Metabolic Modeling methods represent one way to compute whole cell function starting from the genome sequence of an organism and contribute towards understanding and predicting the genotype-phenotype relationship. About 80 models spanning all the kingdoms of life from archaea to eukaryotes have been built till date and used to interrogate cell phenotype under varying conditions. These models have been used to not only understand the flux distribution in evolutionary conserved pathways like glycolysis and the Krebs cycle but also in applications ranging from value added product formation in Escherichia coli to predicting inborn errors of Homo sapiens metabolism. This chapter describes a protocol that delineates the process of genome scale metabolic modeling for analysing host-pathogen behavior and interaction using flux balance analysis (FBA). The steps discussed in the process include (1) reconstruction of a metabolic network from the genome sequence, (2) its representation in a precise mathematical framework, (3) its translation to a model, and (4) the analysis using linear algebra and optimization. The methods for biological interpretations of computed cell phenotypes in the context of individual host and pathogen models and their integration are also discussed.

Links between Natural Variation in the Microbiome and Host Fitness in Wild Mammals.

PubMed

Suzuki, Taichi A

2017-10-01

Recent studies in model organisms have shown that compositional variation in the microbiome can affect a variety of host phenotypes including those related to digestion, development, immunity, and behavior. Natural variation in the microbiome within and between natural populations and species may also affect host phenotypes and thus fitness in the wild. Here, I review recent evidence that compositional variation in the microbiome may affect host phenotypes and fitness in wild mammals. Studies over the last decade indicate that natural variation in the mammalian microbiome may be important in the assistance of energy uptake from different diet types, detoxification of plant secondary compounds, protection from pathogens, chemical communication, and behavior. I discuss the importance of combining both field observations and manipulative experiments in a single system to fully characterize the functions and fitness effects of the microbiome. Finally, I discuss the evolutionary consequences of mammal-microbiome associations by proposing a framework to test how natural selection on hosts is mediated by the microbiome. © The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Genetics of behavior in the silver fox.

PubMed

Kukekova, Anna V; Temnykh, Svetlana V; Johnson, Jennifer L; Trut, Lyudmila N; Acland, Gregory M

2012-02-01

The silver fox provides a rich resource for investigating the genetics of behavior, with strains developed by intensely selective breeding that display markedly different behavioral phenotypes. Until recently, however, the tools for conducting molecular genetic investigations in this species were very limited. In this review, the history of development of this resource and the tools to exploit it are described. Although the focus is on the genetics of domestication in the silver fox, there is a broader context. In particular, one expectation of the silver fox research is that it will be synergistic with studies in other species, including humans, to yield a more comprehensive understanding of the molecular mechanisms and evolution of a wider range of social cognitive behaviors.

Change in the Behavioral Phenotype of Adolescents and Adults with FXS: Role of the Family Environment.

PubMed

Smith, Leann E; Hong, Jinkuk; Greenberg, Jan S; Mailick, Marsha R

2016-05-01

The present study examined trajectories of adaptive behavior, behavior problems, psychological symptoms, and autism symptoms in adolescents and adults with fragile X syndrome (n = 147) over a three-year period. Adaptive behavior significantly increased over time, particularly for adolescents, and the severity of behavior problems decreased over time. Family environmental factors predicted phenotypic variables net of gender, intellectual disability status, and medication use. Maternal warmth was associated with higher levels of adaptive behavior, lower levels of autism symptoms, and decreases in behavior problems over time. Maternal depressive symptoms and criticism were associated with higher levels of psychological symptoms. Implications for interventions are discussed.

Reversible switching between epigenetic states in honeybee behavioral subcastes

PubMed Central

Herb, Brian R.; Wolschin, Florian; Hansen, Kasper D.; Aryee, Martin J.; Langmead, Ben; Irizarry, Rafael; Amdam, Gro V.; Feinberg, Andrew P.

2012-01-01

In honeybee societies, distinct caste phenotypes are created from the same genotype, suggesting a role for epigenetics in deriving these behaviorally different phenotypes. We found no differences in DNA methylation between irreversible worker/queen castes, but substantial differences between nurses and forager subcastes. Reverting foragers back to nurses reestablished methylation levels for a majority of genes and provided the first evidence in any organism of reversible epigenetic changes associated with behavior. PMID:22983211

Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis.

PubMed

Singh, Seema; Choudhury, Arnab; Gusain, Priya; Parvez, Suhel; Palit, Gautam; Shukla, Shubha; Ganguly, Surajit

2016-04-01

Aberrations in cellular acetate-utilization processes leading to global histone hypoacetylation have been implicated in the etiology of neuropsychiatric disorders like schizophrenia. Here, we investigated the role of acetate supplementation in the form of glyceryl triacetate (GTA) for the ability to restore the N-methyl D-aspartate (NMDA) receptor-induced histone hypoacetylation and to ameliorate associated behavioral phenotypes in mice. Taking cues from the studies in SH-SY5Y cells, we monitored acetylation status of specific lysine residues of histones H3 and H4 (H3K9 and H4K8) to determine the impact of oral GTA supplementation in vivo. Mice treated chronically with MK-801 (10 days; 0.15 mg/kg daily) induced hypoacetylation of H3K9 and H4K8 in the hippocampus. Daily oral supplementation of GTA (2.9 g/kg) was able to prevent this MK801-induced hypoacetylation significantly. Though MK-801-stimulated decreases in acetyl-H3K9 and acetyl-H4K8 were found to be associated with ERK1/2 activation, GTA seemed to act independent of this pathway. Simultaneously, GTA administration was able to attenuate the chronic MK-801-induced cognitive behavior phenotypes in elevated plus maze and novel object recognition tests. Not only MK-801, GTA also demonstrated protective effects against behavioral phenotypes generated by another NMDA receptor antagonist, ketamine. Acute (single injection) ketamine-mediated hyperactivity phenotype and chronic (10 days treatment) ketamine-induced phenotype of exaggerated immobility in forced swim test were ameliorated by GTA. The signature behavioral phenotypes induced by acute and chronic regimen of NMDA receptor antagonists seemed to be attenuated by GTA. This study thus provides a therapeutic paradigm of using dietary acetate supplement in psychiatric disorders.

Is Sensory Over-Responsivity Distinguishable from Childhood Behavior Problems? A Phenotypic and Genetic Analysis

ERIC Educational Resources Information Center

Van Hulle, Carol A.; Schmidt, Nicole L.; Goldsmith, H. Hill

2012-01-01

Background: Although impaired sensory processing accompanies various clinical conditions, the question of its status as an independent disorder remains open. Our goal was to delineate the comorbidity (or lack thereof) between childhood psychopathology and sensory over-responsivity (SOR) in middle childhood using phenotypic and behavior-genetic…

Examination of Clock and Adcyap1 gene variation in a neotropical migratory passerine

PubMed Central

Bridge, Eli S.; Ross, Jeremy D.; Shipley, J. Ryan; Kelly, Jeffrey F.

2018-01-01

Complex behavioral traits, such as those making up a migratory phenotype, are regulated by multiple environmental factors and multiple genes. We investigated possible relationships between microsatellite variation at two candidate genes implicated in the control of migratory behavior, Clock and Adcyap1, and several aspects of migratory life-history and evolutionary divergence in the Painted Bunting (Passerina ciris), a species that shows wide variation in migratory and molting strategies across a disjunct distribution. We focused on Clock and Adcyap1 microsatellite variation across three Painted Bunting populations in Oklahoma, Louisiana, and North Carolina, and for the Oklahoma breeding population we used published migration tracking data on adult males to explore phenotypic variation in individual migratory behavior. We found no correlation between microsatellite allele size within either Clock and Adcyap1 relative to the initiation or duration of fall migration in adult males breeding in Oklahoma. We also show the lack of significant correlations with aspects of the migratory phenotype for the Louisiana population. Our research highlights the limitations of studying microsatellite allelic mutations that are of undetermined functional influence relative to complex behavioral phenotypes. PMID:29324772

Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice.

PubMed

Bhattacharya, Aditi; Kaphzan, Hanoch; Alvarez-Dieppa, Amanda C; Murphy, Jaclyn P; Pierre, Philippe; Klann, Eric

2012-10-18

Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS. Copyright © 2012 Elsevier Inc. All rights reserved.

Autistic-like symptomatology in Prader-Willi syndrome: a review of recent findings.

PubMed

Dimitropoulos, Anastasia; Schultz, Robert T

2007-04-01

Prader-Willi syndrome (PWS) is caused by either the structural loss of material or the absence of gene expression from the paternally inherited copy of chromosome 15 in the q11-q13 region. In addition to a well-described behavioral phenotype that includes hyperphagia, obsessive-compulsive symptoms, disruptive behavior, and an increased risk for mood disorders, recent evidence also suggests that some individuals with PWS have repetitive behavior and social deficits reminiscent of autism spectrum disorders. In particular, it appears as if those with maternal uniparental disomy (UPD) as the cause of PWS are at greater risk for autistic symptomatology than those with paternal deletions of 15q11-q13. These findings are particularly intriguing in light of data implicating maternal duplications and triplications of the same chromosomal interval in idiopathic autism, as well as evidence that functional alterations of genes in this region are associated with social deficits found in a variety of neurodevelopmental disorders. This paper will review the recent evidence for phenotypic similarities between autism and PWS and the risk of symptomatology for the UPD subtype.

Neuropeptide Y-Y2 receptor knockout mice: influence of genetic background on anxiety-related behaviors.

PubMed

Zambello, E; Zanetti, L; Hédou, G F; Angelici, O; Arban, R; Tasan, R O; Sperk, G; Caberlotto, L

2011-03-10

Neuropeptide Y (NPY) has been extensively studied in relation to anxiety and depression but of the seven NPY receptors known to date, it is not yet clear which one is mainly involved in mediating its effects in emotional behavior. Mice lacking the NPY-Y2 receptors were previously shown to be less anxious due to their improved ability to cope with stressful situations. In the present study, the behavioral phenotype including the response to challenges was analyzed in NPY-Y2 knockout (KO) mice backcrossed in to congenic C57BL/6 background. In the elevated plus-maze (EPM) and the forced swim test (FST), the anxiolytic-like or antidepressant-like phenotype of the NPY-Y2 KO mice could not be confirmed, although this study differs from the previous one only with regard to the genetic background of the mice. In addition, no differences in response to acute stress or to the antidepressant desipramine in the FST were detected between wild type (WT) and NPY-Y2 KO animals. These results suggest that the genetic background of the animals appears to have a strong influence on the behavioral phenotype of NPY-Y2 KO mice. Additionally, to further characterize the animals by their biochemical response to a challenge, the neurochemical changes induced by the anxiogenic compound yohimbine were measured in the medial prefrontal cortex (mPFC) of NPY-Y2 KO and compared to WT mice. Dopamine (DA) levels were significantly increased by yohimbine in the WT but unaffected in the KO mice, suggesting that NPY-Y2 receptor exerts a direct control over both the tonic and phasic release of DA and that, although the anxiety-like behavior of these NPY-Y2 KO mice is unaltered, there are clear modifications of DA dynamics. However, yohimbine led to a significant increase in noradrenaline (NA) concentration and a slight reduction in serotonin concentration that were identical for both phenotypes. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Neuroendocrinology of Sexual Plasticity in Teleost Fishes

PubMed Central

Godwin, John

2010-01-01

The study of sex differences has produced major insights into the organization of animal phenotypes and the regulatory mechanisms generating phenotypic variation from similar genetic templates. Teleost fishes display the greatest diversity of sexual expression among vertebrate animals. This diversity appears to arise from diversity in the timing of sex determination and less functional interdependence among the components of sexuality relative to tetrapod vertebrates. Teleost model systems therefore provide powerful models for understanding gonadal and non-gonadal influences on behavioral and physiological variation. This review addresses socially controlled sex change and alternate male phenotypes in fishes. These sexual patterns are informative natural experiments that illustrate how variation in conserved neuroendocrine pathways can give rise to a wide range of reproductive adaptations. Key regulatory factors underlying sex change and alternative male phenotypes that have been identified to date include steroid hormones and the neuropeptides GnRH and arginine vasotocin, but genomic approaches are now implicating a diversity of other influences as well. PMID:20176046

Comprehensive Behavioral Phenotyping of Ts65Dn Mouse Model of Down Syndrome: Activation of β1-Adrenergic Receptor by Xamoterol as a Potential Cognitive Enhancer

PubMed Central

Faizi, Mehrdad; Bader, Patrick L.; Tun, Christine; Encarnacion, Angelo; Kleschevnikov, Alexander; Belichenko, Pavel; Saw, Nay; Priestley, Matthew; Tsien, Richard W; Mobley, William C; Shamloo, Mehrdad

2012-01-01

Down Syndrome (DS) is the most prevalent form of mental retardation caused by genetic abnormalities in humans. This has been successfully modeled in mice to generate the Ts65Dn mouse, a genetic model of DS. This transgenic mouse model shares a number of physical and functional abnormalities with people with DS, including changes in the structure and function of neuronal circuits. Significant abnormalities in noradrenergic (NE-ergic) afferents from the locus coeruleus to the hippocampus, as well as deficits in NE-ergic neurotransmission are detected in these animals. In the current study we characterized in detail the behavioral phenotype of Ts65Dn mice, in addition to using pharmacological tools for identification of target receptors mediating the learning and memory deficits observed in this model of DS. We undertook a comprehensive approach to mouse phenotyping using a battery of standard and novel tests encompassing: i) locomotion (Activity Chamber, PhenoTyper, and CatWalk), ii) learning and memory (spontaneous alternation, delayed matching-to-place water maze, fear conditioning, and Intellicage), and iii) social behavior. Ts65Dn mice showed increased locomotor activity in novel and home cage environments. There were significant and reproducible deficits in learning and memory tests including spontaneous alternation, delayed matching-to-place water maze, Intellicage place avoidance and contextual fear conditioning. Although Ts65Dn mice showed no deficit in sociability in the 3-chamber test, a marked impairment in social memory was detected. Xamoterol, a β1-adrenergic receptor (β1-ADR) agonist, effectively restored the memory deficit in contextual fear conditioning, spontaneous alternation and novel object recognition. These behavioral improvements were reversed by betaxolol, a selective β1-ADR antagonist. In conclusion, our results demonstrate that this mouse model of Down Syndrome display cognitive deficits which is mediated by imbalance in noradrenergic system. In this experimental model of Down Syndrome a selective activation of β1-ADR does restore some of these behavioral deficits. Further mechanistic studies will be needed to investigate the failure of noradrenergic system and the role of β1-ADR in cognitive deficit and pathogenesis of DS in people. Restoring NE neurotransmission or a selective activation of β1-ADR need to be further investigated for development of any potential therapeutic strategies for symptomatic relieve of memory deficit in DS. Furthermore, due to the significant involvement of noradrenergic system in the cardiovascular function further safety and translational studies will be needed to ensure the safety and efficacy of this approach. PMID:21527343

Advances in research on the neurological and neuropsychiatric phenotype of Klinefelter syndrome.

PubMed

Savic, Ivanka

2012-04-01

Klinefelter syndrome, 47,XXY is the most common chromosomal aberration among men. It represents a naturally occurring human model for studies of both X-chromosome gene expression and potential androgen effects on brain development and function. The aim of this review is to combine available brain imaging and behavioral data to provide an overview of what we have learned about the neural underpinnings of cognitive, emotional and behavioral dysunctions in Klinefelter syndrome. The behavioral phenotype of 47,XXY is characterized by language, executive and psychomotor dysfunction, as well as socioemotional impairment. The prevalence of schizophrenia, attention deficit hyperactivity disorder, autism spectrum disorders and affective regulation problems is increased. Neuroimaging studies of children and adults with Klinefelter syndrome syndrome show characteristic structural changes from typical individuals. There are increases in the grey matter volume of the sensorimotor and parietooccipital regions, as well as significant reductions in amygdala, hippocampal, insular, temporal and inferior-frontal grey matter volumes. Widespread white matter abnormalities have been revealed, with reductions in some areas (including anterior cingulate, bilaterally) but increases in others (such as left parietal lobe). Mechanisms underlying these developmental anomalies could include imbalance in gene dosage relative to typical men or women, as well as the potential consequence of endocrinological deficits. Studies of Klinefelter syndrome could generate important information about the impact of anomalies in sex chromosome gene regulation on the development of cerebral grey and white matter and, ultimately, on human behavior.

Toward a Mouse Neuroethology in the Laboratory Environment

PubMed Central

Hellier, Jennifer L.; Ly, Xuan; Koka, Kanthaiah; Tollin, Daniel J.; Restrepo, Diego

2010-01-01

In this report we demonstrate that differences in cage type brought unexpected effects on aggressive behavior and neuroanatomical features of the mouse olfactory bulb. A careful characterization of two cage types, including a comparison of the auditory and temperature environments, coupled with a demonstration that naris occlusion abolishes the neuroanatomical changes, lead us to conclude that a likely important factor mediating the phenotypic changes we find is the olfactory environment of the two cages. We infer that seemingly innocuous changes in cage environment can affect sensory input relevant to mice and elicit profound effects on neural output. Study of the neural mechanisms underlying animal behavior in the laboratory environment should be broadened to include neuroethological approaches to examine how the laboratory environment (beyond animal well-being and enrichment) influences neural systems and behavior. PMID:20613876

Hatching behavior in turtles.

PubMed

Spencer, Ricky-John; Janzen, Fredric J

2011-07-01

Incubation temperature plays a prominent role in shaping the phenotypes and fitness of embryos, including affecting developmental rates. In many taxa, including turtles, eggs are deposited in layers such that thermal gradients alter developmental rates within a nest. Despite this thermal effect, a nascent body of experimental work on environmentally cued hatching in turtles has revealed unexpected synchronicity in hatching behavior. This review discusses environmental cues for hatching, physiological mechanisms behind synchronous hatching, proximate and ultimate causes for this behavior, and future directions for research. Four freshwater turtle species have been investigated experimentally, with hatching in each species elicited by different environmental cues and responding via various physiological mechanisms. Hatching of groups of eggs in turtles apparently involves some level of embryo-embryo communication and thus is not a purely passive activity. Although turtles are not icons of complex social behavior, life-history theory predicts that the group environment of the nest can drive the evolution of environmentally cued hatching.

Behavioral and genetic investigations of low exploratory behavior in Il18r1−/− mice: We can’t always blame it on the targeted gene

PubMed Central

Eisener-Dorman, Amy F.; Lawrence, David A.; Bolivar, Valerie J.

2010-01-01

The development of gene targeting technologies has enabled research with immune system-related knockout mouse strains to advance our understanding of how cytokines and their receptors interact and influence a number of body systems, including the central nervous system. A critical issue when we are interpreting phenotypic data from these knockout strains is the potential role of genes other than the targeted one. Although many of the knockout strains have been made congenic on a C57BL/6 (B6) genetic background, there remains a certain amount of genetic material from the129 substrain that was used in the development of these strains. This genetic material could result in phenotypes incorrectly attributed to the targeted gene. We recently reported low activity behavior in Il10−/− mice that was linked to this genetic material rather than the targeted gene itself. In the current study we confirm the generalizability of those earlier findings, by assessing behavior in Il18−/− and Il18r1−/− knockout mice. We identified low activity and high anxiety-like behaviors in Il18r1−/− mice, whereas Il18−/− mice displayed little anxiety-like behavior. Although Il18r1−/− mice are considered a congenic strain, we have identified substantial regions of 129P2-derived genetic material not only flanking the ablated Il18r1 on Chromosome 1, but also on Chromosomes 4, 5, 8, 10, and 14. Our studies suggest that residual 129-derived gene(s), rather than the targeted Il18r1 gene, is/are responsible for the low level of activity seen in the Il18r1−/− mice. Mapping studies are necessary to identify the gene or genes contributing to the low activity phenotype. PMID:20580925

Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.

PubMed

Heikkinen, Taneli; Lehtimäki, Kimmo; Vartiainen, Nina; Puoliväli, Jukka; Hendricks, Susan J; Glaser, Jack R; Bradaia, Amyaouch; Wadel, Kristian; Touller, Chrystelle; Kontkanen, Outi; Yrjänheikki, Juha M; Buisson, Bruno; Howland, David; Beaumont, Vahri; Munoz-Sanjuan, Ignacio; Park, Larry C

2012-01-01

Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.

Behavioral Characteristics of Ubiquitin-Specific Peptidase 46-Deficient Mice

PubMed Central

Imai, Saki; Kano, Makoto; Nonoyama, Keiko; Ebihara, Shizufumi

2013-01-01

We have previously identified Usp46, which encodes for ubiquitin-specific peptidase 46, as a quantitative trait gene affecting the immobility time of mice in the tail suspension test (TST) and forced swimming test. The mutation that we identified was a 3-bp deletion coding for lysine (Lys 92), and mice with this mutation (MT mice), as well as Usp46 KO mice exhibited shorter TST immobility times. Behavioral pharmacology suggests that the gamma aminobutyric acid A (GABAA) receptor is involved in regulating TST immobility time. In order to understand how far Usp46 controls behavioral phenotypes, which could be related to mental disorders in humans, we subjected Usp46 MT and KO mice to multiple behavioral tests, including the open field test, ethanol preference test, ethanol-induced loss of righting reflex test, sucrose preference test, novelty-suppressed feeding test, marble burying test, and novel object recognition test. Although behavioral phenotypes of the Usp46 MT and KO mice were not always identical, deficiency of Usp46 significantly affected performance in all these tests. In the open field test, activity levels were lower in Usp46 KO mice than wild type (WT) or MT mice. Both MT and KO mice showed lower ethanol preference and shorter recovery times after ethanol administration. Compared to WT mice, Usp46 MT and KO mice exhibited decreased sucrose preference, took longer latency periods to bite pellets, and buried more marbles in the sucrose preference test, novelty-suppressed feeding test, and marble burying test, respectively. In the novel object recognition test, neither MT nor KO mice showed an increase in exploration of a new object 24 hours after training. These findings indicate that Usp46 regulates a wide range of behavioral phenotypes that might be related to human mental disorders and provides insight into the function of USP46 deubiquitinating enzyme in the neural system. PMID:23472206

Upper gastrointestinal tract phenotype of Crohn's disease is associated with early surgery and further hospitalization.

PubMed

Chow, Dorothy K L; Sung, Joseph J Y; Wu, Justin C Y; Tsoi, Kelvin K F; Leong, Rupert W L; Chan, Francis K L

2009-04-01

According to the Montreal Classification, upper gastrointestinal tract phenotype L4 is uncommon in Caucasian patients with Crohn's disease (CD) but carries excess risk of recurrence. We studied the clinical course of CD in Chinese patients presenting with the L4 phenotype and factors predicting its occurrence upon longitudinal follow-up. This prospective cohort study included 132 Chinese CD patients (median age at diagnosis, 30.0 years, range: 14.0-77.0 years) who were followed for 770 person-years. Demographic data including disease behavior and location, details of surgery, and hospitalization were collected. The Kaplan-Meier method was used to estimate the probabilities of further hospitalization and major surgery followed by Cox proportional hazards regression to determine if clinical variables independently predicted the endpoints. The L4 phenotype was found in 30 (22.7%) patients at presentation. There were significantly more stricturing (46.7% versus 18.6%) and penetrating (30.0% versus 3.9%) phenotypes in the L4 group than in the non-L4 group (P < 0.0001). The 3-year cumulative probability of further hospitalization was 86.9% (95% confidence interval [CI]: 73.8%-100.0%) in the L4 group as compared with 49.3% (95% CI: 39.3%-59.3%) in the non-L4 group (log-rank test, P < 0.0001). The L4 phenotype independently predicted further hospitalization (adjusted hazards ratio [HR]: 2.1; 95% CI: 1.3-3.5). The cumulative probability of major surgery was significantly higher in the L4 than in the non-L4 group (P < 0.0001). Eighteen (17.6%) patients developed the L4 phenotype on follow-up and the stricturing phenotype predicted its occurrence (adjusted HR: 5.5; 95% CI: 2.2-14.0). Chinese CD patients more often had the L4 phenotype, which predicted the need of subsequent hospitalization.

Mouse Behavior on ISS: The Emergence of a Distinctive, Organized Group Circling Behavior Unique to Spaceflight

NASA Technical Reports Server (NTRS)

Ronca, A. E.; Moyer, E. L.; Talyansky, Y.; Solomides, P.; Choi, S.; Gong, C.; Globus, R. K.

2017-01-01

As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. Only a handful of papers have previously reported behavior of mice and rats in the weightless environment of space (Andreev-Andrievskiy, et al., 2013; Cancedda et al., 2012; Ronca et al., 2008). The Rodent Research Hardware and Operations Validation Mission (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS. Ten adult (16-week-old) female C57BL6J mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in flight. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the RH during this long duration flight. Video was recorded for 34 days on the ISS, permitting daily assessments of overall health and well being of the mice, and providing a valuable repository for detailed behavioral analysis. As compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allogrooming, and social interactions at similar or greater levels of occurrence. Overall activity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized circling or race-tracking behavior that emerged within the first few days of flight following a common developmental sequence, comprising the primary dark cycle activity of FLT mice. Circling participation by individual mice persisted throughout the mission. Analysis of group behavior over mission days revealed recruitment of mice into the group phenotype, coupled with decreasing numbers of collisions between circling mice. This analysis provides insights into the behavior of mice in microgravity, and clear evidence for the emergence of a distinctive, organized group behavior unique to the weightless space environment. Supported by the NASA Rodent Research Project, Space Biology Program, and Space Life Sciences Training Program.

Language Development in Down Syndrome: From the Prelinguistic Period to the Acquisition of Literacy

ERIC Educational Resources Information Center

Abbeduto, Leonard; Warren, Steven F.; Conners, Frances A.

2007-01-01

Down syndrome (DS) is associated with abnormalities in multiple organ systems and a characteristic phenotype that includes numerous behavioral features. Language, however, is among the most impaired domains of functioning in DS and, perhaps, also the greatest barrier to independent meaningful inclusion in the community. In this article, we review…

Phenotypic Characteristics of Autism Spectrum Disorder in a Diverse Sample of Somali and Other Children

ERIC Educational Resources Information Center

Esler, Amy N.; Hall-Lande, Jennifer; Hewitt, Amy

2017-01-01

The potential for culture to impact diagnosis of autism spectrum disorder (ASD) is high, yet remains largely unstudied. This study examined differences across racial/ethnic groups in ASD symptoms, cognitive and adaptive skills, and related behaviors in children with ASD that included a unique subgroup, children from the Somali diaspora. Somali…

Phenotypic integration in an extended phenotype: among-individual variation in nest-building traits of the alfalfa leafcutting bee (Megachile rotundata)

USDA-ARS?s Scientific Manuscript database

Structures such as nests and burrows are an essential component of many organisms’ life-cycle and requires a complex sequence of behaviors. Because behaviors can vary consistently among individuals and be correlated with one another, we hypothesized that these structures would 1) show evidence of am...

Adapting Phonological Awareness Interventions for Children with Down Syndrome Based on the Behavioral Phenotype: A Promising Approach?

ERIC Educational Resources Information Center

Lemons, Christopher J.; King, Seth A.; Davidson, Kimberly A.; Puranik, Cynthia S.; Fulmer, Deborah; Mrachko, Alicia A.; Partanen, Jane; Al Otaiba, Stephanie; Fidler, Deborah J.

2015-01-01

Many children with Down syndrome demonstrate deficits in phonological awareness, a prerequisite to learning to read in an alphabetic language. The purpose of this study was to determine whether adapting a commercially available phonological awareness program to better align with characteristics associated with the behavioral phenotype of Down…

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

PubMed Central

Maulik, Malabika; Mitra, Swarup; Bult-Ito, Abel; Taylor, Barbara E.; Vayndorf, Elena M.

2017-01-01

Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of α-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans. PMID:28659967

Accounting for the Down syndrome advantage?

PubMed

Esbensen, Anna J; Seltzer, Marsha Mailick

2011-01-01

The authors examined factors that could explain the higher levels of psychosocial well being observed in past research in mothers of individuals with Down syndrome compared with mothers of individuals with other types of intellectual disabilities. The authors studied 155 mothers of adults with Down syndrome, contrasting factors that might validly account for the ?Down syndrome advantage? (behavioral phenotype) with those that have been portrayed in past research as artifactual (maternal age, social supports). The behavioral phenotype predicted less pessimism, more life satisfaction, and a better quality of the mother?child relationship. However, younger maternal age and fewer social supports, as well as the behavioral phenotype, predicted higher levels of caregiving burden. Implications for future research on families of individuals with Down syndrome are discussed.

Dissociation between sensitization and learning-related neuromodulation in an aplysiid species.

PubMed

Erixon, N J; Demartini, L J; Wright, W G

1999-06-14

Previous phylogenetic analyses of learning and memory in an opisthobranch lineage uncovered a correlation between two learning-related neuromodulatory traits and their associated behavioral phenotypes. In particular, serotonin-induced increases in sensory neuron spike duration and excitability, which are thought to underlie several facilitatory forms of learning in Aplysia, appear to have been lost over the course of evolution in a distantly related aplysiid, Dolabrifera dolabrifera. This deficit is paralleled by a behavioral deficit: individuals of Dolabrifera do not express generalized sensitization (reflex enhancement of an unhabituated response after a noxious stimulus is applied outside of the reflex receptive field) or dishabituation (reflex enhancement of a habituated reflex). The goal of the present study was to confirm and extend this correlation by testing for the neuromodulatory traits and generalized sensitization in an additional species, Phyllaplysia taylori, which is closely related to Dolabrifera. Instead, our results indicated a lack of correlation between the neuromodulatory and behavioral phenotypes. In particular, sensory neuron homologues in Phyllaplysia showed the ancestral neuromodulatory phenotype typified by Aplysia. Bath-applied 10 microM serotonin significantly increased homologue spike duration and excitability. However, when trained with the identical apparatus and protocols that produced generalized sensitization in Aplysia, individuals of Phyllaplysia showed no evidence of sensitization. Thus, this species expresses the neuromodulatory phenotype of its ancestors while appearing to express the behavioral phenotype of its near relative. These results suggests that generalized sensitization can be lost during the course of evolution in the absence of a deficit in these two neuromodulatory traits, and raises the possibility that the two traits may support some other form of behavioral plasticity in Phyllaplysia. The results also raise the question of the mechanistic basis of the behavioral deficit in Phyllaplysia.

Deletion 2q37 syndrome: Cognitive-behavioral trajectories and autistic features related to breakpoint and deletion size.

PubMed

Fisch, Gene S; Falk, Rena E; Carey, John C; Imitola, Jaime; Sederberg, Maria; Caravalho, Karen S; South, Sarah

2016-09-01

Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The evolution of courtship behaviors through the origination of a new gene in Drosophila

PubMed Central

Dai, Hongzheng; Chen, Ying; Chen, Sidi; Mao, Qiyan; Kennedy, David; Landback, Patrick; Eyre-Walker, Adam; Du, Wei; Long, Manyuan

2008-01-01

New genes can originate by the combination of sequences from unrelated genes or their duplicates to form a chimeric structure. These chimeric genes often evolve rapidly, suggesting that they undergo adaptive evolution and may therefore be involved in novel phenotypes. Their functions, however, are rarely known. Here, we describe the phenotypic effects of a chimeric gene, sphinx, that has recently evolved in Drosophila melanogaster. We show that a knockout of this gene leads to increased male–male courtship in D. melanogaster, although it leaves other aspects of mating behavior unchanged. Comparative studies of courtship behavior in other closely related Drosophila species suggest that this mutant phenotype of male–male courtship is the ancestral condition because these related species show much higher levels of male–male courtship than D. melanogaster. D. melanogaster therefore seems to have evolved in its courtship behaviors by the recruitment of a new chimeric gene. PMID:18508971

[Genotype/phenotype correlation in autism: genetic models and phenotypic characterization].

PubMed

Bonnet-Brilhault, F

2011-02-01

Autism spectrum disorders are a class of conditions categorized by communication problems, ritualistic behaviors, and deficits in social behaviors. This class of disorders merges a heterogeneous group of neurodevelopmental disorders regarding some phenotypic and probably physiopathological aspects. Genetic basis is well admitted, however, considering phenotypic and genotypic heterogeneity, correspondences between genotype and phenotype have yet to be established. To better identify such correspondences, genetic models have to be identified and phenotypic markers have to be characterized. Recent insights show that a variety of genetic mechanisms may be involved in autism spectrum disorders, i.e. single gene disorders, copy number variations and polygenic mechanisms. These current genetic models are described. Regarding clinical aspects, several approaches can be used in genetic studies. Nosographical approach, especially with the concept of autism spectrum disorders, merges a large group of disorders with clinical heterogeneity and may fail to identify clear genotype/phenotype correlations. Dimensional approach referred in genetic studies to the notion of "Broad Autism Phenotype" related to a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype may provide a potentially important complementary approach for detecting the genes involved in these domains. However, control population used in those studies need to be well characterized too. Identification of endophenotypes seems to offer more promising results. Endophenotypes, which are supposed to be more proximal markers of gene action in the same biological pathway, linking genes and complex clinical symptoms, are thought to be less genetically complex than the broader disease phenotype, indexing a limited aspect of genetic risk for the disorder as a whole. However, strategies useful to characterize such phenotypic markers (for example, electrophysiological markers) have to take into account that autism is an early neurodevelopmental disorder occurring during childhood when brain development and maturation are in process. Recent genetic results have improved our knowledge in genetic basis in autism. Nevertheless, correspondences with phenotypic markers remain challenging according to phenotypic and genotypic heterogeneity. Copyright © 2010 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

The after-hours circadian mutant has reduced phenotypic plasticity in behaviors at multiple timescales and in sleep homeostasis.

PubMed

Maggi, Silvia; Balzani, Edoardo; Lassi, Glenda; Garcia-Garcia, Celina; Plano, Andrea; Espinoza, Stefano; Mus, Liudmila; Tinarelli, Federico; Nolan, Patrick M; Gainetdinov, Raul R; Balci, Fuat; Nieus, Thierry; Tucci, Valter

2017-12-19

Circadian clock is known to adapt to environmental changes and can significantly influence cognitive and physiological functions. In this work, we report specific behavioral, cognitive, and sleep homeostatic defects in the after hours (Afh) circadian mouse mutant, which is characterized by lengthened circadian period. We found that the circadian timing irregularities in Afh mice resulted in higher interval timing uncertainty and suboptimal decisions due to incapability of processing probabilities. Our phenotypic observations further suggested that Afh mutants failed to exhibit the necessary phenotypic plasticity for adapting to temporal changes at multiple time scales (seconds-to-minutes to circadian). These behavioral effects of Afh mutation were complemented by the specific disruption of the Per/Cry circadian regulatory complex in brain regions that govern food anticipatory behaviors, sleep, and timing. We derive statistical predictions, which indicate that circadian clock and sleep are complementary processes in controlling behavioral/cognitive performance during 24 hrs. The results of this study have pivotal implications for understanding how the circadian clock modulates sleep and behavior.

Generating Phenotypical Erroneous Human Behavior to Evaluate Human-automation Interaction Using Model Checking

PubMed Central

Bolton, Matthew L.; Bass, Ellen J.; Siminiceanu, Radu I.

2012-01-01

Breakdowns in complex systems often occur as a result of system elements interacting in unanticipated ways. In systems with human operators, human-automation interaction associated with both normative and erroneous human behavior can contribute to such failures. Model-driven design and analysis techniques provide engineers with formal methods tools and techniques capable of evaluating how human behavior can contribute to system failures. This paper presents a novel method for automatically generating task analytic models encompassing both normative and erroneous human behavior from normative task models. The generated erroneous behavior is capable of replicating Hollnagel’s zero-order phenotypes of erroneous action for omissions, jumps, repetitions, and intrusions. Multiple phenotypical acts can occur in sequence, thus allowing for the generation of higher order phenotypes. The task behavior model pattern capable of generating erroneous behavior can be integrated into a formal system model so that system safety properties can be formally verified with a model checker. This allows analysts to prove that a human-automation interactive system (as represented by the model) will or will not satisfy safety properties with both normative and generated erroneous human behavior. We present benchmarks related to the size of the statespace and verification time of models to show how the erroneous human behavior generation process scales. We demonstrate the method with a case study: the operation of a radiation therapy machine. A potential problem resulting from a generated erroneous human action is discovered. A design intervention is presented which prevents this problem from occurring. We discuss how our method could be used to evaluate larger applications and recommend future paths of development. PMID:23105914

Complex Genetics of Behavior: BXDs in the Automated Home-Cage.

PubMed

Loos, Maarten; Verhage, Matthijs; Spijker, Sabine; Smit, August B

2017-01-01

This chapter describes a use case for the genetic dissection and automated analysis of complex behavioral traits using the genetically diverse panel of BXD mouse recombinant inbred strains. Strains of the BXD resource differ widely in terms of gene and protein expression in the brain, as well as in their behavioral repertoire. A large mouse resource opens the possibility for gene finding studies underlying distinct behavioral phenotypes, however, such a resource poses a challenge in behavioral phenotyping. To address the specifics of large-scale screening we describe how to investigate: (1) how to assess mouse behavior systematically in addressing a large genetic cohort, (2) how to dissect automation-derived longitudinal mouse behavior into quantitative parameters, and (3) how to map these quantitative traits to the genome, deriving loci underlying aspects of behavior.

Diet composition and activity level of at risk and metabolically healthy obese American adults.

PubMed

Hankinson, Arlene L; Daviglus, Martha L; Van Horn, Linda; Chan, Queenie; Brown, Ian; Holmes, Elaine; Elliott, Paul; Stamler, Jeremiah

2013-03-01

Obesity often clusters with other major cardiovascular disease risk factors, yet a subset of the obese appears to be protected from these risks. Two obesity phenotypes are described, (i) "metabolically healthy" obese, broadly defined as body mass index (BMI) ≥ 30 kg/m(2) and favorable levels of blood pressure, lipids, and glucose; and (ii) "at risk" obese, BMI ≥ 30 with unfavorable levels of these risk factors. More than 30% of obese American adults are metabolically healthy. Diet and activity determinants of obesity phenotypes are unclear. We hypothesized that metabolically healthy obese have more favorable behavioral factors, including less adverse diet composition and higher activity levels than at risk obese in the multi-ethnic group of 775 obese American adults ages 40-59 years from the International Population Study on Macro/Micronutrients and Blood Pressure (INTERMAP) cohort. In gender-stratified analyses, mean values for diet composition and activity behavior variables, adjusted for age, race, and education, were compared between metabolically healthy and at risk obese. Nearly one in five (149/775 or 19%) of obese American INTERMAP participants were classified as metabolically healthy obese. Diet composition and most activity behaviors were similar between obesity phenotypes, although metabolically healthy obese women reported higher sleep duration than at risk obese women. These results do not support hypotheses that diet composition and/or physical activity account for the absence of cardiometabolic abnormalities in metabolically healthy obese. Copyright © 2012 The Obesity Society.

Analysis of Adult Female Mouse (Mus musculus) Group Behavior on the International Space Station (ISS)

NASA Technical Reports Server (NTRS)

Solomides, P.; Moyer, E. L.; Talyansky, Y.; Choi, S.; Gong, C.; Globus, R. K.; Ronca, A. E.

2016-01-01

As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. A handful of papers have previously reported behavior of mice and rats in the weightless environment of space. The Rodent Research Hardware and Operations Validation (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS (International Space Station). Ten adult (16-week-old) female C57BL/6 mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in microgravity. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the Rodent Habitat (RH) during this long-duration flight. Video was recorded for 33 days on the ISS, permitting daily assessments of overall health and well-being of the mice, and providing a valuable repository for detailed behavioral analysis. We previously reported that, as compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allo-grooming, and social interactions at similar or greater levels of occurrence. Overall activity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized 'circling' or 'race-tracking' behavior that emerged within the first few days of flight following a common developmental sequence, and comprised the primary dark cycle activity persisting throughout the remainder of the experiment. Participation by individual mice increased dramatically over the course of the flight. Here we present a detailed analysis of 'race-tracking' behavior in which we quantified: (1) Complete lap rotations by individual mice; (2) Numbers of collisions between circling mice; (3) Lap directionality; and (4) Recruitment of mice into a group phenotype. This analysis contributes to the first NASA long-duration study of rodent behavior, providing evidence for the emergence of a distinctive, organized group behavior unique to the weightless space environment.

Long term effects of neonatal exposure to fluoxetine on energy balance: A systematic review of experimental studies.

PubMed

da L D Barros, Manuella; Manhães-de-Castro, Raul; Alves, Daniele T; Quevedo, Omar Guzmán; Toscano, Ana Elisa; Bonnin, Alexandre; Galindo, Ligia

2018-06-08

Serotonin exerts a modulating function on the development of the central nervous system, including hypothalamic circuits controlling feeding behavior and energy expenditure. Based on the developmental plasticity theory, early disturbances of synaptic availability of serotonin may promote phenotypic adaptations and late disorders of energy balance regulation leading to obesity and associated diseases. The aim of this systematic review is to determine the effects of pharmacological neonatal inhibition of serotonin reuptake by fluoxetine, on parameters related to feeding behavior and energy balance. Literature searches were performed in Medline/PubMed and Lilacs databases, out of which 9726 studies were found. Using predefined protocol and registered on CAMARADES website, 23 studies were included for qualitative synthesis. The internal validity was assessed using the SYRCLE's risk of bias toll. Kappa index was also measured for analyzing the concordance between the reviewers. In addition, the PRISMA statement was used for reporting this systematic review. Most of the included studies demonstrated that neonatal serotonin reuptake inhibition is associated with long term reduced body weight, lower fat mass and higher thermogenic capacity and mitochondrial oxygen consumption in key metabolic tissues. Therefore, experimental fluoxetine exposure during neonatal development may promote long-term changes related to energy balance associated with a lean phenotype. Copyright © 2018 Elsevier B.V. All rights reserved.

Auditory Phenotype of Smith–Magenis Syndrome

PubMed Central

Brendal, Megan A.; King, Kelly A.; Zalewski, Christopher K.; Finucane, Brenda M.; Introne, Wendy; Smith, Ann C. M.

2017-01-01

Purpose The purpose of this study was to describe the auditory phenotype of a large cohort with Smith–Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Method Hearing-related data were collected for 133 individuals with SMS aged 1–49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings. Results Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11–49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1–10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings. Conclusions This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care. PMID:28384694

Relationship between the broad autism phenotype, social relationships and mental health for mothers of children with autism spectrum disorder.

PubMed

Pruitt, Megan M; Rhoden, Madeline; Ekas, Naomi V

2018-02-01

This study aimed to examine the mechanisms responsible for the association between the broad autism phenotype and depressive symptoms in mothers of a child with autism spectrum disorder. A total of 98 mothers who had a child with autism spectrum disorder between the ages of 2 and 16 years completed assessments of maternal broad autism phenotype, child behavior problems, romantic relationship satisfaction, friend support, family support, and maternal depressive symptoms. Results indicated that only romantic relationship satisfaction was a significant mediator of the relationship between maternal broad autism phenotype social abnormalities and maternal depressive symptoms, where greater broad autism phenotype social abnormalities were associated with lower relationship satisfaction, which in turn was associated with increased depressive symptoms. Child behavior problems were directly related to increased depressive symptoms. Implications regarding maternal mental health outcomes within this population as well as intervention implications are discussed.

Behavior and emotional disturbance in Prader-Willi syndrome.

PubMed

Einfeld, S L; Smith, A; Durvasula, S; Florio, T; Tonge, B J

1999-01-15

To determine if persons with the Prader-Willi syndrome (PWS) have increased psychopathology when compared with matched controls, and whether there is a specific behavior phenotype in PWS, the behavior of 46 persons with PWS was compared with that of control individuals derived from a community sample (N = 454) of persons with mental retardation (MR). Behaviors were studied using the Developmental Behaviour Checklist, an instrument of established validity in the evaluation of behavioral disturbance in individuals with MR. PWS subjects were found to be more behaviorally disturbed than controls overall, and especially in antisocial behavior. In addition, some individual behaviors were more common in PWS subjects than controls. When these behaviors are considered together with findings from other studies using acceptably rigorous methods, a consensus behavior phenotype for PWS can be formulated. This will provide a valid foundation for studies of the mechanism of genetic pathogenesis of behavior in PWS.

Overexpression of mutant ataxin-3 in mouse cerebellum induces ataxia and cerebellar neuropathology.

PubMed

Nóbrega, Clévio; Nascimento-Ferreira, Isabel; Onofre, Isabel; Albuquerque, David; Conceição, Mariana; Déglon, Nicole; de Almeida, Luís Pereira

2013-08-01

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a fatal, dominant neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Clinical manifestations include cerebellar ataxia and pyramidal signs culminating in severe neuronal degeneration. Currently, there is no therapy able to modify disease progression. In the present study, we aimed at investigating one of the most severely affected brain regions in the disorder--the cerebellum--and the behavioral defects associated with the neuropathology in this region. For this purpose, we injected lentiviral vectors encoding full-length human mutant ataxin-3 in the mouse cerebellum of 3-week-old C57/BL6 mice. We show that circumscribed expression of human mutant ataxin-3 in the cerebellum mediates within a short time frame--6 weeks, the development of a behavioral phenotype including reduced motor coordination, wide-based ataxic gait, and hyperactivity. Furthermore, the expression of mutant ataxin-3 resulted in the accumulation of intranuclear inclusions, neuropathological abnormalities, and neuronal death. These data show that lentiviral-based expression of mutant ataxin-3 in the mouse cerebellum induces localized neuropathology, which is sufficient to generate a behavioral ataxic phenotype. Moreover, this approach provides a physiologically relevant, cost-effective and time-effective animal model to gain further insights into the pathogenesis of MJD and for the evaluation of experimental therapeutics of MJD.

