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Sample records for abnormal behavioral phenotype

  1. The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.

    PubMed

    Curry, Cynthia J; Rosenfeld, Jill A; Grant, Erica; Gripp, Karen W; Anderson, Carol; Aylsworth, Arthur S; Saad, Taha Ben; Chizhikov, Victor V; Dybose, Giedre; Fagerberg, Christina; Falco, Michelle; Fels, Christina; Fichera, Marco; Graakjaer, Jesper; Greco, Donatella; Hair, Jennifer; Hopkins, Elizabeth; Huggins, Marlene; Ladda, Roger; Li, Chumei; Moeschler, John; Nowaczyk, Malgorzata J M; Ozmore, Jillian R; Reitano, Santina; Romano, Corrado; Roos, Laura; Schnur, Rhonda E; Sell, Susan; Suwannarat, Pim; Svaneby, Dea; Szybowska, Marta; Tarnopolsky, Mark; Tervo, Raymond; Tsai, Anne Chun-Hui; Tucker, Megan; Vallee, Stephanie; Wheeler, Ferrin C; Zand, Dina J; Barkovich, A James; Aradhya, Swaroop; Shaffer, Lisa G; Dobyns, William B

    2013-08-01

    Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome. PMID:23813913

  2. Phenotypic abnormalities in long-term surviving cystic fibrosis mice.

    PubMed

    Kent, G; Oliver, M; Foskett, J K; Frndova, H; Durie, P; Forstner, J; Forstner, G G; Riordan, J R; Percy, D; Buchwald, M

    1996-08-01

    Mouse models for cystic fibrosis (CF) with no CFTR function (Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% of Cftr-/- mice survived to 60 d, the majority beyond 100 d. Cftr-/- mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fed Cftr-/- mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives of Cftr-/- mice. PMID:8827771

  3. Association of abnormal plasma bilirubin with aggressive hepatocellular carcinoma phenotype.

    PubMed

    Carr, Brian I; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Ciccarese, Francesca; Ludovico Rapaccini, Gian; Di Marco, Maria; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

    2014-04-01

    Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness. PMID:24787296

  4. Scoliosis and vertebral anomalies: additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement.

    PubMed

    Al-Kateb, Hussam; Khanna, Geetika; Filges, Isabel; Hauser, Natalie; Grange, Dorothy K; Shen, Joseph; Smyser, Christopher D; Kulkarni, Shashikant; Shinawi, Marwan

    2014-05-01

    The typical chromosome 16p11.2 rearrangements are estimated to occur at a frequency of approximately 0.6% of all samples tested clinically and have been identified as a major cause of autism spectrum disorders, developmental delay, behavioral abnormalities, and seizures. Careful examination of patients with these rearrangements revealed association with abnormal head size, obesity, dysmorphism, and congenital abnormalities. In this report, we extend this list of phenotypic abnormalities to include scoliosis and vertebral anomalies. We present detailed characterization of phenotypic and radiological data of 10 new patients, nine with the 16p11.2 deletion and one with the duplication within the coordinates chr16:29,366,195 and 30,306,956 (hg19) with a minimal size of 555 kb. We discuss the phenotypical and radiological findings in our patients and review 5 previously reported patients with 16p11.2 rearrangement and similar skeletal abnormalities. Our data suggest that patients with the recurrent 16p11.2 rearrangement have increased incidence of scoliosis and vertebral anomalies. However, additional studies are required to confirm this observation and to establish the incidence of these anomalies. We discuss the potential implications of our findings on the diagnosis, surveillance and genetic counseling of patients with 16p11.2 rearrangement. PMID:24458548

  5. Behavioral abnormalities in captive nonhuman primates.

    PubMed

    Mallapur, Avanti; Choudhury, B C

    2003-01-01

    In this study, we dealt with 11 species of nonhuman primates across 10 zoos in India. We recorded behavior as instantaneous scans between 9 a.m. and 5 p.m. In the study, we segregated behaviors for analyses into abnormal, undesirable, active, and resting. The 4 types of abnormal behavior exhibited included floating limb, self-biting, self-clasping, and stereotypic pacing. In the study, we recorded 2 types of undesirable behavior: autoerotic stimulation and begging. Langurs and group-housed macaques did not exhibit undesirable behaviors. A male lion-tailed macaque and a male gibbon exhibited begging behavior. autoerotic stimulation and self-biting occurred rarely. Males exhibited higher levels of undesirable behavior than did females. Animals confiscated from touring zoos, circuses, and animal traders exhibited higher levels of abnormal behaviors than did animals reared in larger, recognized zoos. The stump-tailed macaque was the only species to exhibit floating limb, autoerotic stimulation, self-biting, and self-clasping. Our results show that rearing experience and group composition influence the proportions of abnormal behavior exhibited by nonhuman primates in captivity. The history of early social and environmental deprivation in these species of captive nonhuman primates probably is critical in the development of behavioral pathologies. Establishing this will require further research. PMID:14965782

  6. Abnormal behaviors detection using particle motion model

    NASA Astrophysics Data System (ADS)

    Chen, Yutao; Zhang, Hong; Cheng, Feiyang; Yuan, Ding; You, Yuhu

    2015-03-01

    Human abnormal behaviors detection is one of the most challenging tasks in the video surveillance for the public security control. Interaction Energy Potential model is an effective and competitive method published recently to detect abnormal behaviors, but their model of abnormal behaviors is not accurate enough, so it has some limitations. In order to solve this problem, we propose a novel Particle Motion model. Firstly, we extract the foreground to improve the accuracy of interest points detection since the complex background usually degrade the effectiveness of interest points detection largely. Secondly, we detect the interest points using the graphics features. Here, the movement of each human target can be represented by the movements of detected interest points of the target. Then, we track these interest points in videos to record their positions and velocities. In this way, the velocity angles, position angles and distance between each two points can be calculated. Finally, we proposed a Particle Motion model to calculate the eigenvalue of each frame. An adaptive threshold method is proposed to detect abnormal behaviors. Experimental results on the BEHAVE dataset and online videos show that our method could detect fight and robbery events effectively and has a promising performance.

  7. Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism.

    PubMed

    Ellegood, Jacob; Crawley, Jacqueline N

    2015-07-01

    In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on high-resolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery. PMID:26036957

  8. Abnormal Behavior in Relation to Cage Size in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Paulk, H. H.; And Others

    1977-01-01

    Examines the effects of cage size on stereotyped and normal locomotion and on other abnormal behaviors in singly caged animals, whether observed abnormal behaviors tend to co-occur, and if the development of an abnormal behavior repertoire leads to reduction in the number of normal behavior categories. (Author/RK)

  9. Phenotype of two males with abnormal Y chromosomes.

    PubMed

    Mićić, M; Mićić, S; Babić, M; Diklić, V

    1990-05-01

    Two infertile males with sex chromosomal abnormalities and mosaic karyotype, 45,X/46,X,dic(Yq) and 45,X/46,X,ring(Y), had considerably changed physical findings, including tooth sizes and craniofacial dimensions. Spermatogenesis was preserved with abnormal meiotic chromosomal behaviour. Mosaic karyotype and structurally changed Y chromosome in both cases had an influence on physical parameters. Tests were normally developed and spermatogenesis was preserved but depressed in later stages. PMID:2354546

  10. Breakpoint Mapping and Array CGH in Translocations: Comparison of a Phenotypically Normal and an Abnormal Cohort

    PubMed Central

    Baptista, Julia; Mercer, Catherine; Prigmore, Elena; Gribble, Susan M.; Carter, Nigel P.; Maloney, Viv; Thomas, N. Simon; Jacobs, Patricia A.; Crolla, John A.

    2008-01-01

    We report the analyses of breakpoints in 31 phenotypically normal and 14 abnormal carriers of balanced translocations. Our study assesses the differences between balanced translocations in normal carriers and those in abnormal carriers, focusing on the presence of genomic imbalances at the breakpoints or elsewhere in the genome, presence of cryptic chromosome rearrangements, and gene disruption. Our hypothesis is that all four features will be associated with phenotypic abnormalities and absent or much less frequent in a normal population. In the normal cohort, we identified neither genomic imbalances at the breakpoints or elsewhere in the genome nor cryptic chromosome rearrangements. In contrast, we identified candidate disease-causing imbalances in 4/14 abnormal patients. These were three breakpoint associated deletions and three deletions unrelated to the breakpoints. All six de novo deletions originated on the paternally inherited chromosome. Additional complexity was also present in one of these cases. Gene disruption by the breakpoints was present in 16/31 phenotypically normal individuals and in 5/14 phenotypically abnormal patients. Our results show that translocations in phenotypically abnormal patients are molecularly distinct from those in normal individuals: the former are more likely to be associated with genomic imbalances at the breakpoints or elsewhere and with chromosomal complexity, whereas the frequency of gene disruption is similar in both normal and abnormal translocation carriers. PMID:18371933

  11. Abnormal behavior in caged birds kept as pets.

    PubMed

    van Hoek, C S; ten Cate, C

    1998-01-01

    There are a limited number of studies dealing with abnormal behavior in caged birds kept as pets. However, these studies demonstrate the presence of abnormal behavior in both songbirds and parrots. Ethological studies on these birds, as well as studies on domestic and zoo birds, indicate that inappropriate rearing and housing conditions may lead to behavioral abnormalities. Together these data indicate that behavioral abnormalities occur among both wild-caught and domesticated pet birds. The severity and magnitude of these abnormalities is probably underestimated, and there is a need for systematic studies on the nature, origin, variability, species-specificity, and reversibility of behavioral problems in pet birds. Abnormal behavior in caged birds may to some extent be prevented and reduced by environmental enrichment. However, most enrichment studies are anecdotal and not based on a thorough analysis of the behavioral abnormalities, which may lead to measures resulting in a reduction of symptoms rather than the underlying causes. Although it is likely that several of these problems could be reduced by modifying rearing and housing conditions, the current insights into the causal mechanisms underlying abnormal behavior of domesticated and wild-caught pet birds are limited, as are the insights into the possibilities of preventing or curing abnormal behavior. PMID:16363987

  12. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  13. The behavioral phenotype of FMR1 mutations.

    PubMed

    Boyle, Lia; Kaufmann, Walter E

    2010-11-15

    The purpose of this article is to provide an overview of the behavioral phenotype of FMR1 mutations, including fragile X syndrome (FXS) in order to better understand the clinical involvement of individuals affected by mutations in this gene. FXS is associated with a wide range of intellectual and behavioral problems, some relatively mild and others quite severe. FXS is the most common cause of inherited intellectual disability and one of the most prevalent genetic causes of autism spectrum disorder. Learning difficulties, attentional problems, anxiety, aggressive behavior, stereotypies, and mood disorders are also frequent in FXS. Recent studies of children and adults have identified associations between FMR1 premutation and many of the same disorders. We examine the neurobehavioral phenotypes of FXS and FMR1 premutation as they manifest across the lifespan of the individual. PMID:20981777

  14. Three unrelated cases of paracentric inversions of 1p in individuals with abnormal phenotypes

    SciTech Connect

    Estop, A.M.; Karlin, S.M.; Wenger, S.L.; Steele, M.W.; Bansal, V.; Surti, U.; Lin, A.; Levinson, F.