Clustering Suicide Attempters: Impulsive-Ambivalent, Well-Planned, or Frequent.

PubMed

Lopez-Castroman, Jorge; Nogue, Erika; Guillaume, Sebastien; Picot, Marie Christine; Courtet, Philippe

2016-06-01

Attempts to predict suicidal behavior within high-risk populations have so far shown insufficient accuracy. Although several psychosocial and clinical features have been consistently associated with suicide attempts, investigations of latent structure in well-characterized populations of suicide attempters are lacking. We analyzed a sample of 1,009 hospitalized suicide attempters that were recruited between 1999 and 2012. Eleven clinically relevant items related to the characteristics of suicidal behavior were submitted to a Hierarchical Ascendant Classification. Phenotypic profiles were compared between the resulting clusters. A decisional tree was constructed to facilitate the differentiation of individuals classified within the first 2 clusters. Most individuals were included in a cluster characterized by less lethal means and planning ("impulse-ambivalent"). A second cluster featured more carefully planned attempts ("well-planned"), more alcohol or drug use before the attempt, and more precautions to avoid interruptions. Finally, a small, third cluster included individuals reporting more attempts ("frequent"), more often serious or violent attempts, and an earlier age at first attempt. Differences across clusters by demographic and clinical characteristics were also found, particularly with the third cluster whose participants had experienced high levels of childhood abuse. Cluster analysis consistently supported 3 distinct clusters of individuals with specific features in their suicidal behaviors and phenotypic profiles that could help clinicians to better focus prevention strategies. © Copyright 2016 Physicians Postgraduate Press, Inc.

Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee.

PubMed

Rittschof, Clare C; Bukhari, Syed Abbas; Sloofman, Laura G; Troy, Joseph M; Caetano-Anollés, Derek; Cash-Ahmed, Amy; Kent, Molly; Lu, Xiaochen; Sanogo, Yibayiri O; Weisner, Patricia A; Zhang, Huimin; Bell, Alison M; Ma, Jian; Sinha, Saurabh; Robinson, Gene E; Stubbs, Lisa

2014-12-16

Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa.

Responses of large mammals to climate change.

PubMed

Hetem, Robyn S; Fuller, Andrea; Maloney, Shane K; Mitchell, Duncan

2014-01-01

Most large terrestrial mammals, including the charismatic species so important for ecotourism, do not have the luxury of rapid micro-evolution or sufficient range shifts as strategies for adjusting to climate change. The rate of climate change is too fast for genetic adaptation to occur in mammals with longevities of decades, typical of large mammals, and landscape fragmentation and population by humans too widespread to allow spontaneous range shifts of large mammals, leaving only the expression of latent phenotypic plasticity to counter effects of climate change. The expression of phenotypic plasticity includes anatomical variation within the same species, changes in phenology, and employment of intrinsic physiological and behavioral capacity that can buffer an animal against the effects of climate change. Whether that buffer will be realized is unknown, because little is known about the efficacy of the expression of plasticity, particularly for large mammals. Future research in climate change biology requires measurement of physiological characteristics of many identified free-living individual animals for long periods, probably decades, to allow us to detect whether expression of phenotypic plasticity will be sufficient to cope with climate change.

Responses of large mammals to climate change

PubMed Central

Hetem, Robyn S; Fuller, Andrea; Maloney, Shane K; Mitchell, Duncan

2014-01-01

Most large terrestrial mammals, including the charismatic species so important for ecotourism, do not have the luxury of rapid micro-evolution or sufficient range shifts as strategies for adjusting to climate change. The rate of climate change is too fast for genetic adaptation to occur in mammals with longevities of decades, typical of large mammals, and landscape fragmentation and population by humans too widespread to allow spontaneous range shifts of large mammals, leaving only the expression of latent phenotypic plasticity to counter effects of climate change. The expression of phenotypic plasticity includes anatomical variation within the same species, changes in phenology, and employment of intrinsic physiological and behavioral capacity that can buffer an animal against the effects of climate change. Whether that buffer will be realized is unknown, because little is known about the efficacy of the expression of plasticity, particularly for large mammals. Future research in climate change biology requires measurement of physiological characteristics of many identified free-living individual animals for long periods, probably decades, to allow us to detect whether expression of phenotypic plasticity will be sufficient to cope with climate change. PMID:27583293

Radiofrequency treatment alters cancer cell phenotype

NASA Astrophysics Data System (ADS)

Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

2015-07-01

The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila

PubMed Central

King, Lanikea B.; Koch, Marta; Murphy, Keith R.; Velazquez, Yoheilly; Ja, William W.; Tomchik, Seth M.

2016-01-01

Neurofibromatosis I is a common genetic disorder that results in tumor formation, and predisposes individuals to a range of cognitive/behavioral symptoms, including deficits in attention, visuospatial skills, learning, language development, and sleep, and autism spectrum disorder-like traits. The nf1-encoded neurofibromin protein (Nf1) exhibits high conservation, from the common fruit fly, Drosophila melanogaster, to humans. Drosophila provides a powerful platform to investigate the signaling cascades upstream and downstream of Nf1, and the fly model exhibits similar behavioral phenotypes to mammalian models. In order to understand how loss of Nf1 affects motor behavior in flies, we combined traditional activity monitoring with video analysis of grooming behavior. In nf1 mutants, spontaneous grooming was increased up to 7x. This increase in activity was distinct from previously described dopamine-dependent hyperactivity, as dopamine transporter mutants exhibited slightly decreased grooming. Finally, we found that relative grooming frequencies can be compared in standard activity monitors that measure infrared beam breaks, enabling the use of activity monitors as an automated method to screen for grooming phenotypes. Overall, these data suggest that loss of nf1 produces excessive activity that is manifested as increased grooming, providing a platform to dissect the molecular genetics of neurofibromin signaling across neuronal circuits. PMID:26896440

Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila.

PubMed

King, Lanikea B; Koch, Marta; Murphy, Keith R; Velazquez, Yoheilly; Ja, William W; Tomchik, Seth M

2016-04-07

Neurofibromatosis I is a common genetic disorder that results in tumor formation, and predisposes individuals to a range of cognitive/behavioral symptoms, including deficits in attention, visuospatial skills, learning, language development, and sleep, and autism spectrum disorder-like traits. The nf1-encoded neurofibromin protein (Nf1) exhibits high conservation, from the common fruit fly, Drosophila melanogaster, to humans. Drosophila provides a powerful platform to investigate the signaling cascades upstream and downstream of Nf1, and the fly model exhibits similar behavioral phenotypes to mammalian models. In order to understand how loss of Nf1 affects motor behavior in flies, we combined traditional activity monitoring with video analysis of grooming behavior. In nf1 mutants, spontaneous grooming was increased up to 7x. This increase in activity was distinct from previously described dopamine-dependent hyperactivity, as dopamine transporter mutants exhibited slightly decreased grooming. Finally, we found that relative grooming frequencies can be compared in standard activity monitors that measure infrared beam breaks, enabling the use of activity monitors as an automated method to screen for grooming phenotypes. Overall, these data suggest that loss of nf1 produces excessive activity that is manifested as increased grooming, providing a platform to dissect the molecular genetics of neurofibromin signaling across neuronal circuits. Copyright © 2016 King et al.

Integrating alcohol response feedback in a brief intervention for young adult heavy drinkers who smoke: A pilot study.

PubMed

Fridberg, Daniel J; Cao, Dingcai; King, Andrea C

2015-10-01

More effective approaches are needed to enhance drinking and other health behavior (e.g., smoking) outcomes of alcohol brief intervention (BI). Young adult heavy drinkers often engage in other health risk behaviors and show sensitivity to alcohol's stimulating and rewarding effects, which predicts future alcohol-related problems. However, standard alcohol BIs do not address these issues. The current pilot study tested the utility of including feedback on alcohol response phenotype to improve BI outcomes among young adult heavy drinkers who smoke (HDS). Thirty-three young adult (M±SD age=23.8±2.1 years) HDS (8.7±4.3 binge episodes/month; 23.6±6.3 smoking days/month) were randomly assigned to standard alcohol BI (BI-S; n=11), standard alcohol BI with personalized alcohol response feedback (BI-ARF; n=10), or a health behavior attention control BI (AC; n=11). Alcohol responses (stimulation, sedation, reward, and smoking urge) for the BI-ARF were recorded during a separate alcohol challenge session (.8g/kg). Outcomes were past-month drinking and smoking behavior assessed at 1- and 6-months post-intervention. At 6-month follow-up, the BI-ARF produced significant reductions in binge drinking, alcohol-smoking co-use, drinking quantity and frequency, and smoking frequency, but not maximum drinks per occasion, relative to baseline. Overall, the BI-ARF produced larger reductions in drinking/smoking behaviors at follow-up than did the BI-S or AC. Including personalized feedback on alcohol response phenotype may improve BI outcomes for young adult HDS. Additional research is warranted to enhance and refine this approach in a broader sample. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Translational Approaches for Studying Neurodevelopmental Disorders Utilizing in Vivo Proton (+H) Magnetic Resonance Spectroscopic Imaging in Rats

NASA Technical Reports Server (NTRS)

Ronca, April E.

2014-01-01

Intrauterine complications have been implicated in the etiology of neuripsychiatric disorders including schizophrenia, autism and ADHD. This presentation will describe new translational studies derived from in vivo magnetic resonance imaging of developing and adult brain following perinatal asphyxia (PA). Our findings reveal significant effects of PA on neurometabolic profiles at one week of age, and significant relationships between early metabolites and later life phenotypes including behavior and brain morphometry

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome.

PubMed

Fung, Lawrence K; Quintin, Eve-Marie; Haas, Brian W; Reiss, Allan L

2012-04-01

The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well - microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.

Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes

ERIC Educational Resources Information Center

Losh, Molly; Piven, Joseph

2007-01-01

Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

Evidence of Phenotypic and Genetic Relationships between Sociality, Emotional Reactivity and Production Traits in Japanese Quail

PubMed Central

Recoquillay, Julien; Leterrier, Christine; Calandreau, Ludovic; Bertin, Aline; Pitel, Frédérique; Gourichon, David; Vignal, Alain; Beaumont, Catherine; Le Bihan-Duval, Elisabeth; Arnould, Cécile

2013-01-01

The social behavior of animals, which is partially controlled by genetics, is one of the factors involved in their adaptation to large breeding groups. To understand better the relationships between different social behaviors, fear behaviors and production traits, we analyzed the phenotypic and genetic correlations of these traits in Japanese quail by a second generation crossing of two lines divergently selected for their social reinstatement behavior. Analyses of results for 900 individuals showed that the phenotypic correlations between behavioral traits were low with the exception of significant correlations between sexual behavior and aggressive pecks both at phenotypic (0.51) and genetic (0.90) levels. Significant positive genetic correlations were observed between emotional reactivity toward a novel object and sexual (0.89) or aggressive (0.63) behaviors. The other genetic correlations were observed mainly between behavioral and production traits. Thus, the level of emotional reactivity, estimated by the duration of tonic immobility, was positively correlated with weight at 17 and 65 days of age (0.76 and 0.79, respectively) and with delayed egg laying onset (0.74). In contrast, a higher level of social reinstatement behavior was associated with an earlier egg laying onset (-0.71). In addition, a strong sexual motivation was correlated with an earlier laying onset (-0.68) and a higher number of eggs laid (0.82). A low level of emotional reactivity toward a novel object and also a higher aggressive behavior were genetically correlated with a higher number of eggs laid (0.61 and 0.58, respectively). These results bring new insights into the complex determinism of social and emotional reactivity behaviors in birds and their relationships with production traits. Furthermore, they highlight the need to combine animal welfare and production traits in selection programs by taking into account traits of sociability and emotional reactivity. PMID:24324761

Changes in Crohn's disease phenotype over time in the Chinese population: validation of the Montreal classification system.

PubMed

Chow, Dorothy K L; Leong, Rupert W L; Lai, Larry H; Wong, Grace L H; Leung, Wai-Keung; Chan, Francis K L; Sung, Joseph J Y

2008-04-01

Phenotypic evolution of Crohn's disease occurs in whites but has never been described in other populations. The Montreal classification may describe phenotypes more precisely. The aim of this study was to validate the Montreal classification through a longitudinal sensitivity analysis in detecting phenotypic variation compared to the Vienna classification. This was a retrospective longitudinal study of consecutive Chinese Crohn's disease patients. All cases were classified by the Montreal classification and the Vienna classification for behavior and location. The evolution of these characteristics and the need for surgery were evaluated. A total of 109 patients were recruited (median follow-up: 4 years, range: 6 months-18 years). Crohn's disease behavior changed 3 years after diagnosis (P = 0.025), with an increase in stricturing and penetrating phenotypes, as determined by the Montreal classification, but was only detected by the Vienna classification after 5 years (P = 0.015). Disease location remained stable on follow-up in both classifications. Thirty-four patients (31%) underwent major surgery during the follow-up period with the stricturing [P = 0.002; hazard ratio (HR): 3.3; 95% CI: 1.5-7.0] and penetrating (P = 0.03; HR: 5.8; 95% CI: 1.2-28.2) phenotypes according to the Montreal classification associated with the need for major surgery. In contrast, colonic disease was protective against a major operation (P = 0.02; HR: 0.3; 95% CI: 0.08-0.8). This is the first study demonstrating phenotypic evolution of Crohn's disease in a nonwhite population. The Montreal classification is more sensitive to behavior phenotypic changes than is the Vienna classification after excluding perianal disease from the penetrating disease category and was useful in predicting course and the need for surgery.

Disrupted mGluR5-Homer scaffolds mediate abnormal mGluR5 signaling, circuit function and behavior in a mouse model of Fragile X Syndrome

PubMed Central

Ronesi, Jennifer A.; Collins, Katie A.; Hays, Seth A.; Tsai, Nien-Pei; Guo, Weirui; Birnbaum, Shari G.; Hu, Jia-Hua; Worley, Paul F.; Gibson, Jay R.; Huber, Kimberly M.

2012-01-01

Enhanced mGluR5 function is causally associated with the pathophysiology of Fragile X Syndrome (FXS), a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the FXS mouse model, Fmr1 KO. In Fmr1 KO mice mGluR5 is less associated with long Homer isoforms, but more associated with the short Homer1a. Genetic deletion of Homer1a restores mGluR5- long Homer scaffolds and corrects multiple phenotypes in Fmr1 KO mice including altered mGluR5 signaling, neocortical circuit dysfunction, and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wildtype mice mimics many Fmr1 KO phenotypes. In contrast, Homer1a deletion does not rescue altered mGluR-dependent long-term synaptic depression or translational control of FMRP target mRNAs. Our findings reveal novel functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism. PMID:22267161

Patterns of developmental plasticity in response to incubation temperature in reptiles.

PubMed

While, Geoffrey M; Noble, Daniel W A; Uller, Tobias; Warner, Daniel A; Riley, Julia L; Du, Wei-Guo; Schwanz, Lisa E

2018-05-28

Early life environments shape phenotypic development in important ways that can lead to long-lasting effects on phenotype and fitness. In reptiles, one aspect of the early environment that impacts development is temperature (termed 'thermal developmental plasticity'). Indeed, the thermal environment during incubation is known to influence morphological, physiological, and behavioral traits, some of which have important consequences for many ecological and evolutionary processes. Despite this, few studies have attempted to synthesize and collate data from this expansive and important body of research. Here, we systematically review research into thermal developmental plasticity across reptiles, structured around the key papers and findings that have shaped the field over the past 50 years. From these papers, we introduce a large database (the 'Reptile Development Database') consisting of 9,773 trait means across 300 studies examining thermal developmental plasticity. This dataset encompasses data on a range of phenotypes, including morphological, physiological, behavioral, and performance traits along with growth rate, incubation duration, sex ratio, and survival (e.g., hatching success) across all major reptile clades. Finally, from our literature synthesis and data exploration, we identify key research themes associated with thermal developmental plasticity, important gaps in empirical research, and demonstrate how future progress can be made through targeted empirical, meta-analytic, and comparative work. © 2018 Wiley Periodicals, Inc.

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice

PubMed Central

Guo, Weirui; Molinaro, Gemma; Collins, Katie A.; Hays, Seth A.; Paylor, Richard; Worley, Paul F.; Szumlinski, Karen K.

2016-01-01

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5R/R) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5R/R mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. SIGNIFICANCE STATEMENT Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders. PMID:26888925

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

PubMed

Guo, Weirui; Molinaro, Gemma; Collins, Katie A; Hays, Seth A; Paylor, Richard; Worley, Paul F; Szumlinski, Karen K; Huber, Kimberly M

2016-02-17

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders. Copyright © 2016 the authors 0270-6474/16/362131-17$15.00/0.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice.

PubMed

Zhang, R; Asai, M; Mahoney, C E; Joachim, M; Shen, Y; Gunner, G; Majzoub, J A

2017-05-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light-dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder.

PubMed

Campbell, Daniel B; Datta, Dibyadeep; Jones, Shaine T; Batey Lee, Evon; Sutcliffe, James S; Hammock, Elizabeth A D; Levitt, Pat

2011-06-01

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

PubMed Central

Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A

2016-01-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593

Chronic Methamphetamine Abuse and Corticostriatal Deficits Revealed by Neuroimaging

PubMed Central

London, Edythe D.; Kohno, Milky; Morales, Angelica; Ballard, Michael E.

2014-01-01

Despite aggressive efforts to contain it, methamphetamine use disorder continues to be major public health problem; and with generic behavioral therapies still the mainstay of treatment for methamphetamine abuse, rates of attrition and relapse remain high. This review summarizes the findings of structural, molecular, and functional neuroimaging studies of methamphetamine abusers, focusing on cortical and striatal abnormalities and their potential contributions to cognitive and behavioral phenotypes that can serve to promote compulsive drug use. These studies indicate that individuals with a history of chronic methamphetamine abuse often display several signs of corticostriatal dysfunction, including abnormal gray- and white-matter integrity, monoamine neurotransmitter system deficiencies, neuroinflammation, poor neuronal integrity, and aberrant patterns of brain connectivity and function, both when engaged in cognitive tasks and at rest. More importantly, many of these neural abnormalities were found to be linked with certain addiction-related phenotypes that may influence treatment response (e.g., poor self-control, cognitive inflexibility, maladaptive decision-making), raising the possibility that they may represent novel therapeutic targets. PMID:25451127

Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice.

PubMed Central

André, E; Conquet, F; Steinmayr, M; Stratton, S C; Porciatti, V; Becker-André, M

1998-01-01

The orphan nuclear receptor RORbeta is expressed in areas of the central nervous system which are involved in the processing of sensory information, including spinal cord, thalamus and sensory cerebellar cortices. Additionally, RORbeta localizes to the three principal anatomical components of the mammalian timing system, the suprachiasmatic nuclei, the retina and the pineal gland. RORbeta mRNA levels oscillate in retina and pineal gland with a circadian rhythm that persists in constant darkness. RORbeta-/- mice display a duck-like gait, transient male incapability to sexually reproduce, and a severely disorganized retina that suffers from postnatal degeneration. Consequently, adult RORbeta-/- mice are blind, yet their circadian activity rhythm is still entrained by light-dark cycles. Interestingly, under conditions of constant darkness, RORbeta-/- mice display an extended period of free-running rhythmicity. The overall behavioral phenotype of RORbeta-/- mice, together with the chromosomal localization of the RORbeta gene, suggests a close relationship to the spontaneous mouse mutation vacillans described >40 years ago. PMID:9670004

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

PubMed

Chen, Yongchang; Yu, Juehua; Niu, Yuyu; Qin, Dongdong; Liu, Hailiang; Li, Gang; Hu, Yingzhou; Wang, Jiaojian; Lu, Yi; Kang, Yu; Jiang, Yong; Wu, Kunhua; Li, Siguang; Wei, Jingkuan; He, Jing; Wang, Junbang; Liu, Xiaojing; Luo, Yuping; Si, Chenyang; Bai, Raoxian; Zhang, Kunshan; Liu, Jie; Huang, Shaoyong; Chen, Zhenzhen; Wang, Shuang; Chen, Xiaoying; Bao, Xinhua; Zhang, Qingping; Li, Fuxing; Geng, Rui; Liang, Aibin; Shen, Dinggang; Jiang, Tianzi; Hu, Xintian; Ma, Yuanye; Ji, Weizhi; Sun, Yi Eve

2017-05-18

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic Similarities between Compulsive Overeating and Addiction Phenotypes: A Case for "Food Addiction"?

PubMed

Carlier, Nina; Marshe, Victoria S; Cmorejova, Jana; Davis, Caroline; Müller, Daniel J

2015-12-01

There exists a continuous spectrum of overeating, where at the extremes there are casual overindulgences and at the other a 'pathological' drive to consume palatable foods. It has been proposed that pathological eating behaviors may be the result of addictive appetitive behavior and loss of ability to regulate the consumption of highly processed foods containing refined carbohydrates, fats, salt, and caffeine. In this review, we highlight the genetic similarities underlying substance addiction phenotypes and overeating compulsions seen in individuals with binge eating disorder. We relate these similarities to findings from neuroimaging studies on reward processing and clinical diagnostic criteria based on addiction phenotypes. The abundance of similarities between compulsive overeating and substance addictions puts forth a case for a 'food addiction' phenotype as a valid, diagnosable disorder.

The Study to Explore Early Development (SEED): A Multisite Epidemiologic Study of Autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network

ERIC Educational Resources Information Center

Schendel, Diana E.; DiGuiseppi, Carolyn; Croen, Lisa A.; Fallin, M. Daniele; Reed, Philip L.; Schieve, Laura A.; Wiggins, Lisa D.; Daniels, Julie; Grether, Judith; Levy, Susan E.; Miller, Lisa; Newschaffer, Craig; Pinto-Martin, Jennifer; Robinson, Cordelia; Windham, Gayle C.; Alexander, Aimee; Aylsworth, Arthur S.; Bernal, Pilar; Bonner, Joseph D.; Blaskey, Lisa; Bradley, Chyrise; Collins, Jack; Ferretti, Casara J.; Farzadegan, Homayoon; Giarelli, Ellen; Harvey, Marques; Hepburn, Susan; Herr, Matthew; Kaparich, Kristina; Landa, Rebecca; Lee, Li-Ching; Levenseller, Brooke; Meyerer, Stacey; Rahbar, Mohammad H.; Ratchford, Andria; Reynolds, Ann; Rosenberg, Steven; Rusyniak, Julie; Shapira, Stuart K.; Smith, Karen; Souders, Margaret; Thompson, Patrick Aaron; Young, Lisa; Yeargin-Allsopp, Marshalyn

2012-01-01

The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal,…

Candidate Genes and the Behavioral Phenotype in 22q11.2 Deletion Syndrome

ERIC Educational Resources Information Center

Prasad, Sarah E.; Howley, Sarah; Murphy, Kieran C.

2008-01-01

There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk…

Lessons learned from the dog genome.

PubMed

Wayne, Robert K; Ostrander, Elaine A

2007-11-01

Extensive genetic resources and a high-quality genome sequence position the dog as an important model species for understanding genome evolution, population genetics and genes underlying complex phenotypic traits. Newly developed genomic resources have expanded our understanding of canine evolutionary history and dog origins. Domestication involved genetic contributions from multiple populations of gray wolves probably through backcrossing. More recently, the advent of controlled breeding practices has segregated genetic variability into distinct dog breeds that possess specific phenotypic traits. Consequently, genome-wide association and selective sweep scans now allow the discovery of genes underlying breed-specific characteristics. The dog is finally emerging as a novel resource for studying the genetic basis of complex traits, including behavior.

[Care continuity for patients with Prader-Willi syndrome during transition from childhood to adulthood].

PubMed

Saitoh, Shinji

2010-01-01

Prader-Willi syndrome(PWS) is a complex multisystem genetic disorder, of which characteristic phenotypes include neonatal hypotonia, hyperphagia resulting in obesity, mental retardation, hypogonadism, and behavioral and psychiatric problems. The diagnosis can be obtained as early as during neonatal period thanks to development of genetic testing. Clinical features of PWS will change depending on age, although core phenotypes of hyperphagia, obesity and psychiatric issues stay for lifetime. Therefore, integrated multidisciplinary approach starting from neonatal period is mandatory to ensure optimal management to improve lifelong quality of life. For successful transition from childhood to adulthood, multidisciplinary team need to share clinical information, and should keep the same policy about food, environment and psychiatric issues.

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease.

PubMed

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-07-28

To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease (CD). Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 +/- 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 +/- 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

Learned helplessness and social avoidance in the Wistar-Kyoto rat

PubMed Central

Nam, Hyungwoo; Clinton, Sarah M.; Jackson, Nateka L.; Kerman, Ilan A.

2014-01-01

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague–Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression. PMID:24744709

Learned helplessness and social avoidance in the Wistar-Kyoto rat.

PubMed

Nam, Hyungwoo; Clinton, Sarah M; Jackson, Nateka L; Kerman, Ilan A

2014-01-01

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague-Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression.

Endocrine mechanisms, behavioral phenotypes and plasticity: known relationships and open questions.

PubMed

Hau, Michaela; Goymann, Wolfgang

2015-01-01

Behavior of wild vertebrate individuals can vary in response to environmental or social factors. Such within-individual behavioral variation is often mediated by hormonal mechanisms. Hormones also serve as a basis for among-individual variations in behavior including animal personalities and the degree of responsiveness to environmental and social stimuli. How do relationships between hormones and behavioral traits evolve to produce such behavioral diversity within and among individuals? Answering questions about evolutionary processes generating among-individual variation requires characterizing how specific hormones are related to variation in specific behavioral traits, whether observed hormonal variation is related to individual fitness and, whether hormonal traits are consistent (repeatable) aspects of an individual's phenotype. With respect to within-individual variation, we need to improve our insight into the nature of the quantitative relationships between hormones and the traits they regulate, which in turn will determine how they may mediate behavioral plasticity of individuals. To address these questions, we review the actions of two steroid hormones, corticosterone and testosterone, in mediating changes in vertebrate behavior, focusing primarily on birds. In the first part, we concentrate on among-individual variation and present examples for how variation in corticosterone concentrations can relate to behaviors such as exploration of novel environments and parental care. We then review studies on correlations between corticosterone variation and fitness, and on the repeatability over time of corticosterone concentrations. At the end of this section, we suggest that further progress in our understanding of evolutionary patterns in the hormonal regulation of behavior may require, as one major tool, reaction norm approaches to characterize hormonal phenotypes as well as their responses to environments. In the second part, we discuss types of quantitative relationships between hormones and behavioral traits within individuals, using testosterone as an example. We review conceptual models for testosterone-behavior relationships and discuss the relevance of these models for within-individual plasticity in behavior. Next, we discuss approaches for testing the nature of quantitative relationships between testosterone and behavior, concluding that again reaction norm approaches might be a fruitful way forward. We propose that an integration of new tools, especially of reaction norm approaches into the field of behavioral endocrinology will allow us to make significant progress in our understanding of the mechanisms, the functional implications and the evolution of hormone-behavior relationships that mediate variation both within and among individuals. This knowledge will be crucial in light of already ongoing habitat alterations due to global change, as it will allow us to evaluate the mechanisms as well as the capacity of wild populations to adjust hormonally-mediated behaviors to altered environmental conditions.

Identification of candidate mimicry proteins involved in parasite-driven phenotypic changes.

PubMed

Hebert, Francois Olivier; Phelps, Luke; Samonte, Irene; Panchal, Mahesh; Grambauer, Stephan; Barber, Iain; Kalbe, Martin; Landry, Christian R; Aubin-Horth, Nadia

2015-04-15

Endoparasites with complex life cycles are faced with several biological challenges, as they need to occupy various ecological niches throughout their development. Host phenotypes that increase the parasite's transmission rate to the next host have been extensively described, but few mechanistic explanations have been proposed to describe their proximate causes. In this study we explore the possibility that host phenotypic changes are triggered by the production of mimicry proteins from the parasite by using an ecological model system consisting of the infection of the threespine stickleback (Gasterosteus aculeatus) by the cestode Schistocephalus solidus. Using RNA-seq data, we assembled 9,093 protein-coding genes from which ORFs were predicted to generate a reference proteome. Based on a previously published method, we built two complementary analysis pipelines to i) establish a general classification of protein similarity among various species (pipeline A) and ii) identify candidate mimicry proteins showing specific host-parasite similarities (pipeline B), a key feature underlying the possibility of molecular mimicry. Ninety-four tapeworm proteins showed high local sequence homology with stickleback proteins. Four of these candidates correspond to secreted or membrane proteins that could be produced by the parasite and eventually be released in or be in contact with the host to modulate physiological pathways involved in various phenotypes (e.g. behaviors). One of these candidates belongs to the Wnt family, a large group of signaling molecules involved in cell-to-cell interactions and various developmental pathways. The three other candidates are involved in ion transport and post-translational protein modifications. We further confirmed that these four candidates are expressed in three different developmental stages of the cestode by RT-PCR, including the stages found in the host. In this study, we identified mimicry candidate peptides from a behavior-altering cestode showing specific sequence similarity with host proteins. Despite their potential role in modulating host pathways that could lead to parasite-induced phenotypic changes and despite our confirmation that they are expressed in the developmental stage corresponding to the altered host behavior, further investigations will be needed to confirm their mechanistic role in the molecular cross-talk taking place between S. solidus and the threespine stickleback.

Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice.

PubMed

Steinmetz, Adam B; Stern, Sarah A; Kohtz, Amy S; Descalzi, Giannina; Alberini, Cristina M

2018-01-24

Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR T + Itpr3 tf /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin-like growth factor II (IGF-II), a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II receptor, but not via IGF-I receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD. SIGNIFICANCE STATEMENT Currently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin-like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD. Copyright © 2018 the authors 0270-6474/18/371015-15$15.00/0.

Relational machine learning for electronic health record-driven phenotyping.

PubMed

Peissig, Peggy L; Santos Costa, Vitor; Caldwell, Michael D; Rottscheit, Carla; Berg, Richard L; Mendonca, Eneida A; Page, David

2014-12-01

Electronic health records (EHR) offer medical and pharmacogenomics research unprecedented opportunities to identify and classify patients at risk. EHRs are collections of highly inter-dependent records that include biological, anatomical, physiological, and behavioral observations. They comprise a patient's clinical phenome, where each patient has thousands of date-stamped records distributed across many relational tables. Development of EHR computer-based phenotyping algorithms require time and medical insight from clinical experts, who most often can only review a small patient subset representative of the total EHR records, to identify phenotype features. In this research we evaluate whether relational machine learning (ML) using inductive logic programming (ILP) can contribute to addressing these issues as a viable approach for EHR-based phenotyping. Two relational learning ILP approaches and three well-known WEKA (Waikato Environment for Knowledge Analysis) implementations of non-relational approaches (PART, J48, and JRIP) were used to develop models for nine phenotypes. International Classification of Diseases, Ninth Revision (ICD-9) coded EHR data were used to select training cohorts for the development of each phenotypic model. Accuracy, precision, recall, F-Measure, and Area Under the Receiver Operating Characteristic (AUROC) curve statistics were measured for each phenotypic model based on independent manually verified test cohorts. A two-sided binomial distribution test (sign test) compared the five ML approaches across phenotypes for statistical significance. We developed an approach to automatically label training examples using ICD-9 diagnosis codes for the ML approaches being evaluated. Nine phenotypic models for each ML approach were evaluated, resulting in better overall model performance in AUROC using ILP when compared to PART (p=0.039), J48 (p=0.003) and JRIP (p=0.003). ILP has the potential to improve phenotyping by independently delivering clinically expert interpretable rules for phenotype definitions, or intuitive phenotypes to assist experts. Relational learning using ILP offers a viable approach to EHR-driven phenotyping. Copyright © 2014 Elsevier Inc. All rights reserved.

Genetic variability of environmental sensitivity revealed by phenotypic variation in body weight and (its) correlations to physiological and behavioral traits

PubMed Central

Quillet, Edwige; Bégout, Marie-Laure; Aupérin, Benoit; Khaw, Hooi Ling; Millot, Sandie; Valotaire, Claudiane; Kernéis, Thierry; Labbé, Laurent; Prunet, Patrick; Dupont-Nivet, Mathilde

2017-01-01

Adaptive phenotypic plasticity is a key component of the ability of organisms to cope with changing environmental conditions. Fish have been shown to exhibit a substantial level of phenotypic plasticity in response to abiotic and biotic factors. In the present study, we investigate the link between environmental sensitivity assessed globally (revealed by phenotypic variation in body weight) and more targeted physiological and behavioral indicators that are generally used to assess the sensitivity of a fish to environmental stressors. We took advantage of original biological material, the rainbow trout isogenic lines, which allowed the disentangling of the genetic and environmental parts of the phenotypic variance. Ten lines were characterized for the changes of body weight variability (weight measurements taken every month during 18 months), the plasma cortisol response to confinement stress (3 challenges) and a set of selected behavioral indicators. This study unambiguously demonstrated the existence of genetic determinism of environmental sensitivity, with some lines being particularly sensitive to environmental fluctuations and others rather insensitive. Correlations between coefficient of variation (CV) for body weight and behavioral and physiological traits were observed. This confirmed that CV for body weight could be used as an indicator of environmental sensitivity. As the relationship between indicators (CV weight, risk-taking, exploration and cortisol) was shown to be likely depending on the nature and intensity of the stressor, the joint use of several indicators should help to investigate the biological complexity of environmental sensitivity. PMID:29253015

Automated Video Analysis System Reveals Distinct Diurnal Behaviors in C57BL/6 and C3H/HeN Mice

PubMed Central

Adamah-Biassi, E. B.; Stepien, I.; Hudson, R.L.; Dubocovich, M.L.

2013-01-01

Advances in rodent behavior dissection using automated video recording and analysis allows detailed phenotyping. This study compared and contrasted 15 diurnal behaviors recorded continuously using an automated behavioral analysis system for a period of 14 days under a 14/10 light/dark cycle in single housed C3H/HeN (C3H) or C57BL/6 (C57) male mice. Diurnal behaviors, recorded with minimal experimental interference and analyzed using phenotypic array and temporal distribution analysis showed bimodal and unimodal profiles in the C57 and C3H mice, respectively. Phenotypic array analysis revealed distinct behavioral rhythms in activity-like behaviors (i.e. walk, hang, jump, come down) (ALB), exploration-like behaviors (i.e. dig, groom, rear up, sniff, stretch) (ELB), ingestion-like behaviors (i.e. drink, eat) (ILB) and resting-like behaviors (i.e. awake, remain low, rest, twitch) (RLB) of C3H and C57 mice. Temporal analysis demonstrated that strain and time of day affects the magnitude and distribution of the spontaneous homecage behaviors. Wheel running activity, water and food measurements correlated with timing of homecage behaviors. Subcutaneous (3 mg/kg, sc) or oral (0.02 mg/ml, oral) melatonin treatments in C57 mice did not modify either the total 24 hr magnitude or temporal distribution of homecage behaviors when compared with vehicle treatments. We conclude that C3H and C57 mice show different spontaneous activity and behavioral rhythms specifically during the night period which are not modulated by melatonin. PMID:23337734

Developing Novel Automated Apparatus for Studying Battery of Social Behaviors in Mutant Mouse Models for Autism

DTIC Science & Technology

2013-06-01

Psychiatry, 2008. 13(1): p. 4-26. 2. McFarlane, H.G., et al., Autism -like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav, 2008. 7(2): p. 152...63. 3. Brodkin, E.S., BALB/c mice: low sociability and other phenotypes that may be relevant to autism . Behav Brain Res, 2007. 176(1): p. 53-65. 4...S.S., et al., Development of a mouse test for repetitive, restricted behaviors: relevance to autism . Behav Brain Res, 2008. 188(1): p. 178-94. 6

Phenotypic instability between the near isogenic substrains BALB/cJ and BALB/cByJ.

PubMed

Sittig, Laura J; Jeong, Choongwon; Tixier, Emily; Davis, Joe; Barrios-Camacho, Camila M; Palmer, Abraham A

2014-12-01

Closely related substrains of inbred mice often show phenotypic differences that are presumed to be caused by recent mutations. The substrains BALB/cJ and BALB/cByJ, which were separated in 1935, have been reported to show numerous highly significant behavioral and morphological differences. In an effort to identify some of the causal mutations, we phenotyped BALB/cJ and BALB/cByJ mice as well as their F1, F2, and N2 progeny for behavioral and morphological phenotypes. We also generated whole-genome sequence data for both inbred strains (~3.5× coverage) with the intention of identifying polymorphic markers to be used for linkage analysis. We observed significant differences in body weight, the weight of the heart, liver, spleen and brain, and corpus callosum length between the two substrains. We also observed that BALB/cJ animals showed greater anxiety-like behavior in the open field test, less depression-like behavior in the tail suspension test, and reduced aggression compared to BALB/cByJ mice. Some but not all of these physiological and behavioral results were inconsistent with prior publications. These inconsistencies led us to suspect that the differences were due to, or modified by, non-genetic factors. Thus, we did not perform linkage analysis. We provide a comprehensive summary of the prior literature about phenotypic differences between these substrains as well as our current findings. We conclude that many differences between these strains are unstable and therefore ill-suited to linkage analysis; the source of this instability is unclear. We discuss the broader implications of these observations for the design of future studies.

Phenotypic instability between the near isogenic substrains BALB/cJ and BALB/cByJ

PubMed Central

Sittig, Laura J.; Jeong, Choongwon; Tixier, Emily; Davis, Joe; Barrios Camacho, Camila M.; Palmer, Abraham A.

2014-01-01

Closely related substrains of inbred mice often show phenotypic difzferences that are presumed to be caused by recent mutations. The substrains BALB/cJ and BALB/cByJ, which were separated in 1935, have been reported to show numerous highly significant behavioral and morphological differences. In an effort to identify some of the causal mutations, we phenotyped BALB/cJ and BALB/cByJ mice as well as their F1, F2, and N2 progeny for behavioral and morphological phenotypes. We also generated whole genome sequence data for both inbred strains (∼3.5× coverage) with the intention of identifying polymorphic markers to be used for linkage analysis. We observed significant differences in body weight, the weight of the heart, liver, spleen and brain, and corpus callosum length between the two substrains. We also observed that BALB/cJ animals showed greater anxiety-like behavior in the open field test, less depression-like behavior in the tail suspension test, and reduced aggression compared to BALB/cByJ mice. Some but not all of these physiological and behavioral results were inconsistent with prior publications. These inconsistencies led us to suspect that the differences were due to, or modified by, non-genetic factors. Thus, we did not perform linkage analysis. We provide a comprehensive summary of the prior literature about phenotypic differences between these substrains as well as our current findings. We conclude that many differences between these strains are unstable and therefore ill-suited to linkage analysis; the source of this instability is unclear. We discuss the broader implications of these observations for the design of future studies. PMID:24997021

Contrasting invertebrate immune defense behaviors caused by a single gene, the Caenorhabditis elegans neuropeptide receptor gene npr-1.

PubMed

Nakad, Rania; Snoek, L Basten; Yang, Wentao; Ellendt, Sunna; Schneider, Franziska; Mohr, Timm G; Rösingh, Lone; Masche, Anna C; Rosenstiel, Philip C; Dierking, Katja; Kammenga, Jan E; Schulenburg, Hinrich

2016-04-11

The invertebrate immune system comprises physiological mechanisms, physical barriers and also behavioral responses. It is generally related to the vertebrate innate immune system and widely believed to provide nonspecific defense against pathogens, whereby the response to different pathogen types is usually mediated by distinct signalling cascades. Recent work suggests that invertebrate immune defense can be more specific at least at the phenotypic level. The underlying genetic mechanisms are as yet poorly understood. We demonstrate in the model invertebrate Caenorhabditis elegans that a single gene, a homolog of the mammalian neuropeptide Y receptor gene, npr-1, mediates contrasting defense phenotypes towards two distinct pathogens, the Gram-positive Bacillus thuringiensis and the Gram-negative Pseudomonas aeruginosa. Our findings are based on combining quantitative trait loci (QTLs) analysis with functional genetic analysis and RNAseq-based transcriptomics. The QTL analysis focused on behavioral immune defense against B. thuringiensis, using recombinant inbred lines (RILs) and introgression lines (ILs). It revealed several defense QTLs, including one on chromosome X comprising the npr-1 gene. The wildtype N2 allele for the latter QTL was associated with reduced defense against B. thuringiensis and thus produced an opposite phenotype to that previously reported for the N2 npr-1 allele against P. aeruginosa. Analysis of npr-1 mutants confirmed these contrasting immune phenotypes for both avoidance behavior and nematode survival. Subsequent transcriptional profiling of C. elegans wildtype and npr-1 mutant suggested that npr-1 mediates defense against both pathogens through p38 MAPK signaling, insulin-like signaling, and C-type lectins. Importantly, increased defense towards P. aeruginosa seems to be additionally influenced through the induction of oxidative stress genes and activation of GATA transcription factors, while the repression of oxidative stress genes combined with activation of Ebox transcription factors appears to enhance susceptibility to B. thuringiensis. Our findings highlight the role of a single gene, npr-1, in fine-tuning nematode immune defense, showing the ability of the invertebrate immune system to produce highly specialized and potentially opposing immune responses via single regulatory genes.

Organelles – understanding noise and heterogeneity in cell biology at an intermediate scale

PubMed Central

Chang, Amy Y.

2017-01-01

ABSTRACT Many studies over the years have shown that non-genetic mechanisms for producing cell-to-cell variation can lead to highly variable behaviors across genetically identical populations of cells. Most work to date has focused on gene expression noise as the primary source of phenotypic heterogeneity, yet other sources may also contribute. In this Commentary, we explore organelle-level heterogeneity as a potential secondary source of cellular ‘noise’ that contributes to phenotypic heterogeneity. We explore mechanisms for generating organelle heterogeneity and present evidence of functional links between organelle morphology and cellular behavior. Given the many instances in which molecular-level heterogeneity has been linked to phenotypic heterogeneity, we posit that organelle heterogeneity may similarly contribute to overall phenotypic heterogeneity and underline the importance of studying organelle heterogeneity to develop a more comprehensive understanding of phenotypic heterogeneity. Finally, we conclude with a discussion of the medical challenges associated with phenotypic heterogeneity and outline how improved methods for characterizing and controlling this heterogeneity may lead to improved therapeutic strategies and outcomes for patients. PMID:28183729

Clinical management of behavioral characteristics of Prader-Willi syndrome.

PubMed

Ho, Alan Y; Dimitropoulos, Anastasia

2010-05-06

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by an abnormality on the long arm of chromosome 15 (q11-q13) that results in a host of phenotypic characteristics, dominated primarily by hyperphagia and insatiable appetite. Characteristic behavioral disturbances in PWS include excessive interest in food, skin picking, difficulty with a change in routine, temper tantrums, obsessive and compulsive behaviors, and mood fluctuations. Individuals with PWS typically have intellectual disabilities (borderline to mild/moderate mental retardation) and exhibit a higher overall behavior disturbance compared to individuals with similar intellectual disability. Due to its multisystem disorder, family members, caregivers, physicians, dieticians, and speech-language pathologists all play an important role in the management and treatment of symptoms in an individual with PWS. This article reviews current research on behavior and cognition in PWS and discusses management guidelines for this disorder.

The role of biofilms: are we hitting the right target?

PubMed

Wolcott, Randall; Dowd, Scot

2011-01-01

Chronic infections affect 17 million people yearly, and approximately 550,000 people die each year from, or with, their chronic infections. Acute and chornic infection differences are well known to clinicians, but the role of bacteria in producing these clinical differences remains poorly understood. This review relies on basic science, clinical studies, and a general review of the medical biofilm literature. The basic science studies are level A and B quality of evidence. The clinical studies are mainly retrospective cohort (level B) and case studies (level C). The biofilm literature includes reviews with varying levels of evidence. All articles have been peer reviewed and meet the standard of evidence-based medicine. Acute infections are associated with planktonic bacteria and must be diagnosed rapidly and accurately to prevent tissue damage and/or death. In contrast, biofilm behavior pursues a more parasitic course by producing sustained host hyperinflammation, with the biofilm feeding on plasma exudate. Chronic infections vacillate over long periods of time, responding only partially to antibiotics and reemerging once the antibiotics are withdrawn. Chronic wounds exhibit similar clinical behavior seen in other chronic infections and are associated with biofilm phenotype bacteria on their surface. Biofilm infections, such as chronic wounds, cannot be adequately diagnosed with current clinical cultures; therefore, molecular methods are necessary. Biofilm phenotype bacteria require multiple concurrent strategies, including débridement and targeted antibiofilm agents. Biofilm phenotype bacteria predominate on the surface of wounds, and biofilm-based management improves wound healing outcomes, indicating that biofilm is the right target for managing the bioburden barrier of chronic wounds.