    1994-02-15

    Paracentric inversions, involving a rearrangement within one chromosome arm, are rare. Although carriers of balanced paracentric inversions should theoretically not be at risk for abnormal offspring, such cases have been reported. The authors report on 2 unrelated cases of inherited paracentric inversions of 1p with breakpoints at p32 and p36.1 and p32.3 and p36.22 in individuals with abnormal phenotypes. Another case of 2 abnormal monozygotic twins with a de novo paracentric inversion of 1p with breakpoints at p22 and p34 is presented as well. 21 refs., 2 figs., 1 tab.

  15. Neurobiology of social behavior abnormalities in autism and Williams syndrome.

    PubMed

    Barak, Boaz; Feng, Guoping

    2016-04-26

    Social behavior is a basic behavior mediated by multiple brain regions and neural circuits, and is crucial for the survival and development of animals and humans. Two neuropsychiatric disorders that have prominent social behavior abnormalities are autism spectrum disorders (ASD), which is characterized mainly by hyposociability, and Williams syndrome (WS), whose subjects exhibit hypersociability. Here we review the unique properties of social behavior in ASD and WS, and discuss the major theories in social behavior in the context of these disorders. We conclude with a discussion of the research questions needing further exploration to enhance our understanding of social behavior abnormalities. PMID:27116389

  16. Chronic stress does not further exacerbate the abnormal psychoneuroendocrine phenotype of Cbg-deficient male mice.

    PubMed

    de Medeiros, Gabriela F; Minni, Amandine M; Helbling, Jean-Christophe; Moisan, Marie-Pierre

    2016-08-01

    Chronic stress leads to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis which can constitute a base for pathophysiological consequences. Using mice totally deficient in Corticosteroid binding globulin (CBG), we have previously demonstrated the important role of CBG in eliciting an adequate response to an acute stressor. Here, we have studied its role in chronic stress situations. We have submitted Cbg ko and wild-type (WT) male mice to two different chronic stress paradigms - the unpredictable chronic mild stress and the social defeat. Then, their impact on neuroendocrine function - through corticosterone and CBG measurement - and behavioral responses - via anxiety and despair-like behavioral tests - was evaluated. Both chronic stress paradigms increased the display of despair-like behavior in WT mice, while that from Cbg ko mice - which was already high - was not aggravated. We have also found that control and defeated (stressed) Cbg ko mice show no difference in the social interaction test, while defeated WT mice reduce their interaction time when compared to unstressed WT mice. Interestingly, the same pattern was observed for corticosterone levels, where both chronic stress paradigms lowered the corticosterone levels of WT mice, while those from Cbg ko mice remained low and unaltered. Plasma CBG binding capacity remained unaltered in WT mice regardless of the stress paradigm. Through the use of the Cbg ko mice, which only differs genetically from WT mice by the absence of CBG, we demonstrated that CBG is crucial in modulating the effects of stress on plasma corticosterone levels and consequently on behavior. In conclusion, individuals with CBG deficiency, whether genetically or environmentally-induced, are vulnerable to acute stress but do not have their abnormal psychoneuroendocrine phenotype further affected by chronic stress. PMID:27153522

  17. Freud Was Right. . . about the Origins of Abnormal Behavior

    ERIC Educational Resources Information Center

    Muris, Peter

    2006-01-01

    Freud's psychodynamic theory is predominantly based on case histories of patients who displayed abnormal behavior. From a scientific point of view, Freud's analyses of these cases are unacceptable because the key concepts of his theory cannot be tested empirically. However, in one respect, Freud was totally right: most forms of abnormal behavior…

  18. Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype

    PubMed Central

    Sismani, Carolina; Kitsiou-Tzeli, Sofia; Ioannides, Marios; Christodoulou, Christodoulos; Anastasiadou, Violetta; Stylianidou, Goula; Papadopoulou, Eleftheria; Kanavakis, Emanuel; Kosmaidou-Aravidou, Zoe; Patsalis, Philippos C

    2008-01-01

    Background Carriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of de novo cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six de novo and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all de novo cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype. Results Chromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two de novo (2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a de novo t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a de novo t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution. Conclusion This study investigated both de novo and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on de novo cases. This study provides additional evidence that cryptic

  19. Phenotyping structural abnormalities in mouse embryos using high-resolution episcopic microscopy

    PubMed Central

    Weninger, Wolfgang J.; Geyer, Stefan H.; Martineau, Alexandrine; Galli, Antonella; Adams, David J.; Wilson, Robert; Mohun, Timothy J.

    2014-01-01

    The arrival of simple and reliable methods for 3D imaging of mouse embryos has opened the possibility of analysing normal and abnormal development in a far more systematic and comprehensive manner than has hitherto been possible. This will not only help to extend our understanding of normal tissue and organ development but, by applying the same approach to embryos from genetically modified mouse lines, such imaging studies could also transform our knowledge of gene function in embryogenesis and the aetiology of developmental disorders. The International Mouse Phenotyping Consortium is coordinating efforts to phenotype single gene knockouts covering the entire mouse genome, including characterising developmental defects for those knockout lines that prove to be embryonic lethal. Here, we present a pilot study of 34 such lines, utilising high-resolution episcopic microscopy (HREM) for comprehensive 2D and 3D imaging of homozygous null embryos and their wild-type littermates. We present a simple phenotyping protocol that has been developed to take advantage of the high-resolution images obtained by HREM and that can be used to score tissue and organ abnormalities in a reliable manner. Using this approach with embryos at embryonic day 14.5, we show the wide range of structural abnormalities that are likely to be detected in such studies and the variability in phenotypes between sibling homozygous null embryos. PMID:25256713

  20. Familial Constitutional Rearrangement of Chromosomes 4 & 8: Phenotypically Normal Mother and Abnormal Progeny

    PubMed Central

    Kunwar, Fulesh

    2016-01-01

    Balanced chromosome translocations carriers mostly do not have recognizable phenotypic expression but may have more risk of recurrent spontaneous abortions &/or children with serious birth defects due to unbalanced chromosome complements. Unbalanced chromosomal rearrangements have variable clinical expression and are rare. We present here a case report of three siblings affected with intellectual disability and minor dysmorphic features of face and limbs, born to a non-consanguineous couple in which mother had 5 abortions. The constitutional chromosome analysis revealed balanced translocation t (4;8) in mother and all the three siblings were karyotypically normal. Chromosomal microarray in one of the probands revealed partial monosomy 8pter-p23 and a partial trisomy 4pter-p16. Phenotypic features were recorded in 3 probands using Human Phenotype Ontology terms to query web-based tool Phenomizer. The harmonized description using globally accepted ontology is very important especially in case of rare genetic conditions and the heterogeneous phenotypes which make it even more challenging. The prevalence of sub-microscopic unbalanced translocations may be under-reported due to lesser use of molecular genetic analysis. The familial expression of abnormal phenotypes including intellectual disability make the individuals candidate for molecular genetic analysis and phenotyping to help defer the status of idiopathic mental retardation and identify sub-entity of genetic condition. PMID:27190830

  1. Sb (111) Abnormal Behavior under Ion Etching

    NASA Astrophysics Data System (ADS)

    Smirnov, A. A.; Bozhko, S. I.; Ionov, A. M.; Protasova, S. G.; Chekmazov, S. V.; Kapustin, A. A.

    Due to a strong spin-orbit interaction (SOI), the surface states of Sb (111) are similar to those for topological insulators (TI) Sugawara et al. (2006). The surface states are protected by time-reversal symmetry and energy dispersion is a linear function of momentum. Defects in crystal structure lead to a local break of the surface translational symmetry and can modify surface states. It is the primary reason to study defects of Sb crystal structure and their effect on the surface states dispersion. Etching of the Sb (111) surface using Ar+ ions is a common way to create defects both in a bulk and on the surface of the crystal. Sb (111) ion etching at room temperature reveals anomalous behavior of surface crystal structure. It results in formation of flat terraces of 2 nm in size. Investigation of electronic structure of the etched Sb (111) surface has demonstrated increase of density of states (DOS) at the Fermi level. The results are discussed in terms of local break of conditions of Peierls transition.

  2. Abnormal hemoglobin phenotypes in carriers of mild anemia in Latin America.

    PubMed

    Zamaro, P J A; Bonini-Domingos, C R

    2010-01-01

    We looked for abnormal hemoglobins in blood samples sent for diagnosis of anemia. Identification of the hemoglobins was made using electrophoretic, chromatographic and molecular procedures. The 2020 blood samples were of patients from various regions of Brazil and from some other Latin American countries. Among the abnormal hemoglobins that we found, 3.5% are known to be rare, while 51% had an electrophoretic profile similar to that of Hb S at alkaline pH. Differentiation was possible only by combining electrophoretic and chromatographic methods. Hb Hasharon, an alpha globin chain mutant, was the most frequently found variant hemoglobin; it accounted for 14.3% of the abnormal DNA samples. The other abnormal hemoglobin phenotypes displayed distinct electrophoretic profiles; most of them migrated faster than Hb A. The frequencies of the different abnormal hemoglobin profiles that we found reflect the miscegenation of the Latin American population and indicate the importance of hemoglobin studies using various methods in combination for accurate diagnosis and appropriate counseling of carriers and their families. PMID:20309827

  3. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.

    PubMed

    Hsiao, Elaine Y; McBride, Sara W; Hsien, Sophia; Sharon, Gil; Hyde, Embriette R; McCue, Tyler; Codelli, Julian A; Chow, Janet; Reisman, Sarah E; Petrosino, Joseph F; Patterson, Paul H; Mazmanian, Sarkis K

    2013-12-19

    Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders. PMID:24315484

  4. Personality theory, abnormal psychology, and psychological measurement. A psychological behaviorism.

    PubMed

    Staats, A W

    1993-01-01

    Behaviorism, because it has not had a theory of personality, has been separated from the rest of psychology, unable in large part to draw from or contribute to it. Traditional psychology has not had a theory of personality that says what personality is, how it comes about, or how it functions. An antagonism has resulted that weakens rather than complements each tradition. Psychological behaviorism presents a new type of theory of personality. Derived from experimentation, it is constructed from basic theories of emotion, language, and sensory-motor behavior. It says personality is composed of learned basic behavioral repertoires (BBRs) that affect behavior. Personality measurement instruments are analyzed in terms of the BBRs, beginning the behaviorization of this field and calling for much additional research. These multilevel developments are then basic in psychological behaviorism's theory of abnormal behavior and of clinical treatment. The approach opens many new avenues of empirical and theoretical work. PMID:8439278

  5. Developmental trajectories in cognitive-behavioral phenotypes: Introduction.

    PubMed

    Fisch, Gene S

    2015-06-01

    Developmental trajectories in behavioral phenotypes are important areas for systematic research and have been for more than 30 years. They interweave several important strands related to human growth: that of individuals born with some form of intellectual impairment or disability (ID); second, the genetics associated with intellectual ability and disability; and third, at the behavioral level, the dynamic expression and variability of specific abnormalities as individuals age. ID, and the genetic disorders that produce ID, were often not well-received by earlier societies. While the inheritance of behavior and intellectual ability has probably been observed throughout human history, the systematic investigation of the inheritance of intellectual ability probably begins with Sir Francis Galton, in his treatise Hereditary Genius in 1869. The dynamic features of ID have its roots in late 19th century developmental psychology and early 20th century pediatrics. Alfred Binet, along with his colleague Theodore Simon, created the first methods of formal intelligence testing of children for the French school system. Scores based on the items administered would then be used to distinguish children who were prepared for enrollment in a standard educational program from those who were not. The confluence of these research topics brings us to the subject of our Special Issue. PMID:25959524