Genes located in a chromosomal inversion are correlated with territorial song in white-throated sparrows

PubMed Central

Zinzow-Kramer, Wendy M.; Horton, Brent M.; McKee, Clifton D.; Michaud, Justin M.; Tharp, Gregory K.; Thomas, James W.; Tuttle, Elaina M.; Yi, Soojin; Maney, Donna L.

2016-01-01

The genome of the white-throated sparrow (Zonotrichia albicollis) contains an inversion polymorphism on chromosome 2 that is linked to predictable variation in a suite of phenotypic traits including plumage color, aggression, and parental behavior. Differences in gene expression between the two color morphs, which represent the two common inversion genotypes (ZAL2/ZAL2 and ZAL2/ZAL2m), are therefore of potential interest toward understanding the molecular underpinnings of these phenotypes. To identify genes that are differentially expressed between the two morphs and correlated with behavior, we quantified both behavior and brain gene expression in a population of free-living white-throated sparrows. We quantified behavioral responses to simulated territorial intrusions (STIs) early during the breeding season. In the same birds, we then performed a transcriptome-wide analysis of gene expression in two regions, the medial amygdala and hypothalamus. Both regions are part of a ‘social behavior network’, which is rich in steroid hormone receptors and previously linked with territorial behavior. Using network analyses, we identified modules of genes that were correlated with both morph and STI-induced singing behavior. The majority of these genes were located within the inversion, demonstrating the profound effect the inversion has on the expression of genes captured by the rearrangement. Gene pathway analyses revealed that in the medial amygdala, the most prominent pathways were those related to steroid hormone receptor activity. Within these pathways, the only gene encoding such a receptor was ESR1 (estrogen receptor alpha). Our results thus suggest that ESR1 and related genes are important for behavioral differences between the morphs. PMID:26463687

Systematic autistic-like behavioral phenotyping of 4 mouse strains using a novel wheel-running assay.

PubMed

Karvat, Golan; Kimchi, Tali

2012-08-01

Three core symptoms of autistic spectrum disorders are stereotypic movements, resistance to change in routines and deficits in social interaction. In order to understand their neuronal mechanisms, there is a dire need for behavioral paradigms to assess those symptoms in rodents. Here we present a novel method which is based on positive reward in a customized wheel-running apparatus to assess these symptoms. As a proof of concept, 4 mouse strains were tested in the new behavioral paradigm; 2 control lines (C57BL/6 and ICR) and 2 mouse-models of autism (BTBR T+ tf/J and Nlgn3(tm1Sud)). We found that the C57BL/6, ICR and Nlgn3(tm1Sud) mice showed a significant reduction in stereotypical behavior in the presence of the running wheel, ability to forfeit the running habit when the running-wheel was jammed, and preference of interacting with a social stimulus over the jammed running-wheel. No difference was found between genotypes of the Nlgn3(tm1Sud) mice. On the other hand, the BTBR mice exhibited persistent, elevated levels of stereotypical behavior. In addition, they presented a deficit in their ability to adjust to a changing environment, as manifested in persistence to interact with the wheel even when it was jammed. Lastly, the BTBR mice exhibited no significant preference to interact with the stranger mouse over the jammed running-wheel. These results were validated by a set of commonly used behavioral tests. Overall, our novel behavioral paradigm detects multiple components of autistic-like phenotypes, including cognitive rigidity, stereotypic behavior and social deficiency. Copyright © 2012 Elsevier B.V. All rights reserved.

Can the Five Factor Model of Personality Account for the Variability of Autism Symptom Expression? Multivariate Approaches to Behavioral Phenotyping in Adult Autism Spectrum Disorder

ERIC Educational Resources Information Center

Schwartzman, Benjamin C.; Wood, Jeffrey J.; Kapp, Steven K.

2016-01-01

The present study aimed to: determine the extent to which the five factor model of personality (FFM) accounts for variability in autism spectrum disorder (ASD) symptomatology in adults, examine differences in average FFM personality traits of adults with and without ASD and identify distinct behavioral phenotypes within ASD. Adults (N = 828;…

A cell culture technique for human epiretinal membranes to describe cell behavior and membrane contraction in vitro.

PubMed

Wertheimer, Christian; Eibl-Lindner, Kirsten H; Compera, Denise; Kueres, Alexander; Wolf, Armin; Docheva, Denitsa; Priglinger, Siegfried G; Priglinger, Claudia; Schumann, Ricarda G

2017-11-01

To introduce a human cell culture technique for investigating in-vitro behavior of primary epiretinal cells and membrane contraction of fibrocellular tissue surgically removed from eyes with idiopathic macular pucker. Human epiretinal membranes were harvested from ten eyes with idiopathic macular pucker during standard vitrectomy. Specimens were fixed on cell culture plastic using small entomological pins to apply horizontal stress to the tissue, and then transferred to standard cell culture conditions. Cell behavior of 400 epiretinal cells from 10 epiretinal membranes was observed in time-lapse microscopy and analyzed in terms of cell migration, cell velocity, and membrane contraction. Immunocytochemistry was performed for cell type-specific antigens. Cell specific differences in migration behavior were observed comprising two phenotypes: (PT1) epiretinal cells moving fast, less directly, with small round phenotype and (PT2) epiretinal cells moving slowly, directly, with elongated large phenotype. No mitosis, no outgrowth and no migration onto the plastic were seen. Horizontal contraction measurements showed variation between specimens. Masses of epiretinal cells with a myofibroblast-like phenotype expressed cytoplasmatic α-SMA stress fibers and correlated with cell behavior characteristics (PT2). Fast moving epiretinal cells (PT1) were identified as microglia by immunostaining. This in-vitro technique using traction application allows for culturing surgically removed epiretinal membranes from eyes with idiopathic macular pucker, demonstrating cell behavior and membrane contraction of primary human epiretinal cells. Our findings emphasize the abundance of myofibroblasts, the presence of microglia and specific differences of cell behavior in these membranes. This technique has the potential to improve the understanding of pathologies at the vitreomacular interface and might be helpful in establishing anti-fibrotic treatment strategies.

Probing Prokaryotic Social Behaviors with Bacterial “Lobster Traps”

PubMed Central

Connell, Jodi L.; Wessel, Aimee K.; Parsek, Matthew R.; Ellington, Andrew D.; Whiteley, Marvin; Shear, Jason B.

2010-01-01

Bacteria are social organisms that display distinct behaviors/phenotypes when present in groups. These behaviors include the abilities to construct antibiotic-resistant sessile biofilm communities and to communicate with small signaling molecules (quorum sensing [QS]). Our understanding of biofilms and QS arises primarily from in vitro studies of bacterial communities containing large numbers of cells, often greater than 108 bacteria; however, in nature, bacteria often reside in dense clusters (aggregates) consisting of significantly fewer cells. Indeed, bacterial clusters containing 101 to 105 cells are important for transmission of many bacterial pathogens. Here, we describe a versatile strategy for conducting mechanistic studies to interrogate the molecular processes controlling antibiotic resistance and QS-mediated virulence factor production in high-density bacterial clusters. This strategy involves enclosing a single bacterium within three-dimensional picoliter-scale microcavities (referred to as bacterial “lobster traps”) defined by walls that are permeable to nutrients, waste products, and other bioactive small molecules. Within these traps, bacteria divide normally into extremely dense (1012 cells/ml) clonal populations with final population sizes similar to that observed in naturally occurring bacterial clusters. Using these traps, we provide strong evidence that within low-cell-number/high-density bacterial clusters, QS is modulated not only by bacterial density but also by population size and flow rate of the surrounding medium. We also demonstrate that antibiotic resistance develops as cell density increases, with as few as ~150 confined bacteria exhibiting an antibiotic-resistant phenotype similar to biofilm bacteria. Together, these findings provide key insights into clinically relevant phenotypes in low-cell-number/high-density bacterial populations. PMID:21060734

Long-term outcomes of youth who manifested the CBCL-Pediatric Bipolar Disorder phenotype during childhood and/or adolescence.

PubMed

Meyer, Stephanie E; Carlson, Gabrielle A; Youngstrom, Eric; Ronsaville, Donna S; Martinez, Pedro E; Gold, Philip W; Hakak, Rashelle; Radke-Yarrow, Marian

2009-03-01

Recent studies have identified a Child Behavior Checklist (CBCL) profile that characterizes children with severe aggression, inattention, and mood instability. This profile has been coined the CBCL-Pediatric Bipolar Disorder (PBD) phenotype, because it is commonly seen among children with bipolar disorder. However, mounting evidence suggests that the CBCL-PBD may be a better tool for identifying children with severe functional impairment and broad-ranging psychiatric comorbidities rather than bipolar disorder itself. No studies have followed individuals with the CBCL-PBD profile through adulthood, so its long-term implications remain unclear. The present authors examined diagnostic and functional trajectories of individuals with the CBCL-PBD profile from early childhood through young adulthood using data from a longitudinal high-risk study. Participants (n=101) are part of a 23-year study of youth at risk for major mood disorder who have completed diagnostic and functional assessments at regular intervals. Across development, participants with the CBCL-PBD phenotype exhibited marked psychosocial impairment, increased rates of suicidal thoughts and behaviors and heightened risk for comorbid anxiety, bipolar disorder, cluster B personality disorders and ADHD in young adulthood, compared to participants without this presentation. However, diagnostic accuracy for any one particular disorder was found to be low. Children with the CBCL-PBD profile are at risk for ongoing, severe, psychiatric symptomatology including behavior and emotional comorbidities in general, and bipolar disorder, anxiety, ADHD, cluster B personality disorders in particular. However, the value of this profile may be in predicting ongoing comorbidity and impairment, rather than any one specific DSM-IV diagnosis.

External validity of a hierarchical dimensional model of child and adolescent psychopathology: Tests using confirmatory factor analyses and multivariate behavior genetic analyses.

PubMed

Waldman, Irwin D; Poore, Holly E; van Hulle, Carol; Rathouz, Paul J; Lahey, Benjamin B

2016-11-01

Several recent studies of the hierarchical phenotypic structure of psychopathology have identified a General psychopathology factor in addition to the more expected specific Externalizing and Internalizing dimensions in both youth and adult samples and some have found relevant unique external correlates of this General factor. We used data from 1,568 twin pairs (599 MZ & 969 DZ) age 9 to 17 to test hypotheses for the underlying structure of youth psychopathology and the external validity of the higher-order factors. Psychopathology symptoms were assessed via structured interviews of caretakers and youth. We conducted phenotypic analyses of competing structural models using Confirmatory Factor Analysis and used Structural Equation Modeling and multivariate behavior genetic analyses to understand the etiology of the higher-order factors and their external validity. We found that both a General factor and specific Externalizing and Internalizing dimensions are necessary for characterizing youth psychopathology at both the phenotypic and etiologic levels, and that the 3 higher-order factors differed substantially in the magnitudes of their underlying genetic and environmental influences. Phenotypically, the specific Externalizing and Internalizing dimensions were slightly negatively correlated when a General factor was included, which reflected a significant inverse correlation between the nonshared environmental (but not genetic) influences on Internalizing and Externalizing. We estimated heritability of the general factor of psychopathology for the first time. Its moderate heritability suggests that it is not merely an artifact of measurement error but a valid construct. The General, Externalizing, and Internalizing factors differed in their relations with 3 external validity criteria: mother's smoking during pregnancy, parent's harsh discipline, and the youth's association with delinquent peers. Multivariate behavior genetic analyses supported the external validity of the 3 higher-order factors by suggesting that the General, Externalizing, and Internalizing factors were correlated with peer delinquency and parent's harsh discipline for different etiologic reasons. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Diagnosis, treatment, and neurobiology of autism in children.

PubMed

Lainhart, J E; Piven, J

1995-08-01

Autism is a developmental neuropsychiatric disorder defined by the presence of social and communicative deficits, restricted and repetitive behaviors and interests, and a characteristic course. Research suggests that hereditary factors play a principal role in the etiology of most cases. A phenotype broader than autism, including milder social and language-based cognitive deficits, appears to be inherited. Although the pathogenesis is unknown, neurobiologic mechanisms clearly underlie the disorder. Neuropathologic studies have demonstrated abnormalities in limbic structures, the cerebellum, and the cortex. New advances in behavioral therapies and pharmacologic treatment are important components of successful multidisciplinary treatment of this disorder.

Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy.

PubMed

Jansson, Erik Karl Håkan; Clemens, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

2014-01-01

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

Reduced Motivation in the BACHD Rat Model of Huntington Disease Is Dependent on the Choice of Food Deprivation Strategy

PubMed Central

Riess, Olaf; Nguyen, Huu Phuc

2014-01-01

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models. PMID:25144554

Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs.

PubMed

vonHoldt, Bridgett M; Shuldiner, Emily; Koch, Ilana Janowitz; Kartzinel, Rebecca Y; Hogan, Andrew; Brubaker, Lauren; Wanser, Shelby; Stahler, Daniel; Wynne, Clive D L; Ostrander, Elaine A; Sinsheimer, Janet S; Udell, Monique A R

2017-07-01

Although considerable progress has been made in understanding the genetic basis of morphologic traits (for example, body size and coat color) in dogs and wolves, the genetic basis of their behavioral divergence is poorly understood. An integrative approach using both behavioral and genetic data is required to understand the molecular underpinnings of the various behavioral characteristics associated with domestication. We analyze a 5-Mb genomic region on chromosome 6 previously found to be under positive selection in domestic dog breeds. Deletion of this region in humans is linked to Williams-Beuren syndrome (WBS), a multisystem congenital disorder characterized by hypersocial behavior. We associate quantitative data on behavioral phenotypes symptomatic of WBS in humans with structural changes in the WBS locus in dogs. We find that hypersociability, a central feature of WBS, is also a core element of domestication that distinguishes dogs from wolves. We provide evidence that structural variants in GTF2I and GTF2IRD1 , genes previously implicated in the behavioral phenotype of patients with WBS and contained within the WBS locus, contribute to extreme sociability in dogs. This finding suggests that there are commonalities in the genetic architecture of WBS and canine tameness and that directional selection may have targeted a unique set of linked behavioral genes of large phenotypic effect, allowing for rapid behavioral divergence of dogs and wolves, facilitating coexistence with humans.

Morphometricity as a measure of the neuroanatomical signature of a trait.

PubMed

Sabuncu, Mert R; Ge, Tian; Holmes, Avram J; Smoller, Jordan W; Buckner, Randy L; Fischl, Bruce

2016-09-27

Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer's disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques.

Morphometricity as a measure of the neuroanatomical signature of a trait

PubMed Central

Sabuncu, Mert R.; Ge, Tian; Holmes, Avram J.; Smoller, Jordan W.; Buckner, Randy L.; Fischl, Bruce

2016-01-01

Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer’s disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques. PMID:27613854

Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse.

PubMed

Pacey, Laura K K; Doss, Lilian; Cifelli, Carlo; van der Kooy, Derek; Heximer, Scott P; Hampson, David R

2011-03-01

Fragile X syndrome (FXS), the most common cause of inherited mental retardation, is caused by the loss of the mRNA binding protein, FMRP. Persons with FXS also display epileptic seizures, social anxiety, hyperactivity, and autistic behaviors. The metabotropic glutamate receptor theory of FXS postulates that in the absence of FMRP, enhanced signaling though G-protein coupled group I metabotropic glutamate receptors in the brain contributes to many of the abnormalities observed in the disorder. However, recent evidence suggests that alterations in cellular signaling through additional G-protein coupled receptors may also be involved in the pathogenesis of FXS, thus providing impetus for examining downstream molecules. One group of signaling molecules situated downstream of the receptors is the regulator of G-protein signaling (RGS) proteins. Notably, RGS4 is highly expressed in brain and has been shown to negatively regulate signaling through Group I mGluRs and GABA(B) receptors. To examine the potential role for RGS4 in the pathogenesis of FXS, we generated FXS/RGS4 double knockout mice. Characterization of these mice revealed that a subset of FXS related phenotypes, including increased body weight, altered synaptic protein expression, and abnormal social behaviors, were rescued in the double knockout mice. Other phenotypes, such as hyperactivity and macroorchidism, were not affected by the loss of RGS4. These findings suggest that tissue and cell-type specific differences in GPCR signaling and RGS function may contribute to the spectrum of phenotypic differences observed in FXS. Copyright © 2010 Elsevier Inc. All rights reserved.

Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice.

PubMed

McInnis, Christine M; Bonthuis, Paul J; Rissman, Emilie F; Park, Jin Ho

2016-04-01

The importance of gonadal steroids in modulating male sexual behavior is well established. Individual differences in male sexual behavior, independent of gonadal steroids, are prevalent across a wide range of species, including man. However, the genetic mechanisms underlying steroid-independent male sexual behavior are poorly understood. A high proportion of B6D2F1 hybrid male mice demonstrates steroid-independent male sexual behavior (identified as "maters"), providing a mouse model that opens up avenues of investigation into the mechanisms regulating male sexual behavior in the absence of gonadal hormones. Recent studies have revealed several proteins that play a significant factor in regulating steroid-independent male sexual behavior in B6D2F1 male mice, including amyloid precursor protein (APP), tau, and synaptophysin. The specific goals of our study were to determine whether steroid-independent male sexual behavior was a heritable trait by determining if it was dependent upon the behavioral phenotype of the B6D2F1 sire, and whether the differential expression of APP, tau, and synaptophysin in the medial preoptic area found in the B6D2F1 sires that did and did not mate after gonadectomy was similar to those found in their male offspring. After adult B6D2F1 male mice were bred with C57BL/6J female mice, they and their male offspring (BXB1) were orchidectomized and identified as either maters or "non-maters". A significant proportion of the BXB1 maters was sired only from B6D2F1 maters, indicating that the steroid-independent male sexual behavior behavioral phenotype of the B6D2F1 hybrid males, when crossed with C57BL/6J female mice, is inherited by their male offspring. Additionally, APP, tau, and synaptophysin were elevated in in the medial preoptic area in both the B6D2F1 and BXB1 maters relative to the B6D2F1 and BXB1 non-maters, respectively, suggesting a potential genetic mechanism for the inheritance of steroid-independent male sexual behavior. Copyright © 2016 Elsevier Inc. All rights reserved.

Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice

PubMed Central

McInnis, Christine M.; Bonthuis, Paul J.; Rissman, Emilie F.; Park, Jin Ho

2016-01-01

The importance of gonadal steroids in modulating male sexual behavior is well established. Individual differences in male sexual behavior, independent of gonadal steroids, are prevalent across a wide range of species, including man. However, the genetic mechanisms underlying steroid-independent male sexual behavior are poorly understood. A high proportion of B6D2F1 hybrid male mice demonstrate steroid-independent male sexual behavior (identified as “maters”), providing a mouse model that opens up avenues of investigation into the mechanisms regulating male sexual behavior in the absence of gonadal hormones. Recent studies have revealed several proteins that play a significant factor in regulating steroid-independent male sexual behavior in B6D2F1 male mice, including amyloid precursor protein (APP), tau, and synaptophysin. The specific goals of our study were to determine whether steroid-independent male sexual behavior was a heritable trait by determining if it was dependent upon the behavioral phenotype of the B6D2F1 sire, and whether the differential expression of APP, tau, and synaptophysin in the medial preoptic area found in the B6D2F1 sires that did and did not mate after gonadectomy was similar to those found in their male offspring. After adult B6D2F1 male mice were bred with C57BL/6J female mice, they and their male offspring (BXB1) were orchidectomized and identified as either maters or “non-maters.” A significant proportion of the BXB1 maters were sired only from B6D2F1 maters, indicating that the steroid-independent male sexual behavior behavioral phenotype of the B6D2F1 hybrid males, when crossed with C57BL/6J female mice, is inherited by their male offspring. Additionally, APP, tau, and synaptophysin were elevated in in the medial preoptic area in both the B6D2F1 and BXB1 maters relative to the B6D2F1 and BXB1 non-maters, respectively, suggesting a potential genetic mechanism for the inheritance of steroid-independent male sexual behavior. PMID:26940434

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes.

PubMed

Stringer, Megan; Abeysekera, Irushi; Thomas, Jared; LaCombe, Jonathan; Stancombe, Kailey; Stewart, Robert J; Dria, Karl J; Wallace, Joseph M; Goodlett, Charles R; Roper, Randall J

2017-08-01

Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2-3mg per day (~40-60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4mg/mL] or a water control, with treatments yielding average daily intakes of ~50mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)-which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking-and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone. Copyright © 2017 Elsevier Inc. All rights reserved.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

PubMed

Gupta, Deepali; Thangaraj, Devadoss; Radhakrishnan, Mahesh

2016-01-15

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions. Copyright © 2015 Elsevier B.V. All rights reserved.

Cortisol in mother's milk across lactation reflects maternal life history and predicts infant temperament.

PubMed

Hinde, Katie; Skibiel, Amy L; Foster, Alison B; Del Rosso, Laura; Mendoza, Sally P; Capitanio, John P

2015-01-01

The maternal environment exerts important influences on offspring mass/growth, metabolism, reproduction, neurobiology, immune function, and behavior among birds, insects, reptiles, fish, and mammals. For mammals, mother's milk is an important physiological pathway for nutrient transfer and glucocorticoid signaling that potentially influences offspring growth and behavioral phenotype. Glucocorticoids in mother's milk have been associated with offspring behavioral phenotype in several mammals, but studies have been handicapped by not simultaneously evaluating milk energy density and yield. This is problematic as milk glucocorticoids and nutrients likely have simultaneous effects on offspring phenotype. We investigated mother's milk and infant temperament and growth in a cohort of rhesus macaque ( Macaca mulatta ) mother-infant dyads at the California National Primate Research Center ( N = 108). Glucocorticoids in mother's milk, independent of available milk energy, predicted a more Nervous, less Confident temperament in both sons and daughters. We additionally found sex differences in the windows of sensitivity and the magnitude of sensitivity to maternal-origin glucocorticoids. Lower parity mothers produced milk with higher cortisol concentrations. Lastly, higher cortisol concentrations in milk were associated with greater infant weight gain across time. Taken together, these results suggest that mothers with fewer somatic resources, even in captivity, may be "programming" through cortisol signaling, behaviorally cautious offspring that prioritize growth. Glucocorticoids ingested through milk may importantly contribute to the assimilation of available milk energy, development of temperament, and orchestrate, in part, the allocation of maternal milk energy between growth and behavioral phenotype.

Cortisol in mother’s milk across lactation reflects maternal life history and predicts infant temperament

PubMed Central

Skibiel, Amy L.; Foster, Alison B.; Del Rosso, Laura; Mendoza, Sally P.; Capitanio, John P.

2015-01-01

The maternal environment exerts important influences on offspring mass/growth, metabolism, reproduction, neurobiology, immune function, and behavior among birds, insects, reptiles, fish, and mammals. For mammals, mother’s milk is an important physiological pathway for nutrient transfer and glucocorticoid signaling that potentially influences offspring growth and behavioral phenotype. Glucocorticoids in mother’s milk have been associated with offspring behavioral phenotype in several mammals, but studies have been handicapped by not simultaneously evaluating milk energy density and yield. This is problematic as milk glucocorticoids and nutrients likely have simultaneous effects on offspring phenotype. We investigated mother’s milk and infant temperament and growth in a cohort of rhesus macaque (Macaca mulatta) mother–infant dyads at the California National Primate Research Center (N = 108). Glucocorticoids in mother’s milk, independent of available milk energy, predicted a more Nervous, less Confident temperament in both sons and daughters. We additionally found sex differences in the windows of sensitivity and the magnitude of sensitivity to maternal-origin glucocorticoids. Lower parity mothers produced milk with higher cortisol concentrations. Lastly, higher cortisol concentrations in milk were associated with greater infant weight gain across time. Taken together, these results suggest that mothers with fewer somatic resources, even in captivity, may be “programming” through cortisol signaling, behaviorally cautious offspring that prioritize growth. Glucocorticoids ingested through milk may importantly contribute to the assimilation of available milk energy, development of temperament, and orchestrate, in part, the allocation of maternal milk energy between growth and behavioral phenotype. PMID:25713475

Automated video analysis system reveals distinct diurnal behaviors in C57BL/6 and C3H/HeN mice.

PubMed

Adamah-Biassi, E B; Stepien, I; Hudson, R L; Dubocovich, M L

2013-04-15

Advances in rodent behavior dissection using automated video recording and analysis allows detailed phenotyping. This study compared and contrasted 15 diurnal behaviors recorded continuously using an automated behavioral analysis system for a period of 14 days under a 14/10 light/dark cycle in single housed C3H/HeN (C3H) or C57BL/6 (C57) male mice. Diurnal behaviors, recorded with minimal experimental interference and analyzed using phenotypic array and temporal distribution analysis showed bimodal and unimodal profiles in the C57 and C3H mice, respectively. Phenotypic array analysis revealed distinct behavioral rhythms in Activity-Like Behaviors (i.e. walk, hang, jump, come down) (ALB), Exploration-Like Behaviors (i.e. dig, groom, rear up, sniff, stretch) (ELB), Ingestion-Like Behaviors (i.e. drink, eat) (ILB) and Resting-Like Behaviors (i.e. awake, remain low, rest, twitch) (RLB) of C3H and C57 mice. Temporal distribution analysis demonstrated that strain and time of day affects the magnitude and distribution of the spontaneous homecage behaviors. Wheel running activity, water and food measurements correlated with timing of homecage behaviors. Subcutaneous (3 mg/kg, sc) or oral (0.02 mg/ml, oral) melatonin treatments in C57 mice did not modify either the total 24 h magnitude or temporal distribution of homecage behaviors when compared with vehicle treatments. We conclude that C3H and C57 mice show different spontaneous activity and behavioral rhythms specifically during the night period which are not modulated by melatonin. Copyright © 2013 Elsevier B.V. All rights reserved.

Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice.

PubMed

Nam, So Hee; Seo, Su Jin; Goo, Jun Seo; Kim, Jee Eun; Choi, Sun Il; Lee, Hae Ryun; Hwang, In Sik; Jee, Seung Wan; Lee, Su Hae; Bae, Chang Jun; Park, Jung Youn; Kim, Hye Sung; Shim, Sun Bo; Hwang, Dae Youn

2011-12-01

Pen-2 is a key regulator of the γ-secretase complex, which is involved in the production of the amyloid β (Aβ)-42 peptides, which ultimately lead to Alzheimer's disease (AD). While Pen-2 has been studied in vitro, Pen-2 function in vivo in the brains of transgenic (Tg) mice overexpressing human Pen-2 (hPen-2) protein has not been studied. This study aimed to determine whether Pen-2 overexpression could regulate the AD-like phenotypes in Tg mice. NSE/hPen-2 Tg mice were produced by the microinjection of the NSE/hPen-2 gene into the pronucleus of fertilized eggs. The expression of the hPen-2 gene under the control of the NSE promoter was successfully detected only in the brain and kidney tissue of NSE/hPen-2 Tg mice. Also, 12-month-old NSE/hPen-2 Tg mice displayed behavioral dysfunction in the water maze test, motor activity and feeding behavior dysfunction in food intake/water intake/motor activity monitoring system. In addition, tissue samples displayed dense staining with antibody to the Aβ-42 peptide. Furthermore, NSE/hPen-2 Tg mice exhibiting feeding behavior dysfunction were significantly more apt to display symptoms related to diabetes and obesity. These results suggest that Pen-2 overexpression in NSE/hPen-2 Tg mice may induce all the AD-like phenotypes, including behavioral deficits, motor activity and feeding behavior dysfunction, Aβ-42 peptide deposition and chronic disease induction.

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome

PubMed Central

Fung, Lawrence K.; Quintin, Eve-Marie; Haas, Brian W.

2013-01-01

Purpose of review The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Recent findings Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive–behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well – microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Summary Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene–brain–behavior links occurring in neurodevelopmental disorders. PMID:22395002

Effect of lithium on behavioral disinhibition induced by electrolytic lesion of the median raphe nucleus

PubMed Central

Pezzato, Fernanda A.; Can, Adem; Hoshino, Katsumasa; Horta, José de Anchieta C.; Mijares, Miriam G.

2014-01-01

Rationale Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder. Objective Assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions. Methods MnR electrolytic lesions were performed in C57BL/6J mice, with sham operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing. Results MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing. Conclusions Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium’s relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms. PMID:25345734

The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies

PubMed Central

Modi, Meera E.; Young, Larry J.

2012-01-01

Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID:22206823

Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology

PubMed Central

Fleet, Tiffany; Stashi, Erin; Zhu, Bokai; Rajapakshe, Kimal; Marcelo, Kathrina L.; Kettner, Nicole M.; Gorman, Blythe K.; Coarfa, Cristian; Fu, Loning; O’Malley, Bert W.; York, Brian

2017-01-01

Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2. We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2−/− and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver. PMID:27432117

Increased expression of a cGMP-dependent protein kinase in rotation-adapted western corn rootworm (Diabrotica virgifera virgifera L.).

PubMed

Garabagi, Freydoun; Wade French, B; Schaafsma, Arthur W; Peter Pauls, K

2008-07-01

A new 'variant' behavior in western corn rootworm (WCR) has resulted in egg-laying into non-cornfields, compared to 'normal' deposition of eggs in cornfields, allowing these insects to circumvent crop rotation. No morphological or genetic characteristics have been defined to differentiate between the normal and variant biotypes. Cyclic GMP-dependent protein kinases (PKG) have been implicated in the regulation of behaviors in vertebrates, insects, and nematodes, including foraging behavior in Drosophila. A cDNA with homology to the Drosophila melanogaster foraging gene (called Dvfor1) was cloned from WCR. The deduced DvFOR1 protein is approximately 70% similar to FOR proteins in Drosophila, silkworm (Bombyx mori) and honeybee (Apis mellifera). It contains a coiled-coil region, two tandem cyclic nucleotide-binding domains, a serine/threonine kinase catalytic domain, and a serine/threonine kinase catalytic domain extension, which are all characteristically found in PKG proteins. Real-time PCR assays of foraging transcript levels in heads of normal and rotation adapted females of WCR obtained from lab-reared insect colonies indicated that the variants had higher levels (25%) of PKG expression than normals. The magnitude of this increase is similar to that observed in Drosophila rover phenotypes compared to sitter phenotypes. However, Diabrotica contains at least two different foraging gene transcripts, which complicates establishing a direct link between the level of gene expression and insect behavior.

Predicting Flowering Behavior and Exploring Its Genetic Determinism in an Apple Multi-family Population Based on Statistical Indices and Simplified Phenotyping.

PubMed

Durand, Jean-Baptiste; Allard, Alix; Guitton, Baptiste; van de Weg, Eric; Bink, Marco C A M; Costes, Evelyne

2017-01-01

Irregular flowering over years is commonly observed in fruit trees. The early prediction of tree behavior is highly desirable in breeding programmes. This study aims at performing such predictions, combining simplified phenotyping and statistics methods. Sequences of vegetative vs. floral annual shoots (AS) were observed along axes in trees belonging to five apple related full-sib families. Sequences were analyzed using Markovian and linear mixed models including year and site effects. Indices of flowering irregularity, periodicity and synchronicity were estimated, at tree and axis scales. They were used to predict tree behavior and detect QTL with a Bayesian pedigree-based analysis, using an integrated genetic map containing 6,849 SNPs. The combination of a Biennial Bearing Index (BBI) with an autoregressive coefficient (γ g ) efficiently predicted and classified the genotype behaviors, despite few misclassifications. Four QTLs common to BBIs and γ g and one for synchronicity were highlighted and revealed the complex genetic architecture of the traits. Irregularity resulted from high AS synchronism, whereas regularity resulted from either asynchronous locally alternating or continual regular AS flowering. A relevant and time-saving method, based on a posteriori sampling of axes and statistical indices is proposed, which is efficient to evaluate the tree breeding values for flowering regularity and could be transferred to other species.

MicroRNA-133 Inhibits Behavioral Aggregation by Controlling Dopamine Synthesis in Locusts

PubMed Central

Wang, Yanli; Guo, Xiaojiao; He, Jing; Kang, Le

2014-01-01

Phenotypic plasticity is ubiquitous and primarily controlled by interactions between environmental and genetic factors. The migratory locust, a worldwide pest, exhibits pronounced phenotypic plasticity, which is a population density-dependent transition that occurs between the gregarious and solitary phases. Genes involved in dopamine synthesis have been shown to regulate the phase transition of locusts. However, the function of microRNAs in this process remains unknown. In this study, we report the participation of miR-133 in dopamine production and the behavioral transition by negatively regulating two critical genes, henna and pale, in the dopamine pathway. miR-133 participated in the post-transcriptional regulation of henna and pale by binding to their coding region and 3′ untranslated region, respectively. miR-133 displayed cellular co-localization with henna/pale in the protocerebrum, and its expression in the protocerebrum was negatively correlated with henna and pale expression. Moreover, miR-133 agomir delivery suppressed henna and pale expression, which consequently decreased dopamine production, thus resulting in the behavioral shift of the locusts from the gregarious phase to the solitary phase. Increasing the dopamine content could rescue the solitary phenotype, which was induced by miR-133 agomir delivery. Conversely, miR-133 inhibition increased the expression of henna and pale, resulting in the gregarious-like behavior of solitary locusts; this gregarious phenotype could be rescued by RNA interference of henna and pale. This study shows the novel function and modulation pattern of a miRNA in phenotypic plasticity and provides insight into the underlying molecular mechanisms of the phase transition of locusts. PMID:24586212

MicroRNA-133 inhibits behavioral aggregation by controlling dopamine synthesis in locusts.

PubMed

Yang, Meiling; Wei, Yuanyuan; Jiang, Feng; Wang, Yanli; Guo, Xiaojiao; He, Jing; Kang, Le

2014-02-01

Phenotypic plasticity is ubiquitous and primarily controlled by interactions between environmental and genetic factors. The migratory locust, a worldwide pest, exhibits pronounced phenotypic plasticity, which is a population density-dependent transition that occurs between the gregarious and solitary phases. Genes involved in dopamine synthesis have been shown to regulate the phase transition of locusts. However, the function of microRNAs in this process remains unknown. In this study, we report the participation of miR-133 in dopamine production and the behavioral transition by negatively regulating two critical genes, henna and pale, in the dopamine pathway. miR-133 participated in the post-transcriptional regulation of henna and pale by binding to their coding region and 3' untranslated region, respectively. miR-133 displayed cellular co-localization with henna/pale in the protocerebrum, and its expression in the protocerebrum was negatively correlated with henna and pale expression. Moreover, miR-133 agomir delivery suppressed henna and pale expression, which consequently decreased dopamine production, thus resulting in the behavioral shift of the locusts from the gregarious phase to the solitary phase. Increasing the dopamine content could rescue the solitary phenotype, which was induced by miR-133 agomir delivery. Conversely, miR-133 inhibition increased the expression of henna and pale, resulting in the gregarious-like behavior of solitary locusts; this gregarious phenotype could be rescued by RNA interference of henna and pale. This study shows the novel function and modulation pattern of a miRNA in phenotypic plasticity and provides insight into the underlying molecular mechanisms of the phase transition of locusts.

Phenotypic plasticity as an adaptation to a functional trade-off

PubMed Central

Yi, Xiao; Dean, Antony M

2016-01-01

We report the evolution of a phenotypically plastic behavior that circumvents the hardwired trade-off that exists when resources are partitioned between growth and motility in Escherichia coli. We propagated cultures in a cyclical environment, alternating between growth up to carrying capacity and selection for chemotaxis. Initial adaptations boosted overall swimming speed at the expense of growth. The effect of the trade-off was subsequently eased through a change in behavior; while individual cells reduced motility during exponential growth, the faction of the population that was motile increased as the carrying capacity was approached. This plastic behavior was produced by a single amino acid replacement in FliA, a regulatory protein central to the chemotaxis network. Our results illustrate how phenotypic plasticity potentiates evolvability by opening up new regions of the adaptive landscape. DOI: http://dx.doi.org/10.7554/eLife.19307.001 PMID:27692064

Functional Coding Variation in Recombinant Inbred Mouse Lines Reveals Novel Serotonin Transporter-Associated Phenotypes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carneiro, Ana; Airey, David; Thompson, Brent

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology or treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism and obsessive-compulsive disorder (OCD). Here we utilize naturally occurring polymorphisms in recombinant inbred (RI) lines to identify novel phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by two nonsynonymous coding variants (Gly39 and Lys152 (GK)). At these positions, many other mouse lines, including DBA/2J, encode Glu39 and Arg152 (ER haplotype), assignments found also in hSERT. Synaptosomal 5-HT transport studies revealed reduced uptake associated with the GKmore » variant. Heterologous expression studies confirmed a reduced SERT turnover rate for the GK variant. Experimental and in silico approaches using RI lines (C57Bl/6J X DBA/2J=BXD) identifies multiple anatomical, biochemical and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are multiple traits associated with anxiety and alcohol consumption, as well as of the control of dopamine (DA) signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates ironregulated DA phenotypes. Our studies provide a novel example of the power of coordinated in vitro, in vivo and in silico approaches using murine RI lines to elucidate and quantify the system-level impact of gene variation.« less

Habit Reversal Therapy for Body-Focused Repetitive Behaviors in Williams Syndrome: A Case Study

PubMed Central

Klein-Tasman, Bonita P.

2013-01-01

Williams syndrome (WS) is genetic neurodevelopmental disorder with a well-characterized cognitive and behavioral phenotype. Research has consistently demonstrated high rates of psychopathology in this population; however, little research has examined the use of empirically-supported psychosocial interventions in those with WS. The current case study reports on the use of Habit Reversal Therapy (HRT) to treat multiple body-focused repetitive behaviors in a child with WS. Although HRT is a well-established cognitive-behavioral intervention for body-focused repetitive behaviors, it has been infrequently used in populations with developmental disabilities. An etiologically-informed approach was used to adapt HRT to fit the known behavioral and cognitive phenotype of WS. Results suggest that HRT may be beneficial for this population. Modified treatment elements are described and future research areas highlighted. PMID:24357918

A phenotype of early infancy predicts reactivity of the amygdala in male adults.

PubMed

Schwartz, C E; Kunwar, P S; Greve, D N; Kagan, J; Snidman, N C; Bloch, R B

2012-10-01

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala has a central role in the processing of novelty and emotion in the brain. Although there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four-month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here, we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioral assessment made in the laboratory at 4 months of age. This is the earliest known human behavioral phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or 'endophenotypes') indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically defined disorder. As the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the 4-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.

Mapping, fine mapping, and molecular dissection of quantitative trait Loci in domestic animals.

PubMed

Georges, Michel

2007-01-01

Artificial selection has created myriad breeds of domestic animals, each characterized by unique phenotypes pertaining to behavior, morphology, physiology, and disease. Most domestic animal populations share features with isolated founder populations, making them well suited for positional cloning. Genome sequences are now available for most domestic species, and with them a panoply of tools including high-density single-nucleotide polymorphism panels. As a result, domestic animal populations are becoming invaluable resources for studying the molecular architecture of complex traits and of adaptation. Here we review recent progress and issues in the positional identification of genes underlying complex traits in domestic animals. As many phenotypes studied in animals are quantitative, we focus on mapping, fine mapping, and cloning of quantitative trait loci.

Sequential social experiences interact to modulate aggression but not brain gene expression in the honey bee (Apis mellifera).

PubMed

Rittschof, Clare C

2017-01-01

In highly structured societies, individuals behave flexibly and cooperatively in order to achieve a particular group-level outcome. However, even in social species, environmental inputs can have long lasting effects on individual behavior, and variable experiences can even result in consistent individual differences and constrained behavioral flexibility. Despite the fact that such constraints on behavior could have implications for behavioral optimization at the social group level, few studies have explored how social experiences accumulate over time, and the mechanistic basis of these effects. In the current study, I evaluate how sequential social experiences affect individual and group level aggressive phenotypes, and individual brain gene expression, in the highly social honey bee ( Apis mellifera ). To do this, I combine a whole colony chronic predator disturbance treatment with a lab-based manipulation of social group composition. Compared to the undisturbed control, chronically disturbed individuals show lower aggression levels overall, but also enhanced behavioral flexibility in the second, lab-based social context. Disturbed bees display aggression levels that decline with increasing numbers of more aggressive, undisturbed group members. However, group level aggressive phenotypes are similar regardless of the behavioral tendencies of the individuals that make up the group, suggesting a combination of underlying behavioral tendency and negative social feedback influences the aggressive behaviors displayed, particularly in the case of disturbed individuals. An analysis of brain gene expression showed that aggression related biomarker genes reflect an individual's disturbance history, but not subsequent social group experience or behavioral outcomes. In highly social animals with collective behavioral phenotypes, social context may mask underlying variation in individual behavioral tendencies. Moreover, gene expression patterns may reflect behavioral tendency, while behavioral outcomes are further regulated by social cues perceived in real-time.

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn’s disease

PubMed Central

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-01-01

AIM: To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn’s disease (CD). METHODS: Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 ± 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. RESULTS: A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 ± 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. CONCLUSION: Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients. PMID:19630105

Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior.

PubMed

Vollert, Craig; Ohia, Odochi; Akasaka, Hironari; Berridge, Casey; Ruan, Ke-He; Eriksen, Jason L

2014-01-01

Prostacyclin is an endogenous lipid metabolite with properties of vasodilation and anti-platelet aggregation. While the effects of prostacyclin on the vascular protection have been well-documented, the role of this eicosanoid in the central nervous system has not been extensively studied. Recently, a transgenic mouse containing a hybrid enzyme, of cyclooxygenase-1 linked to prostacyclin synthase, was developed that produces elevated levels of prostacyclin in vivo. The goal of this study was to investigate whether increased prostacyclin biosynthesis could affect behavioral phenotypes in mice. Our results uncovered that elevated levels of prostacyclin broadly affect both cognitive and non-cognitive behaviors, including decreased anxiety-like behavior and improved learning in the fear-conditioning memory test. This study demonstrates that prostacyclin plays an important, but previously unrecognized, role in central nervous system function and behavior. Copyright © 2013 Elsevier B.V. All rights reserved.

Habituation of medaka (Oryzias latipes) demonstrated by open-field testing.

PubMed

Matsunaga, Wataru; Watanabe, Eiji

2010-10-01

Habituation to novel environments is frequently studied to analyze cognitive phenotypes in animals, and an open-field test is generally conducted to investigate the changes that occur in animals during habituation. The test has not been used in behavioral studies of medaka (Oryzias latipes), which is recently being used in behavioral research. Therefore, we examined the open-field behavior of medaka on the basis of temporal changes in 2 conventional indexes of locomotion and position. The findings of our study clearly showed that medaka changed its behavior through multiple temporal phases as it became more familiar with new surroundings; this finding is consistent with those of other ethological studies in animals. During repeated open-field testing on 2 consecutive days, we observed that horizontal locomotion on the second day was less than that on the first day, which suggested that habituation is retained in fish for days. This temporal habituation was critically affected by water factors or visual cues of the tank, thereby suggesting that fish have spatial memory of their surroundings. Thus, the data from this study will afford useful fundamental information for behavioral phenotyping of medaka and for elucidating cognitive phenotypes in animals. Copyright (c) 2010 Elsevier B.V. All rights reserved.

The pharmacogenetics of body odor: as easy as ABCC?

PubMed

Brown, Sara

2013-07-01

ABCC11 genotype affects apocrine secretory cell function and determines individual body odor phenotype. Rodriguez et al. have applied genetic epidemiology using predetermined phenotype data to demonstrate an association between a single-nucleotide polymorphism (rs17822931) and the human behavior of deodorant application. Individuals with the ABCC11 genotype predicting a nonodorous phenotype report a significantly lower frequency of deodorant use.

Advanced transgenic approaches to understand alcohol-related phenotypes in animals.

PubMed

Bilbao, Ainhoa

2013-01-01

During the past two decades, the use of genetically manipulated animal models in alcohol research has greatly improved the understanding of the mechanisms underlying alcohol addiction. In this chapter, we present an overview of the progress made in this field by summarizing findings obtained from studies of mice harboring global and conditional mutations in genes that influence alcohol-related phenotypes. The first part reviews behavioral paradigms for modeling the different phases of the alcohol addiction cycle and other alcohol-induced behavioral phenotypes in mice. The second part reviews the current data available using genetic models targeting the main neurotransmitter and neuropeptide systems involved in the reinforcement and stress pathways, focusing on the phenotypes modeling the alcohol addiction cycle. Finally, the third part will discuss the current findings and future directions, and proposes advanced transgenic mouse models for their potential use in alcohol research.

GENOMIC DIVERSITY AND THE MICROENVIRONMENT AS DRIVERS OF PROGRESSION IN DCIS

DTIC Science & Technology

2017-10-01

stains, including quantitative analysis, 7) Identification of upstaged DCIS cases for the radiology aim, 8) Development of image analysis methods for...goals of the project? Aim 1. Determine whether genetic diversity of DCIS is greater in DCIS with adjacent invasive disease compared to DCIS without... compared to DCIS without IDC. Since genomics is not the sole driver of tumor behavior, we will phenotypically characterize DCIS and its

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features.