  6. Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes

    PubMed Central

    Rosenfeld, Jill A; Traylor, Ryan N; Schaefer, G Bradley; McPherson, Elizabeth W; Ballif, Blake C; Klopocki, Eva; Mundlos, Stefan; Shaffer, Lisa G; Aylsworth, Arthur S

    2012-01-01

    Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a ‘partial' TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. Otherwise, phenotypic features varied among individuals with these microdeletions and microduplications. The recurrent, proximal 1q21.1 microduplications are enriched in our population undergoing genetic testing compared with control populations. Therefore, CNVs in proximal 1q21.1 can be a contributing factor for the development of abnormal phenotypes in some carriers. PMID:22317977

  7. Possible Electromagnetic Effects on Abnormal Animal Behavior Before an Earthquake

    PubMed Central

    Hayakawa, Masashi

    2013-01-01

    Simple Summary Possible electromagnetic effects on abnormal animal behavior before earthquakes. Abstract The former statistical properties summarized by Rikitake (1998) on unusual animal behavior before an earthquake (EQ) have first been presented by using two parameters (epicentral distance (D) of an anomaly and its precursor (or lead) time (T)). Three plots are utilized to characterize the unusual animal behavior; (i) EQ magnitude (M) versus D, (ii) log T versus M, and (iii) occurrence histogram of log T. These plots are compared with the corresponding plots for different seismo-electromagnetic effects (radio emissions in different frequency ranges, seismo-atmospheric and -ionospheric perturbations) extensively obtained during the last 15–20 years. From the results of comparisons in terms of three plots, it is likely that lower frequency (ULF (ultra-low-frequency, f ≤ 1 Hz) and ELF (extremely-low-frequency, f ≤ a few hundreds Hz)) electromagnetic emissions exhibit a very similar temporal evolution with that of abnormal animal behavior. It is also suggested that a quantity of field intensity multiplied by the persistent time (or duration) of noise would play the primary role in abnormal animal behavior before an EQ. PMID:26487307

  8. Effects of a lifestyle modification trial among phenotypically obese metabolically normal and phenotypically obese metabolically abnormal adolescents in comparison with phenotypically normal metabolically obese adolescents.

    PubMed

    Kelishadi, Roya; Hashemipour, Mahin; Sarrafzadegan, Nizal; Mohammadifard, Noushin; Alikhasy, Hasan; Beizaei, Maryam; Sajjadi, Firouzeh; Poursafa, Parinaz; Amin, Zahra; Ghatreh-Samani, Shohreh; Khavarian, Noushin; Siadat, Zahra Dana

    2010-07-01

    This study aimed to assess the effects of a 2-month lifestyle modification trial on cardio-metabolic abnormalities and C-reactive protein (CRP) among obese adolescents with metabolic syndrome [phenotypically obese metabolically abnormal (POMA)] and obese adolescents without a cardio-metabolic disorder [phenotypically obese metabolically normal (POMN)], as well as in normal-weight adolescents with at least one cardio-metabolic disorder [phenotypically normal metabolically obese (PNMO)]. The study comprised 360 adolescents assigned in three groups of equal number of POMN, POMA and PNMO. They were enrolled in a trial consisting of aerobic activity classes, diet and behaviour modification, and were recalled after 6 months. Overall, 94.7% of participants completed the 2-month trial, and 87.3% of them returned after 6 months. The mean CRP was not significantly different between the POMA and PNMO groups, but was higher than in the POMN group. After the trial, body mass index (BMI) and waist circumference (WC) decreased in obese participants, and the mean body fat mass decreased in all groups. At 2 months, the mean total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and CRP decreased in the POMA and PNMO groups. After 2 and 6 months, the decrease in mean TC, LDL-C, TG, CRP and systolic blood pressure was greater in the POMA than in the POMN group. The magnitude of decrease in CRP correlated with that of BMI, WC, fat mass, TG, TC and LDL-C. Lifestyle modification programmes for primordial/primary prevention of chronic diseases would be beneficial at the population level and should not be limited to obese children. PMID:20929499

  9. Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study.

    PubMed

    Dobryakova, Ekaterina; Rocca, Maria Assunta; Valsasina, Paola; Ghezzi, Angelo; Colombo, Bruno; Martinelli, Vittorio; Comi, Giancarlo; DeLuca, John; Filippi, Massimo

    2016-06-01

    The Stroop interference task is a cognitively demanding task of executive control, a cognitive ability that is often impaired in patients with multiple sclerosis (MS). The aim of this study was to compare effective connectivity patterns within a network of brain regions involved in the Stroop task performance between MS patients with three disease clinical phenotypes [relapsing-remitting (RRMS), benign (BMS), and secondary progressive (SPMS)] and healthy subjects. Effective connectivity analysis was performed on Stroop task data using a novel method based on causal Bayes networks. Compared with controls, MS phenotypes were slower at performing the task and had reduced performance accuracy during incongruent trials that required increased cognitive control. MS phenotypes also exhibited connectivity abnormalities reflected as weaker shared connections, presence of extra connections (i.e., connections absent in the HC connectivity pattern), connection reversal, and loss. In SPMS and the BMS groups but not in the RRMS group, extra connections were associated with deficits in the Stroop task performance. In the BMS group, the response time associated with correct responses during the congruent condition showed a positive correlation with the left posterior parietal → dorsal anterior cingulate connection. In the SPMS group, performance accuracy during the congruent condition showed a negative correlation with the right insula → left insula connection. No associations between extra connections and behavioral performance measures were observed in the RRMS group. These results suggest that, depending on the phenotype, patients with MS use different strategies when cognitive control demands are high and rely on different network connections. Hum Brain Mapp, 37:2293-2304, 2016. © 2016 Wiley Periodicals, Inc. PMID:26956182

  10. Spent fuel behavior under abnormal thermal transients during dry storage

    SciTech Connect

    Stahl, D.; Landow, M.P.; Burian, R.J.; Pasupathi, V.

    1986-01-01

    This study was performed to determine the effects of abnormally high temperatures on spent fuel behavior. Prior to testing, calculations using the CIRFI3 code were used to determine the steady-state fuel and cask component temperatures. The TRUMP code was used to determine transient heating rates under postulated abnormal events during which convection cooling of the cask surfaces was obstructed by a debris bed covering the cask. The peak rate of temperature rise during the first 6 h was calculated to be about 15/sup 0/C/h, followed by a rate of about 1/sup 0/C/h. A Turkey Point spent fuel rod segment was heated to approx. 800/sup 0/C. The segment deformed uniformly with an average strain of 17% at failure and a local strain of 60%. Pretest characterization of the spent fuel consisted of visual examination, profilometry, eddy-current examination, gamma scanning, fission gas collection, void volume measurement, fission gas analysis, hydrogen analysis of the cladding, burnup analysis, cladding metallography, and fuel ceramography. Post-test characterization showed that the failure was a pinhole cladding breach. The results of the tests showed that spent fuel temperatures in excess of 700/sup 0/C are required to produce a cladding breach in fuel rods pressurized to 500 psing (3.45 MPa) under postulated abnormal thermal transient cask conditions. The pinhole cladding breach that developed would be too small to compromise the confinement of spent fuel particles during an abnormal event or after normal cooling conditions are restored. This behavior is similar to that found in other slow ramp tests with irradiated and nonirradiated rod sections and nonirradiated whole rods under conditions that bracketed postulated abnormal heating rates. This similarity is attributed to annealing of the irradiation-strengthened Zircaloy cladding during heating. In both cases, the failure was a benign, ductile pinhole rupture.

  11. Autism-related behavioral abnormalities in synapsin knockout mice

    PubMed Central

    Greco, Barbara; Managò, Francesca; Tucci, Valter; Kao, Hung-Teh; Valtorta, Flavia; Benfenati, Fabio

    2013-01-01

    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. PMID:23280234

  12. Genomic imprinting as a probable explanation for variable intrafamilial phenotypic expression of an unusual chromosome 3 abnormality

    SciTech Connect

    Fryburg, J.S.; Shashi, V.; Kelly, T.E.

    1994-09-01

    We present a 4 generation family in which an abnormal chromosome 3 with dup(3)(q25) segregated from great-grandmother to grandmother to son without phenotypic effect. The son`s 2 daughters have dysmorphic features, mild developmental delays and congenital heart disease. Both girls have the abnormal chr. 3 but are the only family members with the abnormality to have phenotypic effects. An unaffected son of the father has normal chromosomes. FISH with whole chromosome paints for chromosomes 1, 2, 6, 7, 8, 14, 18, and 22 excluded these as the origin of the extra material. Chromosome 3-specific paint revealed a uniform pattern, suggesting that the extra material is from chromosome 3. Comparative genomic hybridization and DNA studies are pending. Possible explanations for the discordance in phenotypes between the 4th generation offspring and the first 3 generations include: an undetected rearrangement in the previous generations that is unbalanced in the two affected individuals; the chromosome abnormality may be a benign variant and unrelated to the phenotype; or, most likely, genomic imprinting. Genomic imprinting is suggested by the observation that a phenotypic effect was only seen after the chromosome was inherited from the father. The mothers in the first two generations appear to have passed the abnormal chr. 3 on without effect. This is an opportunity to delineate a region of the human genome affected by paternal imprinting.

  13. FISH Mapping of De Novo Apparently Balanced Chromosome Rearrangements Identifies Characteristics Associated with Phenotypic Abnormality

    PubMed Central

    Fantes, J.A.; Boland, E.; Ramsay, J.; Donnai, D.; Splitt, M.; Goodship, J.A.; Stewart, H.; Whiteford, M.; Gautier, P.; Harewood, L.; Holloway, S.; Sharkey, F.; Maher, E.; van Heyningen, V.; Clayton-Smith, J.; Fitzpatrick, D.R.; Black, G.C.M.

    2008-01-01

    We report fluorescence in situ hybridization (FISH) mapping of 152, mostly de novo, apparently balanced chromosomal rearrangement (ABCR) breakpoints in 76 individuals, 30 of whom had no obvious phenotypic abnormality (control group) and 46 of whom had an associated disease (case group). The aim of this study was to identify breakpoint characteristics that could discriminate between these groups and which might be of predictive value in de novo ABCR (DN-ABCR) cases detected antenatally. We found no difference in the proportion of breakpoints that interrupted a gene, although in three cases, direct interruption or deletion of known autosomal-dominant or X-linked recessive Mendelian disease genes was diagnostic. The only significant predictor of phenotypic abnormality in the group as a whole was the localization of one or both breakpoints to an R-positive (G-negative) band with estimated predictive values of 0.69 (95% CL 0.54–0.81) and 0.90 (95% CL 0.60–0.98), respectively. R-positive bands are known to contain more genes and have a higher guanine-cytosine (GC) content than do G-positive (R-negative) bands; however, whether a gene was interrupted by the breakpoint or the GC content in the 200kB around the breakpoint had no discriminant ability. Our results suggest that the large-scale genomic context of the breakpoint has prognostic utility and that the pathological mechanism of mapping to an R-band cannot be accounted for by direct gene inactivation. PMID:18374296

  14. Possible Electromagnetic Effects on Abnormal Animal Behavior Before an Earthquake.

    PubMed

    Hayakawa, Masashi

    2013-01-01

    The former statistical properties summarized by Rikitake (1998) on unusual animal behavior before an earthquake (EQ) have first been presented by using two parameters (epicentral distance (D) of an anomaly and its precursor (or lead) time (T)). Three plots are utilized to characterize the unusual animal behavior; (i) EQ magnitude (M) versus D, (ii) log T versus M, and (iii) occurrence histogram of log T. These plots are compared with the corresponding plots for different seismo-electromagnetic effects (radio emissions in different frequency ranges, seismo-atmospheric and -ionospheric perturbations) extensively obtained during the last 15-20 years. From the results of comparisons in terms of three plots, it is likely that lower frequency (ULF (ultra-low-frequency, f ≤ 1 Hz) and ELF (extremely-low-frequency, f ≤ a few hundreds Hz)) electromagnetic emissions exhibit a very similar temporal evolution with that of abnormal animal behavior. It is also suggested that a quantity of field intensity multiplied by the persistent time (or duration) of noise would play the primary role in abnormal animal behavior before an EQ. PMID:26487307

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

    SciTech Connect

    Brunner, H.G. ); Nelen, M.; Ropers, H.H.; van Oost, B.A. )

    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 complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.

  16. Behavioral abnormalities in mice lacking mesenchyme-specific Pten.

    PubMed

    Borniger, Jeremy C; Cissé, Yasmine M; Cantemir-Stone, Carmen Z; Bolon, Brad; Nelson, Randy J; Marsh, Clay B

    2016-05-01

    Phosphatase and tensin homolog (Pten) is a negative regulator of cell proliferation and growth. Using a Cre-recombinase approach with Lox sequences flanking the fibroblast-specific protein 1 (Fsp1 aka S100A4; a mesenchymal marker), we probed sites of expression using a β-galactosidase Rosa26(LoxP) reporter allele; the transgene driving deletion of Pten (exons 4-5) was found throughout the brain parenchyma and pituitary, suggesting that deletion of Pten in Fsp1-positive cells may influence behavior. Because CNS-specific deletion of Pten influences social and anxiety-like behaviors and S100A4 is expressed in astrocytes, we predicted that loss of Pten in Fsp1-expressing cells would result in deficits in social interaction and increased anxiety. We further predicted that environmental enrichment would compensate for genetic deficits in these behaviors. We conducted a battery of behavioral assays on Fsp1-Cre;Pten(LoxP/LoxP) male and female homozygous knockouts (Pten(-/-)) and compared their behavior to Pten(LoxP/LoxP) (Pten(+/+)) conspecifics. Despite extensive physical differences (including reduced hippocampal size) and deficits in sensorimotor function, Pten(-/-) mice behaved remarkably similar to control mice on nearly all behavioral tasks. These results suggest that the social and anxiety-like phenotypes observed in CNS-specific Pten(-/-) mice may depend on neuronal Pten, as lack of Pten in Fsp1-expressing cells of the CNS had little effect on these behaviors. PMID:26876012

  17. Towards a Behavioral Phenotype for Rett Syndrome.

    ERIC Educational Resources Information Center

    Mount, Rebecca H.; Hastings, Richard P.; Reilly, Sheena; Cass, Hilary; Charman, Tony

    2003-01-01

    A study compared 143 girls (ages 6-14) with Rett syndrome with 85 girls with severe mental retardation on the Developmental Behavior Checklist. Girls with Rett syndrome presented more "autistic relating" and fewer antisocial behaviors. When compared to children with autism, they did not present with classic autistic behavioral features. (Contains…

  18. Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

    PubMed Central

    Rosenfeld, Jill A; Stephens, Lindsey E; Coppinger, Justine; Ballif, Blake C; Hoo, Joe J; French, Beatrice N; Banks, Valerie C; Smith, Wendy E; Manchester, David; Tsai, Anne Chun-Hui; Merrion, Katrina; Mendoza-Londono, Roberto; Dupuis, Lucie; Schultz, Roger; Torchia, Beth; Sahoo, Trilochan; Bejjani, Bassem; Weaver, David D; Shaffer, Lisa G

    2011-01-01

    Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader–Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4–BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3–BP4 interval and an additional four individuals with deletions of the BP3–BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3–BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3–BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3–BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals. PMID:21248749

  19. Abnormal magnetization behaviors in Sm-Ni-Fe-Cu alloys

    NASA Astrophysics Data System (ADS)

    Yang, W. Y.; Zhang, Y. F.; Zhao, H.; Chen, G. F.; Zhang, Y.; Du, H. L.; Liu, S. Q.; Wang, C. S.; Han, J. Z.; Yang, Y. C.; Yang, J. B.

    2016-06-01

    The magnetization behaviors in Sm-Ni-Fe-Cu alloys at low temperatures have been investigated. It was found that the hysteresis loops show wasp-waisted character at low temperatures, which has been proved to be related to the existence of multi-phases, the Fe/Ni soft magnetic phases and the CaCu5-type hard magnetic phase. A smooth-jump behavior of the magnetization is observed at T>5 K, whereas a step-like magnetization process appears at T<5 K. The CaCu5-type phase is responsible for such abnormal magnetization behavior. The magnetic moment reversal model with thermal activation is used to explain the relation of the critical magnetic field (Hcm) to the temperature (T>5 K). The reversal of the moment direction has to cross over an energy barrier of about 6.6×10-15 erg. The step-like jumps of the magnetization below 5 K is proposed to be resulted from a sharp increase of the sample temperature under the heat released by the irreversible domain wall motion.

  20. Behavioral phenotypes of genetic mouse models of autism

    PubMed Central

    Kazdoba, T. M.; Leach, P. T.; Crawley, J. N.

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. PMID:26403076

  1. Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature.

    PubMed

    Kozma, C

    2001-01-15

    Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid (VPA). It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies, and central nervous system dysfunction. In this study, two siblings who were exposed to monotherapy with VPA are described with documentation of long-term follow up. Both children had craniofacial findings, multiple systemic and orthopedic abnormalities, an overgrowth pattern, and developmental deficits. The literature from 1978-2000 is reviewed. A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified. The clinical manifestations of FVS encompass a wide spectrum of abnormalities including consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth. The facial appearance is characterized by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities. Less frequently encountered abnormalities included brain, eye, kidney, and hearing defects. Neural tube defects were seen in 3% of the sample. Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation. Although 15% of patients had growth retardation, an overgrowth pattern was seen in 9%. The data from this comprehensive review especially the developmental outcome should be added to the teratogenic risk, that arises in association with the use of VPA during pregnancy. PMID:11223853

  2. Behavioral idiosyncrasy reveals genetic control of phenotypic variability

    PubMed Central

    Ayroles, Julien F.; Buchanan, Sean M.; O’Leary, Chelsea; Skutt-Kakaria, Kyobi; Grenier, Jennifer K.; Clark, Andrew G.; Hartl, Daniel L.; de Bivort, Benjamin L.

    2015-01-01

    Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype. PMID:25953335

  3. Behavioral abnormalities are common and severe in patients with distal 22q11.2 microdeletions and microduplications

    PubMed Central

    Lindgren, Valerie; McRae, Anne; Dineen, Richard; Saulsberry, Alexandria; Hoganson, George; Schrift, Michael

    2015-01-01

    We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low-copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D–E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype–phenotype correlations which are still being generated for these chromosomal anomalies. PMID:26247050

  4. Abnormal Elastic and Vibrational Behaviors of Magnetite at High Pressures

    NASA Astrophysics Data System (ADS)

    Lin, Jung-Fu; Wu, Junjie; Zhu, Jie; Mao, Zhu; Said, Ayman H.; Leu, Bogdan M.; Cheng, Jinguang; Uwatoko, Yoshiya; Jin, Changqing; Zhou, Jianshi

    2014-09-01

    Magnetite exhibits unique electronic, magnetic, and structural properties in extreme conditions that are of great research interest. Previous studies have suggested a number of transitional models, although the nature of magnetite at high pressure remains elusive. We have studied a highly stoichiometric magnetite using inelastic X-ray scattering, X-ray diffraction and emission, and Raman spectroscopies in diamond anvil cells up to ~20 GPa, while complementary electrical conductivity measurements were conducted in a cubic anvil cell up to 8.5 GPa. We have observed an elastic softening in the diagonal elastic constants (C11 and C44) and a hardening in the off-diagonal constant (C12) at ~8 GPa where significant elastic anisotropies in longitudinal and transverse acoustic waves occur, especially along the [110] direction. An additional vibrational Raman band between the A1g and T2g modes was also detected at the transition pressure. These abnormal elastic and vibrational behaviors of magnetite are attributed to the occurrence of the octahedrally-coordinated Fe2+-Fe3+-Fe2+ ions charge-ordering along the [110] direction in the inverse spinel structure. We propose a new phase diagram of magnetite in which the temperature for the metal-insulator and distorted structural transitions decreases with increasing pressure while the charge-ordering transition occurs at ~8 GPa and room temperature.

  5. Abnormal Elastic and Vibrational Behaviors of Magnetite at High Pressures

    PubMed Central

    Lin, Jung-Fu; Wu, Junjie; Zhu, Jie; Mao, Zhu; Said, Ayman H.; Leu, Bogdan M.; Cheng, Jinguang; Uwatoko, Yoshiya; Jin, Changqing; Zhou, Jianshi

    2014-01-01

    Magnetite exhibits unique electronic, magnetic, and structural properties in extreme conditions that are of great research interest. Previous studies have suggested a number of transitional models, although the nature of magnetite at high pressure remains elusive. We have studied a highly stoichiometric magnetite using inelastic X-ray scattering, X-ray diffraction and emission, and Raman spectroscopies in diamond anvil cells up to ~20 GPa, while complementary electrical conductivity measurements were conducted in a cubic anvil cell up to 8.5 GPa. We have observed an elastic softening in the diagonal elastic constants (C11 and C44) and a hardening in the off-diagonal constant (C12) at ~8 GPa where significant elastic anisotropies in longitudinal and transverse acoustic waves occur, especially along the [110] direction. An additional vibrational Raman band between the A1g and T2g modes was also detected at the transition pressure. These abnormal elastic and vibrational behaviors of magnetite are attributed to the occurrence of the octahedrally-coordinated Fe2+-Fe3+-Fe2+ ions charge-ordering along the [110] direction in the inverse spinel structure. We propose a new phase diagram of magnetite in which the temperature for the metal-insulator and distorted structural transitions decreases with increasing pressure while the charge-ordering transition occurs at ~8 GPa and room temperature. PMID:25186916

  6. Abnormal elastic and vibrational behaviors of magnetite at high pressures.

    PubMed

    Lin, Jung-Fu; Wu, Junjie; Zhu, Jie; Mao, Zhu; Said, Ayman H; Leu, Bogdan M; Cheng, Jinguang; Uwatoko, Yoshiya; Jin, Changqing; Zhou, Jianshi

    2014-01-01

    Magnetite exhibits unique electronic, magnetic, and structural properties in extreme conditions that are of great research interest. Previous studies have suggested a number of transitional models, although the nature of magnetite at high pressure remains elusive. We have studied a highly stoichiometric magnetite using inelastic X-ray scattering, X-ray diffraction and emission, and Raman spectroscopies in diamond anvil cells up to ~20 GPa, while complementary electrical conductivity measurements were conducted in a cubic anvil cell up to 8.5 GPa. We have observed an elastic softening in the diagonal elastic constants (C11 and C44) and a hardening in the off-diagonal constant (C12) at ~8 GPa where significant elastic anisotropies in longitudinal and transverse acoustic waves occur, especially along the [110] direction. An additional vibrational Raman band between the A1g and T2g modes was also detected at the transition pressure. These abnormal elastic and vibrational behaviors of magnetite are attributed to the occurrence of the octahedrally-coordinated Fe(2+)-Fe(3+)-Fe(2+) ions charge-ordering along the [110] direction in the inverse spinel structure. We propose a new phase diagram of magnetite in which the temperature for the metal-insulator and distorted structural transitions decreases with increasing pressure while the charge-ordering transition occurs at ~8 GPa and room temperature. PMID:25186916

  7. Reversible Behavioral Phenotypes in a Conditional Mouse Model of TDP-43 Proteinopathies

    PubMed Central

    Alfieri, Julio A.; Pino, Natalia S.