PubMed

Lamb, Allen N; Rosenfeld, Jill A; Neill, Nicholas J; Talkowski, Michael E; Blumenthal, Ian; Girirajan, Santhosh; Keelean-Fuller, Debra; Fan, Zheng; Pouncey, Jill; Stevens, Cathy; Mackay-Loder, Loren; Terespolsky, Deborah; Bader, Patricia I; Rosenbaum, Kenneth; Vallee, Stephanie E; Moeschler, John B; Ladda, Roger; Sell, Susan; Martin, Judith; Ryan, Shawnia; Jones, Marilyn C; Moran, Rocio; Shealy, Amy; Madan-Khetarpal, Suneeta; McConnell, Juliann; Surti, Urvashi; Delahaye, Andrée; Heron-Longe, Bénédicte; Pipiras, Eva; Benzacken, Brigitte; Passemard, Sandrine; Verloes, Alain; Isidor, Bertrand; Le Caignec, Cedric; Glew, Gwen M; Opheim, Kent E; Descartes, Maria; Eichler, Evan E; Morton, Cynthia C; Gusella, James F; Schultz, Roger A; Ballif, Blake C; Shaffer, Lisa G

2012-04-01

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene. © 2012 Wiley Periodicals, Inc.

Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD.

PubMed

Abbott, Charles W; Rohac, David J; Bottom, Riley T; Patadia, Sahil; Huffman, Kelly J

2017-07-06

Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrβ and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The light spot test: Measuring anxiety in mice in an automated home-cage environment.

PubMed

Aarts, Emmeke; Maroteaux, Gregoire; Loos, Maarten; Koopmans, Bastijn; Kovačević, Jovana; Smit, August B; Verhage, Matthijs; Sluis, Sophie van der

2015-11-01

Behavioral tests of animals in a controlled experimental setting provide a valuable tool to advance understanding of genotype-phenotype relations, and to study the effects of genetic and environmental manipulations. To optimally benefit from the increasing numbers of genetically engineered mice, reliable high-throughput methods for comprehensive behavioral phenotyping of mice lines have become a necessity. Here, we describe the development and validation of an anxiety test, the light spot test, that allows for unsupervised, automated, high-throughput testing of mice in a home-cage system. This automated behavioral test circumvents bias introduced by pretest handling, and enables recording both baseline behavior and the behavioral test response over a prolonged period of time. We demonstrate that the light spot test induces a behavioral response in C57BL/6J mice. This behavior reverts to baseline when the aversive stimulus is switched off, and is blunted by treatment with the anxiolytic drug Diazepam, demonstrating predictive validity of the assay, and indicating that the observed behavioral response has a significant anxiety component. Also, we investigated the effectiveness of the light spot test as part of sequential testing for different behavioral aspects in the home-cage. Two learning tests, administered prior to the light spot test, affected the light spot test parameters. The light spot test is a novel, automated assay for anxiety-related high-throughput testing of mice in an automated home-cage environment, allowing for both comprehensive behavioral phenotyping of mice, and rapid screening of pharmacological compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

Rapid loss of behavioral plasticity and immunocompetence under intense sexual selection.

PubMed

van Lieshout, Emile; McNamara, Kathryn B; Simmons, Leigh W

2014-09-01

Phenotypic plasticity allows animals to maximize fitness by conditionally expressing the phenotype best adapted to their environment. Although evidence for such adjustment in reproductive tactics is common, little is known about how phenotypic plasticity evolves in response to sexual selection. We examined the effect of sexual selection intensity on phenotypic plasticity in mating behavior using the beetle Callosobruchus maculatus. Male genital spines harm females during mating and females exhibit copulatory kicking, an apparent resistance trait aimed to dislodge mating males. After exposing individuals from male- and female-biased experimental evolution lines to male- and female-biased sociosexual environments, we examined behavioral plasticity in matings with standard partners. While females from female-biased lines kicked sooner after exposure to male-biased sociosexual contexts, in male-biased lines this plasticity was lost. Ejaculate size did not diverge in response to selection history, but males from both treatments exhibited plasticity consistent with sperm competition intensity models, reducing size as the number of competitors increased. Analysis of immunocompetence revealed reduced immunity in both sexes in male-biased lines, pointing to increased reproductive costs under high sexual selection. These results highlight how male and female reproductive strategies are shaped by interactions between phenotypically plastic and genetic mechanisms of sexual trait expression. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4.

PubMed

Ey, E; Yang, M; Katz, A M; Woldeyohannes, L; Silverman, J L; Leblond, C S; Faure, P; Torquet, N; Le Sourd, A-M; Bourgeron, T; Crawley, J N

2012-11-01

Mutations in NLGN4X have been identified in individuals with autism spectrum disorders and other neurodevelopmental disorders. A previous study reported that adult male mice lacking neuroligin4 (Nlgn4) displayed social approach deficits in the three-chambered test, altered aggressive behaviors and reduced ultrasonic vocalizations. To replicate and extend these findings, independent comprehensive analyses of autism-relevant behavioral phenotypes were conducted in later generations of the same line of Nlgn4 mutant mice at the National Institute of Mental Health in Bethesda, MD, USA and at the Institut Pasteur in Paris, France. Adult social approach was normal in all three genotypes of Nlgn4 mice tested at both sites. Reciprocal social interactions in juveniles were similarly normal across genotypes. No genotype differences were detected in ultrasonic vocalizations in pups separated from the nest or in adults during reciprocal social interactions. Anxiety-like behaviors, self-grooming, rotarod and open field exploration did not differ across genotypes, and measures of developmental milestones and general health were normal. Our findings indicate an absence of autism-relevant behavioral phenotypes in subsequent generations of Nlgn4 mice tested at two locations. Testing environment and methods differed from the original study in some aspects, although the presence of normal sociability was seen in all genotypes when methods taken from Jamain et al. (2008) were used. The divergent results obtained from this study indicate that phenotypes may not be replicable across breeding generations, and highlight the significant roles of environmental, generational and/or procedural factors on behavioral phenotypes. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

The real-time fMRI neurofeedback based stratification of Default Network Regulation Neuroimaging data repository.

PubMed

McDonald, Amalia R; Muraskin, Jordan; Dam, Nicholas T Van; Froehlich, Caroline; Puccio, Benjamin; Pellman, John; Bauer, Clemens C C; Akeyson, Alexis; Breland, Melissa M; Calhoun, Vince D; Carter, Steven; Chang, Tiffany P; Gessner, Chelsea; Gianonne, Alyssa; Giavasis, Steven; Glass, Jamie; Homann, Steven; King, Margaret; Kramer, Melissa; Landis, Drew; Lieval, Alexis; Lisinski, Jonathan; Mackay-Brandt, Anna; Miller, Brittny; Panek, Laura; Reed, Hayley; Santiago, Christine; Schoell, Eszter; Sinnig, Richard; Sital, Melissa; Taverna, Elise; Tobe, Russell; Trautman, Kristin; Varghese, Betty; Walden, Lauren; Wang, Runtang; Waters, Abigail B; Wood, Dylan C; Castellanos, F Xavier; Leventhal, Bennett; Colcombe, Stanley J; LaConte, Stephen; Milham, Michael P; Craddock, R Cameron

2017-02-01

This data descriptor describes a repository of openly shared data from an experiment to assess inter-individual differences in default mode network (DMN) activity. This repository includes cross-sectional functional magnetic resonance imaging (fMRI) data from the Multi Source Interference Task, to assess DMN deactivation, the Moral Dilemma Task, to assess DMN activation, a resting state fMRI scan, and a DMN neurofeedback paradigm, to assess DMN modulation, along with accompanying behavioral and cognitive measures. We report technical validation from n=125 participants of the final targeted sample of 180 participants. Each session includes acquisition of one whole-brain anatomical scan and whole-brain echo-planar imaging (EPI) scans, acquired during the aforementioned tasks and resting state. The data includes several self-report measures related to perseverative thinking, emotion regulation, and imaginative processes, along with a behavioral measure of rapid visual information processing. Technical validation of the data confirms that the tasks deactivate and activate the DMN as expected. Group level analysis of the neurofeedback data indicates that the participants are able to modulate their DMN with considerable inter-subject variability. Preliminary analysis of behavioral responses and specifically self-reported sleep indicate that as many as 73 participants may need to be excluded from an analysis depending on the hypothesis being tested. The present data are linked to the enhanced Nathan Kline Institute, Rockland Sample and builds on the comprehensive neuroimaging and deep phenotyping available therein. As limited information is presently available about individual differences in the capacity to directly modulate the default mode network, these data provide a unique opportunity to examine DMN modulation ability in relation to numerous phenotypic characteristics. Copyright © 2016 Elsevier Inc. All rights reserved.

The contributions of oxytocin and vasopressin pathway genes to human behavior.

PubMed

Ebstein, Richard P; Knafo, Ariel; Mankuta, David; Chew, Soo Hong; Lai, Poh San

2012-03-01

Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress

PubMed Central

Licznerski, Pawel; Duric, Vanja; Banasr, Mounira; Alavian, Kambiz N.; Ota, Kristie T.; Kang, Hyo Jung; Jonas, Elizabeth A.; Ursano, Robert; Krystal, John H.; Duman, Ronald S.

2015-01-01

Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology. PMID:26506154

Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2).

PubMed

Gropman, Andrea L; Duncan, Wallace C; Smith, Ann C M

2006-05-01

The Smith-Magenis syndrome is a rare, complex multisystemic disorder featuring, mental retardation and multiple congenital anomalies caused by a heterozygous interstitial deletion of chromosome 17p11.2. The phenotype of Smith-Magenis syndrome is characterized by a distinct pattern of features including infantile hypotonia, generalized complacency and lethargy in infancy, minor skeletal (brachycephaly, brachydactyly) and craniofacial features, ocular abnormalities, middle ear and laryngeal abnormalities including hoarse voice, as well as marked early expressive speech and language delays, psychomotor and growth retardation, and a 24-hour sleep disturbance. A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age. The diagnosis of Smith-Magenis syndrome is based upon the clinical recognition of a constellation of physical, developmental, and behavioral features in combination with a sleep disorder characterized by inverted circadian rhythm of melatonin secretion. Many of the features of Smith-Magenis syndrome are subtle in infancy and early childhood, and become more recognizable with advancing age. Infants are described as looking "cherubic" with a Down syndrome-like appearance, whereas with age the facial appearance is that of relative prognathism. Early diagnosis requires awareness of the often subtle clinical and neurobehavioral phenotype of the infant period. Speech delay with or without hearing loss is common. Most children are diagnosed in mid-childhood when the features of the disorder are most recognizable and striking. While improvements in cytogenetic analysis help to bring cases to clinical recognition at an earlier age, this review seeks to increase clinical awareness about Smith-Magenis syndrome by presenting the salient features observed at different ages including descriptions of the neurologic and behavioral features. Detailed review of the circadian rhythm disturbance unique to Smith-Magenis syndrome is presented. Suggestions for management of the behavioral and sleep difficulties are discussed in the context of the authors' personal experience in the setting of an ongoing Smith-Magenis syndrome natural history study.

Neurogenomics and the role of a large mutational target on rapid behavioral change.

PubMed

Stanley, Craig E; Kulathinal, Rob J

2016-11-08

Behavior, while complex and dynamic, is among the most diverse, derived, and rapidly evolving traits in animals. The highly labile nature of heritable behavioral change is observed in such evolutionary phenomena as the emergence of converged behaviors in domesticated animals, the rapid evolution of preferences, and the routine development of ethological isolation between diverging populations and species. In fact, it is believed that nervous system development and its potential to evolve a seemingly infinite array of behavioral innovations played a major role in the successful diversification of metazoans, including our own human lineage. However, unlike other rapidly evolving functional systems such as sperm-egg interactions and immune defense, the genetic basis of rapid behavioral change remains elusive. Here we propose that the rapid divergence and widespread novelty of innate and adaptive behavior is primarily a function of its genomic architecture. Specifically, we hypothesize that the broad diversity of behavioral phenotypes present at micro- and macroevolutionary scales is promoted by a disproportionately large mutational target of neurogenic genes. We present evidence that these large neuro-behavioral targets are significant and ubiquitous in animal genomes and suggest that behavior's novelty and rapid emergence are driven by a number of factors including more selection on a larger pool of variants, a greater role of phenotypic plasticity, and/or unique molecular features present in large genes. We briefly discuss the origins of these large neurogenic genes, as they relate to the remarkable diversity of metazoan behaviors, and highlight key consequences on both behavioral traits and neurogenic disease across, respectively, evolutionary and ontogenetic time scales. Current approaches to studying the genetic mechanisms underlying rapid phenotypic change primarily focus on identifying signatures of Darwinian selection in protein-coding regions. In contrast, the large mutational target hypothesis places genomic architecture and a larger allelic pool at the forefront of rapid evolutionary change, particularly in genetic systems that are polygenic and regulatory in nature. Genomic data from brain and neural tissues in mammals as well as a preliminary survey of neurogenic genes from comparative genomic data support this hypothesis while rejecting both positive and relaxed selection on proteins or higher mutation rates. In mammals and invertebrates, neurogenic genes harbor larger protein-coding regions and possess a richer regulatory repertoire of miRNA targets and transcription factor binding sites. Overall, neurogenic genes cover a disproportionately large genomic fraction, providing a sizeable substrate for evolutionary, genetic, and molecular mechanisms to act upon. Readily available comparative and functional genomic data provide unexplored opportunities to test whether a distinct neurogenomic architecture can promote rapid behavioral change via several mechanisms unique to large genes, and which components of this large footprint are uniquely metazoan. The large mutational target hypothesis highlights the eminent roles of mutation and functional genomic architecture in generating rapid developmental and evolutionary change. It has broad implications on our understanding of the genetics of complex adaptive traits such as behavior by focusing on the importance of mutational input, from SNPs to alternative transcripts to transposable elements, on driving evolutionary rates of functional systems. Such functional divergence has important implications in promoting behavioral isolation across short- and long-term timescales. Due to genome-scaled polygenic adaptation, the large target effect also contributes to our inability to identify adapted behavioral candidate genes. The presence of large neurogenic genes, particularly in the mammalian brain and other neural tissues, further offers emerging insight into the etiology of neurodevelopmental and neurodegenerative diseases. The well-known correlation between neurological spectrum disorders in children and paternal age may simply be a direct result of aging fathers accumulating mutations across these large neurodevelopmental genes. The large mutational target hypothesis can also explain the rapid evolution of other functional systems covering a large genomic fraction such as male fertility and its preferential association with hybrid male sterility among closely related taxa. Overall, a focus on mutational potential may increase our power in understanding the genetic basis of complex phenotypes such as behavior while filling a general gap in understanding their evolution.

Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders

PubMed Central

Scattoni, Maria Luisa; Crawley, Jacqueline; Ricceri, Laura

2009-01-01

In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behavior of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. All these vocalizations are becoming an increasingly valuable assay for behavioral phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models of neurodevelopmental disorders. Here we also show that the modulation of vocalizations by maternal cues (maternal potentiation paradigm) – originally identified and investigated in rats - can be measured in C57Bl/6 mouse pups with appropriate modifications of the rat protocol and can likely be applied to mouse behavioral phenotyping. In addition we suggest that a detailed qualitative evaluation of neonatal calls together with analysis of adult mouse vocalization patterns in both sexes in social settings, may lead to a greater understanding of the communication value of vocalizations in mice. Importantly, both neonatal and adult USV altered patterns can be determined during the behavioural phenotyping of mouse models of human neurodevelopmental and neuropsychiatric disorders, starting from those in which deficits in communication are a primary symptom. PMID:18771687

The Neurodevelopmental Basis of Early Childhood Disruptive Behavior: Irritable and Callous Phenotypes as Exemplars.

PubMed

Wakschlag, Lauren S; Perlman, Susan B; Blair, R James; Leibenluft, Ellen; Briggs-Gowan, Margaret J; Pine, Daniel S

2018-02-01

The arrival of the Journal's 175th anniversary occurs at a time of recent advances in research, providing an ideal opportunity to present a neurodevelopmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early-childhood-onset neurodevelopmental conditions, which emerge when experience-dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neurodevelopmental research on early childhood disruptive behavior within the historical context of the Journal. The authors highlight irritability and callous behavior as two core exemplars of early disruptive behavior. Both phenotypes can be reliably differentiated from normative variation as early as the first years of life. Both link to discrete pathophysiology: irritability with disruptions in prefrontal regulation of emotion, and callous behavior with abnormal fear processing. Each phenotype also possesses clinical and predictive utility. Based on a nomologic net of evidence, the authors conclude that early disruptive behavior is neurodevelopmental in nature and should be reclassified as an early-childhood-onset neurodevelopmental condition in DSM-5. Rapid translation from neurodevelopmental discovery to clinical application has transformative potential for psychiatric approaches of the millennium. [AJP at 175: Remembering Our Past As We Envision Our Future November 1938: Electroencephalographic Analyses of Behavior Problem Children Herbert Jasper and colleagues found that brain abnormalities revealed by EEG are a potential causal factor in childhood behavioral disorders. (Am J Psychiatry 1938; 95:641-658 )].

Humans display a reduced set of consistent behavioral phenotypes in dyadic games.

PubMed

Poncela-Casasnovas, Julia; Gutiérrez-Roig, Mario; Gracia-Lázaro, Carlos; Vicens, Julian; Gómez-Gardeñes, Jesús; Perelló, Josep; Moreno, Yamir; Duch, Jordi; Sánchez, Angel

2016-08-01

Socially relevant situations that involve strategic interactions are widespread among animals and humans alike. To study these situations, theoretical and experimental research has adopted a game theoretical perspective, generating valuable insights about human behavior. However, most of the results reported so far have been obtained from a population perspective and considered one specific conflicting situation at a time. This makes it difficult to extract conclusions about the consistency of individuals' behavior when facing different situations and to define a comprehensive classification of the strategies underlying the observed behaviors. We present the results of a lab-in-the-field experiment in which subjects face four different dyadic games, with the aim of establishing general behavioral rules dictating individuals' actions. By analyzing our data with an unsupervised clustering algorithm, we find that all the subjects conform, with a large degree of consistency, to a limited number of behavioral phenotypes (envious, optimist, pessimist, and trustful), with only a small fraction of undefined subjects. We also discuss the possible connections to existing interpretations based on a priori theoretical approaches. Our findings provide a relevant contribution to the experimental and theoretical efforts toward the identification of basic behavioral phenotypes in a wider set of contexts without aprioristic assumptions regarding the rules or strategies behind actions. From this perspective, our work contributes to a fact-based approach to the study of human behavior in strategic situations, which could be applied to simulating societies, policy-making scenario building, and even a variety of business applications.

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

PubMed

Reijnders, Margot R F; Miller, Kerry A; Alvi, Mohsan; Goos, Jacqueline A C; Lees, Melissa M; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B A; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A L; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W E; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M; Cremer, Kirsten; Strom, Tim M; Bird, Lynne M; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S; Edery, Patrick; Yap, Patrick; Terhal, Paulien A; van der Spek, Peter J; Lakeman, Phillis; Taylor, Rachel L; Littlejohn, Rebecca O; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P A; Kant, Sarina G; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M A; Douzgou, Sofia; Wall, Steven A; Küry, Sébastien; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J; Twigg, Stephen R F; Mathijssen, Irene M J; Nellaker, Christoffer; Brunner, Han G; Wilkie, Andrew O M

2018-06-07

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

A network approach to discerning the identities of C. elegans in a free moving population

NASA Astrophysics Data System (ADS)

Winter, Peter B.; Brielmann, Renee M.; Timkovich, Nicholas P.; Navarro, Helio T.; Teixeira-Castro, Andreia; Morimoto, Richard I.; Amaral, Luis A. N.

2016-10-01

The study of C. elegans has led to ground-breaking discoveries in gene-function, neuronal circuits, and physiological responses. Subtle behavioral phenotypes, however, are often difficult to measure reproducibly. We have developed an experimental and computational infrastructure to simultaneously record and analyze the physical characteristics, movement, and social behaviors of dozens of interacting free-moving nematodes. Our algorithm implements a directed acyclic network that reconstructs the complex behavioral trajectories generated by individual C. elegans in a free moving population by chaining hundreds to thousands of short tracks into long contiguous trails. This technique allows for the high-throughput quantification of behavioral characteristics that require long-term observation of individual animals. The graphical interface we developed will enable researchers to uncover, in a reproducible manner, subtle time-dependent behavioral phenotypes that will allow dissection of the molecular mechanisms that give rise to organism-level behavior.

Behavioral Actions of Alcohol: Phenotypic Relations from Multivariate Analysis of Mutant Mouse Data

PubMed Central

Blednov, Yuri A.; Mayfield, R. Dayne; Belknap, John; Harris, R. Adron

2012-01-01

Behavioral studies of genetically diverse mice have proven powerful for determining relationships between phenotypes and have been widely used in alcohol research. Most of these studies rely on naturally occurring genetic polymorphisms among inbred strains and selected lines. Another approach is to introduce variation by engineering single gene mutations in mice. We have tested 37 different mutant mice and their wild type controls for a variety (31) of behaviors and have mined this dataset by K-means clustering and analysis of correlations. We found a correlation between a stress-related response (activity in a novel environment) and alcohol consumption and preference for saccharin. We confirmed several relationships detected in earlier genetic studies including positive correlation of alcohol consumption with saccharin consumption, and negative correlations with conditioned taste aversion and alcohol withdrawal severity. Introduction of single gene mutations either eliminated or greatly diminished these correlations. The three tests of alcohol consumption used (continuous two bottle choice, and two limited access tests: Drinking In the Dark and Sustained High Alcohol Consumption) share a relationship with saccharin consumption, but differ from each other in their correlation networks. We suggest that alcohol consumption is controlled by multiple physiological systems where single gene mutations can disrupt the networks of such systems. PMID:22405477

Predictive oncology: multidisciplinary, multi-scale in-silico modeling linking phenotype, morphology and growth

PubMed Central

Sanga, Sandeep; Frieboes, Hermann B.; Zheng, Xiaoming; Gatenby, Robert; Bearer, Elaine L.; Cristini, Vittorio

2007-01-01

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically review advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we propose and discuss a multi-scale, i.e., from the molecular to the gross tumor scale, mathematical and computational “first-principle” approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We demonstrate that this methodology, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as phenotype-diagnostic tool and thus to predict collective and individual tumor cell invasion of surrounding host. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior. PMID:17629503

Evolving Digital Ecological Networks

PubMed Central

Wagner, Aaron P.; Ofria, Charles

2013-01-01

“It is hard to realize that the living world as we know it is just one among many possibilities” [1]. Evolving digital ecological networks are webs of interacting, self-replicating, and evolving computer programs (i.e., digital organisms) that experience the same major ecological interactions as biological organisms (e.g., competition, predation, parasitism, and mutualism). Despite being computational, these programs evolve quickly in an open-ended way, and starting from only one or two ancestral organisms, the formation of ecological networks can be observed in real-time by tracking interactions between the constantly evolving organism phenotypes. These phenotypes may be defined by combinations of logical computations (hereafter tasks) that digital organisms perform and by expressed behaviors that have evolved. The types and outcomes of interactions between phenotypes are determined by task overlap for logic-defined phenotypes and by responses to encounters in the case of behavioral phenotypes. Biologists use these evolving networks to study active and fundamental topics within evolutionary ecology (e.g., the extent to which the architecture of multispecies networks shape coevolutionary outcomes, and the processes involved). PMID:23533370

Slk19p of Saccharomyces cerevisiae Regulates Anaphase Spindle Dynamics Through Two Independent Mechanisms

PubMed Central

Havens, Kyle A.; Gardner, Melissa K.; Kamieniecki, Rebecca J.; Dresser, Michael E.; Dawson, Dean S.

2010-01-01

Slk19p is a member of the Cdc-14 early anaphase release (FEAR) pathway, a signaling network that is responsible for activation of the cell-cycle regulator Cdc14p in Saccharomyces cerevisiae. Disruption of the FEAR pathway results in defects in anaphase, including alterations in the assembly and behavior of the anaphase spindle. Many phenotypes of slk19Δ mutants are consistent with a loss of FEAR signaling, but other phenotypes suggest that Slk19p may have FEAR-independent roles in modulating the behavior of microtubules in anaphase. Here, a series of SLK19 in-frame deletion mutations were used to test whether Slk19p has distinct roles in anaphase that can be ascribed to specific regions of the protein. Separation-of-function alleles were identified that are defective for either FEAR signaling or aspects of anaphase spindle function. The data suggest that in early anaphase one region of Slk19p is essential for FEAR signaling, while later in anaphase another region is critical for maintaining the coordination between spindle elongation and the growth of interpolar microtubules. PMID:20923975

Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes

PubMed Central

Jones, Paul; Chase, Kevin; Martin, Alan; Davern, Pluis; Ostrander, Elaine A.; Lark, Karl G.

2008-01-01

Phenotypic stereotypes are traits, often polygenic, that have been stringently selected to conform to specific criteria. In dogs, Canis familiaris, stereotypes result from breed standards set for conformation, performance (behaviors), etc. As a consequence, phenotypic values measured on a few individuals are representative of the breed stereotype. We used DNA samples isolated from 148 dog breeds to associate SNP markers with breed stereotypes. Using size as a trait to test the method, we identified six significant quantitative trait loci (QTL) on five chromosomes that include candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Less well-documented data for behavioral stereotypes tentatively identified loci for herding, pointing, boldness, and trainability. Four significant loci were identified for longevity, a breed characteristic not under direct selection, but inversely correlated with breed size. The strengths and limitations of the approach are discussed as well as its potential to identify loci regulating the within-breed incidence of specific polygenic diseases. PMID:18505865

Brain nuclei in actively courting red-sided garter snakes: a paradigm of neural trimorphism.

PubMed

Krohmer, Randolph W; DeMarchi, Geno A; Baleckaitis, Daniel D; Lutterschmidt, Deborah I; Mason, Robert T

2011-03-28

During the breeding season, two distinct male phenotypes are exhibited by red-sided garter snakes (Thamnophis sirtalis parietalis), with courtship behavior being directed not only toward females, but also toward a sub-population of males called she-males. She-males are morphologically identical to other males except for a circulating androgen level three times that of normal males and their ability to produce a female-like pheromone. As in other vertebrates, limbic nuclei in the red-sided garter snake brain are involved in the control of sexual behaviors. For example, an intact anterior hypothalamus pre-optic area (AHPOA) is essential for the initiation and maintenance of reproduction. To determine if brain morphology varies among the three behavioral phenotypes (i.e., males, she-males, and females) during the breeding season, we examined the volume, cell size and cell density of the AHPOA as well as a control region, the external nucleus of the optic tract (ENOT). We used Luxol Fast Blue and Ziehl's Fuchsin to visualize neurons and glial cells, respectively. No significant differences were observed among the three behavioral phenotypes in the volume, cell size or density in the control region. In contrast, the volume, cell size and density of the AHPOA of she-males were significantly greater than those of both male and female snakes. While the volume of the AHPOA was significantly greater in females compared to males, no differences were observed in cell size or density. These differences in brain morphology suggest a possible underlying mechanism for phenotypic-specific behavioral patterns. Copyright © 2010 Elsevier Inc. All rights reserved.

Pleiotropic Contribution of MECOM and AVPR1A to Aggression and Subcortical Brain Volumes

PubMed Central

van Donkelaar, Marjolein M. J.; Hoogman, Martine; Pappa, Irene; Tiemeier, Henning; Buitelaar, Jan K.; Franke, Barbara; Bralten, Janita

2018-01-01

Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in the development of aggressive behavior. Imaging studies implicate brain structures related to social behavior in aggression etiology, most notably the amygdala and striatum. This study aimed to gain more insight into the pathways from genetic risk factors for aggression to aggression phenotypes. To this end, we conducted genome-wide gene-based cross-trait meta-analyses of aggression with the volumes of amygdala, nucleus accumbens and caudate nucleus to identify genes influencing both aggression and aggression-related brain volumes. We used data of large-scale genome-wide association studies (GWAS) of: (a) aggressive behavior in children and adolescents (EAGLE, N = 18,988); and (b) Magnetic Resonance Imaging (MRI)-based volume measures of aggression-relevant subcortical brain regions (ENIGMA2, N = 13,171). Second, the identified genes were further investigated in a sample of healthy adults (mean age (SD) = 25.28 (4.62) years; 43% male) who had genome-wide genotyping data and questionnaire data on aggression subtypes available (Brain Imaging Genetics, BIG, N = 501) to study their effect on reactive and proactive subtypes of aggression. Our meta-analysis identified two genes, MECOM and AVPR1A, significantly associated with both aggression risk and nucleus accumbens (MECOM) and amygdala (AVPR1A) brain volume. Subsequent in-depth analysis of these genes in healthy adults (BIG), including sex as an interaction term in the model, revealed no significant subtype-specific gene-wide associations. Using cross-trait meta-analysis of brain measures and psychiatric phenotypes, this study generated new hypotheses about specific links between genes, the brain and behavior. Results indicate that MECOM and AVPR1A may exert an effect on aggression through mechanisms involving nucleus accumbens and amygdala volumes, respectively. PMID:29666571

Seasonal Effects on the Population, Morphology and Reproductive Behavior of Narnia femorata (Hemiptera: Coreidae).

PubMed

Cirino, Lauren A; Miller, Christine W

2017-01-17

Many insects are influenced by the phenology of their host plants. In North Central Florida, Narnia femorata (Hemiptera: Coreidae) spends its entire life cycle living and feeding on Opuntia mesacantha ssp. lata . This cactus begins producing flower buds in April that lead to unripe green fruit in June that ripen into red fruit through December. Many morphological and behavioral characteristics of N. femorata are known to be affected by cactus phenology in a controlled laboratory setting, including the degree of sexual dimorphism and mating behavior. Our goal with this study was to determine if similar phenotypic changes of N. femorata occurred over time in the wild, and the extent to which these changes were concordant with phenological changes in its host plant. Further, we investigate the length of the insect mouthparts (beak) over time. Ongoing work has suggested that beak length may change across cohorts of developing insects in response to feeding deep within cactus fruit where seed and pulp depth decrease as the fruit ripens. Our results revealed a drop in cactus fruit abundance between the months of July through October 2015 as cactus fruits turned red and ripened. Simultaneously, the average body size of both males and females of N. femorata declined at two sampled sites. Male hind femora (a sexually-selected weapon) decreased disproportionately in size over time so that males later in the year had relatively smaller hind femora for their body size. The sex-specific patterns of morphological change led to increased sexual-size dimorphism and decreased sexual dimorphism for hind femora later in the year. Further, we found that beak length decreased across cohorts of insects as cactus fruit ripened, suggesting phenotypic plasticity in mouthpart length. Behavioral studies revealed that female readiness to mate increased as the season progressed. In sum, we found pronounced changes in the phenotypes of these insects in the field. Although this study is far from comprehensive, it provides tantalizing patterns that suggest many directions for future research.

Often Asked but Rarely Answered: Can Asians Meet DSM-5/ICD-10 Autism Spectrum Disorder Criteria?

PubMed Central

Kim, So Hyun; Koh, Yun-Joo; Lim, Eun-Chung; Kim, Soo-Jeong; Leventhal, Bennett L.

2016-01-01

Abstract Objectives: To evaluate whether Asian (Korean children) populations can be validly diagnosed with autism spectrum disorder (ASD) using Western-based diagnostic instruments and criteria based on Diagnostic and Statistical Manual on Mental Disorders, 5th edition (DSM-5). Methods: Participants included an epidemiologically ascertained 7–14-year-old (N = 292) South Korean cohort from a larger prevalence study (N = 55,266). Main outcomes were based on Western-based diagnostic methods for Korean children using gold standard instruments, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. Factor analysis and ANOVAs were performed to examine factor structure of autism symptoms and identify phenotypic differences between Korean children with ASD and non-ASD diagnoses. Results: Using Western-based diagnostic methods, Korean children with ASD were successfully identified with moderate-to-high diagnostic validity (sensitivities/specificities ranging 64%–93%), strong internal consistency, and convergent/concurrent validity. The patterns of autism phenotypes in a Korean population were similar to those observed in a Western population with two symptom domains (social communication and restricted and repetitive behavior factors). Statistically significant differences in the use of socially acceptable communicative behaviors (e.g., direct gaze, range of facial expressions) emerged between ASD versus non-ASD cases (mostly p < 0.001), ensuring that these can be a similarly valid part of the ASD phenotype in both Asian and Western populations. Conclusions: Despite myths, biases, and stereotypes about Asian social behavior, Asians (at least Korean children) typically use elements of reciprocal social interactions similar to those in the West. Therefore, standardized diagnostic methods widely used for ASD in Western culture can be validly used as part of the assessment process and research with Koreans and, possibly, other Asians. PMID:27315155

Persistent post-stroke depression in mice following unilateral medial prefrontal cortical stroke

PubMed Central

Vahid-Ansari, F; Lagace, D C; Albert, P R

2016-01-01

Post-stroke depression (PSD) is a common outcome following stroke that is associated with poor recovery. To develop a preclinical model of PSD, we targeted a key node of the depression–anxiety circuitry by inducing a unilateral ischemic lesion to the medial prefrontal cortex (mPFC) stroke. Microinjection of male C57/BL6 mice with endothelin-1 (ET-1, 1600 pmol) induced a small (1 mm3) stroke consistently localized within the left mPFC. Compared with sham control mice, the stroke mice displayed a robust behavioral phenotype in four validated tests of anxiety including the elevated plus maze, light–dark, open-field and novelty-suppressed feeding tests. In addition, the stroke mice displayed depression-like behaviors in both the forced swim and tail suspension test. In contrast, there was no effect on locomotor activity or sensorimotor function in the horizontal ladder, or cylinder and home cage activity tests, indicating a silent stroke due to the absence of motor abnormalities. When re-tested at 6 weeks post stroke, the stroke mice retained both anxiety and depression phenotypes. Surprisingly, at 6 weeks post stroke the lesion site was infiltrated by neurons, suggesting that the ET-1-induced neuronal loss in the mPFC was reversible over time, but was insufficient to promote behavioral recovery. In summary, unilateral ischemic lesion of the mPFC results in a pronounced and persistent anxiety and depression phenotype with no evident sensorimotor deficits. This precise lesion of the depression circuitry provides a reproducible model to study adaptive cellular changes and preclinical efficacy of novel interventions to alleviate PSD symptoms. PMID:27483381

Hispanic Americans and Non-Hispanic White Americans Have a Similar Inflammatory Bowel Disease Phenotype: A Systematic Review with Meta-Analysis.

PubMed

Avalos, Danny J; Mendoza-Ladd, Antonio; Zuckerman, Marc J; Bashashati, Mohammad; Alvarado, Andres; Dwivedi, Alok; Damas, Oriana M

2018-06-01

Inflammatory bowel disease (IBD) is a devastating immune-mediated disease on the rise in Hispanics living in the USA. Prior observational studies comparing IBD characteristics between Hispanics and non-Hispanic whites (NHW) have yielded mixed results. We performed a meta-analysis of observational studies examining IBD phenotype in Hispanics compared to NHW. We conducted a systematic search of US-based studies comparing IBD subtype (Ulcerative Colitis: UC or Crohn's disease: CD) and phenotype (disease location and behavior) between Hispanics and NHW. We evaluated differences in age at IBD diagnosis, the presence of family history and smoking history. A random effects model was chosen "a priori." Categorical and continuous variables were analyzed using odds ratio (OR) or standard mean difference (SMD), respectively. Seven studies were included with 687 Hispanics and 1586 NHW. UC was more common in Hispanics compared to NHW (OR 2.07, CI 1.13-3.79, p = 0.02). Location of disease was similar between Hispanics and NHW except for the presence of upper gastrointestinal CD, which was less common in Hispanics (OR 0.58, CI 0.32-1.06, p = 0.07). Hispanics were less likely to smoke (OR 0.48, CI 0.26-0.89, p = 0.02) or have a family history of IBD (OR 0.35, CI 0.22-0.55, p < 0.001). CD behavior classified by Montreal classification and age at IBD diagnosis were similar between Hispanics and NHW. UC was more common among US Hispanics compared to NHW. Age at IBD diagnosis is similar for both Hispanics and NHW. For CD, disease behavior is similar, but Hispanics show a trend for less upper gastrointestinal involvement. A family history of IBD and smoking history were less common in Hispanics.

Comprehensive behavioral analysis of voltage-gated calcium channel beta-anchoring and -regulatory protein knockout mice

PubMed Central

Nakao, Akito; Miki, Takafumi; Shoji, Hirotaka; Nishi, Miyuki; Takeshima, Hiroshi; Miyakawa, Tsuyoshi; Mori, Yasuo

2015-01-01

Calcium (Ca2+) influx through voltage-gated Ca2+ channels (VGCCs) induces numerous intracellular events such as neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation. It has been shown that genes related to Ca2+ signaling, such as the CACNA1C, CACNB2, and CACNA1I genes that encode VGCC subunits, are associated with schizophrenia and other psychiatric disorders. Recently, VGCC beta-anchoring and -regulatory protein (BARP) was identified as a novel regulator of VGCC activity via the interaction of VGCC β subunits. To examine the role of the BARP in higher brain functions, we generated BARP knockout (KO) mice and conducted a comprehensive battery of behavioral tests. BARP KO mice exhibited greatly reduced locomotor activity, as evidenced by decreased vertical activity, stereotypic counts in the open field test, and activity level in the home cage, and longer latency to complete a session in spontaneous T-maze alteration test, which reached “study-wide significance.” Acoustic startle response was also reduced in the mutants. Interestingly, they showed multiple behavioral phenotypes that are seemingly opposite to those seen in the mouse models of schizophrenia and its related disorders, including increased working memory, flexibility, prepulse inhibition, and social interaction, and decreased locomotor activity, though many of these phenotypes are statistically weak and require further replications. These results demonstrate that BARP is involved in the regulation of locomotor activity and, possibly, emotionality. The possibility was also suggested that BARP KO mice may serve as a unique tool for investigating the pathogenesis/pathophysiology of schizophrenia and related disorders. Further evaluation of the molecular and physiological phenotypes of the mutant mice would provide new insights into the role of BARP in higher brain functions. PMID:26136667

Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

PubMed

Alboni, S; van Dijk, R M; Poggini, S; Milior, G; Perrotta, M; Drenth, T; Brunello, N; Wolfer, D P; Limatola, C; Amrein, I; Cirulli, F; Maggi, L; Branchi, I

2017-04-01

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

Hybrid multiscale modeling and prediction of cancer cell behavior

PubMed Central

Habibi, Jafar

2017-01-01

Background Understanding cancer development crossing several spatial-temporal scales is of great practical significance to better understand and treat cancers. It is difficult to tackle this challenge with pure biological means. Moreover, hybrid modeling techniques have been proposed that combine the advantages of the continuum and the discrete methods to model multiscale problems. Methods In light of these problems, we have proposed a new hybrid vascular model to facilitate the multiscale modeling and simulation of cancer development with respect to the agent-based, cellular automata and machine learning methods. The purpose of this simulation is to create a dataset that can be used for prediction of cell phenotypes. By using a proposed Q-learning based on SVR-NSGA-II method, the cells have the capability to predict their phenotypes autonomously that is, to act on its own without external direction in response to situations it encounters. Results Computational simulations of the model were performed in order to analyze its performance. The most striking feature of our results is that each cell can select its phenotype at each time step according to its condition. We provide evidence that the prediction of cell phenotypes is reliable. Conclusion Our proposed model, which we term a hybrid multiscale modeling of cancer cell behavior, has the potential to combine the best features of both continuum and discrete models. The in silico results indicate that the 3D model can represent key features of cancer growth, angiogenesis, and its related micro-environment and show that the findings are in good agreement with biological tumor behavior. To the best of our knowledge, this paper is the first hybrid vascular multiscale modeling of cancer cell behavior that has the capability to predict cell phenotypes individually by a self-generated dataset. PMID:28846712

Female Mecp2+/− mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies

PubMed Central

Samaco, Rodney C.; McGraw, Christopher M.; Ward, Christopher S.; Sun, Yaling; Neul, Jeffrey L.; Zoghbi, Huda Y.

2013-01-01

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2+/− mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2+/− mice, we analyzed Mecp2+/− mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2+/− mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2+/− mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT. PMID:23026749

Hybrid multiscale modeling and prediction of cancer cell behavior.

PubMed

Zangooei, Mohammad Hossein; Habibi, Jafar

2017-01-01

Understanding cancer development crossing several spatial-temporal scales is of great practical significance to better understand and treat cancers. It is difficult to tackle this challenge with pure biological means. Moreover, hybrid modeling techniques have been proposed that combine the advantages of the continuum and the discrete methods to model multiscale problems. In light of these problems, we have proposed a new hybrid vascular model to facilitate the multiscale modeling and simulation of cancer development with respect to the agent-based, cellular automata and machine learning methods. The purpose of this simulation is to create a dataset that can be used for prediction of cell phenotypes. By using a proposed Q-learning based on SVR-NSGA-II method, the cells have the capability to predict their phenotypes autonomously that is, to act on its own without external direction in response to situations it encounters. Computational simulations of the model were performed in order to analyze its performance. The most striking feature of our results is that each cell can select its phenotype at each time step according to its condition. We provide evidence that the prediction of cell phenotypes is reliable. Our proposed model, which we term a hybrid multiscale modeling of cancer cell behavior, has the potential to combine the best features of both continuum and discrete models. The in silico results indicate that the 3D model can represent key features of cancer growth, angiogenesis, and its related micro-environment and show that the findings are in good agreement with biological tumor behavior. To the best of our knowledge, this paper is the first hybrid vascular multiscale modeling of cancer cell behavior that has the capability to predict cell phenotypes individually by a self-generated dataset.

Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial

PubMed Central

van Sluijs, Esther M. F.; Marteau, Theresa M.; Sutton, Stephen

2016-01-01

Background Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk of type 2 diabetes in a parallel group, open, randomized controlled trial. Methods and Findings We recruited 569 healthy middle-aged adults from the Fenland Study, an ongoing population-based, observational study in the east of England (Cambridgeshire, UK). We used a computer-generated random list to assign participants in blocks of six to receive either standard lifestyle advice alone (control group, n = 190) or in combination with a genetic (n = 189) or a phenotypic (n = 190) risk estimate for type 2 diabetes (intervention groups). After 8 wk, we measured the primary outcome, objectively measured physical activity (kJ/kg/day), and also measured several secondary outcomes (including self-reported diet, self-reported weight, worry, anxiety, and perceived risk). The study was powered to detect a between-group difference of 4.1 kJ/kg/d at follow-up. 557 (98%) participants completed the trial. There were no significant intervention effects on physical activity (difference in adjusted mean change from baseline: genetic risk group versus control group 0.85 kJ/kg/d (95% CI −2.07 to 3.77, p = 0.57); phenotypic risk group versus control group 1.32 (95% CI −1.61 to 4.25, p = 0.38); and genetic risk group versus phenotypic risk group −0.47 (95% CI −3.40 to 2.46, p = 0.75). No significant differences in self-reported diet, self-reported weight, worry, and anxiety were observed between trial groups. Estimates of perceived risk were significantly more accurate among those who received risk information than among those who did not. Key limitations include the recruitment of a sample that may not be representative of the UK population, use of self-reported secondary outcome measures, and a short follow-up period. Conclusions In this study, we did not observe short-term changes in behavior associated with the communication of an estimate of genetic or phenotypic risk of type 2 diabetes. We also did not observe changes in worry or anxiety in the study population. Additional research is needed to investigate the conditions under which risk information might enhance preventive strategies. (Current Controlled Trials ISRCTN09650496; Date applied: April 4, 2011; Date assigned: June 10, 2011). Trial Registration The trial is registered with Current Controlled Trials, ISRCTN09650496. PMID:27898672

Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial.

PubMed

Godino, Job G; van Sluijs, Esther M F; Marteau, Theresa M; Sutton, Stephen; Sharp, Stephen J; Griffin, Simon J

2016-11-01

Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk of type 2 diabetes in a parallel group, open, randomized controlled trial. We recruited 569 healthy middle-aged adults from the Fenland Study, an ongoing population-based, observational study in the east of England (Cambridgeshire, UK). We used a computer-generated random list to assign participants in blocks of six to receive either standard lifestyle advice alone (control group, n = 190) or in combination with a genetic (n = 189) or a phenotypic (n = 190) risk estimate for type 2 diabetes (intervention groups). After 8 wk, we measured the primary outcome, objectively measured physical activity (kJ/kg/day), and also measured several secondary outcomes (including self-reported diet, self-reported weight, worry, anxiety, and perceived risk). The study was powered to detect a between-group difference of 4.1 kJ/kg/d at follow-up. 557 (98%) participants completed the trial. There were no significant intervention effects on physical activity (difference in adjusted mean change from baseline: genetic risk group versus control group 0.85 kJ/kg/d (95% CI -2.07 to 3.77, p = 0.57); phenotypic risk group versus control group 1.32 (95% CI -1.61 to 4.25, p = 0.38); and genetic risk group versus phenotypic risk group -0.47 (95% CI -3.40 to 2.46, p = 0.75). No significant differences in self-reported diet, self-reported weight, worry, and anxiety were observed between trial groups. Estimates of perceived risk were significantly more accurate among those who received risk information than among those who did not. Key limitations include the recruitment of a sample that may not be representative of the UK population, use of self-reported secondary outcome measures, and a short follow-up period. In this study, we did not observe short-term changes in behavior associated with the communication of an estimate of genetic or phenotypic risk of type 2 diabetes. We also did not observe changes in worry or anxiety in the study population. Additional research is needed to investigate the conditions under which risk information might enhance preventive strategies. (Current Controlled Trials ISRCTN09650496; Date applied: April 4, 2011; Date assigned: June 10, 2011). The trial is registered with Current Controlled Trials, ISRCTN09650496.