    2014-01-01

    Transactive response DNA-binding protein 43 (TDP-43) mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically localized form of TDP-43 (TDP-43-ΔNLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive, and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test, and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-ΔNLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. To determine whether these symptoms were reversible, we suppressed Tg expression for 14 d in 1.5-month-old mice showing an established behavioral phenotype but modest neurodegeneration and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When Tg expression was suppressed in 6.5-month-old mice showing overt neurodegeneration, motor deficits were irreversible. These results indicate that TDP-43-ΔNLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies. PMID:25392493

  8. Adams Oliver syndrome: Description of a new phenotype with cerebellar abnormalities in a family

    PubMed Central

    D’Amico, Alessandra; Melis, Daniela; D’Arco, Felice; Di Paolo, Nilde; Carotenuto, Barbara; D’Anna, Gennaro; Russo, Carmela; Boemio, Pasquale; Brunetti, Arturo

    2013-01-01

    Summary Background To describe cerebellar abnormalities in a family composed by a father and two affected sibs with Adams Oliver syndrome (AOS) (OMIM 100300). Material/Methods Brain MRI and MR angiography were performed at 1.5T. Results The siblings presented cerebellar cortex dysplasia characterized by the presence of cysts. Conclusions Abnormalities of CNS are an unusual manifestation of AOS. To our knowledge, this is the first report of cerebellar cortical dysplasia in a family with AOS. PMID:24505229

  9. BETA-ENDORPHIN LEVELS IN LONGTAILED AND PIGTAILED MACAQUES VARY BY ABNORMAL BEHAVIOR RATING AND SEX

    PubMed Central

    Crockett, Carolyn M.; Sackett, Gene P.; Sandman, Curt A.; Chicz-DeMet, Aleksandra; Bentson, Kathleen L.

    2007-01-01

    Frequent or severe abnormal behavior may be associated with the release of endorphins that positively reinforce the behavior with an opiate euphoria or analgesia. One line of research exploring this association involves the superhormone, proopiomelanocortin (POMC). The products of POMC appear to be dysregulated in some human subjects who exhibit self-injurious behavior (SIB). Macaque monkeys have POMC very similar to humans, and some laboratory macaques display SIB or frequent stereotypies. We investigated associations between plasma levels of three immunoreactive POMC fragments with possible opioid action and abnormal behavior ratings in macaques. In 58 adult male and female macaques (24 Macaca fascicularis and 34 M. nemestrina), plasma levels of intact beta-endorphin (βE) and the N-terminal fragment (BEN) were significantly higher in animals with higher levels of abnormal behavior. The C-terminal fragment (BEC) was significantly higher in males but unrelated to ratings of abnormal behavior. Levels of ACTH, cortisol, and (βE-ACTH)/βE dysregulation index were unrelated to abnormal behavior. None of the POMC products differed significantly by subjects' species, age, or weight. The finding that intact beta-endorphin is positively related to abnormal behavior in two species of macaque is consistent with some previous research on human subjects and nonprimates. The positive relation of the N-terminal fragment of βE to abnormal behavior is a new finding. PMID:17719139

  10. Normal behavior and the clinical implications of abnormal behavior in guinea pigs.

    PubMed

    Bradley, T A

    2001-09-01

    Cavies are becoming more popular as pets because they are relatively easy to care for and provide never-ending love and entertainment with their curious but gentle nature. As with other species, the best way to learn about guinea pig behavior is to own guinea pigs. Understanding normal behavior provides the practitioner with the ability to more easily recognize pathology and abnormal behavior. This allows the veterinarian to provide necessary supportive care and pain management more quickly while performing diagnostics and determining the need for therapeutics. Understanding the behavior of cavies allows the clinician to better educate guinea pig-owning clients and to better and more quickly serve the needs of their guinea pig patients. PMID:11601108

  11. Decomposition of abnormal free locomotor behavior in a rat model of Parkinson's disease

    PubMed Central

    Grieb, Benjamin; von Nicolai, Constantin; Engler, Gerhard; Sharott, Andrew; Papageorgiou, Ismini; Hamel, Wolfgang; Engel, Andreas K.; Moll, Christian K.

    2013-01-01

    Poverty of spontaneous movement, slowed execution and reduced amplitudes of movement (akinesia, brady- and hypokinesia) are cardinal motor manifestations of Parkinson's disease that can be modeled in experimental animals by brain lesions affecting midbrain dopaminergic neurons. Most behavioral investigations in experimental parkinsonism have employed short-term observation windows to assess motor impairments. We postulated that an analysis of longer-term free exploratory behavior could provide further insights into the complex fine structure of altered locomotor activity in parkinsonian animals. To this end, we video-monitored 23 h of free locomotor behavior and extracted several behavioral measures before and after the expression of a severe parkinsonian phenotype following bilateral 6-hydroxydopamine (6-OHDA) lesions of the rat dopaminergic substantia nigra. Unbiased stereological cell counting verified the degree of midbrain tyrosine hydroxylase positive cell loss in the substantia nigra and ventral tegmental area. In line with previous reports, overall covered distance and maximal motion speed of lesioned animals were found to be significantly reduced compared to controls. Before lesion surgery, exploratory rat behavior exhibited a bimodal distribution of maximal speed values obtained for single movement episodes, corresponding to a “first” and “second gear” of motion. 6-OHDA injections significantly reduced the incidence of second gear motion episodes and also resulted in an abnormal prolongation of these fast motion events. Likewise, the spatial spread of such episodes was increased in 6-OHDA rats. The increase in curvature of motion tracks was increased in both lesioned and control animals. We conclude that the discrimination of distinct modes of motion by statistical decomposition of longer-term spontaneous locomotion provides useful insights into the fine structure of fluctuating motor functions in a rat analog of Parkinson's disease. PMID:24348346

  12. Behavioral Phenotype and Autism Spectrum Disorders in Cornelia de Lange Syndrome.

    PubMed

    Parisi, Lucia; Di Filippo, Teresa; Roccella, Michele

    2015-09-30

    Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Cornelia de Lange syndrome is associated with abnormalities on chromosomes 5, 10 and X. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), are responsible for approximately 50-60% of CdLS cases. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in CdLS. However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. A significantly higher prevalence of self-injury are evident in CdLS. Self-injury was associated with repetitive and impulsive behavior. This study describes the behavioral phenotype of four children with Cornelia de Lange syndrome and ASDs and rehabilitative intervention that must be implemented. PMID:26605036

  13. Behavioral Phenotype and Autism Spectrum Disorders in Cornelia de Lange Syndrome

    PubMed Central

    Parisi, Lucia; Di Filippo, Teresa; Roccella, Michele

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Cornelia de Lange syndrome is associated with abnormalities on chromosomes 5, 10 and X. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), are responsible for approximately 50-60% of CdLS cases. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in CdLS. However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. A significantly higher prevalence of self-injury are evident in CdLS. Self-injury was associated with repetitive and impulsive behavior. This study describes the behavioral phenotype of four children with Cornelia de Lange syndrome and ASDs and rehabilitative intervention that must be implemented. PMID:26605036

  14. Sugar-sweetened beverages and prevalence of the metabolically abnormal phenotype in the Framingham Heart Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to examine the relationship between usual sugar-sweetened beverage (SSB) consumption and prevalence of abnormal metabolic health across body mass index (BMI) categories. The metabolic health of 6,842 non-diabetic adults was classified using cross-sectional data from the...

  15. Abnormal behavior and associated risk factors in captive baboons (Papio hamadryas spp.).

    PubMed

    Lutz, Corrine K; Williams, Priscilla C; Sharp, R Mark

    2014-04-01

    Abnormal behavior, ranging from motor stereotypies to self-injurious behavior, has been documented in captive nonhuman primates, with risk factors including nursery rearing, single housing, and veterinary procedures. Much of this research has focused on macaque monkeys; less is known about the extent of and risk factors for abnormal behavior in baboons. Because abnormal behavior can be indicative of poor welfare, either past or present, the purpose of this study was to survey the presence of abnormal behavior in captive baboons and to identify potential risk factors for these behaviors with an aim of prevention. Subjects were 144 baboons (119 females, 25 males) aged 3-29 (median = 9.18) years temporarily singly housed for research or clinical reasons. A 15-min focal observation was conducted on each subject using the Noldus Observer® program. Abnormal behavior was observed in 26% of the subjects, with motor stereotypy (e.g., pace, rock, swing) being the most common. Motor stereotypy was negatively associated with age when first singly housed (P < 0.005) while self-directed behavior (e.g., hair pull, self-bite) was positively associated with the lifetime number of days singly housed (P < 0.05) and the average number of blood draws per year (P < 0.05). In addition, abnormal appetitive behavior was associated with being male (P < 0.05). Although the baboons in this study exhibited relatively low levels of abnormal behavior, the risk factors for these behaviors (e.g., social restriction, routine veterinary procedures, and sex) appear to remain consistent across primate species. PMID:24323406

  16. An abnormal lymphatic phenotype is associated with subcutaneous adipose tissue deposits in Dercum’s disease

    PubMed Central

    Rasmussen, John C.; Herbst, Karen L.; Aldrich, Melissa B.; Darne, Chinmay D.; Tan, I-Chih; Zhu, Banghe; Guilliod, Renie; Fife, Caroline A.; Maus, Erik A.; Sevick-Muraca, Eva M.