A Behavior Analytic Approach to Exploratory Motor Behavior: How Can Caregivers Teach EM Behavior to Infants with Down Syndrome?

ERIC Educational Resources Information Center

Bauer, Sara M.; Jones, Emily A.

2014-01-01

Impairment in exploratory motor (EM) behavior is part of the Down syndrome behavioral phenotype. Exploratory motor behavior may be a pivotal skill for early intervention with infants with Down syndrome. Exploratory motor impairments are often attributed to general delays in motor development in infants with Down syndrome. A behavior analytic…

Conceptual shifts needed to understand the dynamic interactions of genes, environment, epigenetics, social processes, and behavioral choices.

PubMed

Jackson, Fatimah L C; Niculescu, Mihai D; Jackson, Robert T

2013-10-01

Social and behavioral research in public health is often intimately tied to profound, but frequently neglected, biological influences from underlying genetic, environmental, and epigenetic events. The dynamic interplay between the life, social, and behavioral sciences often remains underappreciated and underutilized in addressing complex diseases and disorders and in developing effective remediation strategies. Using a case-study format, we present examples as to how the inclusion of genetic, environmental, and epigenetic data can augment social and behavioral health research by expanding the parameters of such studies, adding specificity to phenotypic assessments, and providing additional internal control in comparative studies. We highlight the important roles of gene-environment interactions and epigenetics as sources of phenotypic change and as a bridge between the life and social and behavioral sciences in the development of robust interdisciplinary analyses.

Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice.

PubMed

Bozdagi, Ozlem; Sakurai, Takeshi; Dorr, Nathan; Pilorge, Marion; Takahashi, Nagahide; Buxbaum, Joseph D

2012-01-01

Copy number variation (CNV) at the 15q11.2 region, which includes a gene that codes for CYFIP1 (cytoplasmic FMR1 interacting protein 1), has been implicated in autism, intellectual disability and additional neuropsychiatric phenotypes. In the current study we studied the function of Cyfip1 in synaptic physiology and behavior, using mice with a disruption of the Cyfip1 gene. We observed that in Cyfip1 heterozygous mice metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) induced by paired-pulse low frequency stimulation (PP-LFS) was significantly increased in comparison to wildtype mice. In addition, mGluR-LTD was not affected in the presence of protein synthesis inhibitor in the Cyfip1 heterozygous mice, while the same treatment inhibited LTD in wildtype littermate controls. mGluR-agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD was also significantly increased in hippocampal slices from Cyfip1 heterozygous mice and again showed independence from protein synthesis only in the heterozygous animals. Furthermore, we observed that the mammalian Target of Rapamycin (mTOR) inhibitor rapamycin was only effective at reducing mGluR-LTD in wildtype animals. Behaviorally, Cyfip1 heterozygous mice showed enhanced extinction of inhibitory avoidance. Application of both mGluR5 and mGluR1 antagonist to slices from Cyfip1 heterozygous mice reversed the increase in DHPG-induced LTD in these mice. These results demonstrate that haploinsufficiency of Cyfip1 mimics key aspects of the phenotype of Fmr1 knockout mice and are consistent with the hypothesis that these effects are mediated by interaction of Cyfip1 and Fmrp in regulating activity-dependent translation. The data provide support for a model where CYFIP1 haploinsufficiency in patients results in intermediate phenotypes increasing risk for neuropsychiatric disorders.

A naturalistic exploratory study of the impact of demographic, phenotypic and comorbid features in pediatric obsessive-compulsive disorder.

PubMed

Masi, Gabriele; Millepiedi, Stefania; Perugi, Giulio; Pfanner, Chiara; Berloffa, Stefano; Pari, Cinzia; Mucci, Maria; Akiskal, Hagop S

2010-01-01

Few studies have examined the impact of gender, age at onset, phenotype and comorbidity in pediatric obsessive-compulsive disorder (OCD) in children. In this naturalistic study we consider these characteristics of OCD in the framework of the 4 OCD phenotypes (contamination/cleaning, order/symmetry, obsessions/checking and hoarding) proposed by Leckman et al. A consecutive series of 257 patients aged 13.6 +/- 2.8 years, diagnosed using a DSM-IV-based clinical interview (Schedule for Affective Disorders and Schizophrenia for School Age Children - Present and Lifetime Version), were included. Patients with OCD onset before 12 years of age presented a higher frequency of comorbid tic disorder and disruptive behavior disorders. The type of obsession varied with gender: order/symmetry was more frequent in males, contamination/cleaning in females. Order/symmetry had the highest comorbidity with tics, contamination/cleaning was the least severe according to the Clinical Global Impression Severity, and was associated with a high rate of comorbid anxiety and depression, similarly to sexual-religious obsessions. Hoarding was the severest according to the Clinical Global Impression Severity, and was associated with a high comorbidity with social phobia and bipolar disorder. Tic comorbidity was more prevalent in males, had an earlier onset, and a heavier comorbidity with attention deficit hyperactivity disorder and other disruptive behavior disorders. A comorbid attention deficit hyperactivity disorder was associated with an earlier onset of OCD and a poorer response to treatments. OCD phenotypes and comorbidities may have marked clinical and prognostic implications. Tertiary care population results may not generalize to less impaired juvenile populations. Copyright 2010 S. Karger AG, Basel.

Cognitive Dysfunctions in Intellectual Disabilities: The Contributions of the Ras-MAPK and PI3K-AKT-mTOR Pathways.

PubMed

Borrie, Sarah C; Brems, Hilde; Legius, Eric; Bagni, Claudia

2017-08-31

The Ras-MAPK and PI3K-AKT-mTOR signaling cascades were originally identified as cancer regulatory pathways but have now been demonstrated to be critical for synaptic plasticity and behavior. Neurodevelopmental disorders arising from mutations in these pathways exhibit related neurological phenotypes, including cognitive dysfunction, autism, and intellectual disability. The downstream targets of these pathways include regulation of transcription and protein synthesis. Other disorders that affect protein translation include fragile X syndrome (an important cause of syndromal autism), and other translational regulators are now also linked to autism. Here, we review how mechanisms of synaptic plasticity have been revealed by studies of mouse models for Ras-MAPK, PI3K-AKT-mTOR, and translation regulatory pathway disorders. We discuss the face validity of these mouse models and review current progress in clinical trials directed at ameliorating cognitive and behavioral symptoms.

Novel Synthesis and Phenotypic Analysis of Mutant Clouds for Hepatitis E Virus Genotype 1.

PubMed

Agarwal, Shubhra; Baccam, Prasith; Aggarwal, Rakesh; Veerapu, Naga Suresh

2018-02-15

Many RNA viruses exist as an ensemble of genetically diverse, replicating populations known as a mutant cloud. The genetic diversity (cloud size) and composition of this mutant cloud may influence several important phenotypic features of the virus, including its replication capacity. We applied a straightforward, bacterium-free approach using error-prone PCR coupled with reverse genetics to generate infectious mutant RNA clouds with various levels of genetic diversity from a genotype 1 strain of hepatitis E virus (HEV). Cloning and sequencing of a genomic fragment encompassing 70% of open reading frame 1 ( ORF1 ) or of the full genome from variants in the resultant clouds showed the occurrence of nucleotide mutations at a frequency on the order of 10 -3 per nucleotide copied and the existence of marked genetic diversity, with a high normalized Shannon entropy value. The mutant clouds showed transient replication in cell culture, while wild-type HEV did not. Cross-sectional data from these cell cultures supported the existence of differential effects of clouds of various sizes and compositions on phenotypic characteristics, such as the replication level of (+)-RNA progeny, the amounts of double-stranded RNA (a surrogate for the rate of viral replication) and ORF1 protein, and the expression of interferon-stimulated genes. Since mutant cloud size and composition influenced the viral phenotypic properties, a better understanding of this relationship may help to provide further insights into virus evolution and prediction of emerging viral diseases. IMPORTANCE Several biological or practical limitations currently prevent the study of phenotypic behavior of a mutant cloud in vitro We developed a simple and rapid method for synthesizing mutant clouds of hepatitis E virus (HEV), a single-stranded (+)-RNA [ss(+) RNA] virus, with various and controllable levels of genetic diversity, which could then be used in a cell culture system to study the effects of cloud size and composition on viral phenotype. In a cross-sectional analysis, we demonstrated that a particular mutant cloud which had an extremely high genetic diversity had a replication rate exceeding that of wild-type HEV. This method should thus provide a useful model for understanding the phenotypic behavior of ss(+) RNA viruses. Copyright © 2018 American Society for Microbiology.

Ontogeny and adolescent alcohol exposure in Wistar rats: open field conflict, light/dark box and forced swim test.

PubMed

Desikan, Anita; Wills, Derek N; Ehlers, Cindy L

2014-07-01

Epidemiological studies have demonstrated that heavy drinking and alcohol abuse and dependence peak during the transition between late adolescence and early adulthood. Studies in animal models have demonstrated that alcohol exposure during adolescence can cause a modification in some aspects of behavioral development, causing the "adolescent phenotype" to be retained into adulthood. However, the "adolescent phenotype" has not been studied for a number of behavioral tests. The objective of the present study was to investigate the ontogeny of behaviors over adolescence/young adulthood in the light/dark box, open field conflict and forced swim test in male Wistar rats. These data were compared to previously published data from rats that received intermittent alcohol vapor exposure during adolescence (AIE) to test whether they retained the "adolescent phenotype" in these behavioral tests. Three age groups of rats were tested (post-natal day (PD) 34-42; PD55-63; PD69-77). In the light/dark box test, younger rats escaped the light box faster than older adults, whereas AIE rats returned to the light box faster and exhibited more rears in the light than controls. In the open field conflict test, both younger and AIE rats had shorter times to first enter the center, spent more time in the center of the field, were closer to the food, and consumed more food than controls. In the forced swim test no clear developmental pattern emerged. The results of the light/dark box and the forced swim test do not support the hypothesis that adolescent ethanol vapor exposure can "lock-in" all adolescent phenotypes. However, data from the open field conflict test suggest that the adolescent and the AIE rats both engaged in more "disinhibited" and food motivated behaviors. These data suggest that, in some behavioral tests, AIE may result in a similar form of behavioral disinhibition to what is seen in adolescence. Copyright © 2014. Published by Elsevier Inc.

Revealing Behavioral Learning Deficit Phenotypes Subsequent to In Utero Exposure to Benzo(a)pyrene

PubMed Central

McCallister, Monique M.; Li, Zhu; Zhang, Tongwen; Ramesh, Aramandla; Clark, Ryan S.; Maguire, Mark; Hutsell, Blake; Newland, M. Christopher; Hood, Darryl B.

2016-01-01

To characterize behavioral deficits in pre-adolescent offspring exposed in utero to Benzo(a)pyrene [B(a)P], timed-pregnant Long Evans Hooded rats were treated with B(a)P (150, 300, 600, and 1200 µg/kg BW) or peanut oil (vehicle) on E14, 15, 16, and 17. Following birth, during the pre-weaning period, B(a)P metabolites were examined in plasma and whole brain or cerebral cortex from exposed and control offspring. Tissue concentrations of B(a)P metabolites were (1) dose-dependent and (2) followed a time-dependence for elimination with ∼60% reduction by PND5 in the 1200 µg/kg BW experimental group. Spatial discrimination-reversal learning was utilized to evaluate potential behavioral neurotoxicity in P40–P60 offspring. Late-adolescent offspring exposed in utero to 600 and 1200 µg/kg BW were indistinguishable from their control counterparts for ability to acquire an original discrimination (OD) and reach criterion. However, a dose-dependent effect of in utero B(a)P-exposure was evident upon a discrimination reversal as exposed offspring perseverated on the previously correct response. This newly characterized behavioral deficit phenotype for the first reversal was not apparent in either the (1) OD or (2) subsequent reversal sessions relative to the respective control offspring. Furthermore, the expression of activity related-cytoskeletal-associated protein (Arc), an experience-dependent cortical protein marker known to be up-regulated in response to acquisition of a novel behavior, was greater in B(a)P-exposed offspring included in the spatial discrimination cohort versus home cage controls. Collectively, these findings support the hypothesis that in utero exposure to B(a)P during critical windows of development representing peak periods of neurogenesis results in behavioral deficits in later life. PMID:26420751

A familial pericentric inversion of chromosome 11 associated with a microdeletion of 163 kb and microduplication of 288 kb at 11p13 and 11q22.3 without aniridia or eye anomalies.

PubMed

Balay, Lara; Totten, Ellen; Okada, Luna; Zell, Sidney; Ticho, Benjamin; Israel, Jeannette; Kogan, Jillene

2016-01-01

Interstitial deletions of 11p13 involving MPPED2, DCDC5, DCDC1, DNAJC24, IMMP1L, and ELP4 are previously reported to have downstream transcriptional effects on the expression of PAX6, due to a downstream regulatory region (DRR). Currently, no clear genotype-phenotype correlations have been established allowing for conclusive information regarding the exact location of the PAX6 DRR, though its location has been approximated in mouse models to be within the Elp4 gene. Of the clinical reports currently published examining patients with intact PAX6 genes but harboring deletions identified in genes downstream of PAX6, 100% indicate phenotypes which include aniridia, whereas approximately half report additional eye deformities, autism, or intellectual disability. In this clinical report, we present a 12-year-old male patient, his brother, and mother with pericentric inversions of chromosome 11 associated with submicroscopic interstitial deletions of 11p13 and duplications of 11q22.3. The inversions were identified by standard cytogenetic analysis; microarray and FISH detected the chromosomal imbalance. The patient's phenotype includes intellectual disability, speech abnormalities, and autistic behaviors, but interestingly neither the patient, his brother, nor mother have aniridia or other eye anomalies. To the best of our knowledge, these findings in three family members represent the only reported cases with 11p13 deletions downstream of PAX6 not demonstrating phenotypic characteristics of aniridia or abnormal eye development. Although none of the deleted genes are obvious candidates for the patient's phenotype, the absence of aniridia in the presence of this deletion in all three family members further delineates the location of the DRR for PAX6. © 2015 Wiley Periodicals, Inc.

Family function, Parenting Style and Broader Autism Phenotype as Predicting Factors of Psychological Adjustment in Typically Developing Siblings of Children with Autism Spectrum Disorders.

PubMed

Mohammadi, Mohammadreza; Zarafshan, Hadi

2014-04-01

Siblings of children with autism are at a greater risk of experiencing behavioral and social problems. Previous researches had focused on environmental variables such as family history of autism spectrum disorders (ASDs), behavior problems in the child with an ASD, parental mental health problems, stressful life events and "broader autism phenotype" (BAP), while variables like parenting style and family function that are shown to influence children's behavioral and psychosocial adjustment are overlooked. The aim of the present study was to reveal how parenting style and family function as well as BAP effect psychological adjustment of siblings of children with autism. The Participants included 65 parents who had one child with an Autism Spectrum Disorder and one typically developing child. Of the children with ASDs, 40 were boys and 25 were girls; and they were diagnosed with ASDs by a psychiatrist based on DSM-IV-TR criteria and Autism Diagnostic Interview-Revised (ADI-R). The Persian versions of the six scales were used to collect data from the families. Pearson's correlation test and regression analysis were used to determine which variables were related to the psychological adjustment of sibling of children with ASDs and which variables predicted it better. Significant relationships were found between Strengths and Difficulties Questionnaire (SDQ) total difficulties, prosocial behaviors and ASDs symptoms severity, parenting styles and some aspects of family function. In addition, siblings who had more BAP characteristics had more behavior problems and less prosocial behavior. Behavioral problems increased and prosocial behavior decreased with permissive parenting style. Besides, both of authoritarian and authoritative parenting styles led to a decrease in behavioral problems and an increase in prosocial behaviors. Our findings revealed that some aspects of family function (affective responsiveness, roles, problem solving and behavior control) were significantly correlated with behavioral problems and prosocial behaviors in typically developing (TD) siblings of children with ASDs. Siblings of children with ASDs, due to genetic liability, are at a greater risk of psychological maladjustment. Furthermore, environmental factors like parenting styles and family function also have a significant effect on psychological maladjustment.

Prenatal lipopolysaccharide exposure affects sexual dimorphism in different germlines of mice with a depressive phenotype.

PubMed

Reis-Silva, Thiago M; Cohn, Daniel W H; Sandini, Thaísa M; Udo, Mariana S B; Teodorov, Elizabeth; Bernardi, Maria Martha

2016-03-15

The objective of the present study was to investigate whether prenatal lipopolysaccharide (LPS) administration modifies the expression of depressive and non-depressive-like behavior in male and female mice across two generations. The sexual dimorphism of these mice was also examined in the open-field test. Male and female mice of the parental (F0) generation were selected for depressive- or non-depressive-like behavioral profiles using the tail suspension test (TST). Animals with similar profiles were matched for further mating. On gestation day (GD) 15, pregnant F0 mice received LPS (100μg/kg, i.p.) and were allowed to nurture their offspring freely. Adult male and female of the F1 generation were then selected according to behavioral profiles and observed in the open field. Male and female mice of the two behavioral profiles were then mated to obtain the F2 generation. Adults from the F2 generation were also behaviorally phenotyped, and open field behavior was assessed. Male mice that were selected for depressive- and non-depressive-like behaviors and treated or not with LPS in the parental generation exhibited similar proportions of behavioral profiles in both filial lines, but LPS exposure increased the number of depressive-like behavior. An effect of gender was observed in the F1 and F2 generations, in which male mice were more sensitive to the intergenerational effects of LPS in the TST. These data indicate that prenatal LPS exposure on GD15 in the F0 generation influenced the transmission of depressive- and non-depressive-like behavior across filial lines, with sexual dimorphism between phenotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

Vicarious social defeat stress: Bridging the gap between physical and emotional stress.

PubMed

Sial, Omar K; Warren, Brandon L; Alcantara, Lyonna F; Parise, Eric M; Bolaños-Guzmán, Carlos A

2016-01-30

Animal models capable of differentiating the neurobiological intricacies between physical and emotional stress are scarce. Current models rely primarily on physical stressors (e.g., chronic unpredictable or mild stress, social defeat, learned helplessness), and neglect the impact of psychological stress alone. This is surprising given extensive evidence that a traumatic event needs not be directly experienced to produce enduring perturbations on an individual's health and psychological well-being. Post-traumatic stress disorder (PTSD), a highly debilitating neuropsychiatric disorder characterized by intense fear of trauma-related stimuli, often occurs in individuals that have only witnessed a traumatic event. By modifying the chronic social defeat stress (CSDS) paradigm to include a witness component (witnessing the social defeat of another mouse), we demonstrate a novel behavioral paradigm capable of inducing a robust behavioral syndrome reminiscent of PTSD in emotionally stressed adult mice. We describe the vicarious social defeat stress (VSDS) model that is capable of inducing a host of behavioral deficits that include social avoidance and other depressive- and anxiety-like phenotypes in adult male mice. VSDS exposure induces weight loss and spike in serum corticosterone (CORT) levels. A month after stress, these mice retain the social avoidant phenotype and have an increased CORT response when exposed to subsequent stress. The VSDS is a novel paradigm capable of inducing emotional stress by isolating physical stress/confrontation in mice. The VSDS model can be used to study the short- and long-term neurobiological consequences of exposure to emotional stress in mice. Copyright © 2015 Elsevier B.V. All rights reserved.

Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in the Drosophila Voltage-Gated Sodium Channel Gene paralytic

PubMed Central

Kasuya, Junko; Ueda, Atsushi; Iyengar, Atulya; Wu, Chun-Fang

2016-01-01

Abstract Shudderer (Shu) is an X-linked dominant mutation in Drosophila melanogaster identified more than 40 years ago. A previous study showed that Shu caused spontaneous tremors and defects in reactive climbing behavior, and that these phenotypes were significantly suppressed when mutants were fed food containing lithium, a mood stabilizer used in the treatment of bipolar disorder (Williamson, 1982). This unique observation suggested that the Shu mutation affects genes involved in lithium-responsive neurobiological processes. In the present study, we identified Shu as a novel mutant allele of the voltage-gated sodium (Nav) channel gene paralytic (para). Given that hypomorphic para alleles and RNA interference–mediated para knockdown reduced the severity of Shu phenotypes, Shu was classified as a para hypermorphic allele. We also demonstrated that lithium could improve the behavioral abnormalities displayed by other Nav mutants, including a fly model of the human generalized epilepsy with febrile seizures plus. Our electrophysiological analysis of Shu showed that lithium treatment did not acutely suppress Nav channel activity, indicating that the rescue effect of lithium resulted from chronic physiological adjustments to this drug. Microarray analysis revealed that lithium significantly alters the expression of various genes in Shu, including those involved in innate immune responses, amino acid metabolism, and oxidation-reduction processes, raising the interesting possibility that lithium-induced modulation of these biological pathways may contribute to such adjustments. Overall, our findings demonstrate that Nav channel mutants in Drosophila are valuable genetic tools for elucidating the effects of lithium on the nervous system in the context of neurophysiology and behavior. PMID:27844061

Human Laboratory Paradigms in Alcohol Research

PubMed Central

Plebani, Jennifer G.; Ray, Lara A.; Morean, Meghan E.; Corbin, William R.; Mackillop, James; Amlung, Michael; King, Andrea C.

2014-01-01

Human laboratory studies have a long and rich history in the field of alcoholism. Human laboratory studies have allowed for advances in alcohol research in a variety of ways, including elucidating of the neurobehavioral mechanisms of risk, identifying phenotypically distinct sub-types of alcohol users, investigating of candidate genes underlying experimental phenotypes for alcoholism, and testing mechanisms of action of alcoholism pharmacotherapies on clinically-relevant translational phenotypes, such as persons exhibiting positive-like alcohol effects or alcohol craving. Importantly, the field of human laboratory studies in addiction has progressed rapidly over the past decade and has built upon earlier findings of alcohol's neuropharmacological effects to advancing translational research on alcoholism etiology and treatment. To that end, the new generation of human laboratory studies has focused on applying new methodologies, further refining alcoholism phenotypes, and translating these findings to studies of alcoholism genetics, medication development, and pharmacogenetics. The combination of experimental laboratory approaches with recent developments in neuroscience and pharmacology has been particularly fruitful in furthering our understanding of the impact of individual differences in alcoholism risk and in treatment response. This review of the literature focuses on human laboratory studies of subjective intoxication, alcohol craving, anxiety, and behavioral economics. Each section discusses opportunities for phenotype refinement under laboratory conditions, as well as its application to translational science of alcoholism. A summary and recommendations for future research are also provided. PMID:22309888

Direct Correlation between Motile Behavior and Protein Abundance in Single Cells

PubMed Central

Gillet, Sébastien; Frankel, Nicholas W.; Weibel, Douglas B.

2016-01-01

Understanding how stochastic molecular fluctuations affect cell behavior requires the quantification of both behavior and protein numbers in the same cells. Here, we combine automated microscopy with in situ hydrogel polymerization to measure single-cell protein expression after tracking swimming behavior. We characterized the distribution of non-genetic phenotypic diversity in Escherichia coli motility, which affects single-cell exploration. By expressing fluorescently tagged chemotaxis proteins (CheR and CheB) at different levels, we quantitatively mapped motile phenotype (tumble bias) to protein numbers using thousands of single-cell measurements. Our results disagreed with established models until we incorporated the role of CheB in receptor deamidation and the slow fluctuations in receptor methylation. Beyond refining models, our central finding is that changes in numbers of CheR and CheB affect the population mean tumble bias and its variance independently. Therefore, it is possible to adjust the degree of phenotypic diversity of a population by adjusting the global level of expression of CheR and CheB while keeping their ratio constant, which, as shown in previous studies, confers functional robustness to the system. Since genetic control of protein expression is heritable, our results suggest that non-genetic diversity in motile behavior is selectable, supporting earlier hypotheses that such diversity confers a selective advantage. PMID:27599206

The RDoC initiative and the structure of psychopathology.

PubMed

Krueger, Robert F; DeYoung, Colin G

2016-03-01

The NIMH Research Domain Criteria (RDoC) project represents a welcome effort to circumvent the limitations of psychiatric categories as phenotypes for psychopathology research. Here, we describe the hierarchical and dimensional structure of phenotypic psychopathology and illustrate how this structure provides phenotypes suitable for RDoC research on neural correlates of psychopathology. A hierarchical and dimensional approach to psychopathology phenotypes holds great promise for delineating connections between neuroscience constructs and the patterns of affect, cognition, and behavior that constitute manifest psychopathology. © 2016 Society for Psychophysiological Research.

Multiscale Characterization of Bacterial Swarming Illuminates Principles Governing Directed Surface Motility

NASA Astrophysics Data System (ADS)

Strickland, Ben; Hoeger, Kentaro; Ursell, Tristan

In many systems, individual characteristics interact, leading to the spontaneous emergence of order and complexity. In biological settings like microbes, such collective behaviors can imbue a variety of benefits to constituent individuals, including increased spatial range, improved access to nutrients, and enhanced resistance to antibiotic threats. To untangle the biophysical underpinnings of collective motility, we use passive tracers and a curated genetic library of Bacillus subtilis, including motile, non-motile, biofilm-deficient, and non-chemotactic mutants. We characterize and connect individual behavior on the microscopic scale to macroscopic colony morphology and motility of dendritic swarming. We analyze the persistence and dynamics of coordinated movement on length scales up to 4 orders of magnitude larger than that of individual cells, revealing rapid and directed responses of microbial groups to external stimuli, such as avoidance dynamics across chemical gradients. Our observations uncover the biophysical interplay between individual motility, surface wetness, phenotypic diversity, and external physical forces that robustly precipitate coordinated group behavior in microbes, and suggest general principles that govern the transition from individual to group behavior.

Phenotypic Variability in Resting-State Functional Connectivity: Current Status

PubMed Central

Gordon, Evan M.

2013-01-01

Abstract We reviewed the extant literature with the goal of assessing the extent to which resting-state functional connectivity is associated with phenotypic variability in healthy and disordered populations. A large corpus of work has accumulated to date (125 studies), supporting the association between intrinsic functional connectivity and individual differences in a wide range of domains—not only in cognitive, perceptual, motoric, and linguistic performance, but also in behavioral traits (e.g., impulsiveness, risky decision making, personality, and empathy) and states (e.g., anxiety and psychiatric symptoms) that are distinguished by cognitive and affective functioning, and in neurological conditions with cognitive and motor sequelae. Further, intrinsic functional connectivity is sensitive to remote (e.g., early-life stress) and enduring (e.g., duration of symptoms) life experience, and it exhibits plasticity in response to recent experience (e.g., learning and adaptation) and pharmacological treatment. The most pervasive associations were observed with the default network; associations were also widespread between the cingulo-opercular network and both cognitive and affective behaviors, while the frontoparietal network was associated primarily with cognitive functions. Associations of somatomotor, frontotemporal, auditory, and amygdala networks were relatively restricted to the behaviors linked to their respective putative functions. Surprisingly, visual network associations went beyond visual function to include a variety of behavioral traits distinguished by affective function. Together, the reviewed evidence sets the stage for testing causal hypothesis about the functional role of intrinsic connectivity and augments its potential as a biomarker for healthy and disordered brain function. PMID:23294010

Removal of GABAA Receptor γ2 Subunits from Parvalbumin Neurons Causes Wide-Ranging Behavioral Alterations

PubMed Central

Leppä, Elli; Linden, Anni-Maija; Vekovischeva, Olga Y.; Swinny, Jerome D.; Rantanen, Ville; Toppila, Esko; Höger, Harald; Sieghart, Werner; Wulff, Peer; Wisden, William; Korpi, Esa R.

2011-01-01

We investigated the behavioral significance of fast synaptic inhibition by αβγ2-type GABAA receptors on parvalbumin (Pv) cells. The GABAA receptor γ2 subunit gene was selectively inactivated in Pv-positive neurons by Cre/loxP recombination. The resulting Pv-Δγ2 mice were relatively healthy in the first postnatal weeks; but then as Cre started to be expressed, the mice progressively developed wide-ranging phenotypic alterations including low body weight, motor deficits and tremor, decreased anxiety levels, decreased pain sensitivity and deficient prepulse inhibition of the acoustic startle reflex and impaired spatial learning. Nevertheless, the deletion was not lethal, and mice did not show increased mortality even after one year. Autoradiography with t-butylbicyclophosphoro[35S]thionate suggested an increased amount of GABAA receptors with only α and β subunits in central nervous system regions that contained high levels of parvalbumin neurons. Using BAC-transgenesis, we reduced some of the Pv-Δγ2 phenotype by selectively re-expressing the wild-type γ2 subunit back into some Pv cells (reticular thalamic neurons and cerebellar Pv-positive neurons). This produced less severe impairments of motor skills and spatial learning compared with Pv-Δγ2 mice, but all other deficits remained. Our results reveal the widespread significance of fast GABAergic inhibition onto Pv-positive neurons for diverse behavioral modalities, such as motor coordination, sensorimotor integration, emotional behavior and nociception. PMID:21912668

Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2)

PubMed Central

Walz, Katherina; Paylor, Richard; Yan, Jiong; Bi, Weimin; Lupski, James R.

2006-01-01

Genomic disorders are conditions that result from DNA rearrangements, such as deletions or duplications. The identification of the dosage-sensitive gene(s) within the rearranged genomic interval is important for the elucidation of genes responsible for complex neurobehavioral phenotypes. Smith-Magenis syndrome is associated with a 3.7-Mb deletion in 17p11.2, and its clinical presentation is caused by retinoic acid inducible 1 (RAI1) haploinsufficiency. The reciprocal microduplication syndrome, dup(17)(p11.2p11.2), manifests several neurobehavioral abnormalities, but the responsible dosage-sensitive gene(s) remain undefined. We previously generated a mouse model for dup(17)(p11.2p11.2), Dp(11)17/+, that recapitulated most of the phenotypes observed in human patients. We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17] in one chromosome 11 along with a null allele of Rai1 in the other chromosome 11 homologue [Dp(11)17/Rai1– mice] in order to study the relationship between Rai1 gene copy number and the Dp(11)17/+ phenotypes. Normal disomic Rai1 gene dosage was sufficient to rescue the complex physical and behavioral phenotypes observed in Dp(11)17/+ mice, despite altered trisomic copy number of the other 18 genes present in the rearranged genomic interval. These data provide a model for variation in copy number of single genes that could influence common traits such as obesity and behavior. PMID:17024248

Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on αv integrins.

PubMed

Carduner, L; Leroy-Dudal, J; Picot, C R; Gallet, O; Carreiras, F; Kellouche, S

2014-08-01

At least one-third of patients with epithelial ovarian cancer (OC) present ascites at diagnosis and almost all have ascites at recurrence. The presence of ascites, which acts as a dynamic reservoir of active molecules and cellular components, correlates with the OC peritoneal metastasis and is associated with poor prognosis. Since epithelial-mesenchymal transition (EMT) is involved in different phases of OC progression, we have investigated the effect of the unique ascitic tumor microenvironment on the EMT status and the behavior of OC cells. The exposure of three OC cell lines to ascites leads to changes in cellular morphologies. Within ascites, OC cells harboring an initial intermediate epithelial phenotype are characterized by marked dislocation of epithelial markers (E-cadherin, ZO-1 staining) while OC cells initially harboring an intermediate mesenchymal phenotype strengthen their mesenchymal markers (N-cadherin, vimentin). Ascites differentially triggers a dissemination phenotype related to the initial cell features by either allowing the proliferation and the formation of spheroids and the extension of colonies for cells that present an initial epithelial intermediate phenotype, or favoring the migration of cells with a mesenchymal intermediate phenotype. In an ascitic microenvironment, a redeployment of αv integrins into cells was observed and the ascites-induced accentuation of the two different invasive phenotypes (i.e. spheroids formation or migration) was shown to involve αv integrins. Thus, ascites induces a shift toward an unstable intermediate state of the epithelial-mesenchymal spectrum and confers a more aggressive cell behavior that takes on a different pathway based on the initial epithelial-mesenchymal cell features.

A Low-Cost, Reliable, High-Throughput System for Rodent Behavioral Phenotyping in a Home Cage Environment

PubMed Central

Parkison, Steven A.; Carlson, Jay D.; Chaudoin, Tammy R.; Hoke, Traci A.; Schenk, A. Katrin; Goulding, Evan H.; Pérez, Lance C.; Bonasera, Stephen J.

2016-01-01

Inexpensive, high-throughput, low maintenance systems for precise temporal and spatial measurement of mouse home cage behavior (including movement, feeding, and drinking) are required to evaluate products from large scale pharmaceutical design and genetic lesion programs. These measurements are also required to interpret results from more focused behavioral assays. We describe the design and validation of a highly-scalable, reliable mouse home cage behavioral monitoring system modeled on a previously described, one-of-a-kind system [1]. Mouse position was determined by solving static equilibrium equations describing the force and torques acting on the system strain gauges; feeding events were detected by a photobeam across the food hopper, and drinking events were detected by a capacitive lick sensor. Validation studies show excellent agreement between mouse position and drinking events measured by the system compared with video-based observation – a gold standard in neuroscience. PMID:23366406

Change in the Behavioral Phenotype of Adolescents and Adults with FXS: Role of the Family Environment

ERIC Educational Resources Information Center

Smith, Leann E.; Hong, Jinkuk; Greenberg, Jan S.; Mailick, Marsha R.

2016-01-01

The present study examined trajectories of adaptive behavior, behavior problems, psychological symptoms, and autism symptoms in adolescents and adults with fragile X syndrome (n = 147) over a three-year period. Adaptive behavior significantly increased over time, particularly for adolescents, and the severity of behavior problems decreased over…

Assessing Sociability, Social Memory, and Pup Retrieval in Mice.

PubMed

Zimprich, Annemarie; Niessing, Jörn; Cohen, Lior; Garrett, Lillian; Einicke, Jan; Sperling, Bettina; Schmidt, Mathias V; Hölter, Sabine M

2017-12-20

Adaptive social behavior is important in mammals, both for the well-being of the individual and for the thriving of the species. Dysfunctions in social behavior occur in many neurodevelopmental and psychiatric diseases, and research into the genetic components of disease-relevant social deficits can open up new avenues for understanding the underlying biological mechanisms and therapeutic interventions. Genetically modified mouse models are particularly useful in this respect, and robust experimental protocols are needed to reliably assess relevant social behavior phenotypes. Here we describe in detail three protocols to quantitatively measure sociability, one of the most frequently investigated social behavior phenotypes in mice, using a three-chamber sociability test. These protocols can be extended to also assess social memory. In addition, we provide a detailed protocol on pup retrieval, which is a particularly robust maternal behavior amenable to various scientific questions. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Fitness consequences of maternal and embryonic responses to environmental variation: using reptiles as models for studies of developmental plasticity.

PubMed

Warner, Daniel A

2014-11-01

Environmental factors strongly influence phenotypic variation within populations. The environment contributes to this variation in two ways: (1) by acting as a determinant of phenotypic variation (i.e., plastic responses) and (2) as an agent of selection that "chooses" among existing phenotypes. Understanding how these two environmental forces contribute to phenotypic variation is a major goal in the field of evolutionary biology and a primary objective of my research program. The objective of this article is to provide a framework to guide studies of environmental sources of phenotypic variation (specifically, developmental plasticity and maternal effects, and their adaptive significance). Two case studies from my research on reptiles are used to illustrate the general approaches I have taken to address these conceptual topics. Some key points for advancing our understanding of environmental influences on phenotypic variation include (1) merging laboratory-based research that identifies specific environmental effects with field studies to validate ecological relevance; (2) using controlled experimental approaches that mimic complex environments found in nature; (3) integrating data across biological fields (e.g., genetics, morphology, physiology, behavior, and ecology) under an evolutionary framework to provide novel insights into the underlying mechanisms that generate phenotypic variation; (4) assessing fitness consequences using measurements of survival and/or reproductive success across ontogeny (from embryos to adults) and under multiple ecologically-meaningful contexts; and (5) quantifying the strength and form of natural selection in multiple populations over multiple periods of time to understand the spatial and temporal consistency of phenotypic selection. Research programs that focus on organisms that are amenable to these approaches will provide the most promise for advancing our understanding of the environmental factors that generate the remarkable phenotypic diversity observed within populations. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Fragile X Syndrome and Targeted Treatment Trials

PubMed Central

Lauterborn, Julie; Au, Jacky; Berry-Kravis, Elizabeth

2014-01-01

Work in recent years has revealed an abundance of possible new treatment targets for fragile X syndrome (FXS). The use of animal models, including the fragile X knockout mouse which manifests a phenotype very similar to FXS in humans, has resulted in great strides in this direction of research. The lack of Fragile X Mental Retardation Protein (FMRP) in FXS causes dysregulation and usually overexpression of a number of its target genes, which can cause imbalances of neurotransmission and deficits in synaptic plasticity. The use of metabotropic glutamate receptor (mGluR) blockers and gamma amino-butyric acid (GABA) agonists have been shown to be efficacious in reversing cellular and behavioral phenotypes, and restoring proper brain connectivity in the mouse and fly models. Proposed new pharmacological treatments and educational interventions are discussed in this chapter. In combination, these various targeted treatments show promising preliminary results in mitigating or even reversing the neurobiological abnormalities caused by loss of FMRP, with possible translational applications to other neurodevelopmental disorders including autism. PMID:22009360

Fragile X syndrome and targeted treatment trials.

PubMed

Hagerman, Randi; Lauterborn, Julie; Au, Jacky; Berry-Kravis, Elizabeth

2012-01-01

Work in recent years has revealed an abundance of possible new treatment targets for fragile X syndrome (FXS). The use of animal models, including the fragile X knockout mouse which manifests a phenotype very similar to FXS in humans, has resulted in great strides in this direction of research. The lack of Fragile X Mental Retardation Protein (FMRP) in FXS causes dysregulation and usually overexpression of a number of its target genes, which can cause imbalances of neurotransmission and deficits in synaptic plasticity. The use of metabotropic glutamate receptor (mGluR) blockers and gamma amino-butyric acid (GABA) agonists have been shown to be efficacious in reversing cellular and behavioral phenotypes, and restoring proper brain connectivity in the mouse and fly models. Proposed new pharmacological treatments and educational interventions are discussed in this chapter. In combination, these various targeted treatments show promising preliminary results in mitigating or even reversing the neurobiological abnormalities caused by loss of FMRP, with possible translational applications to other neurodevelopmental disorders including autism.

Innate Immune Cytokines, Fibroblast Phenotypes, and Regulation of Extracellular Matrix in Lung.

PubMed

Richards, Carl D

2017-02-01

Chronic inflammation can be caused by adaptive immune responses in autoimmune and allergic conditions, driven by a T lymphocyte subset balance (TH1, TH2, Th17, Th22, and/or Treg) and skewed cellular profiles in an antigen-specific manner. However, several chronic inflammatory diseases have no clearly defined adaptive immune mechanisms that drive chronicity. These conditions include those that affect the lung such as nonatopic asthma or idiopathic pulmonary fibrosis comprising significant health problems. The remodeling of extracellular matrix (ECM) causes organ dysfunction, and it is largely generated by fibroblasts as the major cell controlling net ECM. As such, these are potential targets of treatment approaches in the context of ECM pathology. Fibroblast phenotypes contribute to ECM and inflammatory cell accumulation, and they are integrated into chronic disease mechanisms including cancer. Evidence suggests that innate cytokine responses may be critical in nonallergic/nonautoimmune disease, and they enable environmental agent exposure mechanisms that are independent of adaptive immunity. Innate immune cytokines derived from macrophage subsets (M1/M2) and innate lymphoid cell (ILC) subsets can directly regulate fibroblast function. We also suggest that STAT3-activating gp130 cytokines can sensitize fibroblasts to the innate cytokine milieu to drive phenotypes and exacerbate existing adaptive responses. Here, we review evidence exploring innate cytokine regulation of fibroblast behavior.

Stock structure of sea otters (Enhydra lutris kenyoni) in Alaska

USGS Publications Warehouse

Gorbics, C.S.; Bodkin, James L.

2001-01-01

Sea otters in Alaska are recognized as a single subspecies (Enhydra lutris kenyoni) and currently managed as a single, interbreeding population. However, geographic and behavioral mechanisms undoubtably constrain sea otter movements on much smaller scales. This paper applies the phylogeographic method (Dizon et al. 1992) and considers distribution, population response, phenotype and genotype data to identify stocks of sea otters within Alaska. The evidence for separate stock identity is genotypic (all stocks), phenotypic (Southcentral and Southwest stocks), and geographic distribution (Southeast stock), whereas population response data are equivocal (all stocks). Differences in genotype frequencies and the presence of unique genotypes among areas indicate restricted gene flow. Genetic exchange may be limited by little or no movement across proposed stock boundaries and discontinuities in distribution at proposed stock boundaries. Skull size differences (phenotypic) between Southwest and Southcentral Alaska populations further support stock separation. Population response information was equivocal in either supporting or refuting stock identity. On the basis of this review, we suggest the following: (1) a Southeast stock extending from Dixon Entrance to Cape Yakataga; (2) a Southcentral stock extending from Cape Yakataga to Cape Douglas including Prince William Sound and Kenai peninsula coast; and (3) a Southwest stock including Alaska Peninsula coast, the Aleutians to Attu Island, Barren, Kodiak, Pribilof Islands, and Bristol Bay.

Reduced Tissue Levels of Noradrenaline Are Associated with Behavioral Phenotypes of the TgCRND8 Mouse Model of Alzheimer's Disease

PubMed Central

Francis, Beverly M; Yang, Jimao; Hajderi, Enid; Brown, Mary E; Michalski, Bernadeta; McLaurin, JoAnne; Fahnestock, Margaret; Mount, Howard T J

2012-01-01

Noradrenergic cell loss is well documented in Alzheimer's disease (AD). We have measured the tissue levels of catecholamines in an amyloid precursor protein-transgenic ‘TgCRND8' mouse model of AD and found reductions in noradrenaline (NA) within hippocampus, temporoparietal and frontal cortices, and cerebellum. An age-related increase in cortical NA levels was observed in non-Tg controls, but not in TgCRND8 mice. In contrast, NA levels declined with aging in the TgCRND8 hippocampus. Dopamine levels were unaffected. Reductions in the tissue content of NA were found to coincide with altered expression of brain-derived neurotrophic factor (BDNF) mRNA and to precede the onset of object memory impairment and behavioral despair. To test whether these phenotypes might be associated with diminished NA, we treated mice with dexefaroxan, an antagonist of presynaptic inhibitory α2-adrenoceptors on noradrenergic and cholinergic terminals. Mice 12 weeks of age were infused systemically for 28 days with dexefaroxan or rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved TgCRND8 behavioral phenotypes and increased BDNF mRNA expression without affecting amyloid-β peptide levels. Our results highlight the importance of noradrenergic depletion in AD-like phenotypes of TgCRND8 mice. PMID:22491352

Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma*

PubMed Central

Scott, Milcah C.; Sarver, Aaron L.; Tomiyasu, Hirotaka; Cornax, Ingrid; Van Etten, Jamie; Varshney, Jyotika; O'Sullivan, M. Gerard; Subramanian, Subbaya; Modiano, Jaime F.

2015-01-01

We previously identified two distinct molecular subtypes of osteosarcoma through gene expression profiling. These subtypes are associated with distinct tumor behavior and clinical outcomes. Here, we describe mechanisms that give rise to these molecular subtypes. Using bioinformatic analyses, we identified a significant association between deregulation of the retinoblastoma (RB)-E2F pathway and the molecular subtype with worse clinical outcomes. Xenotransplantation models recapitulated the corresponding behavior for each osteosarcoma subtype; thus, we used cell lines to validate the role of the RB-E2F pathway in regulating the prognostic gene signature. Ectopic RB resets the patterns of E2F regulated gene expression in cells derived from tumors with worse clinical outcomes (molecular phenotype 2) to those comparable with those observed in cells derived from tumors with less aggressive outcomes (molecular phenotype 1), providing a functional association between RB-E2F dysfunction and altered gene expression in osteosarcoma. DNA methyltransferase and histone deacetylase inhibitors similarly reset the transcriptional state of the molecular phenotype 2 cells from a state associated with RB deficiency to one seen with RB sufficiency. Our data indicate that deregulation of RB-E2F pathway alters the epigenetic landscape and biological behavior of osteosarcoma. PMID:26378234

Phenotype of a child with Angelman syndrome born to a woman with Prader-Willi syndrome.

PubMed

Ostergaard, John R

2015-09-01

This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader-Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting. © 2015 Wiley Periodicals, Inc.

Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

PubMed

Rodríguez, Guadalupe; Neugebauer, Nichole M; Yao, Katherine Lan; Meltzer, Herbert Y; Csernansky, John G; Dong, Hongxin

2017-08-01

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Δ9-THC, while mice that received Δ9-THC and PCP+Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic and environmental relationships of metabolic and weight phenotypes to metabolic syndrome and diabetes: the healthy twin study.

PubMed

Song, Yun-Mi; Sung, Joohon; Lee, Kayoung

2015-02-01

We aimed to examine the relationships, including genetic and environmental correlations, between metabolic and weight phenotypes and factors related to diabetes and metabolic syndrome. Participants of the Healthy Twin Study without diabetes (n=2687; 895 monozygotic and 204 dizygotic twins, and 1588 nontwin family members; mean age, 42.5±13.1 years) were stratified according to body mass index (BMI) (<25 vs. ≥25 kg/m(2)) and metabolic syndrome categories at baseline. The metabolic traits, namely diabetes and metabolic syndrome, metabolic syndrome components, glycated hemoglobin (HbA1c) level, and homeostasis model assessment of insulin resistance (HOMA-IR), were assessed after 2.5±2.1 years. In a multivariate-adjusted model, those who had metabolic syndrome or overweight phenotypes at baseline were more likely to have higher HbA1C and HOMA-IR levels and abnormal metabolic syndrome components at follow-up as compared to the metabolically healthy normal weight subgroup. The incidence of diabetes was 4.4-fold higher in the metabolically unhealthy but normal weight individuals and 3.3-fold higher in the metabolically unhealthy and overweight individuals as compared with the metabolically healthy normal weight individuals. The heritability of the metabolic syndrome/weight phenotypes was 0.40±0.03. Significant genetic and environmental correlations were observed between the metabolic syndrome/weight phenotypes at baseline and the metabolic traits at follow-up, except for incident diabetes, which only had a significant common genetic sharing with the baseline phenotypes. The genetic and environmental relationships between the metabolic and weight phenotypes at baseline and the metabolic traits at follow-up suggest pleiotropic genetic mechanisms and the crucial role of lifestyle and behavioral factors.

Phenotypic and genetic associations between the big five and trait emotional intelligence.

PubMed

Vernon, Philip A; Villani, Vanessa C; Schermer, Julie Aitken; Petrides, K V

2008-10-01

This study reports the first behavioral genetic investigation of the extent to which genetic and/or environmental factors contribute to the relationship between the Big Five personality factors and trait emotional intelligence. 213 pairs of adult monozygotic twins and 103 pairs of same-sex dizygotic twins completed the NEO-PI-R and the Trait Emotional Intelligence Questionnaire (TEIQue). Replicating previous non-twin studies, many significant phenotypic correlations were found between the Big Five factors - especially Neuroticism, Extraversion, and Conscientiousness - and the facets, factors, and global scores derived from the TEIQue. Bivariate behavioral genetic model-fitting analyses revealed that these phenotypic correlations were primarily attributable to correlated genetic factors and secondarily to correlated non-shared environmental factors. The results support the feasibility of incorporating EI as a trait within existing personality taxonomies.

The role of the sociotype in managing chronic disease: integrating bio-psycho-sociology with systems biology.

PubMed

Berry, Elliot M

2011-10-01

Attempts have been made to replace the bio-medical approach with that of systems biology, which considers dynamic human behavior (internal factors) for chronic (rather than acute) disease management. They have not yet incorporated the Bio-psycho-social (BPS) model of Engel which adds patients' background and cultural beliefs (external factors) contributing to their susceptibility to, and coping strategies for, non-communicable diseases (NCDs) the increasing domain of global Public Health. The problem is how to include the social determinants of disease in a comprehensive model of care, especially in the management of chronic disease. The concept of "sociotype" is proposed as a framework for understanding the interactions between the social, cultural and environmental inputs that influence the growth, development and life-long behavior of a person, including relationships, lifestyle and coping strategies. Pre-/peri-natal influences on development and subsequent susceptibility to chronic disease are examples of interactions between the sociotype, genotype and phenotype. Disorders of the sociotype, encompassing social determinants (e.g. poverty, education, networking), of disease are major contributors to the increase in NCDs, as well as for mental illness and absenteeism. Thus, people are the product of a threefold cord--genotype, phenotype and sociotype. WHAT NEXT?: Holistic management of patients through the BPS model have to be aligned with the relevant elements of systems biology--context, space, time and robustness--that pertain to the sociotype. Medical curricula should balance basic sciences with disciplines such as psychology, sociology, anthropology and public health that attempt to explain human behavior and the social determinants of disease. This requires methodologies combining qualitative and quantitative research to study simultaneous interactions (and their possible mechanisms) between systems biology and the BPS model. The neologism "sociotype" highlights the importance of the social dimension of the BPS model in a novel and useful way. The sociotype, with its effects on genotype and phenotype, will bring psychosocial variables into a paradigm of medical practice to promote health and improve the management of chronic illness. Copyright © 2011 Elsevier Ltd. All rights reserved.

Social Behavior and Cortisol Reactivity in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hessl, David; Glaser, Bronwyn; Dyer-Friedman, Jennifer; Reiss, Allan L.

2006-01-01

Objective: To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS). Method: Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full…

Modelling fragile X syndrome in the laboratory setting: A behavioral perspective.

PubMed

Melancia, Francesca; Trezza, Viviana

2018-04-25

Fragile X syndrome is the most common form of inherited mental retardation and the most frequent monogenic cause of syndromic autism spectrum disorders. The syndrome is caused by the loss of the Fragile X Mental Retardation Protein (FMRP), a key RNA-binding protein involved in synaptic plasticity and neuronal morphology. Patients show intellectual disability, social deficits, repetitive behaviors and impairments in social communication. The aim of this review is to outline the importance of behavioral phenotyping of animal models of FXS from a developmental perspective, by showing how the behavioral characteristics of FXS at the clinical level can be translated into effective, developmentally-specific and clinically meaningful behavioral readouts in the laboratory setting. After introducing the behavioral features, diagnostic criteria and off-label pharmacotherapy of FXS, we outline how FXS-relevant behavioral features can be modelled in laboratory animals in the course of development: we review the progress to date, discuss how behavioral phenotyping in animal models of FXS is essential to identify potential treatments, and discuss caveats and future directions in this research field. Copyright © 2018. Published by Elsevier B.V.

SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth

PubMed Central

Corradi, Anna; Fadda, Manuela; Piton, Amélie; Patry, Lysanne; Marte, Antonella; Rossi, Pia; Cadieux-Dion, Maxime; Gauthier, Julie; Lapointe, Line; Mottron, Laurent; Valtorta, Flavia; Rouleau, Guy A.; Fassio, Anna; Benfenati, Fabio; Cossette, Patrick

2014-01-01

An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This ‘synaptic autism pathway’ notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2  knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2  as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD. PMID:23956174

Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

PubMed Central

Fears, Scott C.; Service, Susan K.; Kremeyer, Barbara; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Franco, Juliana; Lopez, Maria C.; Montoya, Gabriel; Montoya, Patricia; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Ericson, Marissa; Jalbrzikowski, Maria; Luykx, Jurjen J.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier; Glahn, David C.; Ospina-Duque, Jorge; Risch, Neil; Ruiz-Linares, Andrés; Thompson, Paul M.; Cantor, Rita M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Freimer, Nelson B.; Bearden, Carrie E.

2014-01-01

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). PARTICIPANTS 738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I. MAIN OUTCOME MEASURE Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes. RESULTS Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE This is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I-association within families that is consistent with expectations from case-control studies. Together these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder. PMID:24522887

High-fertility phenotypes: two outbred mouse models exhibit substantially different molecular and physiological strategies warranting improved fertility.

PubMed

Langhammer, Martina; Michaelis, Marten; Hoeflich, Andreas; Sobczak, Alexander; Schoen, Jennifer; Weitzel, Joachim M

2014-01-01

Animal models are valuable tools in fertility research. Worldwide, there are more than 400 transgenic or knockout mouse models available showing a reproductive phenotype; almost all of them exhibit an infertile or at least subfertile phenotype. By contrast, animal models revealing an improved fertility phenotype are barely described. This article summarizes data on two outbred mouse models exhibiting a 'high-fertility' phenotype. These mouse lines were generated via selection over a time period of more than 40 years and 161 generations. During this selection period, the number of offspring per litter and the total birth weight of the entire litter nearly doubled. Concomitantly with the increased fertility phenotype, several endocrine parameters (e.g. serum testosterone concentrations in male animals), physiological parameters (e.g. body weight, accelerated puberty, and life expectancy), and behavioral parameters (e.g. behavior in an open field and endurance fitness on a treadmill) were altered. We demonstrate that the two independently bred high-fertility mouse lines warranted their improved fertility phenotype using different molecular and physiological strategies. The fertility lines display female- as well as male-specific characteristics. These genetically heterogeneous mouse models provide new insights into molecular and cellular mechanisms that enhance fertility. In view of decreasing fertility in men, these models will therefore be a precious information source for human reproductive medicine. Translated abstract A German translation of abstract is freely available at http://www.reproduction-online.org/content/147/4/427/suppl/DC1.

Microcephalic osteodysplastic primordial dwarfism, with the fascinating history of "Mademoiselle Crachami".

PubMed

Bozkaya, O Giray

2013-01-01

This review critically examines the findings which characterize the dysmorphic, radiologic and behavioral phenotype of Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) and has an historical perspective on it. MOPD is a group of primordial dwarfism syndromes with prenatal onset growth retardation, a typical craniofacial appearance and behavioral phenotype. In 1959, Mann and Russell have described the first case in a detailed report, and named "microcephalic midget of extreme type". In their report; based on historical records and a small painting, they pointed "Mademoiselle Crachami" as the oldest known case.

A genome-wide scan for signatures of directional selection in domesticated pigs.

PubMed

Moon, Sunjin; Kim, Tae-Hun; Lee, Kyung-Tai; Kwak, Woori; Lee, Taeheon; Lee, Si-Woo; Kim, Myung-Jick; Cho, Kyuho; Kim, Namshin; Chung, Won-Hyong; Sung, Samsun; Park, Taesung; Cho, Seoae; Groenen, Martien Am; Nielsen, Rasmus; Kim, Yuseob; Kim, Heebal

2015-02-25

Animal domestication involved drastic phenotypic changes driven by strong artificial selection and also resulted in new populations of breeds, established by humans. This study aims to identify genes that show evidence of recent artificial selection during pig domestication. Whole-genome resequencing of 30 individual pigs from domesticated breeds, Landrace and Yorkshire, and 10 Asian wild boars at ~16-fold coverage was performed resulting in over 4.3 million SNPs for 19,990 genes. We constructed a comprehensive genome map of directional selection by detecting selective sweeps using an F ST-based approach that detects directional selection in lineages leading to the domesticated breeds and using a haplotype-based test that detects ongoing selective sweeps within the breeds. We show that candidate genes under selection are significantly enriched for loci implicated in quantitative traits important to pig reproduction and production. The candidate gene with the strongest signals of directional selection belongs to group III of the metabolomics glutamate receptors, known to affect brain functions associated with eating behavior, suggesting that loci under strong selection include loci involved in behaviorial traits in domesticated pigs including tameness. We show that a significant proportion of selection signatures coincide with loci that were previously inferred to affect phenotypic variation in pigs. We further identify functional enrichment related to behavior, such as signal transduction and neuronal activities, for those targets of selection during domestication in pigs.

Genetics Home Reference: FG syndrome

MedlinePlus

... inheritance is that fathers cannot pass X-linked traits to their sons. Related Information What does it ... Opitz JO. Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys. Am J ...

X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brunner, H.G.; Nelen, M.R.; Zandvoort, P. van

The authors have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) monoamine metabolism. Thesemore » data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency. 34 refs., 4 figs., 4 tabs.« less

AVPR1A Variant Associated with Preschoolers' Lower Altruistic Behavior

PubMed Central

Avinun, Reut; Israel, Salomon; Shalev, Idan; Gritsenko, Inga; Bornstein, Gary; Ebstein, Richard P.; Knafo, Ariel

2011-01-01

The genetic origins of altruism, defined here as a costly act aimed to benefit non-kin individuals, have not been examined in young children. However, previous findings concerning adults pointed at the arginine vasopressin receptor 1A (AVPR1A) gene as a possible candidate. AVPR1A has been associated with a range of behaviors including aggressive, affiliative and altruistic phenotypes, and recently a specific allele (327 bp) of one of its promoter region polymorphisms (RS3) has been singled out in particular. We modeled altruistic behavior in preschoolers using a laboratory-based economic paradigm, a modified dictator game (DG), and tested for association between DG allocations and the RS3 “target allele.” Using both population and family-based analyses we show a significant link between lower allocations and the RS3 “target allele,” associating it, for the first time, with a lower proclivity toward altruistic behavior in children. This finding helps further the understanding of the intricate mechanisms underlying early altruistic behavior. PMID:21980412

Prader-Willi syndrome: atypical psychoses and motor dysfunctions.

PubMed

Verhoeven, Willem M A; Tuinier, Siegfried

2006-01-01

Prader-Willi syndrome (PWS) is the result of a lack of expression of genes on the paternally derived chromosome 15q11-q13 and can be considered as a hypothalamic disorder. Its behavioral phenotype is characterized by ritualistic, stereotyped, and compulsive behaviors as well as motor abnormalities. After adolescence, recurrent affective psychoses are relatively frequent, especially in patients with uniparental disomy. These psychotic states have a subacute onset with complete recovery and comprise an increase of psychomotor symptoms that show resemblance with catatonia. Some evidence has emerged that gamma-aminobutyric acid (GABA) dysfunctionality is involved in both PWS and catatonia. Treatment of these atypical psychoses should preferably include GABA mimetic compounds like lorazepam, valproic acid, and possibly topiramate.

Systems and methods for modeling and analyzing networks

DOEpatents

Hill, Colin C; Church, Bruce W; McDonagh, Paul D; Khalil, Iya G; Neyarapally, Thomas A; Pitluk, Zachary W

2013-10-29

The systems and methods described herein utilize a probabilistic modeling framework for reverse engineering an ensemble of causal models, from data and then forward simulating the ensemble of models to analyze and predict the behavior of the network. In certain embodiments, the systems and methods described herein include data-driven techniques for developing causal models for biological networks. Causal network models include computational representations of the causal relationships between independent variables such as a compound of interest and dependent variables such as measured DNA alterations, changes in mRNA, protein, and metabolites to phenotypic readouts of efficacy and toxicity.

Autism and Related Disorders

PubMed Central

McPartland, James; Volkmar, Fred R.

2012-01-01

The Pervasive Developmental Disorders are a group of neurodevelopmental disorders that include Autistic Disorder, Asperger’s Disorder, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), Childhood Disintegrative Disorder (CDD), and Rett’s Disorder. All feature childhood onset with a constellation of symptoms spanning social interaction and communication and including atypical behavior patterns. The first three disorders (Autistic Disorder, Asperger’s Disorder, and PDD-NOS) are currently referred to as Autism Spectrum Disorders, reflecting divergent phenotypic and etiologic characteristics compared to Rett’s Disorder and CDD. This chapter reviews relevant research and clinical information relevant to appropriate medical diagnosis and treatment. PMID:22608634

Inoculation Stress Hypothesis of Environmental Enrichment

PubMed Central

Crofton, Elizabeth J.; Zhang, Yafang; Green, Thomas A.

2014-01-01

One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. PMID:25449533

Inoculation stress hypothesis of environmental enrichment.

PubMed

Crofton, Elizabeth J; Zhang, Yafang; Green, Thomas A

2015-02-01

One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Overlap Between Autism Spectrum Disorders and Attention Deficit Hyperactivity Disorder: Searching for Distinctive/Common Clinical Features.

PubMed

Craig, Francesco; Lamanna, Anna Linda; Margari, Francesco; Matera, Emilia; Simone, Marta; Margari, Lucia

2015-06-01

Recent studies support several overlapping traits between autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD), assuming the existence of a combined phenotype. The aim of our study was to evaluate the common or distinctive clinical features between ASD and ADHD in order to identify possible different phenotypes that could have a clinical value. We enrolled 181 subjects divided into four diagnostic groups: ADHD group, ASD group, ASD+ADHD group (that met diagnostic criteria for both ASD and ADHD), and control group. Intelligent quotient (IQ), emotional and behavior problems, ADHD symptoms, ASD symptoms, and adaptive behaviors were investigated through the following test: Wechsler Intelligence Scale for Children, Wechsler Preschool and Primary Scale of Intelligence or Leiter International Performances Scale Revised, Child Behavior Checklist, Conners' Rating Scales-Revised, SNAP-IV Rating Scale, the Social Communication Questionnaire, Vineland Adaptive Behavior Scales. The ASD+ADHD group differs from ADHD or ASD in some domains such as lower IQ mean level and a higher autistic symptoms severity. However, the ASD+ADHD group shares inattention and hyperactivity deficit and some emotional and behavior problems with the ADHD group, while it shares adaptive behavior impairment with ASD group. These findings provide a new understanding of clinical manifestation of ASD+ADHD phenotype, they may also inform a novel treatment target. © 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

Dynamic nuclear envelope phenotype in rats overexpressing mutated human torsinA protein.

PubMed

Yu-Taeger, Libo; Gaiser, Viktoria; Lotzer, Larissa; Roenisch, Tina; Fabry, Benedikt Timo; Stricker-Shaver, Janice; Casadei, Nicolas; Walter, Michael; Schaller, Martin; Riess, Olaf; Nguyen, Huu Phuc; Ott, Thomas; Grundmann-Hauser, Kathrin

2018-05-08

A three-base-pair deletion in the human TOR1A gene is causative for the most common form of primary dystonia, the early-onset dystonia type 1 (DYT1 dystonia). The pathophysiological consequences of this mutation are still unknown.To study the pathology of the mutant torsinA (TOR1A) protein, we have generated a transgenic rat line that overexpresses the human mutant protein under the control of the human TOR1A promoter. This new animal model was phenotyped with several approaches, including behavioral tests and neuropathological analyses. A motor phenotype and cellular and ultrastructural key features of torsinA pathology were found in this new transgenic rat line supporting that it can be used as a model system for investigating the disease development. Analyses of mutant TOR1A protein expression in various brain regions also showed a dynamic expression pattern and a reversible nuclear envelope pathology. These findings suggest the differential vulnerabilities of distinct neuronal subpopulations. Furthermore the reversibility of the nuclear envelope pathology might be a therapeutic target to treat the disease. © 2018. Published by The Company of Biologists Ltd.

Complete genomes of Hairstreak butterflies, their speciation, and nucleo-mitochondrial incongruence

PubMed Central

Cong, Qian; Shen, Jinhui; Borek, Dominika; Robbins, Robert K.; Otwinowski, Zbyszek; Grishin, Nick V.

2016-01-01

Comparison of complete genomes of closely related species enables research on speciation and how phenotype is determined by genotype. Lepidoptera, an insect order of 150,000 species with diverse phenotypes, is well-suited for such comparative genomics studies if new genomes, which cover additional Lepidoptera families are acquired. We report a 729 Mbp genome assembly of the Calycopis cecrops, the first genome from the family Lycaenidae and the largest available Lepidoptera genome. As detritivore, Calycopis shows expansion in detoxification and digestion enzymes. We further obtained complete genomes of 8 Calycopis specimens: 3 C. cecrops and 5 C. isobeon, including a dry specimen stored in the museum for 30 years. The two species differ subtly in phenotype and cannot be differentiated by mitochondrial DNA. However, nuclear genomes revealed a deep split between them. Genes that can clearly separate the two species (speciation hotspots) mostly pertain to circadian clock, mating behavior, transcription regulation, development and cytoskeleton. The speciation hotspots and their function significantly overlap with those we previously found in Pterourus, suggesting common speciation mechanisms in these butterflies. PMID:27120974

The human clinical phenotypes of altered CHRNA7 copy number.

PubMed

Gillentine, Madelyn A; Schaaf, Christian P

2015-10-15

Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR). Several of these CNVs have been overrepresented in individuals with neuropsychiatric disorders; yet variable expressivity and incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene, which encodes for the α7 nicotinic acetylcholine receptor in the human brain, has been proposed to have a major contribution to the observed cognitive and behavioral phenotypes, as it represents the smallest region of overlap to all the 15q13.3 deletions and duplications. Individuals with zero to four copies of CHRNA7 have been reported in the literature, and represent a range of clinical severity, with deletions causing generally more severe and more highly penetrant phenotypes. Potential mechanisms to account for the variable expressivity within each group of 15q13.3 CNVs will be discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes.

PubMed

Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei; Swann, John W; Zoghbi, Huda Y

2015-11-18

Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I1,2

PubMed Central

Ivakine, Evgueni A.; Lam, Emily; Deurloo, Marielle; Dida, Joana; Zirngibl, Ralph A.

2015-01-01

Abstract Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src thl/thl) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src thl/thl mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I). Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane. Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I. PMID:26464974

Complete genomes of Hairstreak butterflies, their speciation, and nucleo-mitochondrial incongruence.

PubMed

Cong, Qian; Shen, Jinhui; Borek, Dominika; Robbins, Robert K; Otwinowski, Zbyszek; Grishin, Nick V

2016-04-28

Comparison of complete genomes of closely related species enables research on speciation and how phenotype is determined by genotype. Lepidoptera, an insect order of 150,000 species with diverse phenotypes, is well-suited for such comparative genomics studies if new genomes, which cover additional Lepidoptera families are acquired. We report a 729 Mbp genome assembly of the Calycopis cecrops, the first genome from the family Lycaenidae and the largest available Lepidoptera genome. As detritivore, Calycopis shows expansion in detoxification and digestion enzymes. We further obtained complete genomes of 8 Calycopis specimens: 3 C. cecrops and 5 C. isobeon, including a dry specimen stored in the museum for 30 years. The two species differ subtly in phenotype and cannot be differentiated by mitochondrial DNA. However, nuclear genomes revealed a deep split between them. Genes that can clearly separate the two species (speciation hotspots) mostly pertain to circadian clock, mating behavior, transcription regulation, development and cytoskeleton. The speciation hotspots and their function significantly overlap with those we previously found in Pterourus, suggesting common speciation mechanisms in these butterflies.

Modeling fragile X syndrome in the Fmr1 knockout mouse

PubMed Central

Kazdoba, Tatiana M.; Leach, Prescott T.; Silverman, Jill L.; Crawley, Jacqueline N.

2014-01-01

Summary Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS. PMID:25606362

Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

PubMed Central

Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Anderson, George M.; Snyder, Isaac; Blakely, Randy D.; Gershon, Michael D.

2016-01-01

Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4–mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

Naturally occurring variation in tadpole morphology and performance linked to predator regime

Treesearch

James B. Johnson; Daniel Saenz; Cory K. Adams; Toby J. Hibbitts

2015-01-01

Divergent natural selection drives a considerable amount of the phenotypic and genetic variation observed in natural populations. For example, variation in the predator community can generate conflicting selection on behavioral, life-history, morphological, and performance traits. Differences in predator regime can subsequently increase phenotypic and genetic...

Biosocial Influences on Fraudulent Behaviors

ERIC Educational Resources Information Center

Beaver, Kevin M.; Holtfreter, Kristy

2009-01-01

A wealth of empirical research has revealed that antisocial behavioral phenotypes result from genetic and environmental factors working independently and interactively. However, much of this research has focused on traditional forms of antisocial behavior, such as aggression and violence. At the same time, research has been slow to examine whether…

Strategy Revealing Phenotypic Differences among Synthetic Oscillator Designs

PubMed Central

2015-01-01

Considerable progress has been made in identifying and characterizing the component parts of genetic oscillators, which play central roles in all organisms. Nonlinear interaction among components is sufficiently complex that mathematical models are required to elucidate their elusive integrated behavior. Although natural and synthetic oscillators exhibit common architectures, there are numerous differences that are poorly understood. Utilizing synthetic biology to uncover basic principles of simpler circuits is a way to advance understanding of natural circadian clocks and rhythms. Following this strategy, we address the following questions: What are the implications of different architectures and molecular modes of transcriptional control for the phenotypic repertoire of genetic oscillators? Are there designs that are more realizable or robust? We compare synthetic oscillators involving one of three architectures and various combinations of the two modes of transcriptional control using a methodology that provides three innovations: a rigorous definition of phenotype, a procedure for deconstructing complex systems into qualitatively distinct phenotypes, and a graphical representation for illuminating the relationship between genotype, environment, and the qualitatively distinct phenotypes of a system. These methods provide a global perspective on the behavioral repertoire, facilitate comparisons of alternatives, and assist the rational design of synthetic gene circuitry. In particular, the results of their application here reveal distinctive phenotypes for several designs that have been studied experimentally as well as a best design among the alternatives that has yet to be constructed and tested. PMID:25019938

Model-Independent Phenotyping of C. elegans Locomotion Using Scale-Invariant Feature Transform

PubMed Central

Koren, Yelena; Sznitman, Raphael; Arratia, Paulo E.; Carls, Christopher; Krajacic, Predrag; Brown, André E. X.; Sznitman, Josué

2015-01-01

To uncover the genetic basis of behavioral traits in the model organism C. elegans, a common strategy is to study locomotion defects in mutants. Despite efforts to introduce (semi-)automated phenotyping strategies, current methods overwhelmingly depend on worm-specific features that must be hand-crafted and as such are not generalizable for phenotyping motility in other animal models. Hence, there is an ongoing need for robust algorithms that can automatically analyze and classify motility phenotypes quantitatively. To this end, we have developed a fully-automated approach to characterize C. elegans’ phenotypes that does not require the definition of nematode-specific features. Rather, we make use of the popular computer vision Scale-Invariant Feature Transform (SIFT) from which we construct histograms of commonly-observed SIFT features to represent nematode motility. We first evaluated our method on a synthetic dataset simulating a range of nematode crawling gaits. Next, we evaluated our algorithm on two distinct datasets of crawling C. elegans with mutants affecting neuromuscular structure and function. Not only is our algorithm able to detect differences between strains, results capture similarities in locomotory phenotypes that lead to clustering that is consistent with expectations based on genetic relationships. Our proposed approach generalizes directly and should be applicable to other animal models. Such applicability holds promise for computational ethology as more groups collect high-resolution image data of animal behavior. PMID:25816290

Experimental elevation of testosterone lowers fitness in female dark-eyed juncos.

PubMed

Gerlach, Nicole M; Ketterson, Ellen D

2013-05-01

Testosterone (T) is often referred to as the "male hormone," but it can influence aggression, parental behavior, and immune function in both males and females. By experimentally relating hormone-induced changes in phenotype to fitness, it is possible to ask whether existing phenotypes perform better or worse than alternative phenotypes, and hence to predict how selection might act on a novel or rare phenotype. In a songbird, the dark-eyed junco (Junco hyemalis), we have examined the effects of experimentally elevated T in females on fitness-related behaviors such as parental care. In this study, we implanted female juncos with exogenous T and examined its effect on fitness (survival, reproduction, and extra-pair mating) to assess whether T-altered phenotypes would prove to be adaptive or deleterious for females. Experimental elevation of T decreased the likelihood that a female would breed successfully, and T-implanted females had lower total reproductive success at every stage of the reproductive cycle. They did not, however, differ from control females in fledgling quality, extra-pair offspring production, survival, or reproduction in the following year. Previous work in this system has shown that experimental elevation of T in males alters behavior and physiology and decreases survival but increases the production of extra-pair offspring, leading to higher net fitness relative to control animals. Our results suggest that increased T has divergent effects on male and female fitness in this species, and that prevailing levels in females may be adaptive for them. These findings are consistent with sexual conflict. Copyright © 2013 Elsevier Inc. All rights reserved.

Autism beyond diagnostic categories: characterization of autistic phenotypes in schizophrenia.

PubMed

Kästner, Anne; Begemann, Martin; Michel, Tanja Maria; Everts, Sarah; Stepniak, Beata; Bach, Christiane; Poustka, Luise; Becker, Joachim; Banaschewski, Tobias; Dose, Matthias; Ehrenreich, Hannelore

2015-05-13

Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schizophrenia to prepare the ground for biological pathway analyses. Specific items of the Positive and Negative Syndrome Scale were employed and summed up to form a dimensional autism severity score (PAUSS). The score was created in a schizophrenia sample (N = 1156) and validated in adult high-functioning autism spectrum disorder (ASD) patients (N = 165). To this end, the Autism Diagnostic Observation Schedule (ADOS), the Autism (AQ) and Empathy Quotient (EQ) self-rating questionnaires were applied back to back with the newly developed PAUSS. PAUSS differentiated between ASD, schizophrenia and a disease-control sample and substantially correlated with the Autism Diagnostic Observation Schedule. Patients with ADOS scores ≥12 obtained highest, those with scores <7 lowest PAUSS values. AQ and EQ were not found to vary dependent on ADOS diagnosis. ROC curves for ADOS and PAUSS resulted in AuC values of 0.9 and 0.8, whereas AQ and EQ performed at chance level in the prediction of ASD. This work underscores the convergence of schizophrenia negative symptoms and autistic phenotypes. PAUSS evolved as a measure capturing the continuous nature of autistic behaviors. The definition of extreme-groups based on the dimensional PAUSS may permit future investigations of genetic constellations modulating autistic phenotypes.

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

PubMed Central

Notaras, M; Du, X; Gogos, J; van den Buuse, M; Hill, R A

2017-01-01

The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression. PMID:28926000

Genetic dissection of behavioral flexibility: reversal learning in mice.

PubMed

Laughlin, Rick E; Grant, Tara L; Williams, Robert W; Jentsch, J David

2011-06-01

Behavioral inflexibility is a feature of schizophrenia, attention-deficit/hyperactivity disorder, and behavior addictions that likely results from heritable deficits in the inhibitory control over behavior. Here, we investigate the genetic basis of individual differences in flexibility, measured using an operant reversal learning task. We quantified discrimination acquisition and subsequent reversal learning in a cohort of 51 BXD strains of mice (2-5 mice/strain, n = 176) for which we have matched data on sequence, gene expression in key central nervous system regions, and neuroreceptor levels. Strain variation in trials to criterion on acquisition and reversal was high, with moderate heritability (∼.3). Acquisition and reversal learning phenotypes did not covary at the strain level, suggesting that these traits are effectively under independent genetic control. Reversal performance did covary with dopamine D2 receptor levels in the ventral midbrain, consistent with a similar observed relationship between impulsivity and D2 receptors in humans. Reversal, but not acquisition, is linked to a locus on mouse chromosome 10 with a peak likelihood ratio statistic at 86.2 megabase (p < .05 genome-wide). Variance in messenger RNA levels of select transcripts expressed in neocortex, hippocampus, and striatum correlated with the reversal learning phenotype, including Syn3, Nt5dc3, and Hcfc2. This work demonstrates the clear trait independence between, and genetic control of, discrimination acquisition and reversal and illustrates how globally coherent data sets for a single panel of highly related strains can be interrogated and integrated to uncover genetic sources and molecular and neuropharmacological candidates of complex behavioral traits relevant to human psychopathology. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Attention and working memory deficits in a perinatal nicotine exposure mouse model.

PubMed

Zhang, Lin; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

2018-01-01

Cigarette smoking by pregnant women is associated with a significant increase in the risk for cognitive disorders in their children. Preclinical models confirm this risk by showing that exposure of the developing brain to nicotine produces adverse behavioral outcomes. Here we describe behavioral phenotypes resulting from perinatal nicotine exposure in a mouse model, and discuss our findings in the context of findings from previously published studies using preclinical models of developmental nicotine exposure. Female C57Bl/6 mice received drinking water containing nicotine (100μg/ml) + saccharin (2%) starting 3 weeks prior to breeding and continuing throughout pregnancy, and until 3 weeks postpartum. Over the same period, female mice in two control groups received drinking water containing saccharin (2%) or plain drinking water. Offspring from each group were weaned at 3-weeks of age and subjected to behavioral analyses at 3 months of age. We examined spontaneous locomotor activity, anxiety-like behavior, spatial working memory, object based attention, recognition memory and impulsive-like behavior. We found significant deficits in attention and working memory only in male mice, and no significant changes in the other behavioral phenotypes in male or female mice. Exposure to saccharin alone did not produce significant changes in either sex. The perinatal nicotine exposure produced significant deficits in attention and working memory in a sex-dependent manner in that the male but not female offspring displayed these behaviors. These behavioral phenotypes are associated with attention deficit hyperactivity disorder (ADHD) and have been reported in other studies that used pre- or perinatal nicotine exposure. Therefore, we suggest that preclinical models of developmental nicotine exposure could be useful tools for modeling ADHD and related disorders.

Personality and performance are affected by age and early life parameters in a small primate.

PubMed

Zablocki-Thomas, Pauline B; Herrel, Anthony; Hardy, Isabelle; Rabardel, Lucile; Perret, Martine; Aujard, Fabienne; Pouydebat, Emmanuelle

2018-05-01

A whole suite of parameters is likely to influence the behavior and performance of individuals as adults, including correlations between phenotypic traits or an individual's developmental context. Here, we ask the question whether behavior and physical performance traits are correlated and how early life parameters such as birth weight, litter size, and growth can influence these traits as measured during adulthood. We studied 486 captive gray mouse lemurs ( Microcebus murinus ) and measured two behavioral traits and two performance traits potentially involved in two functions: exploration behavior with pull strength and agitation score with bite force. We checked for the existence of behavioral consistency in behaviors and explored correlations between behavior, performance, morphology. We analyzed the effect of birth weight, growth, and litter size, while controlling for age, sex, and body weight. Behavior and performance were not correlated with one another, but were both influenced by age. Growth rate had a positive effect on adult morphology, and birth weight significantly affected emergence latency and bite force. Grip strength was not directly affected by early life traits, but bite performance and exploration behavior were impacted by birth weight. This study shows how early life parameters impact personality and performance.

Which ante mortem clinical features predict progressive supranuclear palsy pathology?

PubMed

Respondek, Gesine; Kurz, Carolin; Arzberger, Thomas; Compta, Yaroslau; Englund, Elisabet; Ferguson, Leslie W; Gelpi, Ellen; Giese, Armin; Irwin, David J; Meissner, Wassilios G; Nilsson, Christer; Pantelyat, Alexander; Rajput, Alex; van Swieten, John C; Troakes, Claire; Josephs, Keith A; Lang, Anthony E; Mollenhauer, Brit; Müller, Ulrich; Whitwell, Jennifer L; Antonini, Angelo; Bhatia, Kailash P; Bordelon, Yvette; Corvol, Jean-Christophe; Colosimo, Carlo; Dodel, Richard; Grossman, Murray; Kassubek, Jan; Krismer, Florian; Levin, Johannes; Lorenzl, Stefan; Morris, Huw; Nestor, Peter; Oertel, Wolfgang H; Rabinovici, Gil D; Rowe, James B; van Eimeren, Thilo; Wenning, Gregor K; Boxer, Adam; Golbe, Lawrence I; Litvan, Irene; Stamelou, Maria; Höglinger, Günter U

2017-07-01

Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Changes in the Autism Behavioral Phenotype during the Transition to Adulthood

PubMed Central

Taylor, Julie Lounds; Seltzer, Marsha Mailick

2010-01-01

We examined whether exiting high school was associated with alterations in rates of change in autism symptoms and maladaptive behaviors. Participants were 242 youth with ASD who had recently exited the school system and were part of our larger longitudinal study; data were collected at five time points over nearly 10 years. Results indicated overall improvement of autism symptoms and internalized behaviors over the study period, but slowing rates of improvement after exit. Youth who did not have an intellectual disability evidenced the greatest slowing in improvement. Lower family income was associated with less improvement. Our findings suggest that adult day activities may not be as intellectually stimulating as educational activities in school, reflected by less phenotypic improvement after exit. PMID:20361245

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

PubMed Central

Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

2013-01-01

Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar. PMID:23560889

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.

PubMed

Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

2013-06-01

There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cyclic adenosine monophosphate metabolism in synaptic growth, strength, and precision: neural and behavioral phenotype-specific counterbalancing effects between dnc phosphodiesterase and rut adenylyl cyclase mutations.

PubMed

Ueda, Atsushi; Wu, Chun-Fang

2012-03-01

Two classic learning mutants in Drosophila, rutabaga (rut) and dunce (dnc), are defective in cyclic adenosine monophosphate (cAMP) synthesis and degradation, respectively, exhibiting a variety of neuronal and behavioral defects. We ask how the opposing effects of these mutations on cAMP levels modify subsets of phenotypes, and whether any specific phenotypes could be ameliorated by biochemical counter balancing effects in dnc rut double mutants. Our study at larval neuromuscular junctions (NMJs) demonstrates that dnc mutations caused severe defects in nerve terminal morphology, characterized by unusually large synaptic boutons and aberrant innervation patterns. Interestingly, a counterbalancing effect led to rescue of the aberrant innervation patterns but the enlarged boutons in dnc rut double mutant remained as extreme as those in dnc. In contrast to dnc, rut mutations strongly affect synaptic transmission. Focal loose-patch recording data accumulated over 4 years suggest that synaptic currents in rut boutons were characterized by unusually large temporal dispersion and a seasonal variation in the amount of transmitter release, with diminished synaptic currents in summer months. Experiments with different rearing temperatures revealed that high temperature (29-30°C) decreased synaptic transmission in rut, but did not alter dnc and wild-type (WT). Importantly, the large temporal dispersion and abnormal temperature dependence of synaptic transmission, characteristic of rut, still persisted in dnc rut double mutants. To interpret these results in a proper perspective, we reviewed previously documented differential effects of dnc and rut mutations and their genetic interactions in double mutants on a variety of physiological and behavioral phenotypes. The cases of rescue in double mutants are associated with gradual developmental and maintenance processes whereas many behavioral and physiological manifestations on faster time scales could not be rescued. We discuss factors that could contribute to the effectiveness of counterbalancing interactions between dnc and rut mutations for phenotypic rescue.

Cyclic-AMP metabolism in synaptic growth, strength and precision: Neural and behavioral phenotype-specific counterbalancing effects between dnc PDE and rut AC mutations

PubMed Central

Ueda, Atsushi; Wu, Chun-Fang

2012-01-01

Two classic learning mutants in Drosophila, rutabaga (rut) and dunce (dnc), are defective in cAMP synthesis and degradation, respectively, exhibiting a variety of neuronal and behavioral defects. We ask how the opposing effects of these mutations on cAMP levels modify subsets of phenotypes, and whether any specific phenotypes could be ameliorated by biochemical counter balancing effects in dnc rut double mutants. Our study at larval neuromuscular junctions (NMJs) demonstrate that dnc mutations caused severe defects in nerve terminal morphology, characterized by unusually large synaptic boutons and aberrant innervation patterns. Interestingly, a counterbalancing effect led to rescue of the aberrant innervation patterns but the enlarged boutons in dnc rut double mutant remained as extreme as those in dnc. In contrast to dnc, rut mutations strongly affect synaptic transmission. Focal loose-patch recording data accumulated over 4 years suggest that synaptic currents in rut boutons were characterized by unusually large temporal dispersion and a seasonal variation in the amount of transmitter release, with diminished synaptic currents in summer months. Experiments with different rearing temperatures revealed that high temperature (29–30 °C) decreased synaptic transmission in rut, but did not alter dnc and WT. Importantly, the large temporal dispersion and abnormal temperature dependence of synaptic transmission, characteristic of rut, still persisted in dnc rut double mutants. To interpret these results in a proper perspective, we reviewed previously documented differential effects of dnc and rut mutations and their genetic interactions in double mutants on a variety of physiological and behavioral phenotypes. The cases of rescue in double mutants are associated with gradual developmental and maintenance processes whereas many behavioral and physiological manifestations on faster time scales could not be rescued. We discuss factors that could contribute to the effectiveness of counter balancing interactions between dnc and rut mutations for phenotypic rescue. PMID:22380612

Sexually dimorphic effects of ancestral exposure to vinclozolin on stress reactivity in rats.

PubMed

Gillette, Ross; Miller-Crews, Isaac; Nilsson, Eric E; Skinner, Michael K; Gore, Andrea C; Crews, David

2014-10-01

How an individual responds to the environment depends upon both personal life history as well as inherited genetic and epigenetic factors from ancestors. Using a 2-hit, 3 generations apart model, we tested how F3 descendants of rats given in utero exposure to the environmental endocrine-disrupting chemical (EDC) vinclozolin reacted to stress during adolescence in their own lives, focusing on sexually dimorphic phenotypic outcomes. In adulthood, male and female F3 vinclozolin- or vehicle-lineage rats, stressed or nonstressed, were behaviorally characterized on a battery of tests and then euthanized. Serum was used for hormone assays, and brains were used for quantitative PCR and transcriptome analyses. Results showed that the effects of ancestral exposure to vinclozolin converged with stress experienced during adolescence in a sexually dimorphic manner. Debilitating effects were seen at all levels of the phenotype, including physiology, behavior, brain metabolism, gene expression, and genome-wide transcriptome modifications in specific brain nuclei. Additionally, females were significantly more vulnerable than males to transgenerational effects of vinclozolin on anxiety but not sociality tests. This fundamental transformation occurs in a manner not predicted by the ancestral exposure or the proximate effects of stress during adolescence, an interaction we refer to as synchronicity.

21st century toolkit for optimizing population health through precision nutrition.

PubMed

O'Sullivan, Aifric; Henrick, Bethany; Dixon, Bonnie; Barile, Daniela; Zivkovic, Angela; Smilowitz, Jennifer; Lemay, Danielle; Martin, William; German, J Bruce; Schaefer, Sara Elizabeth

2017-07-05

Scientific, technological, and economic progress over the last 100 years all but eradicated problems of widespread food shortage and nutrient deficiency in developed nations. But now society is faced with a new set of nutrition problems related to energy imbalance and metabolic disease, which require new kinds of solutions. Recent developments in the area of new analytical tools enable us to systematically study large quantities of detailed and multidimensional metabolic and health data, providing the opportunity to address current nutrition problems through an approach called Precision Nutrition. This approach integrates different kinds of "big data" to expand our understanding of the complexity and diversity of human metabolism in response to diet. With these tools, we can more fully elucidate each individual's unique phenotype, or the current state of health, as determined by the interactions among biology, environment, and behavior. The tools of precision nutrition include genomics, metabolomics, microbiomics, phenotyping, high-throughput analytical chemistry techniques, longitudinal tracking with body sensors, informatics, data science, and sophisticated educational and behavioral interventions. These tools are enabling the development of more personalized and predictive dietary guidance and interventions that have the potential to transform how the public makes food choices and greatly improve population health.

Sexual behavior and testis morphology in the BACHD rat model

PubMed Central

Novati, Arianna; Yu-Taeger, Libo; Gonzalez Menendez, Irene; Quintanilla Martinez, Leticia

2018-01-01

Background Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene, which results in brain neurodegeneration and peripheral pathology affecting different organs including testis. Patients with HD suffer from motor and cognitive impairment, and multiple psychiatric symptoms. Among behavioral abnormalities in HD, sexual disturbances have often been reported, but scarcely investigated in animal models. The BACHD rat model of HD carries the human full-length mutated HTT (mHTT) genomic sequence with 97 CAG-CAA repeats and displays HD-like alterations at neuropathological and behavioral level. Objective This study aims to phenotype the BACHD rats’ sexual behavior and performance as well as testis morphology because alterations in these aspects have been associated to HD. Methods Two rat cohorts at the age of 3 and 7 months were subjected to mating tests to assess different parameters of sexual behavior. Histological analyses for testis morphology were performed in different rat cohorts at 1.5, 7 and 12 months of age whereas immunohistochemical analyses were carried out at 7 and 12 months of age to visualize the presence of mHTT in testicular tissue. Furthermore, western blot analyses were used to assess HTT and mHTT expression levels in striatum and testis at three months of age. Results At 3 months, BACHD rats showed a decreased time exploring the female anogenital area (AGA), decreased latency to mount, increased number of intromissions and ejaculations and enhanced hit rate. At 7 months, all sexual parameters were comparable between genotypes with the exception that BACHD rats explored the AGA less than wild type rats. Testis analyses did not reveal any morphological alteration at any of the examined ages, but showed presence of mHTT limited to Sertoli cells in transgenic rats at both 7 and 12 months. BACHD rat HTT and mHTT expression levels in testis were lower than striatum at 3 months of age. Conclusions The testis phenotype in the BACHD rat model does not mimic the changes observed in human HD testis. The altered sexual behavior in BACHD rats at three months of age could be to a certain extent representative of and share common underlying pathways with some of the sexual disturbances in HD patients. Further investigating the biological causes of the sexual phenotype in BACHD rats may therefore contribute to clarifying the mechanisms at the base of sexual behavior changes in HD. PMID:29883458

Is it all in the family? The effects of early social structure on neural-behavioral systems of prairie voles (Microtus ochrogaster).