    2014-01-01

    Objective Investigational, near-infrared fluorescence (NIRF) lymphatic imaging was used to assess lymphatic architecture and contractile function in participants diagnosed with Dercum’s disease, a rare, poorly understood disorder characterized by painful lipomas in subcutaneous adipose tissues. Design and Methods After informed consent and as part of an FDA-approved feasibility study to evaluate lymphatics in diseases in which their contribution has been implicated, three women diagnosed with Dercum’s disease and four control subjects were imaged. Each participant received multiple intradermal and subcutaneous injections of indocyanine green (ICG, total dose ≤400µg) in arms, legs, and/or trunk. Immediately after injection, ICG was taken up by the lymphatics and NIRF imaging was conducted. Results The lymphatics in the participants with Dercum’s disease were intact and dilated, yet sluggishly propelled lymph when compared to control lymphatics. Palpation of regions containing fluorescent lymphatic pathways revealed tender, fibrotic, tubular structures within the subcutaneous adipose tissue that were associated with painful nodules, and, in some cases, masses of fluorescent tissue indicating that some lipomas may represent tertiary lymphoid tissues. Conclusions These data support the hypothesis that Dercum’s disease may be a lymphovascular disorder and suggest a possible association between abnormal adipose tissue deposition and abnormal lymphatic structure and function. PMID:25044620

  17. Allergies: The Key to Many Childhood Behavior Abnormalities.

    ERIC Educational Resources Information Center

    Vass, Molly; Rasmussen, Betty

    1984-01-01

    Describes the role of allergies in childhood behavior problems and discusses the role of school counselors in identifying allergic responses. Includes a list of references and resources on allergies, nutrition, support groups, and environmental care units. (JAC)

  18. The Cardiac Electrophysiologic Substrate Underlying the ECG Phenotype and Electrogram Abnormalities in Brugada Syndrome Patients

    PubMed Central

    Zhang, Junjie; Sacher, Frédéric; Hoffmayer, Kurt; O’Hara, Thomas; Strom, Maria; Cuculich, Phillip; Silva, Jennifer; Cooper, Daniel; Faddis, Mitchell; Hocini, Mélèze; Haïssaguerre, Michel; Scheinman, Melvin; Rudy, Yoram

    2015-01-01

    Background Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined. Methods and Results Using noninvasive ECG imaging (ECGI), we studied 25 BrS patients to characterize the electrophysiologic substrate, and 6 patients with right bundle branch block (RBBB) for comparison. Seven normal subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract (RVOT) with the following properties (compared to normal controls; p<0.005): (1)ST-segment elevation (STE) and inverted T-wave of unipolar electrograms (EGMs) (2.21±0.67 vs. 0 mV); (2)delayed RVOT activation (82±18 vs. 37±11 ms); (3)low amplitude (0.47±0.16 vs. 3.74±1.60 mV) and fractionated EGMs, suggesting slow discontinuous conduction; (4)prolonged recovery time (RT; 381±30 vs. 311±34 ms) and activation-recovery intervals (ARIs; 318±32 vs. 241±27 ms), indicating delayed repolarization; (5)steep repolarization gradients (ΔRT/Δx= 96±28 vs. 7±6 ms/cm, ΔARI/Δx= 105±24 vs. 7±5 ms/cm) at RVOT borders. With increased heart rate in 6 BrS patients, reduced STE and increased fractionation were observed. Unlike BrS, RBBB had delayed activation in the entire RV, without STE, fractionation, or repolarization abnormalities on EGMs. Conclusions The results indicate that both, slow discontinuous conduction and steep dispersion of repolarization are present in the RVOT of BrS patients. ECGI could differentiate between BrS and RBBB. PMID:25810336

  19. Electrophysiological and behavioral phenotype of insulin receptor defective mice

    PubMed Central

    Das, P.; Parsons, A.D.; Scarborough, J.; Hoffman, J.; Wilson, J.; Thompson, R.N.; Overton, J.M.; Fadool, D.A.

    2009-01-01

    The olfactory bulb expresses one of the highest levels of insulin found in the brain. A high level of expression of the concomitant insulin receptor (IR) kinase is also retained in this brain region, even in the adult. We have previously demonstrated in a heterologous system that insulin modulates the voltage-dependent potassium channel, Kv1.3, through tyrosine phosphorylation of three key residues in the amino and carboxyl terminus of the channel protein. Phosphorylation also induces current suppression of the Kv1.3-contributed current in cultured olfactory bulb neurons (OBNs) of rodents. In order to explore the behavioral importance of this kinase-induced modulation of the channel for the olfactory ability of the animal, mice with a targeted-gene deletion of the insulin receptor were electrophysiologically and behaviorally characterized. Mice heterozygous for the insulin receptor kinase (IR+/−) gene performed the same as wild-type (+/+) mice when challenged with a traditional, non-learning-based task to test gross anosmia. There was also no significant difference across the two genotypes in tests designed to measure exploratory behavior or in a battery of systems physiology experiments designed to assess metabolic energy usage (locomotion, ingestive behaviors, weight, oxygen consumption, and respiratory quotient). Object memory recognition tests suggest that IR+/− mice have an impairment in recognition of familiarized objects; IR+/− mice demonstrate poor performance for both short-term (1 h) and long-term (24 h) memory tests in comparison to that of wild-type mice. Electrophysiological experiments indicate that mitral cell neurons cultured from both heterozygous and homozygous-null mice (IR+/− and IR−/−) have an decreased peak current amplitude compared with that recorded for wild-type (+/+) animals matched for days in vitro (DIV). These data indicate that the loss of one allele of the IR kinase gene modifies the electrical phenotype of the mitral

  20. MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase.

    PubMed

    Stohn, J Patrizia; Martinez, M Elena; Matoin, Kassey; Morte, Beatriz; Bernal, Juan; Galton, Valerie Anne; St Germain, Donald; Hernandez, Arturo

    2016-08-01

    Mice deficient in the type 3 deiodinase (D3KO mice) manifest impaired clearance of thyroid hormone (TH), leading to elevated levels of TH action during development. This alteration causes reduced neonatal viability, growth retardation, and central hypothyroidism. Here we examined how these phenotypes are affected by a deficiency in the monocarboxylate transporter 8 (MCT8), which is a major contributor to the transport of the active thyroid hormone, T3, into the cell. MCT8 deficiency eliminated the neonatal lethality of type 3 deiodinase (D3)-deficient mice and significantly ameliorated their growth retardation. Double-mutant newborn mice exhibited similar peripheral thyrotoxicosis and increased brain expression of T3-dependent genes as mice with D3 deficiency only. Later in neonatal life and adulthood, double-mutant mice manifested central and peripheral TH status similar to mice with single MCT8 deficiency, with low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in the hypothalamus. In double-mutant adult mice, both thyroid gland size and the hypothyroidism-induced rise in TSH were greater than those in mice with single D3 deficiency but less than those in mice with MCT8 deficiency alone. Our results demonstrate that the marked phenotypic abnormalities observed in the D3-deficient mouse, including perinatal mortality, growth retardation, and central hypothyroidism in adult animals, require expression of MCT8, confirming the interdependent relationship between the TH transport into cells and the deiodination processes. PMID:27254003

  1. HINT1 is involved in the behavioral abnormalities induced by social isolation rearing.

    PubMed

    Dang, Yong-hui; Liu, Peng; Ma, Rui; Chu, Zheng; Liu, You-ping; Wang, Jia-bei; Ma, Xian-cang; Gao, Cheng-ge

    2015-10-21

    Social isolation (SI) rearing has been demonstrated to induce behavioral abnormalities like anxiety, impulsivity, aggression, and learning and memory deficits which are relevant to core symptoms in patients with some certain neuropsychiatric disorders. But the underlying pathophysiological mechanisms remain unclear. Recent studies have revealed HINT1 has close relation with diverse neuropsychiatric diseases. In this present study, the SI rearing mice exhibited depression-like and aggressive behavior. Besides, HINT1 protein levels decreased in PFC but increased in HIP. Based on the data obtained, we concluded that HINT1 is involved in the behavioral abnormalities induced by social isolation and exerts distinct roles in different encephalic regions. PMID:26300541

  2. Risk factors for behavioral abnormalities in mild cognitive impairment and mild Alzheimer's disease

    PubMed Central

    Apostolova, Liana G.; Di, Li Jie; Duffy, Erin L.; Brook, Jenny; Elashoff, David; Tseng, Chi-Hong; Fairbanks, Lynn; Cummings, Jeffrey L.

    2014-01-01

    Background Behavioral symptoms are common in both MCI and AD. Methods We analyzed the Neuropsychiatric Inventory Questionnaire data of 3456 MCI and 2641 mild AD NACC participants. Using factor analysis and logistic regression we estimated the effects of age, sex, race, education, MMSE, functional impairment, marital status and family history on presence of behavioral symptoms. We also compared the observed prevalence of behavioral symptoms between amnestic and nonamnestic MCI. Results Four factors were identified: affective behaviors (depression, apathy and anxiety); distress/tension behaviors (irritability and agitation); impulse control behaviors (disinhibition, elation and aberrant motor behavior), and psychotic behaviors (delusions and hallucinations). Male gender was significantly associated with all factors. Younger age was associated with higher prevalence of distress/tension, impulse control and psychotic behaviors. Being married was protective against psychotic behaviors. Lower education was associated with the presence of distress/tension behaviors. Caucasians showed higher prevalence of affective behaviors. Functional impairment was strongly associated with all behavioral abnormalities. Amnestic MCI had more elation and agitation relative to nonamnestic MCI. Conclusions Younger age, male gender and greater functional impairment were associated with higher overall presence of behavioral abnormalities in MCI and mild AD. Marital status, lower education and race had effect on selected behaviors. PMID:24481207

  3. Characterizing abnormal behavior in a large population of zoo-housed chimpanzees: prevalence and potential influencing factors.

    PubMed

    Jacobson, Sarah L; Ross, Stephen R; Bloomsmith, Mollie A

    2016-01-01

    Abnormal behaviors in captive animals are generally defined as behaviors that are atypical for the species and are often considered to be indicators of poor welfare. Although some abnormal behaviors have been empirically linked to conditions related to elevated stress and compromised welfare in primates, others have little or no evidence on which to base such a relationship. The objective of this study was to investigate a recent claim that abnormal behavior is endemic in the captive population by surveying a broad sample of chimpanzees (Pan troglodytes), while also considering factors associated with the origins of these behaviors. We surveyed animal care staff from 26 accredited zoos to assess the prevalence of abnormal behavior in a large sample of chimpanzees in the United States for which we had information on origin and rearing history. Our results demonstrated that 64% of this sample was reported to engage in some form of abnormal behavior in the past two years and 48% of chimpanzees engaged in abnormal behavior other than coprophagy. Logistic regression models were used to analyze the historical variables that best predicted the occurrence of all abnormal behavior, any abnormal behavior that was not coprophagy, and coprophagy. Rearing had opposing effects on the occurrence of coprophagy and the other abnormal behaviors such that mother-reared individuals were more likely to perform coprophagy, whereas non-mother-reared individuals were more likely to perform other abnormal behaviors. These results support the assertion that coprophagy may be classified separately when assessing abnormal behavior and the welfare of captive chimpanzees. This robust evaluation of the prevalence of abnormal behavior in our sample from the U.S. zoo population also demonstrates the importance of considering the contribution of historical variables to present behavior, in order to better understand the causes of these behaviors and any potential relationship to psychological

  4. Characterizing abnormal behavior in a large population of zoo-housed chimpanzees: prevalence and potential influencing factors

    PubMed Central

    Jacobson, Sarah L.; Bloomsmith, Mollie A.

    2016-01-01

    Abnormal behaviors in captive animals are generally defined as behaviors that are atypical for the species and are often considered to be indicators of poor welfare. Although some abnormal behaviors have been empirically linked to conditions related to elevated stress and compromised welfare in primates, others have little or no evidence on which to base such a relationship. The objective of this study was to investigate a recent claim that abnormal behavior is endemic in the captive population by surveying a broad sample of chimpanzees (Pan troglodytes), while also considering factors associated with the origins of these behaviors. We surveyed animal care staff from 26 accredited zoos to assess the prevalence of abnormal behavior in a large sample of chimpanzees in the United States for which we had information on origin and rearing history. Our results demonstrated that 64% of this sample was reported to engage in some form of abnormal behavior in the past two years and 48% of chimpanzees engaged in abnormal behavior other than coprophagy. Logistic regression models were used to analyze the historical variables that best predicted the occurrence of all abnormal behavior, any abnormal behavior that was not coprophagy, and coprophagy. Rearing had opposing effects on the occurrence of coprophagy and the other abnormal behaviors such that mother-reared individuals were more likely to perform coprophagy, whereas non-mother-reared individuals were more likely to perform other abnormal behaviors. These results support the assertion that coprophagy may be classified separately when assessing abnormal behavior and the welfare of captive chimpanzees. This robust evaluation of the prevalence of abnormal behavior in our sample from the U.S. zoo population also demonstrates the importance of considering the contribution of historical variables to present behavior, in order to better understand the causes of these behaviors and any potential relationship to psychological

  5. Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model

    PubMed Central

    Cook, Casey; Kang, Silvia S.; Carlomagno, Yari; Lin, Wen-Lang; Yue, Mei; Kurti, Aishe; Shinohara, Mitsuru; Jansen-West, Karen; Perkerson, Emilie; Castanedes-Casey, Monica; Rousseau, Linda; Phillips, Virginia; Bu, Guojun; Dickson, Dennis W.; Petrucelli, Leonard; Fryer, John D.

    2015-01-01

    Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-TauP301L mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets. PMID:26276810

  6. Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes.

    PubMed

    Lucas, Elizabeth K; Jegarl, Anita; Clem, Roger L

    2014-11-01

    Activity-dependent brain-derived neurotrophic factor (BDNF) signaling through receptor tyrosine kinase B (TrkB) is required for cued fear memory consolidation and extinction. Although BDNF is primarily secreted from glutamatergic neurons, TrkB is expressed by other genetically defined cells whose contributions to the behavioral effects of BDNF remain poorly understood. Parvalbumin (PV)-positive interneurons, which are highly enriched in TrkB, are emerging as key regulators of fear memory expression. We therefore hypothesized that activity-dependent BDNF signaling in PV-interneurons may modulate emotional learning. To test this hypothesis, we utilized the LoxP/Cre system for conditional deletion of TrkB in PV-positive cells to examine the impact of cell-autonomous BDNF signaling on Pavlovian fear conditioning and extinction. However, behavioral abnormalities indicative of vestibular dysfunction precluded the use of homozygous conditional knockouts in tests of higher cognitive functioning. While vestibular dysfunction was apparent in both sexes, female conditional knockouts exhibited an exacerbated phenotype, including extreme motor hyperactivity and circling behavior, compared to their male littermates. Heterozygous conditional knockouts were spared of vestibular dysfunction. While fear memory consolidation was unaffected in heterozygotes of both sexes, males exhibited impaired extinction consolidation compared to their littermate controls. Our findings complement evidence from human and rodent studies suggesting that BDNF signaling promotes consolidation of extinction and point to PV-positive neurons as a discrete population that mediates these effects in a sex-specific manner. PMID:25127683

  7. Abnormal repetitive behaviors in dogs and cats: a guide for practitioners.

    PubMed

    Tynes, Valarie V; Sinn, Leslie

    2014-05-01

    Abnormal repetitive behaviors (ARBs) represent a diverse group of behaviors whose underlying mechanism is poorly understood. Their neurobiology likely involves several different neurotransmitter systems. These behaviors have been referred to as compulsive disorders, obsessive compulsive disorders and stereotypies. Underlying medical conditions and pain can often cause changes in behavior that are mistaken for ARBs. A complete medical work-up is always indicated prior to reaching a presumptive diagnosis. The frequency of ARBs can be reduced but not always eliminated with the use of selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) in conjunction with behavior modification and environmental enrichment. PMID:24766699

  8. Early cognitive changes and nondementing behavioral abnormalities in Parkinson's disease.

    PubMed

    Levin, Bonnie E; Katzen, Heather L

    2005-01-01

    Early cognitive changes in patients with PD are often subtle and influenced by factors that interact with the disease process, including age of disease onset, medication, and the specific constellation of motor symptoms. These factors notwithstanding, ample evidence exists that specific cognitive changes occur early in the course of PD. This evidence does not imply that cognitive deficits are pervasive during the early stages. To the contrary, they are usually subtle and often difficult to detect without formal neuropsychological testing. Executive-function deficits are the most frequently reported cognitive problems and, given that executive skills are an integral part of many tasks, it follows that subtle difficulties may be seen on a wide range of cognitive measures, particularly in working memory and visuospatial dysfunction, two areas that rely heavily on executive skills. Whereas apraxia and language processing deficits occur infrequently, subtle changes in olfaction and contrast sensitivity have also been repeatedly observed. Finally, depressive symptoms are also common in the early stages of the disease. The significance of the early behavioral changes and their prognostic implications are largely unknown. Prospective studies are needed to understand the longitudinal course of early cognitive changes to determine whether they remain as circumscribed impairments or represent a precursor to a more widespread dementia. PMID:16383214

  9. Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

    PubMed Central

    Caprioli, Jessica; Bresin, Elena; Mossali, Chiara; Pianetti, Gaia; Gamba, Sara; Daina, Erica; Fenili, Chiara; Castelletti, Federica; Sorosina, Annalisa; Piras, Rossella; Donadelli, Roberta; Maranta, Ramona; van der Meer, Irene; Conway, Edward M.; Zipfel, Peter F.; Goodship, Timothy H.; Remuzzi, Giuseppe

    2010-01-01

    Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin–producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS. Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases. Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations. Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant. PMID:20595690

  10. Family patterns of development dyslexia, Part II: Behavioral phenotypes

    SciTech Connect

    Wolff, P.H.; Melngailis, I.; Bedrosian, M.

    1995-12-18

    The motor control of bimanual coordination and motor speech was compared between first degree relatives from families with at least 2 dyslexic family members, and families where probands were the only affected family members. Half of affected relatives had motor coordination deficits; and they came from families in which probands also showed impaired motor coordination. By contrast, affected relatives without motor deficits came from dyslexia families where probands did not have motor deficits. Motor coordination deficits were more common and more severe among affected offspring in families where both parents were affected than among affected offspring in families where only one parent was affected. However, motor coordination deficits were also more common and more severe in affected parents when both parents were affected than among affected parents in families where only one parent was affected. We conclude that impaired temporal resolution in motor action identifies a behavioral phenotype in some subtypes of developmental dyslexia. The observed pattern of transmission for motor deficits and reading impairment in about half of dyslexia families was most congruent with a genetic model of dyslexia in which 2 codominant major genes cosegregate in dyslexia pedigrees where the proband is also motorically impaired. 54 refs., 5 figs., 5 tabs.

  11. Abnormalities in the basement membrane structure promote basal keratinocytes in the epidermis of hypertrophic scars to adopt a proliferative phenotype

    PubMed Central

    YANG, SHAOWEI; SUN, YEXIAO; GENG, ZHIJUN; MA, KUI; SUN, XIAOYAN; FU, XIAOBING

    2016-01-01

    The majority of studies on scar formation have mainly focused on the dermis and little is known of the involvement of the epidermis. Previous research has demonstrated that the scar tissue-derived keratinocytes are different from normal cells at both the genetic and cell biological levels; however, the mechanisms responsible for the fundamental abnormalities in keratinocytes during scar development remain elusive. For this purpose, in this study, we used normal, wound edge and hypertrophic scar tissue to examine the morphological changes which occur during epidermal regeneration as part of the wound healing process and found that the histological structure of hypertrophic scar tissues differed from that of normal skin, with a significant increase in epidermal thickness. Notably, staining of the basement membrane (BM) appeared to be absent in the scar tissues. Moreover, immunofluorescence staining for cytokeratin (CK)10, CK14, CK5, CK19 and integrin-β1 indicated the differential expression of cell markers in the epidermal keratinocytes among the normal, wound edge and hypertrophic scar tissues, which corresponded with the altered BM structures. By using a panel of proteins associated with BM components, we validated our hypothesis that the BM plays a significant role in regulating the cell fate decision of epidermal keratinocytes during skin wound healing. Alterations in the structure of the BM promote basal keratinocytes to adopt a proliferative phenotype both in vivo and in vitro. PMID:26986690

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

    PubMed Central

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

    2015-01-01

    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. PMID:25938737

  13. Olfaction in eating disorders and abnormal eating behavior: a systematic review

    PubMed Central

    Islam, Mohammed A.; Fagundo, Ana B.; Arcelus, Jon; Agüera, Zaida; Jiménez-Murcia, Susana; Fernández-Real, José M.; Tinahones, Francisco J.; de la Torre, Rafael; Botella, Cristina; Frühbeck, Gema; Casanueva, Felipe F.; Menchón, José M.; Fernandez-Aranda, Fernando

    2015-01-01

    The study provides a systematic review that explores the current literature on olfactory capacity in abnormal eating behavior. The objective is to present a basis for discussion on whether research in olfaction in eating disorders may offer additional insight with regard to the complex etiopathology of eating disorders (ED) and abnormal eating behaviors. Electronic databases (Medline, PsycINFO, PubMed, Science Direct, and Web of Science) were searched using the components in relation to olfaction and combining them with the components related to abnormal eating behavior. Out of 1352 articles, titles were first excluded by title (n = 64) and then by abstract and fulltext resulting in a final selection of 14 articles (820 patients and 385 control participants) for this review. The highest number of existing literature on olfaction in ED were carried out with AN patients (78.6%) followed by BN patients (35.7%) and obese individuals (14.3%). Most studies were only conducted on females. The general findings support that olfaction is altered in AN and in obesity and indicates toward there being little to no difference in olfactory capacity between BN patients and the general population. Due to the limited number of studies and heterogeneity this review stresses on the importance of more research on olfaction and abnormal eating behavior. PMID:26483708

  14. Teaching a Course in Abnormal Psychology and Behavior Intervention Skills for Nursing Home Aides.

    ERIC Educational Resources Information Center

    Glenwick, David S.; Slutzsky, Mitchel R.; Garfinkel, Eric

    2001-01-01

    Describes an 11-week course given at a nursing home to nursing home aides that focused on abnormal psychology and behavior intervention skills. Discusses the course goals, class composition, and course description. Addresses the problems and issues encountered with teaching this course to a nontraditional population in an unconventional setting.…

  15. Abnormal Nocturnal Behavior due to Hypoglycemia in a Patient with Type 2 Diabetes.

    PubMed

    Yang, Kwang Ik; Kim, Hyung Ki; Baek, Jeehun; Kim, Doh-Eui; Park, Hyung Kook

    2016-04-01

    Abnormal nocturnal behavior can have many causes, including primary sleep disorder, nocturnal seizures, and underlying medical or neurological disorders. A 79-year-old woman with type 2 diabetes was admitted for evaluation of abnormal nocturnal behavior. Every night at around 04:30 she was observed displaying abnormal behavior including leg shaking, fumbling with bedclothes, crawling around the room with her eyes closed, and non-responsiveness to verbal communication. Polysomnography with 20-channel electroencephalography (EEG) was performed. EEG showed that the posterior dominant rhythm was slower than that observed in the initial EEG, with diffuse theta and delta activities intermixed, and no epileptiform activity. The serum glucose level was 35 mg/dL at that time, and both the EEG findings and clinical symptoms were resolved after an intravenous injection of 50 mL of 50% glucose. These results indicate that nocturnal hypoglycemia should be considered as one of the possible etiologies in patients presenting with abnormal nocturnal behavior. PMID:26943712

  16. Abnormal vibrissa-related behavior and loss of barrel field inhibitory neurons in 5xFAD transgenics

    PubMed Central

    Flanigan, Timothy J.; Xue, Yi; Rao, Shailaja Kishan; Anandh, Dhanushkodi; McDonald, Michael P.