PubMed

Greenberg, G D; van Westerhuyzen, J A; Bales, K L; Trainor, B C

2012-08-02

The transition to parenthood is generally associated with a reduction in anxiety or anxiety-like behavior across a wide range of species. In some species, juveniles provide supplementary parental care for younger siblings, a behavior known as alloparenting. Although the fitness consequences of alloparenting behavior have been a focus of evolutionary research, less is known about how alloparenting behavior impacts affective states. In the socially monogamous prairie vole (Microtus ochrogaster), most juveniles exhibit alloparenting behavior, making the species an ideal model for examining the effects of alloparenting on future behavioral outcomes. We randomly assigned juvenile voles to alloparenting (AL) or no alloparenting (NoAL) groups and behaviorally phenotyped them for anxiety-like and social behaviors using the elevated plus maze (EPM), open field test (OFT), startle box, social interaction test, juvenile affiliation test, and partner preference test. AL voles displayed more anxiety-like and less exploratory behaviors than NoAL voles, spending significantly less time in the open arms of the EPM and center of an open field. We dissected the CA1 region of the hippocampus and the bed nucleus of the stria terminalis (BNST) from brains of behaviorally phenotyped voles and nontested siblings as well. Decreased brain-derived neurotrophic factor (BDNF) expression in CA1 has generally been associated with increased anxiety-like behavior in other rodents, while an anxiogenic role for BDNF in BNST is less established. Western blot analyses showed that alloparenting experience increased expression of BDNF in the BNST but decreased BDNF expression in the CA1 region of hippocampus (CA1) of nontested voles. There were similar differences in BNST BDNF of behaviorally phenotyped voles, and BDNF levels within this region were negatively correlated with exploratory behavior (i.e. time in center of OFT). Our results suggest that BDNF signaling in BNST and CA1 fluctuate with alloparenting experience, and they contribute to an increasingly complex "BDNF hypothesis" in which behavioral effects of this molecule are region-specific. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD.

PubMed

Lattante, Serena; de Calbiac, Hortense; Le Ber, Isabelle; Brice, Alexis; Ciura, Sorana; Kabashi, Edor

2015-03-15

Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Behavioral Phenotype in Adults with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Sinnema, Margje; Einfeld, Stewart L.; Schrander-Stumpel, Constance T. R. M.; Maaskant, Marian A.; Boer, Harm; Curfs, Leopold M. G.

2011-01-01

Prader-Willi syndrome (PWS) is characterized by temper tantrums, impulsivity, mood fluctuations, difficulty with change in routine, skinpicking, stubbornness and aggression. Many studies on behavior in PWS are limited by sample size, age range, a lack of genetically confirmed diagnosis of PWS and inconsistent assessment of behavior. The aim of…

Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic

PubMed Central

Jones, Paul; Martin, Alan; Ostrander, Elaine A.; Lark, Karl G.

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis. PMID:19321632

Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic.

PubMed

Chase, Kevin; Jones, Paul; Martin, Alan; Ostrander, Elaine A; Lark, Karl G

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pancreatitis.

A link between thrifty phenotype and maternal care across two generations of intercrossed mice

PubMed Central

Goes, Carolina P.; Forti, Isabela; O. do Monte, Bruno Gabriel; Watanabe, Isabela M.; Cunha, Joao; Peripato, Andrea C.

2017-01-01

Maternal effects are causal influences from mother to offspring beyond genetic information, and have lifelong consequences for multiple traits. Previously, we reported that mice whose mothers did not nurse properly had low birth weight followed by rapid fat accumulation and disturbed development of some organs. That pattern resembles metabolic syndromes known collectively as the thrifty phenotype, which is believed to be an adaptation to a stressful environment which prepares offspring for reduced nutrient supply. The potential link between maternal care, stress reactivity, and the thrifty phenotype, however, has been poorly explored in the human and animal literature: only a couple of studies even mention (much less, test) these concepts under a cohesive framework. Here, we explored this link using mice of the parental inbred strains SM/J and LG/J–who differ dramatically in their maternal care–and the intercrossed generations F1 and F2. We measured individual differences in 15 phenotypes and used structural equation modeling to test our hypotheses. We found a remarkable relationship between thrifty phenotype and lower quality of maternal behaviors, including nest building, pup retrieval, grooming/licking, and nursing. To our knowledge, this is the first study to show, in any mammal, a clear connection between the natural variation in thrifty phenotype and maternal care. Both traits in the mother also had a substantial effect on survival rate in the F3 offspring. To our surprise, however, stress reactivity seemed to play no role in our models. Furthermore, the strain of maternal grandmother, but not of paternal grandmother, affected the variation of maternal care in F2 mice, and this effect was mediated by thrifty phenotype in F2. Since F1 animals were all genetically identical, this finding suggests that maternal effects pass down both maternal care and thrifty phenotype in these mice across generations via epigenetic transmission. PMID:28542485

Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning.

PubMed

Grigsby, Jim; Brega, Angela G; Bennett, Rachael E; Bourgeois, James A; Seritan, Andreea L; Goodrich, Glenn K; Hagerman, Randi J

2016-08-01

To clarify the neuropsychiatric phenotype of fragile X-associated tremor/ataxia syndrome (FXTAS), and assess the extent to which it is mediated by the dysexecutive syndrome that is a major feature of the disorder. We examined the prevalence of clinically meaningful psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, in comparison with men with a normal allele. Measures included the Neuropsychiatric Inventory (NPI), Symptom Checklist-90-R (SCL-90-R), and the Behavioral Dyscontrol Scale, a measure of executive functioning. Between-group differences were evaluated using logistic regression, followed by a mediation analysis with ordinary least squares regression to assess the contribution of dysexecutive syndrome to the observed psychiatric domains. Men with FXTAS showed higher rates of clinically significant symptoms overall and in specific domains: somatization, obsessive compulsive, depression, anxiety, psychoticism, agitation/aggression, apathy/indifference, irritability, and nighttime behavior problems. Post hoc analyses suggested that findings of psychoticism among men with FXTAS may be associated with participants' accurate acknowledgment of cognitive and physical dysfunction, rather than reflecting psychosis. Asymptomatic carriers showed no evidence of clinically significant psychiatric symptoms, but when all carriers were compared with men having a normal FMR1 allele, executive function deficits were found to mediate scores in several domains on both NPI and SCL-90-R. Building on prior research, the results provide evidence that the psychiatric phenotype for men includes clinically meaningful depression, hostility, and irritability, in association with behavioral and attentional disinhibition. It is likely that these problems reflect the effects of impaired executive functioning.

Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology.

PubMed

Pearlstein, Robert A; McKay, Daniel J J; Hornak, Viktor; Dickson, Callum; Golosov, Andrei; Harrison, Tyler; Velez-Vega, Camilo; Duca, José

2017-01-01

Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e.. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, "solving" sets of coupled "molecular differential equations" (i.e. represented by populations of interacting species)via "integration" of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan.

PubMed

Qadeer, Muhammad Imran; Amar, Ali; Mann, J John; Hasnain, Shahida

2017-01-01

Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression.

Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan

PubMed Central

Qadeer, Muhammad Imran; Amar, Ali; Mann, J. John; Hasnain, Shahida

2017-01-01

Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression. PMID:28582390

The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health

PubMed Central

Ezran, Camille; Karanewsky, Caitlin J.; Pendleton, Jozeph L.; Sholtz, Alex; Krasnow, Maya R.; Willick, Jason; Razafindrakoto, Andriamahery; Zohdy, Sarah; Albertelli, Megan A.; Krasnow, Mark A.

2017-01-01

Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs (Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene “knockout” library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while providing an example of how hands-on science education can help transform developing countries. PMID:28592502

The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health.

PubMed

Ezran, Camille; Karanewsky, Caitlin J; Pendleton, Jozeph L; Sholtz, Alex; Krasnow, Maya R; Willick, Jason; Razafindrakoto, Andriamahery; Zohdy, Sarah; Albertelli, Megan A; Krasnow, Mark A

2017-06-01

Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs ( Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene "knockout" library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while providing an example of how hands-on science education can help transform developing countries. Copyright © 2017 by the Genetics Society of America.

Parasitoid wasp usurps its host to guard its pupa against hyperparasitoids and induces rapid behavioral changes in the parasitized host

PubMed Central

2017-01-01

Some parasites have an ability to fabricate the behavior of their host and impel the host to guard parasites' offspring, which is popularly called as bodyguard manipulation. Psalis pennatula larva parasitized by a braconid parasitoid wasp Microplitis pennatula exhibits some behavioral changes including the guarding of the parasitoid pupa from its natural enemies. We hypothesized that these behavioral change exhibited by the parasitized host larva are induced by the parasitoid and can be considered as an example of bodyguard manipulation. Even though hyperparasitoids are the more specialized natural enemy of parasitoids than predators, very few studies tested the success of guarding parasitoid pupa against hyperparasitoids. This study analyzed the success of guarding behavior of the parasitized host against hyperparasitoids. The onsets of parasite-induced phenotypic alterations (PIPAs) in the parasitized host were inspected to analyze whether these behavioral changes in the host larva manifests gradually or abruptly. The study concludes that parasitized host larva defends the parasitoid pupa from hyperparasitoids and the PIPAs in the parasitized host develops abruptly only after the egression of parasitoid prepupa. PMID:28636632

Parasitoid wasp usurps its host to guard its pupa against hyperparasitoids and induces rapid behavioral changes in the parasitized host.

PubMed

Mohan, Prabitha; Sinu, Palatty Allesh

2017-01-01

Some parasites have an ability to fabricate the behavior of their host and impel the host to guard parasites' offspring, which is popularly called as bodyguard manipulation. Psalis pennatula larva parasitized by a braconid parasitoid wasp Microplitis pennatula exhibits some behavioral changes including the guarding of the parasitoid pupa from its natural enemies. We hypothesized that these behavioral change exhibited by the parasitized host larva are induced by the parasitoid and can be considered as an example of bodyguard manipulation. Even though hyperparasitoids are the more specialized natural enemy of parasitoids than predators, very few studies tested the success of guarding parasitoid pupa against hyperparasitoids. This study analyzed the success of guarding behavior of the parasitized host against hyperparasitoids. The onsets of parasite-induced phenotypic alterations (PIPAs) in the parasitized host were inspected to analyze whether these behavioral changes in the host larva manifests gradually or abruptly. The study concludes that parasitized host larva defends the parasitoid pupa from hyperparasitoids and the PIPAs in the parasitized host develops abruptly only after the egression of parasitoid prepupa.

The individuality of mice.

PubMed

Lathe, R

2004-12-01

Mutant mice simulating human CNS disorders are used as models for therapeutic drug development. Drug evaluation requires a coherent correlation between behavioral phenotype and drug status. Variations in behavioral responses could mask such correlations, a problem highlighted by the three-site studies of Crabbe et al. (1999) and Wahlsten et al. (2003a). Factors contributing to variation are considered, focusing on differences between individual animals. Genetic differences due to minisatellite variation suggest that each mouse is genetically distinct. Effects during gestation, including maternal stress, influence later life behavior; while endocrine exchanges between fetus and parent, and between male and female fetuses dependent on intrauterine position, also contribute. Pre and perinatal nutrition and maternal attention also play a role. In adults, endocrine cyclicity in females is a recognized source of behavioral diversity. Notably, there is increasing recognition that groups of wild and laboratory mice have complex social structures, illustrated through consideration of Crowcroft (1966). Dominance status can markedly modify behavior in test paradigms addressing anxiety, locomotion and aggressiveness, to an extent comparable to mutation or drug status. Understanding how such effects amplify the behavioral spectrum displayed by otherwise identical animals will improve testing.

Genetics of Addiction: Future Focus on Gene × Environment Interaction?

PubMed

Vink, Jacqueline M

2016-09-01

The heritability of substance use is moderate to high. Successful efforts to find genetic variants associated with substance use (smoking, alcohol, cannabis) have been undertaken by large consortia. However, the proportion of phenotypic variance explained by the identified genetic variants is small. Interestingly, there is overlap between the genetic variants that influence different substances. Moreover, there are sets of "substance-specific" genes and sets of genes contributing to a "vulnerability for addictive behavior" in general. It is important to recognize that genes alone do not determine addiction phenotypes: Environmental factors such as parental monitoring, peer pressure, or socioeconomic status also play an important role. Despite a rich epidemiologic literature focused on the social determinants of substance use, few studies have examined the moderation of genetic influences like gene-environment (G × E) interactions. Understanding this balance may hold the key to understanding the individual differences in substance use, abuse, and addictive behavior. Recommendations for future research are described in this commentary and include increasing the power of G × E studies by using state-of-the-art methods such as polygenic risk scores instead of single genetic variants and taking genetic overlap between substances into account. Future genetic studies should also investigate environmental risk factors for addictive behavior more extensively to unravel the interaction between nature and nurture. Focusing on G × E interactions not only will give insight into the underlying biological mechanism but will also characterize subgroups (based on environmental factors) at high risk for addictive behaviors. With this information, we could bridge the gap between fundamental research and applications for society.

Noninvasive assessment of altered activity following restraint in mice using an automated physiological monitoring system.

PubMed

Spiers, Jereme G; Chen, Hsiao-Jou Cortina; Steyn, Frederik J; Lavidis, Nickolas A; Woodruff, Trent M; Lee, John D

2017-01-01

In the laboratory setting, typical endocrine and targeted behavioral tests are limited in their ability to provide a direct assessment of stress in animals housed in undisturbed conditions. We hypothesized that an automated phenotyping system would allow the detection of subtle stress-related behavioral changes well beyond the time-frames examined using conventional methods. In this study, we have utilized the TSE PhenoMaster system to continuously record basal behaviors and physiological parameters including activity, body weight, food intake and oxygen consumption in undisturbed and stressed C57Bl/6J male mice (n = 12/group), with a pharmacological intervention using the conventional anxiolytic, diazepam (5 mg kg -1 i.p.; n = 8/group). We observed significant 20-30% reductions in locomotor activity in the dark phase, with subtle reductions in light phase activity for up to 96 h following a single 2 h episode of restraint stress. A single administration of diazepam reduced plasma corticosterone concentrations by 30-35% during stress exposure when compared to mice treated with vehicle. This treatment did not result in significantly different locomotor activity compared to vehicle within the first 48 h following restraint stress. However, diazepam treatment facilitated restoration of locomotor activity at 72 and 96 h after restraint stress exposure in comparison to vehicle-treated mice. Hence, the use of an automated phenotyping system allows a real time assessment of basal behaviors and empirical metabolism following exposure to restraint stress and demonstrates major and subtle changes in activity persist for several days after stress exposure.

Epigenetic Regulation in Plants

PubMed Central

Pikaard, Craig S.; Mittelsten Scheid, Ortrun

2014-01-01

The study of epigenetics in plants has a long and rich history, from initial descriptions of non-Mendelian gene behaviors to seminal discoveries of chromatin-modifying proteins and RNAs that mediate gene silencing in most eukaryotes, including humans. Genetic screens in the model plant Arabidopsis have been particularly rewarding, identifying more than 130 epigenetic regulators thus far. The diversity of epigenetic pathways in plants is remarkable, presumably contributing to the phenotypic plasticity of plant postembryonic development and the ability to survive and reproduce in unpredictable environments. PMID:25452385

Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1.

PubMed

Lee, Cha Gon; Park, Sang-Jin; Yim, Shin-Young; Sohn, Young Bae

2013-08-01

Potocki-Lupski syndrome (PTLS [MIM 610883]) is a recently recognized microduplication syndrome associated with 17p11.2. It is characterized by mild facial dysmorphic features, hypermetropia, infantile hypotonia, failure to thrive, mental retardation, autistic spectrum disorders, behavioral abnormalities, sleep apnea, and cardiovascular anomalies. In several studies, the critical PTLS region was deduced to be 1.3Mb in length, and included RAI1 and 17 other genes. We report a 3-year-old Korean boy with the smallest duplication in 17p11.2 and a milder phenotype. He had no family history of neurologic disease or developmental delay and no history of seizure, autistic features, or behavior problems. He showed subtle facial dysmorphic features (dolichocephaly and a mildly asymmetric smile) and flat feet. All laboratory tests were normal and he had no evidence of internal organ anomalies. He was found to have mild intellectual disabilities (full scale IQ 65 on K-WPPSI) and language developmental delay (age of 2.2year-old on PRESS). Array comparative genomic hybridization (CGH) showed about a 0.25Mb microduplication on chromosome 17p11.2 containing four Refseq (NCBI reference sequence) genes, including RAI1 [arr 17p11.2(17,575,978-17,824,623)×3]. When compared with previously reported cases, the milder phenotype of our patient may be associated with the smallest duplication in 17p11.2, 0.25Mb in length. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Natural History of Aging in Cornelia de Lange Syndrome

PubMed Central

KLINE, ANTONIE D.; GRADOS, MARCO; SPONSELLER, PAUL; LEVY, HOWARD P.; BLAGOWIDOW, NATALIE; SCHOEDEL, CHRISTIANNE; RAMPOLLA, JONI; CLEMENS, DOUGLAS K.; KRANTZ, IAN; KIMBALL, AMY; PICHARD, CARMEN; TUCHMAN, DAVID

2016-01-01

Observations about the natural history of aging in Cornelia de Lange syndrome (CdLS) are made, based on 49 patients from a multidisciplinary clinic for adolescents and adults. The mean age was 17 years. Although most patients remain small, obesity may develop. Gastroesophageal reflux persists or worsens, and there are early long-term sequelae, including Barrett esophagus in 10%; other gastrointestinal findings include risk for volvulus, rumination, and chronic constipation. Submucous cleft palate was found in 14%, most undetected before our evaluation. Chronic sinusitis was noted in 39%, often with nasal polyps. Blepharitis improves with age; cataracts and detached retina may occur. Decreased bone density is observed, with occasional fractures. One quarter have leg length discrepancy and 39% scoliosis. Most females have delayed or irregular menses but normal gynecologic exams and pap smears. Benign prostatic hypertrophy occurred in one male prior to 40 years. The phenotype is variable, but there is a distinct pattern of facial changes with aging. Premature gray hair is frequent; two patients had cutis verticis gyrata. Behavioral issues and specific psychiatric diagnoses, including self-injury, anxiety, attention-deficit disorder, autistic features, depression, and obsessive-compulsive behavior, often worsen with age. This work presents some evidence for accelerated aging in CdLS. Of 53% with mutation analysis, 55% demonstrate a detectable mutation in NIPBL or SMC1A. Although no specific genotype–phenotype correlations have been firmly established, individuals with missense mutations in NIPBL and SMC1A appear milder than those with other mutations. Based on these observations, recommendations for clinical management of adults with CdLS are made. PMID:17640042

A novel approach to PTSD modeling in rats reveals alternating patterns of limbic activity in different types of stress reaction.

PubMed

Ritov, G; Boltyansky, B; Richter-Levin, G

2016-05-01

Human reactions to trauma exposure are extremely diverse, with some individuals exhibiting only time-limited distress and others qualifying for posttraumatic stress disorder diagnosis (PTSD). Furthermore, whereas most PTSD patients mainly display fear-based symptoms, a minority of patients display a co-morbid anhedonic phenotype. We employed an individual profiling approach to model these intriguing facets of the psychiatric condition in underwater-trauma exposed rats. Based on long-term assessments of anxiety-like and anhedonic behaviors, our analysis uncovered three separate phenotypes of stress response; an anxious, fear-based (38%), a co-morbid, fear-anhedonic (15%), and an exposed-unaffected group (47%). Immunohistochemical assessments for cellular activation (c-Fos) and activation of inhibition (c-Fos+GAD67) revealed a differential involvement of limbic regions and distinct co-activity patterns for each of these phenotypes, validating the behavioral categorization. In accordance with recent neurocognitive hypotheses for posttraumatic depression, we show that enhanced pretrauma anxiety predicts the progression of posttraumatic anhedonia only in the fear-anhedonic phenotype.

Commentary.

ERIC Educational Resources Information Center

Burgess, Robert L.; Molenaar, Peter C. M.

1995-01-01

Supports Gottlieb's conclusion that developmental behavior genetics is unsuitable for analyzing developmental coactional processes because it does not concern itself with mechanisms through which genotypes are transformed into phenotypes. But maintains that modern behavior genetics provides an indispensable tool to analyze nonlinear epigenetic…

Zebrafish neurobehavioral phenomics for aquatic neuropharmacology and toxicology research.

PubMed

Kalueff, Allan V; Echevarria, David J; Homechaudhuri, Sumit; Stewart, Adam Michael; Collier, Adam D; Kaluyeva, Aleksandra A; Li, Shaomin; Liu, Yingcong; Chen, Peirong; Wang, JiaJia; Yang, Lei; Mitra, Anisa; Pal, Subharthi; Chaudhuri, Adwitiya; Roy, Anwesha; Biswas, Missidona; Roy, Dola; Podder, Anupam; Poudel, Manoj K; Katare, Deepshikha P; Mani, Ruchi J; Kyzar, Evan J; Gaikwad, Siddharth; Nguyen, Michael; Song, Cai

2016-01-01

Zebrafish (Danio rerio) are rapidly emerging as an important model organism for aquatic neuropharmacology and toxicology research. The behavioral/phenotypic complexity of zebrafish allows for thorough dissection of complex human brain disorders and drug-evoked pathological states. As numerous zebrafish models become available with a wide spectrum of behavioral, genetic, and environmental methods to test novel drugs, here we discuss recent zebrafish phenomics methods to facilitate drug discovery, particularly in the field of biological psychiatry. Additionally, behavioral, neurological, and endocrine endpoints are becoming increasingly well-characterized in zebrafish, making them an inexpensive, robust and effective model for toxicology research and pharmacological screening. We also discuss zebrafish behavioral phenotypes, experimental considerations, pharmacological candidates and relevance of zebrafish neurophenomics to other 'omics' (e.g., genomic, proteomic) approaches. Finally, we critically evaluate the limitations of utilizing this model organism, and outline future strategies of research in the field of zebrafish phenomics. Copyright © 2015 Elsevier B.V. All rights reserved.

Calmodulin point mutations affect Drosophila development and behavior.

PubMed

Nelson, H B; Heiman, R G; Bolduc, C; Kovalick, G E; Whitley, P; Stern, M; Beckingham, K

1997-12-01

Calmodulin (CAM) is recognized as a major intermediary in intracellular calcium signaling, but as yet little is known of its role in developmental and behavioral processes. We have generated and studied mutations to the endogenous Cam gene of Drosophila melanogaster that change single amino acids within the protein coding region. One of these mutations produces a striking pupal lethal phenotype involving failure of head eversion. Various mutant combinations produce specific patterns of ectopic wing vein formation or melanotic scabs on the cuticle. Anaphase chromosome bridging is also seen as a maternal effect during the early embryonic nuclear divisions. In addition, specific behavioral defects such as poor climbing and flightlessness are detected among these mutants. Comparisons with other Drosophila mutant phenotypes suggests potential CAM targets that may mediate these developmental and behavioral effects, and analysis of the CAM crystal structure suggests the structural consequences of the individual mutations.

Calmodulin Point Mutations Affect Drosophila Development and Behavior

PubMed Central

Nelson, H. B.; Heiman, R. G.; Bolduc, C.; Kovalick, G. E.; Whitley, P.; Stern, M.; Beckingham, K.

1997-01-01

Calmodulin (CAM) is recognized as a major intermediary in intracellular calcium signaling, but as yet little is known of its role in developmental and behavioral processes. We have generated and studied mutations to the endogenous Cam gene of Drosophila melanogaster that change single amino acids within the protein coding region. One of these mutations produces a striking pupal lethal phenotype involving failure of head eversion. Various mutant combinations produce specific patterns of ectopic wing vein formation or melanotic scabs on the cuticle. Anaphase chromosome bridging is also seen as a maternal effect during the early embryonic nuclear divisions. In addition, specific behavioral defects such as poor climbing and flightlessness are detected among these mutants. Comparisons with other Drosophila mutant phenotypes suggests potential CAM targets that may mediate these developmental and behavioral effects, and analysis of the CAM crystal structure suggests the structural consequences of the individual mutations. PMID:9409836

General and substance-specific predictors of young adult nicotine dependence, alcohol use disorder, and problem behavior: replication in two samples.

PubMed

Bailey, J A; Samek, D R; Keyes, M A; Hill, K G; Hicks, B M; McGue, M; Iacono, W G; Epstein, M; Catalano, R F; Haggerty, K P; Hawkins, J D

2014-05-01

This paper presents two replications of a heuristic model for measuring environment in studies of gene-environment interplay in the etiology of young adult problem behaviors. Data were drawn from two longitudinal, U.S. studies of the etiology of substance use and related behaviors: the Raising Healthy Children study (RHC; N=1040, 47% female) and the Minnesota Twin Family Study (MTFS; N=1512, 50% female). RHC included a Pacific Northwest, school-based, community sample. MTFS included twins identified from state birth records in Minnesota. Both studies included commensurate measures of general family environment and family substance-specific environments in adolescence (RHC ages 10-18; MTFS age 18), as well as young adult nicotine dependence, alcohol and illicit drug use disorders, HIV sexual risk behavior, and antisocial behavior (RHC ages 24, 25; MTFS age 25). Results from the two samples were highly consistent and largely supported the heuristic model proposed by Bailey et al. (2011). Adolescent general family environment, family smoking environment, and family drinking environment predicted shared variance in problem behaviors in young adulthood. Family smoking environment predicted unique variance in young adult nicotine dependence. Family drinking environment did not appear to predict unique variance in young adult alcohol use disorder. Organizing environmental predictors and outcomes into general and substance-specific measures provides a useful way forward in modeling complex environments and phenotypes. Results suggest that programs aimed at preventing young adult problem behaviors should target general family environment and family smoking and drinking environments in adolescence. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Phylo-Allometric Analyses Showcase the Interplay between Life-History Patterns and Phenotypic Convergence in Cleaner Wrasses.

PubMed

Baliga, Vikram B; Mehta, Rita S

2018-05-01

Phenotypic convergence is a macroevolutionary pattern that need not be consistent across life history. Ontogenetic transitions in dietary specialization clearly illustrate the dynamics of ecological selection as organisms grow. The extent of phenotypic convergence among taxa that share a similar ecological niche may therefore vary ontogenetically. Because ontogenetic processes have been shown to evolve, phylogenetic comparative methods can be useful in examining how the scaling of traits relates to ecology. Cleaning, a behavior in which taxa consume ectoparasites off clientele, is well represented among wrasses (Labridae). Nearly three-fourths of labrids that clean do so predominately as juveniles, transitioning away as adults. We examine the scaling patterns of 33 labrid species to understand how life-history patterns of cleaning relate to ontogenetic patterns of phenotypic convergence. We find that as juveniles, cleaners exhibit convergence in body and cranial traits that enhance ectoparasitivory. We then find that taxa that transition away from cleaning exhibit ontogenetic trajectories that are distinct from those of other wrasses. Obligate and facultative species that continue to clean over ontogeny, however, maintain characteristics that are conducive to cleaning. Collectively, we find that life-history patterns of cleaning behavior are concordant with ontogenetic patterns in phenotype in wrasses.

Seasonal Effects on the Population, Morphology and Reproductive Behavior of Narnia femorata (Hemiptera: Coreidae)

PubMed Central

Cirino, Lauren A.; Miller, Christine W.

2017-01-01

Many insects are influenced by the phenology of their host plants. In North Central Florida, Narnia femorata (Hemiptera: Coreidae) spends its entire life cycle living and feeding on Opuntia mesacantha ssp. lata. This cactus begins producing flower buds in April that lead to unripe green fruit in June that ripen into red fruit through December. Many morphological and behavioral characteristics of N. femorata are known to be affected by cactus phenology in a controlled laboratory setting, including the degree of sexual dimorphism and mating behavior. Our goal with this study was to determine if similar phenotypic changes of N. femorata occurred over time in the wild, and the extent to which these changes were concordant with phenological changes in its host plant. Further, we investigate the length of the insect mouthparts (beak) over time. Ongoing work has suggested that beak length may change across cohorts of developing insects in response to feeding deep within cactus fruit where seed and pulp depth decrease as the fruit ripens. Our results revealed a drop in cactus fruit abundance between the months of July through October 2015 as cactus fruits turned red and ripened. Simultaneously, the average body size of both males and females of N. femorata declined at two sampled sites. Male hind femora (a sexually-selected weapon) decreased disproportionately in size over time so that males later in the year had relatively smaller hind femora for their body size. The sex-specific patterns of morphological change led to increased sexual-size dimorphism and decreased sexual dimorphism for hind femora later in the year. Further, we found that beak length decreased across cohorts of insects as cactus fruit ripened, suggesting phenotypic plasticity in mouthpart length. Behavioral studies revealed that female readiness to mate increased as the season progressed. In sum, we found pronounced changes in the phenotypes of these insects in the field. Although this study is far from comprehensive, it provides tantalizing patterns that suggest many directions for future research. PMID:28106715

The proceedings of the 15th professional conference on Williams Syndrome.

PubMed

Walton, Jennifer R; Martens, Marilee A; Pober, Barbara R

2017-05-01

Williams Syndrome (WS) is a contiguous gene deletion disorder, caused by the deletion of approximately 26-28 genes from chromosome 7 (7q11.23). Individuals with WS have complex medical, developmental, and behavioral features, requiring multidisciplinary and interdisciplinary collaboration. Guidelines detailing the identification, evaluation, and monitoring of individuals with WS need clarification, especially for primary care providers who are first-line in their management. This report summarizes the proceedings of the 2016 Professional Conference on WS in Columbus, OH. Presentations were directed towards primary care providers and subspecialists, emphasizing evidence-based practices for treating the prevalent medical and behavioral features of WS. Included in this report are findings from a panel of cardiovascular experts discussing three case studies on treatment of hypertension and the use of sedation or anesthesia for non-cardiac procedures. Abstracts from individual expert presenters are included, covering various medical and behavioral topics, and providing updates in management of WS individuals. The following topics were discussed: differences in phenotypes of 7q11.23 deletion versus duplication, growth parameters, endocrine concerns, sleep difficulties, behaviors to monitor, and pharmacological options, the neurodevelopmental profile of WS individuals, and the importance of monitoring medical and behavioral concerns as WS individuals transition to adulthood. © 2017 Wiley Periodicals, Inc.

Statistical and methodological considerations for the interpretation of intranasal oxytocin studies

PubMed Central

Walum, Hasse; Waldman, Irwin D.; Young, Larry J.

2015-01-01

Over the last decade, oxytocin (OT) has received focus in numerous studies associating intranasal administration of this peptide with various aspects of human social behavior. These studies in humans are inspired by animal research, especially in rodents, showing that central manipulations of the OT system affect behavioral phenotypes related to social cognition, including parental behavior, social bonding and individual recognition. Taken together, these studies in humans appear to provide compelling, but sometimes bewildering evidence for the role of OT in influencing a vast array of complex social cognitive processes in humans. In this paper we investigate to what extent the human intranasal OT literature lends support to the hypothesis that intranasal OT consistently influences a wide spectrum of social behavior in humans. We do this by considering statistical features of studies within this field, including factors like statistical power, pre-study odds and bias. Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism, and we make recommendations to improve the reliability of human OT studies in the future. PMID:26210057

Overexpression of soluble ADAM33 promotes a hypercontractile phenotype of the airway smooth muscle cell in rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, Yiyuan; Long, Jiaoyue; Chen, Jun

A disintegrin and metalloproteinase 33 (ADAM33) has been identified as a susceptibility gene for asthma, but details of the causality are not fully understood. We hypothesize that soluble ADAM33 (sADAM33) overexpression can alter the mechanical behaviors of airway smooth muscle cells (ASMCs) via regulation of the cell's contractile phenotype, and thus contributes to airway hyperresponsiveness (AHR) in asthma. To test this hypothesis, we either overexpressed or knocked down the sADAM33 in rat ASMCs by transfecting the cells with sADAM33 coding sequence or a small interfering RNA (siRNA) that specifically targets the ADAM33 disintegrin domain, and subsequently assessed the cells formore » stiffness, contractility and traction force, together with the expression level of contractile and proliferative phenotype markers. We also investigated whether these changes were dependent on Rho/ROCK pathway by culturing the ASMCs either in the absence or presence of ROCK inhibitor (H1152). The results showed that the ASMCs with sADAM33 overexpression were stiffer and more contractile, generated greater traction force, exhibited increased expression levels of contractile phenotype markers and markedly enhanced Rho activation. Furthermore these changes were largely attenuated when the cells were cultured in the presence of H-1152. However, the knock-down of ADAM33 seemed insufficient to influence majority of the mechanical behaviors of the ASMCs. Taken together, we demonstrated that sADAM33 overexpression altered the mechanical behaviors of ASMCs in vitro, which was most likely by promoting a hypercontractile phenotype transition of ASMCs through Rho/ROCK pathway. This revelation may establish the previously missing link between ADAM33 expression and AHR, and also provide useful insight for targeting sADAM33 in asthma prevention and therapy. - Highlights: • sADAM33 overexpression enhances the stiffness, traction force and contractility of ASMCs. • sADAM33 overexpression promotes a hypercontractile phenotype of ASMCs. • The hypercontractile phenotype transition was largely mediated via Rho/ROCK pathway. • ADAM33 knock-down had little effect on the stiffness, traction force and contractility of ASMCs.« less

Autism-related behavioral abnormalities in synapsin knockout mice.

PubMed

Greco, Barbara; Managò, Francesca; Tucci, Valter; Kao, Hung-Teh; Valtorta, Flavia; Benfenati, Fabio

2013-08-15

Several synaptic genes predisposing to autism-spectrum disorder (ASD) have been identified. Nonsense and missense mutations in the SYN1 gene encoding for Synapsin I have been identified in families segregating for idiopathic epilepsy and ASD and genetic mapping analyses have identified variations in the SYN2 gene as significantly contributing to epilepsy predisposition. Synapsins (Syn I/II/III) are a multigene family of synaptic vesicle-associated phosphoproteins playing multiple roles in synaptic development, transmission and plasticity. Lack of SynI and/or SynII triggers a strong epileptic phenotype in mice associated with mild cognitive impairments that are also present in the non-epileptic SynIII(-/-) mice. SynII(-/-) and SynIII(-/-) mice also display schizophrenia-like traits, suggesting that Syns could be involved in the regulation of social behavior. Here, we studied social interaction and novelty, social recognition and social dominance, social transmission of food preference and social memory in groups of male SynI(-/-), SynII(-/-) and SynIII(-/-) mice before and after the appearance of the epileptic phenotype and compared their performances with control mice. We found that deletion of Syn isoforms widely impairs social behaviors and repetitive behaviors, resulting in ASD-related phenotypes. SynI or SynIII deletion altered social behavior, whereas SynII deletion extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment and increased self-grooming. Social impairments of SynI(-/-) and SynII(-/-) mice were evident also before the onset of seizures. The results demonstrate an involvement of Syns in generation of the behavioral traits of ASD and identify Syn knockout mice as a useful experimental model of ASD and epilepsy. Copyright © 2013 Elsevier B.V. All rights reserved.

Behavioral characterization of mice lacking histamine H(3) receptors.

PubMed

Toyota, Hiroshi; Dugovic, Christine; Koehl, Muriel; Laposky, Aaron D; Weber, China; Ngo, Karen; Wu, Ying; Lee, Doo Hyun; Yanai, Kazuhiko; Sakurai, Eiko; Watanabe, Takehiko; Liu, Changlu; Chen, Jingcai; Barbier, Ann J; Turek, Fred W; Fung-Leung, Wai-Ping; Lovenberg, Timothy W

2002-08-01

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors. This paper provides the first description of the H(3) receptor-deficient mouse (H(3)(-/-)), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H(3)(-/-) mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H(3)(-/-) mice were insensitive to the wake-promoting effects of the H(3) receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.

Imaging genetics and the neurobiological basis of individual differences in vulnerability to addiction.

PubMed

Sweitzer, Maggie M; Donny, Eric C; Hariri, Ahmad R

2012-06-01

Addictive disorders are heritable, but the search for candidate functional polymorphisms playing an etiological role in addiction is hindered by complexity of the phenotype and the variety of factors interacting to impact behavior. Advances in human genome sequencing and neuroimaging technology provide an unprecedented opportunity to explore the impact of functional genetic variants on variability in behaviorally relevant neural circuitry. Here, we present a model for merging these technologies to trace the links between genes, brain, and addictive behavior. We describe imaging genetics and discuss the utility of its application to addiction. We then review data pertaining to impulsivity and reward circuitry as an example of how genetic variation may lead to variation in behavioral phenotype. Finally, we present preliminary data relating the neural basis of reward processing to individual differences in nicotine dependence. Complex human behaviors such as addiction can be traced to their basic genetic building blocks by identifying intermediate behavioral phenotypes, associated neural circuitry, and underlying molecular signaling pathways. Impulsivity has been linked with variation in reward-related activation in the ventral striatum (VS), altered dopamine signaling, and functional polymorphisms of DRD2 and DAT1 genes. In smokers, changes in reward-related VS activation induced by smoking abstinence may be associated with severity of nicotine dependence. Variation in genes related to dopamine signaling may contribute to heterogeneity in VS sensitivity to reward and, ultimately, to addiction. These findings illustrate the utility of the imaging genetics approach for investigating the neurobiological basis for vulnerability to addiction. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights.

PubMed

Rayner, Genevieve; Jackson, Graeme D; Wilson, Sarah J

2016-11-01

Depression is common but underdiagnosed in epilepsy. A quarter of patients meet criteria for a depressive disorder, yet few receive active treatment. We hypothesize that the presentation of depression is less recognizable in epilepsy because the symptoms are heterogeneous and often incorrectly attributed to the secondary effects of seizures or medication. Extending the ILAE's new phenomenological approach to classification of the epilepsies to include psychiatric comorbidity, we use data-driven profiling of the symptoms of depression to perform a preliminary investigation of whether there is a distinctive symptom-based phenotype of depression in epilepsy that could facilitate its recognition in the neurology clinic. The psychiatric and neuropsychological functioning of 91 patients with focal epilepsy was compared with that of 77 healthy controls (N=168). Cluster analysis of current depressive symptoms identified three clusters: one comprising nondepressed patients and two symptom-based phenotypes of depression. The 'Cognitive' phenotype (base rate=17%) was characterized by symptoms taking the form of self-critical cognitions and dysphoria and was accompanied by pervasive memory deficits. The 'Somatic' phenotype (7%) was characterized by vegetative depressive symptoms and anhedonia and was accompanied by greater anxiety. It is hoped that identification of the features of these two phenotypes will ultimately facilitate improved detection and diagnosis of depression in patients with epilepsy and thereby lead to appropriate and timely treatment, to the benefit of patient wellbeing and the potential efficacy of treatment of the seizure disorder. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy". Copyright © 2016 Elsevier Inc. All rights reserved.

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

PubMed Central

Lorenz-Depiereux, Bettina; Guido, Victoria E.; Johnson, Kenneth R.; Zheng, Qing Yin; Gagnon, Leona H.; Bauschatz, Joiel D.; Davisson, Muriel T.; Washburn, Linda L.; Donahue, Leah Rae; Strom, Tim M.; Eicher, Eva M.

2010-01-01

X-linked hypophosphatemic rickets (XLH) in humans is caused by mutations in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: PhexHyp, Gy, and PhexSka1. Here we report analysis of two new spontaneous mutations in the mouse Phex gene, PhexHyp-2J and PhexHyp-Duk. PhexHyp-2J and PhexHyp-Duk involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the PhexHyp-Duk mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phex-related phenotypes. Cochlear cross-sections from PhexHyp-2J/Y and PhexHyp-Duk/Y males reveal a thickening of the temporal bone surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired PhexHyp-Duk/Y mice, but not in the normal-hearing PhexHyp-2J/Y mice. Analysis of the phenotypes noted in PhexHyp-Duk/Y an PhexHyp-2J/Y males, together with those noted in PhexSka1/Y and PhexHyp/Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in PhexHyp-Duk/Y mice could provide insight into the phenotypic variation of XLH in humans. PMID:15029877

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.

PubMed

Lorenz-Depiereux, Bettina; Guido, Victoria E; Johnson, Kenneth R; Zheng, Qing Yin; Gagnon, Leona H; Bauschatz, Joiel D; Davisson, Muriel T; Washburn, Linda L; Donahue, Leah Rae; Strom, Tim M; Eicher, Eva M

2004-03-01

X-linked hypophosphatemic rickets (XLH) in humans is caused by mutation in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: Phex(Hyp), Gy, and Phex(Ska1). Here we report analysis of two new spontaneous mutation in the mouse Phex gene, Phex(Hyp-2J) and Phex(Hyp-Duk). Phex(Hyp-2J) and Phex(Hyp-Duk) involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the Phex(Hyp-Duk) mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phex-related phenotypes. Cochlear cross-sections from Phex(Hyp-2J)/Y and Phex(Hyp-Duk)/Y males reveal a thickening of the temporal bones surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired Phex(Hyp-Duk)/Y mice, but not in the normal-hearing Phex(Hyp-2J)/Y mice. Analysis of the phenotypes noted in Phex(Hyp-Duk)/Y and Phex(Hyp-2J)/Y males, together with those noted in Phex(Ska1)/Y and Phex(Hyp)/Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in Phex(Hyp-Duk)/Y mice could provide insight into the phenotypic variation of XLH in humans.

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits.

PubMed

Fusco, Carmela; Micale, Lucia; Augello, Bartolomeo; Teresa Pellico, Maria; Menghini, Deny; Alfieri, Paolo; Cristina Digilio, Maria; Mandriani, Barbara; Carella, Massimo; Palumbo, Orazio; Vicari, Stefano; Merla, Giuseppe

2014-01-01

Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry ~3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of ~1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.

Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells.

PubMed

Yang, Min; Ma, Bo; Shao, Hanshuang; Clark, Amanda M; Wells, Alan

2016-07-07

Metastatic progression of breast cancer involves phenotypic plasticity of the carcinoma cells moving between epithelial and mesenchymal behaviors. During metastatic seeding and dormancy, even highly aggressive carcinoma cells take on an E-cadherin-positive epithelial phenotype that is absent from the emergent, lethal metastatic outgrowths. These phenotypes are linked to the metastatic microenvironment, though the specific cells and induction signals are still to be deciphered. Recent evidence suggests that macrophages impact tumor progression, and may alter the balance between cancer cell EMT and MErT in the metastatic microenvironment. Here we explore the role of M1/M2 macrophages in epithelial-mesenchymal plasticity of breast cancer cells by coculturing epithelial and mesenchymal cells lines with macrophages. We found that after polarizing the THP-1 human monocyte cell line, the M1 and M2-types were stable and maintained when co-cultured with breast cancer cells. Surprisingly, M2 macrophages may conferred a growth advantage to the epithelial MCF-7 cells, with these cells being driven to a partial mesenchymal phenotypic as indicated by spindle morphology. Notably, E-cadherin protein expression is significantly decreased in MCF-7 cells co-cultured with M2 macrophages. M0 and M1 macrophages had no effect on the MCF-7 epithelial phenotype. However, the M1 macrophages impacted the highly aggressive mesenchymal-like MDA-MB-231 breast cancer cells to take on a quiescent, epithelial phenotype with re-expression of E-cadherin. The M2 macrophages if anything exacerbated the mesenchymal phenotype of the MDA-MB-231 cells. Our findings demonstrate M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells. Thus EMT and MErT are regulated by selected macrophage phenotype in the liver metastatic microenvironment. These results indicate macrophage could be a potential therapeutic target for limiting death due to malignant metastases in breast cancer.

Severe Affective and Behavioural Dysregulation Is Associated with Significant Psychosocial Adversity and Impairment

ERIC Educational Resources Information Center

Jucksch, Viola; Salbach-Andrae, Harriet; Lenz, Klaus; Goth, Kirstin; Dopfner, Manfred; Poustka, Fritz; Freitag, Christine M.; Lehmkuhl, Gerd; Lehmkuhl, Ulrike; Holtmann, Martin

2011-01-01

Background: Recently, a highly heritable behavioral phenotype of simultaneous deviance on the Anxious/Depressed, Attention Problems, and Aggressive Behavior syndrome scales has been identified on the Child Behavior Checklist (CBCL-Dysregulation Profile, CBCL-DP). This study aims to investigate psychosocial adversity and impairment of the CBCL-DP.…

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors

PubMed Central

Belinson, H; Nakatani, J; Babineau, BA; Birnbaum, RY; Ellegood, J; Bershteyn, M; McEvilly, RJ; Long, JM; Willert, K; Klein, OD; Ahituv, N; Lerch, JP; Rosenfeld, GM; Wynshaw-Boris, A

2015-01-01

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Dishevelled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism. PMID:26830142

Behavioral and neuroanatomical abnormalities in pleiotrophin knockout mice.

PubMed

Krellman, Jason W; Ruiz, Henry H; Marciano, Veronica A; Mondrow, Bracha; Croll, Susan D

2014-01-01

Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

PubMed

Belinson, H; Nakatani, J; Babineau, B A; Birnbaum, R Y; Ellegood, J; Bershteyn, M; McEvilly, R J; Long, J M; Willert, K; Klein, O D; Ahituv, N; Lerch, J P; Rosenfeld, M G; Wynshaw-Boris, A

2016-10-01

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.

Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation

PubMed Central

Hoffman, Ann N.; Parga, Alejandro; Paode, Pooja; Watterson, Lucas R.; Nikulina, Ella M.; Hammer, Ronald P.; Conrad, Cheryl D.

2015-01-01

The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6h/d/21d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40 mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype. PMID:25732249

GNAO1 encephalopathy: Broadening the phenotype and evaluating treatment and outcome.

PubMed

Danti, Federica Rachele; Galosi, Serena; Romani, Marta; Montomoli, Martino; Carss, Keren J; Raymond, F Lucy; Parrini, Elena; Bianchini, Claudia; McShane, Tony; Dale, Russell C; Mohammad, Shekeeb S; Shah, Ubaid; Mahant, Neil; Ng, Joanne; McTague, Amy; Samanta, Rajib; Vadlamani, Gayatri; Valente, Enza Maria; Leuzzi, Vincenzo; Kurian, Manju A; Guerrini, Renzo

2017-04-01

To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1 -related disease. We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

Estimating the actual subject-specific genetic correlations in behavior genetics.

PubMed

Molenaar, Peter C M

2012-10-01

Generalization of the standard behavior longitudinal genetic factor model for the analysis of interindividual phenotypic variation to a genetic state space model for the analysis of intraindividual variation enables the possibility to estimate subject-specific heritabilities.

AN ENVIRONMENTAL ANTIANDROGEN, VINCLOZOLIN, ALTERS THE ORGANIZATION OF PLAY BEHAVIOR

EPA Science Inventory

ABSTRACT

During mammalian sexual differentiation, the androgens, testosterone and dihydrotestosterone are critical for the organization of the male phenotype. In rats, play behavior is sexually dimorphic. Administration of exogenous androgens during the perinatal period r...

Genetic and Modeling Approaches Reveal Distinct Components of Impulsive Behavior

PubMed Central

Nautiyal, Katherine M; Wall, Melanie M; Wang, Shuai; Magalong, Valerie M; Ahmari, Susanne E; Balsam, Peter D; Blanco, Carlos; Hen, René

2017-01-01

Impulsivity is an endophenotype found in many psychiatric disorders including substance use disorders, pathological gambling, and attention deficit hyperactivity disorder. Two behavioral features often considered in impulsive behavior are behavioral inhibition (impulsive action) and delayed gratification (impulsive choice). However, the extent to which these behavioral constructs represent distinct facets of behavior with discrete biological bases is unclear. To test the hypothesis that impulsive action and impulsive choice represent statistically independent behavioral constructs in mice, we collected behavioral measures of impulsivity in a single cohort of mice using well-validated operant behavioral paradigms. Mice with manipulation of serotonin 1B receptor (5-HT1BR) expression were included as a model of disordered impulsivity. A factor analysis was used to characterize correlations between the measures of impulsivity and to identify covariates. Using two approaches, we dissociated impulsive action from impulsive choice. First, the absence of 5-HT1BRs caused increased impulsive action, but not impulsive choice. Second, based on an exploratory factor analysis, a two-factor model described the data well, with measures of impulsive action and choice separating into two independent factors. A multiple-indicator multiple-causes analysis showed that 5-HT1BR expression and sex were significant covariates of impulsivity. Males displayed increased impulsivity in both dimensions, whereas 5-HT1BR expression was a predictor of increased impulsive action only. These data support the conclusion that impulsive action and impulsive choice are distinct behavioral phenotypes with dissociable biological influences that can be modeled in mice. Our work may help inform better classification, diagnosis, and treatment of psychiatric disorders, which present with disordered impulsivity. PMID:27976680

Sickle cell mice exhibit mechanical allodynia and enhanced responsiveness in light touch cutaneous mechanoreceptors

PubMed Central

2012-01-01

Background Sickle cell disease (SCD) is associated with both acute vaso-occlusive painful events as well as chronic pain syndromes, including heightened sensitivity to touch. We have previously shown that mice with severe SCD (HbSS mice; express 100% human sickle hemoglobin in red blood cells; RBCs) have sensitized nociceptors, which contribute to increased mechanical sensitivity. Yet, the hypersensitivity in these neural populations alone may not fully explain the mechanical allodynia phenotype in mouse and humans. Findings Using the Light Touch Behavioral Assay, we found HbSS mice exhibited increased responses to repeated application of both innocuous punctate and dynamic force compared to control HbAA mice (100% normal human hemoglobin). HbSS mice exhibited a 2-fold increase in percent response to a 0.7mN von Frey monofilament when compared to control HbAA mice. Moreover, HbSS mice exhibited a 1.7-fold increase in percent response to the dynamic light touch “puffed” cotton swab stimulus. We further investigated the mechanisms that drive this behavioral phenotype by focusing on the cutaneous sensory neurons that primarily transduce innocuous, light touch. Low threshold cutaneous afferents from HbSS mice exhibited sensitization to mechanical stimuli that manifested as an increase in the number of evoked action potentials to suprathreshold force. Rapidly adapting (RA) Aβ and Aδ D-hair fibers showed the greatest sensitization, each with a 75% increase in suprathreshold firing compared to controls. Slowly adapting (SA) Aβ afferents had a 25% increase in suprathreshold firing compared to HbAA controls. Conclusions These novel findings demonstrate mice with severe SCD exhibit mechanical allodynia to both punctate and dynamic light touch and suggest that this behavioral phenotype may be mediated in part by the sensitization of light touch cutaneous afferent fibers to suprathreshold force. These findings indicate that Aβ fibers can be sensitized to mechanical force and should potentially be examined for sensitization in other tissue injury and disease models. PMID:22963123

Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.

PubMed

Branson, Ruth; Potoczna, Natascha; Kral, John G; Lentes, Klaus-Ulrich; Hoehe, Margret R; Horber, Fritz F

2003-03-20

Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity. We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the alpha melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [+/-SE] age, 41.0+/-0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1+/-2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7+/-2.0 years; body-mass index, 21.6+/-0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected. Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha melanocyte-stimulating hormone. Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior. Copyright 2003 Massachusetts Medical Society

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

PubMed

Yang, Hui; Douglas, Ganka; Monaghan, Kristin G; Retterer, Kyle; Cho, Megan T; Escobar, Luis F; Tucker, Megan E; Stoler, Joan; Rodan, Lance H; Stein, Diane; Marks, Warren; Enns, Gregory M; Platt, Julia; Cox, Rachel; Wheeler, Patricia G; Crain, Carrie; Calhoun, Amy; Tryon, Rebecca; Richard, Gabriele; Vitazka, Patrik; Chung, Wendy K

2015-10-01

Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

A systematic review of treatments for anxiety in youth with autism spectrum disorders.

PubMed

Vasa, Roma A; Carroll, Laura M; Nozzolillo, Alixandra A; Mahajan, Rajneesh; Mazurek, Micah O; Bennett, Amanda E; Wink, Logan K; Bernal, Maria Pilar

2014-12-01

This study systematically examined the efficacy and safety of psychopharmacological and non-psychopharmacological treatments for anxiety in youth with autism spectrum disorders (ASD). Four psychopharmacological, nine cognitive behavioral therapy (CBT), and two alternative treatment studies met inclusion criteria. Psychopharmacological studies were descriptive or open label, sometimes did not specify the anxiety phenotype, and reported behavioral activation. Citalopram and buspirone yielded some improvement, whereas fluvoxamine did not. Non-psychopharmacological studies were mainly randomized controlled trials (RCTs) with CBT demonstrating moderate efficacy for anxiety disorders in youth with high functioning ASD. Deep pressure and neurofeedback provided some benefit. All studies were short-term and included small sample sizes. Large scale and long term RCTs examining psychopharmacological and non-psychopharmacological treatments are sorely needed.

Brief Report: A Longitudinal Study of Excessive Smiling and Laughing in Children with Angelman Syndrome.

PubMed

Adams, Dawn; Horsler, Kate; Mount, Rebecca; Oliver, Chris

2015-08-01

Elevated laughing and smiling is a key characteristic of the Angelman syndrome behavioral phenotype, with cross-sectional studies reporting changes with environment and age. This study compares levels of laughing and smiling in 12 participants across three experimental conditions [full social interaction (with eye contact), social interaction with no eye contact, proximity only] at two data points. No differences were noted in frequency of laughing and smiling over time in any condition. However, with age as a covariate, the frequency of laughing and smiling decreased over time in the full social interaction (with eye contact) condition only. As this is the first longitudinal study to explore these behaviors in Angelman syndrome, the results suggest a gene-environment-time interaction within the behavioral phenotype.

Proinflammatory T Cell Status Associated with Early Life Adversity.

PubMed

Elwenspoek, Martha M C; Hengesch, Xenia; Leenen, Fleur A D; Schritz, Anna; Sias, Krystel; Schaan, Violetta K; Mériaux, Sophie B; Schmitz, Stephanie; Bonnemberger, Fanny; Schächinger, Hartmut; Vögele, Claus; Turner, Jonathan D; Muller, Claude P

2017-12-15

Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA ( n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69 + CD8 + T cells ( p = 0.022), increased numbers of HLA-DR + CD4 and HLA-DR + CD8 T cells ( p < 0.001), as well as increased numbers of CD25 + CD8 + T cells ( p = 0.036). ELA also showed a trend toward higher numbers of CCR4 + CXCR3 - CCR6 + CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells. Copyright © 2017 by The American Association of Immunologists, Inc.

Predicting impaired extinction of traumatic memory and elevated startle.

PubMed

Nalloor, Rebecca; Bunting, Kristopher; Vazdarjanova, Almira

2011-01-01

Emotionally traumatic experiences can lead to debilitating anxiety disorders, such as phobias and Post-Traumatic Stress Disorder (PTSD). Exposure to such experiences, however, is not sufficient to induce pathology, as only up to one quarter of people exposed to such events develop PTSD. These statistics, combined with findings that smaller hippocampal size prior to the trauma is associated with higher risk of developing PTSD, suggest that there are pre-disposing factors for such pathology. Because prospective studies in humans are limited and costly, investigating such pre-dispositions, and thus advancing understanding of the genesis of such pathologies, requires the use of animal models where predispositions are identified before the emotional trauma. Most existing animal models are retrospective: they classify subjects as those with or without a PTSD-like phenotype long after experiencing a traumatic event. Attempts to create prospective animal models have been largely unsuccessful. Here we report that individual predispositions to a PTSD-like phenotype, consisting of impaired rate and magnitude of extinction of an emotionally traumatic event coupled with long-lasting elevation of acoustic startle responses, can be revealed following exposure to a mild stressor, but before experiencing emotional trauma. We compare, in rats, the utility of several classification criteria and report that a combination of criteria based on acoustic startle responses and behavior in an anxiogenic environment is a reliable predictor of a PTSD-like phenotype. There are individual predispositions to developing impaired extinction and elevated acoustic startle that can be identified after exposure to a mildly stressful event, which by itself does not induce such a behavioral phenotype. The model presented here is a valuable tool for studying the etiology and pathophysiology of anxiety disorders and provides a platform for testing behavioral and pharmacological interventions that can reduce the probability of developing pathologic behaviors associated with such disorders.

The roles of sex and serotonin transporter levels in age- and stress-related emotionality in mice.

PubMed

Joeyen-Waldorf, Jennifer; Edgar, Nicole; Sibille, Etienne

2009-08-25

Mood disorders are influenced by genetic make-up and differentially affect men and women. The s/l promoter polymorphism in the serotonin transporter (SERT) gene moderates both trait emotion and the vulnerability to develop depressive states in humans. Similarly, male mice lacking SERT (Knockout/KO) display an elevated emotionality phenotype. We now report that the SERT-KO phenotype is maintained throughout late-adulthood, and that female KO mice develop a larger emotionality phenotype with increasing age. Thus, to test the hypothesis that these findings reflected a putative sexual dimorphism in SERT-mediated modulation of emotionality, we submitted adult male and female wild-type, heterozygous (HZ) and KO mice to unpredictable chronic mild stress (UCMS) and assessed behavioral changes. In males, the elevated SERT-KO emotion-related behavior converged with other groups after UCMS. Conversely, female SERT-KO displayed a normal non-stressed baseline, but highest UCMS-induced emotionality. SERT-HZ displayed variable and intermediate phenotypes in both experiments. Thus, consistent results across different biological modalities (age, stress) revealed a high contribution of SERT genotype for baseline "trait" emotionality in males, and low contribution for females. In contrast, age-correlated and stress-induced behavioral changes resulted in a high SERT genotype-mediated behavioral variance in females, but low in males. This suggests that high emotionality states associated with low SERT were differentially achieved in males (high baseline/trait) compared to females (increased vulnerability to develop high emotionality). This sex-by-SERT double dissociation provides a framework to investigate molecular substrates of emotionality regulation in concert with serotonin function and may contribute to the sexually dimorphic features of mood disorders.

Increased aggressive and affiliative display behavior in intrauterine growth restricted (IUGR) baboons

PubMed Central

Huber, Hillary F; Ford, Susan M; Bartlett, Thad Q; Nathanielsz, Peter W

2016-01-01

Background We hypothesized intrauterine growth restricted offspring (IUGR) demonstrate higher rates of aggression and higher dominance ranks than control (CTR) offspring with normal weight at term; if aggressive behavior is advantageous during resource scarcity, developmental programming may lead to an association between aggression and IUGR. Methods We studied 22 group-housed baboons (ages 3-5 years). CTR (male n=8, female n=5) mothers ate ad libitum. IUGR (male n=4, female n=5) mothers were fed 70% feed eaten by CTR mothers during pregnancy and lactation. Results IUGR showed higher rates of aggressive displays (p<0.01) and friendly displays (p<0.02). Dominance ranks and physical aggression rates did not differ between groups. Conclusions High rates of IUGR aggressive display might reflect developmental programming of behavioral phenotypes enhancing fitness. Friendly displays may reflect reconciliation. Potential mechanisms include neurodevelopment and learning. Exploration of IUGR as a risk factor for behavioral patterns is important for developing diagnostic and therapeutic strategies. PMID:25891005

Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice.

PubMed

Xu, Jian; Marshall, John J; Fernandes, Herman B; Nomura, Toshihiro; Copits, Bryan A; Procissi, Daniele; Mori, Susumu; Wang, Lei; Zhu, Yongling; Swanson, Geoffrey T; Contractor, Anis

2017-02-21

Kainate receptors are members of the glutamate receptor family that regulate synaptic function in the brain. They modulate synaptic transmission and the excitability of neurons; however, their contributions to neural circuits that underlie behavior are unclear. To understand the net impact of kainate receptor signaling, we generated knockout mice in which all five kainate receptor subunits were ablated (5ko). These mice displayed compulsive and perseverative behaviors, including over-grooming, as well as motor problems, indicative of alterations in striatal circuits. There were deficits in corticostriatal input to spiny projection neurons (SPNs) in the dorsal striatum and correlated reductions in spine density. The behavioral alterations were not present in mice only lacking the primary receptor subunit expressed in adult striatum (GluK2 KO), suggesting that signaling through multiple receptor types is required for proper striatal function. This demonstrates that alterations in striatal function dominate the behavioral phenotype in mice without kainate receptors. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Ab initio genotype–phenotype association reveals intrinsic modularity in genetic networks

PubMed Central

Slonim, Noam; Elemento, Olivier; Tavazoie, Saeed

2006-01-01

Microbial species express an astonishing diversity of phenotypic traits, behaviors, and metabolic capacities. However, our molecular understanding of these phenotypes is based almost entirely on studies in a handful of model organisms that together represent only a small fraction of this phenotypic diversity. Furthermore, many microbial species are not amenable to traditional laboratory analysis because of their exotic lifestyles and/or lack of suitable molecular genetic techniques. As an adjunct to experimental analysis, we have developed a computational information-theoretic framework that produces high-confidence gene–phenotype predictions using cross-species distributions of genes and phenotypes across 202 fully sequenced archaea and eubacteria. In addition to identifying the genetic basis of complex traits, our approach reveals the organization of these genes into generic preferentially co-inherited modules, many of which correspond directly to known enzymatic pathways, molecular complexes, signaling pathways, and molecular machines. PMID:16732191

Parent-Reported Symptoms of Sleep-Disordered Breathing Are Associated With Increased Behavioral Problems at 2 Years of Age: The Canadian Healthy Infant Longitudinal Development Birth Cohort Study.

PubMed

Tamana, Sukhpreet K; Smithson, Lisa; Lau, Amanda; Mariasine, Jennifer; Young, Rochelle; Chikuma, Joyce; Lefebvre, Diana L; Subbarao, Padmaja; Becker, Allan B; Turvey, Stuart E; Sears, Malcolm R; Pei, Jacqueline; Mandhane, Piush J

2018-01-01

To examine the association between the age of onset and duration of parent-reported symptoms of sleep-disordered breathing (SDB) and behavioral problems at age 2. Parent-reported SDB symptoms were assessed quarterly between 3 months and 2 years among 583 Canadian Healthy Infant Longitudinal Development Edmonton-site participants. Parent-reported SDB symptoms were clustered into phenotypes using group-based trajectory analysis based on age of onset and duration of symptoms. Home-based polysomnography (PSG) was completed at 1 year. The Child Behavior Checklist preschool-version (Mean T-score 50, standard deviation 10 points) assessed total, externalizing (attention), and internalizing (anxiety, depression) behaviors at 2 years. Four phenotypes were identified: no SDB (64.7%), early-onset SDB (15.7%, peak symptoms at 9 months), late-onset (14.2%, peak symptoms at 18 months), and persistent SDB symptoms (5.3%, peak symptoms from 3 through 24 months). Persistent SDB (9.5 points, 95% CI 1.7, 17.2; p = .02) predicted the greatest magnitude of effect of total behavior problems, compared with children without SDB. Children with early-onset SDB (3.5 points, 95% CI 1.6, 5.4; p ≤ .001) and late-onset SDB (6.1 points 95% CI 4.0, 8.3; p ≤ .001) had increased total behavioral problems than children without SDB to 2 years. Additional analyses showed that the SDB phenotypes' trajectories were important for internalizing but not for externalizing behavior problems. There were no significant associations between home-PSG and parent-reported behavior problems. Findings suggest that the age of onset and duration of parent-reported SDB symptoms prior to age 2 have adverse consequences for overall behavior problems. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Optimization of industrial microorganisms: recent advances in synthetic dynamic regulators.

PubMed

Min, Byung Eun; Hwang, Hyun Gyu; Lim, Hyun Gyu; Jung, Gyoo Yeol

2017-01-01

Production of biochemicals by industrial fermentation using microorganisms requires maintaining cellular production capacity, because maximal productivity is economically important. High-productivity microbial strains can be developed using static engineering, but these may not maintain maximal productivity throughout the culture period as culture conditions and cell states change dynamically. Additionally, economic reasons limit heterologous protein expression using inducible promoters to prevent metabolic burden for commodity chemical and biofuel production. Recently, synthetic and systems biology has been used to design genetic circuits, precisely controlling gene expression or influencing genetic behavior toward a desired phenotype. Development of dynamic regulators can maintain cellular phenotype in a maximum production state in response to factors including cell concentration, oxygen, temperature, pH, and metabolites. Herein, we introduce dynamic regulators of industrial microorganism optimization and discuss metabolic flux fine control by dynamic regulators in response to metabolites or extracellular stimuli, robust production systems, and auto-induction systems using quorum sensing.

Aging Research Using Mouse Models

PubMed Central

Ackert-Bicknell, Cheryl L.; Anderson, Laura; Sheehan, Susan; Hill, Warren G.; Chang, Bo; Churchill, Gary A.; Chesler, Elissa J.; Korstanje, Ron; Peters, Luanne L.

2015-01-01

Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in “health-span”, or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research. Here, we describe a pipeline of phenotypic assays for assessing mouse models of aging. This pipeline includes behavior/cognition testing, body composition analysis, and tests of kidney function, hematopoiesis, immune function and physical parameters. We also describe study design methods for assessing lifespan and health-span, and other important considerations when conducting aging research in the laboratory mouse. The tools and assays provided can assist researchers with understanding the correlative relationships between age-associated phenotypes and, ultimately, the role of specific genes in the aging process. PMID:26069080

Secondary metabolites produced by the marine bacterium Halobacillus salinus that inhibit quorum sensing-controlled phenotypes in gram-negative bacteria.

PubMed

Teasdale, Margaret E; Liu, Jiayuan; Wallace, Joselynn; Akhlaghi, Fatemeh; Rowley, David C

2009-02-01

Certain bacteria use cell-to-cell chemical communication to coordinate community-wide phenotypic expression, including swarming motility, antibiotic biosynthesis, and biofilm production. Here we present a marine gram-positive bacterium that secretes secondary metabolites capable of quenching quorum sensing-controlled behaviors in several gram-negative reporter strains. Isolate C42, a Halobacillus salinus strain obtained from a sea grass sample, inhibits bioluminescence production by Vibrio harveyi in cocultivation experiments. With the use of bioassay-guided fractionation, two phenethylamide metabolites were identified as the active agents. The compounds additionally inhibit quorum sensing-regulated violacein biosynthesis by Chromobacterium violaceum CV026 and green fluorescent protein production by Escherichia coli JB525. Bacterial growth was unaffected at concentrations below 200 microg/ml. Evidence is presented that these nontoxic metabolites may act as antagonists of bacterial quorum sensing by competing with N-acyl homoserine lactones for receptor binding.

Dubowitz syndrome: review of 141 cases including 36 previously unreported patients.

PubMed

Tsukahara, M; Opitz, J M

1996-05-03

We review clinical information on 141 individuals with Dubowitz syndrome, 105 reported since 1965, and 36 previously unreported. We define the Dubowitz syndrome phenotype on the basis of clinical descriptions. The facial appearance is characteristic and present in most patients with Dubowitz syndrome. The phenotypic spectrum is quite variable and ranges from normal growth and head circumference with mild psychomotor retardation and lack of eczema to a condition of severe growth retardation, mental retardation, microcephaly, and eczema. Overall, the condition may involve the cutaneous, ocular, dental, digestive, musculoskeletal, urogenital, cardiovascular, neurological, hematological, and immune systems. Characteristic behavior patterns which have not been cited previously are present in our cases; most patients are hyperactive, shy, hate crowds, and like music, rhythm, and vibrations from music speakers, tape recorders, or transmitted through floors. Dubowitz syndrome is an autosomal recessive disorder with possibly increased frequency of parental consanguinity. Heterogeneity cannot be excluded at this time.

What is abnormal about addiction-related attentional biases?

PubMed

Anderson, Brian A

2016-10-01

The phenotype of addiction includes prominent attentional biases for drug cues, which play a role in motivating drug-seeking behavior and contribute to relapse. In a separate line of research, arbitrary stimuli have been shown to automatically capture attention when previously associated with reward in non-clinical samples. Here, I argue that these two attentional biases reflect the same cognitive process. I outline five characteristics that exemplify attentional biases for drug cues: resistant to conflicting goals, robust to extinction, linked to dorsal striatal dopamine and to biases in approach behavior, and can distinguish between individuals with and without a history of drug dependence. I then go on to describe how attentional biases for arbitrary reward-associated stimuli share all of these features, and conclude by arguing that the attentional components of addiction reflect a normal cognitive process that promotes reward-seeking behavior. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Representation matters: quantitative behavioral variation in wild worm strains

NASA Astrophysics Data System (ADS)

Brown, Andre

Natural genetic variation in populations is the basis of genome-wide association studies, an approach that has been applied in large studies of humans to study the genetic architecture of complex traits including disease risk. Of course, the traits you choose to measure determine which associated genes you discover (or miss). In large-scale human studies, the measured traits are usually taken as a given during the association step because they are expensive to collect and standardize. Working with the nematode worm C. elegans, we do not have the same constraints. In this talk I will describe how large-scale imaging of worm behavior allows us to develop alternative representations of behavior that vary differently across wild populations. The alternative representations yield novel traits that can be used for genome-wide association studies and may reveal basic properties of the genotype-phenotype map that are obscured if only a small set of fixed traits are used.

Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model

PubMed Central

Sidhu, Harpreet; Dansie, Lorraine E.; Hickmott, Peter W.

2014-01-01

Fmr1 knock-out (ko) mice display key features of fragile X syndrome (FXS), including delayed dendritic spine maturation and FXS-associated behaviors, such as poor socialization, obsessive-compulsive behavior, and hyperactivity. Here we provide conclusive evidence that matrix metalloproteinase-9 (MMP-9) is necessary to the development of FXS-associated defects in Fmr1 ko mice. Genetic disruption of Mmp-9 rescued key aspects of Fmr1 deficiency, including dendritic spine abnormalities, abnormal mGluR5-dependent LTD, as well as aberrant behaviors in open field and social novelty tests. Remarkably, MMP-9 deficiency also corrected non-neural features of Fmr1 deficiency—specifically macroorchidism—indicating that MMP-9 dysregulation contributes to FXS-associated abnormalities outside the CNS. Further, MMP-9 deficiency suppressed elevations of Akt, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E phosphorylation seen in Fmr1 ko mice, which are also associated with other autistic spectrum disorders. These findings establish that MMP-9 is critical to the mechanisms responsible for neural and non-neural aspects of the FXS phenotype. PMID:25057190

Why We Should Study the Broader Autism Phenotype in Typically Developing Populations

ERIC Educational Resources Information Center

Landry, Oriane; Chouinard, Philippe A.

2016-01-01

The broader autism phenotype (BAP) is a term applied to individuals with personality and cognitive traits that are similar to but milder than those observed in autism spectrum disorder (ASD). Subtle autistic traits in the core diagnostic domains of social communication and rigid behavior were described in family members of people with an ASD even…

Honing in on the Social Phenotype in Williams Syndrome Using Multiple Measures and Multiple Raters

ERIC Educational Resources Information Center

Klein-Tasman, Bonita P.; Li-Barber, Kirsten T.; Magargee, Erin T.

2011-01-01

The behavioral phenotype of Williams syndrome (WS) is characterized by difficulties with establishment and maintenance of friendships despite high levels of interest in social interaction. Here, parents and teachers rated 84 children with WS ages 4-16 years using two commonly-used measures assessing aspects of social functioning: the Social Skills…

Differences in Spatio-Temporal Behavior of Zebrafish in the Open Tank Paradigm after a Short-Period Confinement into Dark and Bright Environments

PubMed Central

Rosemberg, Denis B.; Rico, Eduardo P.; Mussulini, Ben Hur M.; Piato, Ângelo L.; Calcagnotto, Maria E.; Bonan, Carla D.; Dias, Renato D.; Blaser, Rachel E.; Souza, Diogo O.; de Oliveira, Diogo L.

2011-01-01

The open tank paradigm, also known as novel tank diving test, is a protocol used to evaluate the zebrafish behavior. Several characteristics have been described for this species, including scototaxis, which is the natural preference for dark environments in detriment of bright ones. However, there is no evidence regarding the influence of “natural stimuli” in zebrafish subjected to novelty-based paradigms. In this report, we evaluated the spatio-temporal exploratory activity of the short-fin zebrafish phenotype in the open tank after a short-period confinement into dark/bright environments. A total of 44 animals were individually confined during a 10-min single session into one of three environments: black-painted, white-painted, and transparent cylinders (dark, bright, and transparent groups). Fish were further subjected to the novel tank test and their exploratory profile was recorded during a 15-min trial. The results demonstrated that zebrafish increased their vertical exploratory activity during the first 6-min, where the bright group spent more time and travelled a higher distance in the top area. Interestingly, all behavioral parameters measured for the dark group were similar to the transparent one. These data were confirmed by automated analysis of track and occupancy plots and also demonstrated that zebrafish display a classical homebase formation in the bottom area of the tank. A detailed spatio-temporal study of zebrafish exploratory behavior and the construction of representative ethograms showed that the experimental groups presented significant differences in the first 3-min vs. last 3-min of test. Although the main factors involved in these behavioral responses still remain ambiguous and require further investigation, the current report describes an alternative methodological approach for assessing the zebrafish behavior after a forced exposure to different environments. Additionally, the analysis of ethologically-relevant patterns across time could be a potential phenotyping tool to evaluate the zebrafish exploratory profile in the open tank task. PMID:21559304

Neurochemical, behavioral and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice

PubMed Central

Fox, Meredith A.; Jensen, Catherine L.; French, Helen T.; Stein, Alison R.; Huang, Su-Jan; Tolliver, Teresa J.; Murphy, Dennis L.

2008-01-01

Rationale Serotonin transporter (SERT) knockout (−/−) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life. Objectives To examine the effects of increases in serotonin following administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wildtype (+/+), heterozygous (+/−) and −/− mice. Results 5-HTP increased serotonin in all five brain areas examined, with ~2–5-fold increases in SERT +/+ and +/− mice, and greater 4.5–11.7-fold increases in SERT −/− mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT −/− mice, with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT −/− mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT −/− mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT +/+ and +/− mice, with no effect in SERT −/− mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT −/− mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT +/− and −/− mice. Conclusions These studies demonstrate that SERT −/− mice have exaggerated neurochemical, behavioral and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT −/− mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice. PMID:18712364

Behavioral Screening for Toxicology | Science Inventory | US ...

EPA Pesticide Factsheets

Screening for behavioral toxicity, or neurotoxicity, has been in use for decades; however, only in the past 20 years has this become a standard practice in toxicology. Current screening batteries, such as the functional observational battery (FOB), are derived from protocols used in pharmacology, toxicology, and psychology. Although there is a range of protocols in use today, all focus on detailed observations and specific tests of reflexes and responses. Several neurological functions are typically assessed, including autonomic, neuromuscular, and sensory, as well as levels of activity and excitability. The tests have been shown to be valid in detecting expected effects of known neurotoxicants, and reliable and reproducible whn compared across laboratories. Regardless of the specific protocol used, proper conduct and statistical analyses of the data are critical. Interpretation is based on the information from individual end points as well as the profile, or pattern, of effects observed. As long as continual refinements are made, behavioral screening methods will continue to be important tools with which to protect human health in the future.autonomic function; behavior; behavioral phenotypes; behavioral toxicity; excitability; functional observational battery ; motor activity; mouse; neuromuscular function; positive controls; rat; screening battery ; sensory function Screening for behavioral toxicity, or neurotoxicity, has been in use for decades; how

Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

PubMed

Truong, Dongnhu T; Rendall, Amanda R; Castelluccio, Brian C; Eigsti, Inge-Marie; Fitch, R Holly

2015-12-01

Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder. (c) 2015 APA, all rights reserved).

Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters

PubMed Central

Carr, Brian I.; Giannini, Edoardo G.; Farinati, Fabio; Ciccarese, Francesca; Rapaccini, Gian Ludovico; Marco, Maria Di; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

2014-01-01

Background Previous work has shown that 2 general processes contribute to hepatocellular cancer (HCC) prognosis. They are: a. liver damage, monitored by indices such as blood bilirubin, prothrombin time and AST; as well as b. tumor biology, monitored by indices such as tumor size, tumor number, presence of PVT and blood AFP levels. These 2 processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied Network Phenotyping Strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Aims To validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Methods Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory based approach, which compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Results Without reference to the actual tumor sizes, patients were classified by NPS into 2 subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-Platelets relationship. These trends were combined with patient age, gender and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual scan data) that patients in L phenotype group had 1.5x larger mean tumor masses relative to S, p=6×10−16. Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7 × longer survival compared to L-phenotype. NPS integrated the liver, tumor and basic demographic factors. Cirrhosis associated thrombocytopenia was typical for smaller S-tumors. In L-tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. Summary NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient. PMID:25023357

Serotonin at the Nexus of Impulsivity and Cue Reactivity in Cocaine Addiction

PubMed Central

Cunningham, Kathryn A.; Anastasio, Noelle C.

2014-01-01

Cocaine abuse and addiction remain great challenges on the public health agendas in the U.S. and the world. Increasingly sophisticated perspectives on addiction to cocaine and other drugs of abuse have evolved with concerted research efforts over the last 30 years. Relapse remains a particularly powerful clinical problem as, even upon termination of drug use and initiation of abstinence, the recidivism rates can be very high. The cycling course of cocaine intake, abstinence and relapse is tied to a multitude of behavioral and cognitive processes including impulsivity (a predisposition toward rapid unplanned reactions to stimuli without regard to the negative consequences), and cocaine cue reactivity (responsivity to cocaine-associated stimuli) cited as two key phenotypes that contribute to relapse vulnerability even years into recovery. Preclinical studies suggest that serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in key neural circuits may contribute to these interlocked phenotypes well as the altered neurobiological states evoked by cocaine that precipitate relapse events. As such, 5-HT is an important target in the quest to to understand the neurobiology of relapse-predictive phenotypes, to successfully treat this complex disorder and improve diagnostic and prognostic capabilities. This review emphasizes the role of 5-HT and its receptor proteins in key addiction phenotypes and the implications of current findings to the future of therapeutics in addiction. PMID:23850573

Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy.

PubMed

Polackwich, A S; Shoskes, D A

2016-06-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH Category III Prostatitis is a highly prevalent syndrome with significant impact on quality of life. As a heterogeneous syndrome, there exists no 'one size fits all' therapy with level 1 evidence to guide therapy. This often leads to a nihilistic approach to patients and clinical outcomes are poor. In this review, we examine the evidence for CP/CPPS therapies and discuss our technique of clinical phenotyping combined with multimodal therapy. Review of Medline articles with terms 'non-bacterial prostatitis', 'abacterial prostatitis' and 'chronic pelvic pain syndrome'. Many individual therapies have been evaluated in the treatment of CP/CPPS; antibiotics, anti-inflammatory medications (including bioflavonoids), neuromodulators, alpha blockers, pelvic floor physical therapy and cognitive behavior therapy. Each of these has been found to have varying success in alleviating symptoms. UPOINT is a system of clinical phenotyping for CP/CPPS patients that has 6 defined domains, which guide multimodal therapy. It has been validated to correlate with symptom burden and therapy guided by UPOINT leads to significant symptom improvement in 75-84% of patients based on three independent studies. CP/CPPS is a heterogeneous condition and, much like with prostate cancer, optimal therapy can only be achieved by classifying patients into clinically meaningful phenotypic groups (much like TNM) and letting the phenotype drive therapy.

Genetic Psychophysiology: advances, problems, and future directions

PubMed Central

Anokhin, Andrey P.

2014-01-01

This paper presents an overview of historical advances and the current state of genetic psychophysiology, a rapidly developing interdisciplinary research linking genetics, brain, and human behavior, discusses methodological problems, and outlines future directions of research. The main goals of genetic psychophysiology are to elucidate the neural pathways and mechanisms mediating genetic influences on cognition and emotion, identify intermediate brain-based phenotypes for psychopathology, and provide a functional characterization of genes being discovered by large association studies of behavioral phenotypes. Since the initiation of this neurogenetic approach to human individual differences in the 1970s, numerous twin and family studies have provided strong evidence for heritability of diverse aspects of brain function including resting-state brain oscillations, functional connectivity, and event-related neural activity in a variety of cognitive and emotion processing tasks, as well as peripheral psychophysiological responses. These data indicate large differences in the presence and strength of genetic influences across measures and domains, permitting the selection of heritable characteristics for gene finding studies. More recently, candidate gene association studies began to implicate specific genetic variants in different aspects of neurocognition. However, great caution is needed in pursuing this line of research due to its demonstrated proneness to generate false-positive findings. Recent developments in methods for physiological signal analysis, hemodynamic imaging, and genomic technologies offer new exciting opportunities for the investigation of the interplay between genetic and environmental factors in the development of individual differences in behavior, both normal and abnormal. PMID:24739435

In silico molecular comparisons of C. elegans and mammalian pharmacology identify distinct targets that regulate feeding.

PubMed

Lemieux, George A; Keiser, Michael J; Sassano, Maria F; Laggner, Christian; Mayer, Fahima; Bainton, Roland J; Werb, Zena; Roth, Bryan L; Shoichet, Brian K; Ashrafi, Kaveh

2013-11-01

Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.

How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research.

PubMed

Wacker, Jan; Mueller, Erik M; Hennig, Jürgen; Stemmler, Gerhard

2012-02-01

The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.

A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females.

PubMed

Ekşioğlu, Yaman Z; Pong, Amanda W; Takeoka, Masanori

2011-05-01

ARX, the aristaless-related homeobox gene, is implicated in cerebral, testicular, and pancreatic development. ARX mutations are associated with various forms of epilepsy, developmental delay, and ambiguous genitalia in humans. A mouse model that recapitulates X-linked lissencephaly with ambiguous genitalia (XLAG) is far from elucidating the substrate for phenotypes that different ARX mutations cause. Moreover, despite phenotypic pleomorphism associated with X-linked dominant ARX mutations, heterozygous female carriers have not been thoroughly studied. Reviewing records of patients with ARX mutations, infantile epilepsies, and psychomotor retardation, we analyzed a family harboring a novel ARX mutation with different phenotypes in males and females, including Ohtahara syndrome. Children's Hospital Boston patient records were retrospectively screened for patients with infantile epileptic encephalopathies who underwent ARX sequencing based on clinical suspicion. Identified families were analyzed for genetic and neuropsychiatric phenomena. The proband was a male with Ohtahara syndrome, ambiguous genitalia, psychomotor delay, and central nervous system dysgenesis due to a novel ARX mutation in exon 5, causing a frameshift in the aristaless domain. Heterozygous females demonstrated neurocognitive/psychiatric phenomena including learning difficulties, anxiety, depression, and schizophrenia. This is the first reported case of Ohtahara syndrome with abnormal genital and psychomotor development in the setting of this novel ARX mutation in exon 5. Based on the unique phenotype of the proband and on the presence of heterozygous females with neurocognitive/psychiatric ailments, this study describes the potential roles for ARX mutations in epilepsy and neuropsychiatric disease, underscoring the importance of ARX in interneuron development, cerebral electrical activity, cognition, and behavior. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

PubMed Central

Derrien, Thomas; Axelsson, Erik; Rosengren Pielberg, Gerli; Sigurdsson, Snaevar; Fall, Tove; Seppälä, Eija H.; Hansen, Mark S. T.; Lawley, Cindy T.; Karlsson, Elinor K.; Bannasch, Danika; Vilà, Carles; Lohi, Hannes; Galibert, Francis; Fredholm, Merete; Häggström, Jens; Hedhammar, Åke; André, Catherine; Lindblad-Toh, Kerstin; Hitte, Christophe; Webster, Matthew T.

2011-01-01

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease. PMID:22022279

Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

PubMed

Vaysse, Amaury; Ratnakumar, Abhirami; Derrien, Thomas; Axelsson, Erik; Rosengren Pielberg, Gerli; Sigurdsson, Snaevar; Fall, Tove; Seppälä, Eija H; Hansen, Mark S T; Lawley, Cindy T; Karlsson, Elinor K; Bannasch, Danika; Vilà, Carles; Lohi, Hannes; Galibert, Francis; Fredholm, Merete; Häggström, Jens; Hedhammar, Ake; André, Catherine; Lindblad-Toh, Kerstin; Hitte, Christophe; Webster, Matthew T

2011-10-01

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

BcsZ inhibits biofilm phenotypes and promotes virulence by blocking cellulose production in Salmonella enterica serovar Typhimurium.

PubMed

Ahmad, Irfan; Rouf, Syed Fazle; Sun, Lei; Cimdins, Annika; Shafeeq, Sulman; Le Guyon, Soazig; Schottkowski, Marco; Rhen, Mikael; Römling, Ute

2016-10-19

Cellulose, a 1,4 beta-glucan polysaccharide, is produced by a variety of organisms including bacteria. Although the production of cellulose has a high biological, ecological and economical impact, regulatory mechanisms of cellulose biosynthesis are mostly unknown. Family eight cellulases are regularly associated with cellulose biosynthesis operons in bacteria; however, their function is poorly characterized. In this study, we analysed the role of the cellulase BcsZ encoded by the bcsABZC cellulose biosynthesis operon of Salmonella enterica serovar Typhimurium (S. Typhimurium) in biofilm related behavior. We also investigated the involvement of BcsZ in pathogenesis of S. Typhimurium including a murine typhoid fever infection model. In S. Typhimurium, cellulase BcsZ with a putative periplasmic location negatively regulates cellulose biosynthesis. Moreover, as assessed with a non-polar mutant, BcsZ affects cellulose-associated phenotypes such as the rdar biofilm morphotype, cell clumping, biofilm formation, pellicle formation and flagella-dependent motility. Strikingly, although upregulation of cellulose biosynthesis was not observed on agar plate medium at 37 °C, BcsZ is required for efficient pathogen-host interaction. Key virulence phenotypes of S. Typhimurium such as invasion of epithelial cells and proliferation in macrophages were positively regulated by BcsZ. Further on, a bcsZ mutant was outcompeted by the wild type in organ colonization in the murine typhoid fever infection model. Selected phenotypes were relieved upon deletion of the cellulose synthase BcsA and/or the central biofilm activator CsgD. Although the protein scaffold has an additional physiological role, our findings indicate that the catalytic activity of BcsZ effectively downregulates CsgD activated cellulose biosynthesis. Repression of cellulose production by BcsZ subsequently enables Salmonella to efficiently colonize the host.

A Reverse-Translational Approach to Bipolar Disorder: Rodent and human studies in the Behavioral Pattern Monitor

PubMed Central

Young, Jared W.; Minassian, Arpi; Paulus, Martin P.; Geyer, Mark A.; Perry, William

2007-01-01

Mania is the defining feature of Bipolar Disorder (BD). There has been limited progress in understanding the neurobiological underpinnings of BD mania and developing novel therapeutics, in part due to a paucity of relevant animal models with translational potential. Hyperactivity is a cardinal symptom of mania, traditionally measured in humans using observer-rated scales. Multivariate assessment of unconditioned locomotor behavior using the rat Behavioral Pattern Monitor (BPM) developed in our laboratory has shown that hyperactivity includes complex multifaceted behaviors. The BPM has been used to demonstrate differential effects of drugs on locomotor activity and exploratory behavior in rats. Studies of genetically engineered mice in a mouse BPM have confirmed its utility as a cross-species tool. In a “reverse-translational” approach to this work, we developed the human BPM to characterize motor activity in BD patients. Increased activity, object interactions, and altered locomotor patterns provide multidimensional phenotypes to model in the rodent BPM. This unique approach to modeling BD provides an opportunity to identify the neurobiology underlying BD mania and test novel antimanic agents. PMID:17706782

Impaired Object Recognition but Normal Social Behavior and Ultrasonic Communication in Cofilin1 Mutant Mice

PubMed Central

Sungur, A. Özge; Stemmler, Lea; Wöhr, Markus; Rust, Marco B.

2018-01-01

Autism spectrum disorder (ASD), schizophrenia (SCZ) and intellectual disability (ID) show a remarkable overlap in symptoms, including impairments in cognition, social behavior and communication. Human genetic studies revealed an enrichment of mutations in actin-related genes for these disorders, and some of the strongest candidate genes control actin dynamics. These findings led to the hypotheses: (i) that ASD, SCZ and ID share common disease mechanisms; and (ii) that, at least in a subgroup of affected individuals, defects in the actin cytoskeleton cause or contribute to their pathologies. Cofilin1 emerged as a key regulator of actin dynamics and we previously demonstrated its critical role for synaptic plasticity and associative learning. Notably, recent studies revealed an over-activation of cofilin1 in mutant mice displaying ASD- or SCZ-like behavioral phenotypes, suggesting that dysregulated cofilin1-dependent actin dynamics contribute to their behavioral abnormalities, such as deficits in social behavior. These findings let us hypothesize: (i) that, apart from cognitive impairments, cofilin1 mutants display additional behavioral deficits with relevance to ASD or SCZ; and (ii) that our cofilin1 mutants represent a valuable tool to study the underlying disease mechanisms. To test our hypotheses, we compared social behavior and ultrasonic communication of juvenile mutants to control littermates, and we did not obtain evidence for impaired direct reciprocal social interaction, social approach or social memory. Moreover, concomitant emission of ultrasonic vocalizations was not affected and time-locked to social activity, supporting the notion that ultrasonic vocalizations serve a pro-social communicative function as social contact calls maintaining social proximity. Finally, cofilin1 mutants did not display abnormal repetitive behaviors. Instead, they performed weaker in novel object recognition, thereby demonstrating that cofilin1 is relevant not only for associative learning, but also for “non-matching-to-sample” learning. Here we report the absence of an ASD- or a SCZ-like phenotype in cofilin1 mutants, and we conclude that cofilin1 is relevant specifically for non-social cognition. PMID:29515378

A Gene for an Extended Phenotype

Treesearch

K. Hoover; M. Grove; M. Gardner; D. P. Hughes; J. McNeil; J. Slavicek

2011-01-01

Manipulation of host behavior by parasites and pathogens has been widely observed, but the basis for these behaviors has remained elusive. Gypsy moths infected by a baculovirus climb to the top of trees to die, liquefy, and "rain" virus on the foliage below to infect new hosts. The viral gene that manipulates climbing behavior of the host was identified,...