    2014-01-01

    A recent study reported lower anxiety in the 5xFAD transgenic mouse model of Alzheimer's disease, as measured by reduced time on the open arms of an elevated plus maze. This is important because all behaviors in experimental animals must be interpreted in light of basal anxiety and response to novel environments. We conducted a comprehensive anxiety battery in the 5xFAD transgenics and replicated the plus-maze phenotype. However, we found that it did not reflect reduced anxiety, but rather abnormal avoidance of the closed arms on the part of transgenics and within-session habituation to the closed arms on the part of wild-type controls. We noticed that the 5xFAD transgenics did not engage in the whisker-barbering behavior typical of mice of this background strain. This is suggestive of abnormal social behavior, and we suspected it might be related to their avoidance of the closed arms on the plus maze. Indeed, transgenic mice exhibited excessive home-cage social behavior and impaired social recognition, and did not permit barbering by wild-type mice when pair-housed. When their whiskers were snipped the 5xFAD transgenics no longer avoided the closed arms on the plus maze. Examination of parvalbumin (PV) staining showed a 28.9% reduction in PV+ inhibitory interneurons in the in barrel fields of 5xFAD mice, and loss of PV+ fibers in layers IV and V. This loss of vibrissal inhibition suggests a putatively aversive overstimulation that may be responsible for the transgenics’ avoidance of the closed arms in the plus maze. PMID:24655396

  17. Behavioral changes following a single episode of early life seizures support the latent development of an autistic phenotype

    PubMed Central

    Bernard, Paul B.; Castano, Anna M.; Beitzel, Christy S.; Carlson, Vivian B.; Benke, Tim. A.

    2015-01-01

    We probed the developmental and behavioral consequences of a single early life seizure induced by kainic acid (KA-ELS) in the rat on post natal day 7. Correlates of developmental trajectory were not altered, demonstrating that long term consequences following KA-ELS are not initiated by secondary causes, such as malnourishment or alterations in maternal care. We report reduced marble burying in adult rats, suggestive of restricted interests, a trait common to experimental and clinical autism. We did not detect increased repetitive grooming during habituated cage behavior. However, we did detect reduced grooming in adult KA-ELS rats in the presence of an unfamiliar rat, supporting altered social anxiety following KA-ELS. Reanalysis of a social approach task further indicated abnormal social interactions. Taken together with previous physiological and behavioral data, these data support the hypothesis that KA-ELS lead to a latent autistic phenotype in adult rats not attributable to other early alterations in development. PMID:25659043

  18. A community-based exercise intervention transitions metabolically abnormal obese adults to a metabolically healthy obese phenotype

    PubMed Central

    Dalleck, Lance C; Van Guilder, Gary P; Richardson, Tara B; Bredle, Donald L; Janot, Jeffrey M

    2014-01-01

    Background Lower habitual physical activity and poor cardiorespiratory fitness are common features of the metabolically abnormal obese (MAO) phenotype that contribute to increased cardiovascular disease risk. The aims of the present study were to determine 1) whether community-based exercise training transitions MAO adults to metabolically healthy, and 2) whether the odds of transition to metabolically healthy were larger for obese individuals who performed higher volumes of exercise and/or experienced greater increases in fitness. Methods and results Metabolic syndrome components were measured in 332 adults (190 women, 142 men) before and after a supervised 14-week community-based exercise program designed to reduce cardiometabolic risk factors. Obese (body mass index ≥30 kg · m2) adults with two to four metabolic syndrome components were classified as MAO, whereas those with no or one component were classified as metabolically healthy but obese (MHO). After community exercise, 27/68 (40%) MAO individuals (P<0.05) transitioned to metabolically healthy, increasing the total number of MHO persons by 73% (from 37 to 64). Compared with the lowest quartiles of relative energy expenditure and change in fitness, participants in the highest quartiles were 11.6 (95% confidence interval: 2.1–65.4; P<0.05) and 7.5 (95% confidence interval: 1.5–37.5; P<0.05) times more likely to transition from MAO to MHO, respectively. Conclusion Community-based exercise transitions MAO adults to metabolically healthy. MAO adults who engaged in higher volumes of exercise and experienced the greatest increase in fitness were significantly more likely to become metabolically healthy. Community exercise may be an effective model for primary prevention of cardiovascular disease. PMID:25120373

  19. Incidence and behavioral correlates of epileptiform abnormalities in autism spectrum disorders.

    PubMed

    Mulligan, Caitlin K; Trauner, Doris A

    2014-02-01

    Autism spectrum disorders (ASD) are associated with an increased incidence of epilepsy and of epileptiform discharges on electroencephalograms. It is unknown whether epileptiform discharges correlate with symptoms of ASD. We completed a retrospective chart review of 101 patients with ASD who had overnight electroencephalograms. We looked for a relationship between epileptiform abnormalities and diagnosis, history of regression, communication skills, and other features associated with ASD. There was a higher incidence of epileptiform activity in children with stereotypies and aggressive behavior. The incidence of epileptiform abnormalities was significantly lower in Asperger's compared with more severe forms of autism. Results suggest that increasing severity of autistic symptoms may be associated with higher likelihood of epileptiform abnormalities. Whether treatment alters outcome is unknown. PMID:23872941

  20. Behavioral and Psychiatric Phenotypes in 22q11.2 Deletion Syndrome.

    PubMed

    Tang, Kerri L; Antshel, Kevin M; Fremont, Wanda P; Kates, Wendy R

    2015-10-01

    22q11.2 Deletion syndrome (22q11.2DS) is a chromosomal microdeletion that affects approximately 40 to 50 genes and affects various organs and systems throughout the body. Detection is typically achieved by fluorescence in situ hybridization after diagnosis of one of the major features of the deletion or via chromosomal microarray or noninvasive prenatal testing. The physical phenotype can include congenital heart defects, palatal and pharyngeal anomalies, hypocalcemia/hypoparathyroidism, skeletal abnormalities, and cranial/brain anomalies, although prevalence rates of all these features are variable. Cognitive function is impaired to some degree in most individuals, with prevalence rates of greater than 90% for motor/speech delays and learning disabilities. Attention, executive function, working memory, visual-spatial abilities, motor skills, and social cognition/social skills are affected. The deletion is also associated with an increased risk for behavioral disorders and psychiatric illness. The early onset of psychiatric symptoms common to 22q11.2DS disrupts the development and quality of life of individuals with the syndrome and is also a potential risk factor for later development of a psychotic disorder. This review discusses prevalence, phenotypic features, and management of psychiatric disorders commonly diagnosed in children and adolescents with 22q11.2DS, including autism spectrum disorders, attention deficit/hyperactivity disorder, anxiety disorders, mood disorders, and schizophrenia/psychotic disorders. Guidelines for the clinical assessment and management of psychiatric disorders in youth with this syndrome are provided, as are treatment guidelines for the use of psychiatric medications. PMID:26372046

  1. Omnivores Going Astray: A Review and New Synthesis of Abnormal Behavior in Pigs and Laying Hens

    PubMed Central

    Brunberg, Emma I.; Rodenburg, T. Bas; Rydhmer, Lotta; Kjaer, Joergen B.; Jensen, Per; Keeling, Linda J.

    2016-01-01

    Pigs and poultry are by far the most omnivorous of the domesticated farm animals and it is in their nature to be highly explorative. In the barren production environments, this motivation to explore can be expressed as abnormal oral manipulation directed toward pen mates. Tail biting (TB) in pigs and feather pecking (FP) in laying hens are examples of unwanted behaviors that are detrimental to the welfare of the animals. The aim of this review is to draw these two seemingly similar abnormalities together in a common framework, in order to seek underlying mechanisms and principles. Both TB and FP are affected by the physical and social environment, but not all individuals in a group express these behaviors and individual genetic and neurobiological characteristics play an important role. By synthesizing what is known about environmental and individual influences, we suggest a novel possible mechanism, common for pigs and poultry, involving the brain–gut–microbiota axis. PMID:27500137

  2. Cnga2 Knockout Mice Display Alzheimer's-Like Behavior Abnormities and Pathological Changes.

    PubMed

    Xie, Ao-Ji; Liu, En-Jie; Huang, He-Zhou; Hu, Yu; Li, Ke; Lu, Youming; Wang, Jian-Zhi; Zhu, Ling-Qiang

    2016-09-01

    Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes. PMID:26377105

  3. Omnivores Going Astray: A Review and New Synthesis of Abnormal Behavior in Pigs and Laying Hens.

    PubMed

    Brunberg, Emma I; Rodenburg, T Bas; Rydhmer, Lotta; Kjaer, Joergen B; Jensen, Per; Keeling, Linda J

    2016-01-01

    Pigs and poultry are by far the most omnivorous of the domesticated farm animals and it is in their nature to be highly explorative. In the barren production environments, this motivation to explore can be expressed as abnormal oral manipulation directed toward pen mates. Tail biting (TB) in pigs and feather pecking (FP) in laying hens are examples of unwanted behaviors that are detrimental to the welfare of the animals. The aim of this review is to draw these two seemingly similar abnormalities together in a common framework, in order to seek underlying mechanisms and principles. Both TB and FP are affected by the physical and social environment, but not all individuals in a group express these behaviors and individual genetic and neurobiological characteristics play an important role. By synthesizing what is known about environmental and individual influences, we suggest a novel possible mechanism, common for pigs and poultry, involving the brain-gut-microbiota axis. PMID:27500137

  4. Studies of planning behavior of aircraft pilots in normal, abnormal and emergency situations

    NASA Technical Reports Server (NTRS)

    Johannsen, G.; Rouse, W. B.; Hillmann, K.

    1981-01-01

    A methodology for the study of planning is presented and the results of applying the methodology within two experimental investigations of planning behavior of aircraft pilots in normal, abnormal, and emergency situations are discussed. Beyond showing that the methodology yields consistent results, these experiments also lead to concepts in terms of a dichotomy between event driven and time driven planning, subtle effects of automation on planning, and the relationship of planning to workload and flight performance.

  5. The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.

    PubMed

    Guedj, Faycal; Pennings, Jeroen L A; Ferres, Millie A; Graham, Leah C; Wick, Heather C; Miczek, Klaus A; Slonim, Donna K; Bianchi, Diana W

    2015-09-01

    Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3-21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition. PMID:25975229

  6. Early Social Enrichment Rescues Adult Behavioral and Brain Abnormalities in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Oddi, Diego; Subashi, Enejda; Middei, Silvia; Bellocchio, Luigi; Lemaire-Mayo, Valerie; Guzmán, Manuel; Crusio, Wim E; D'Amato, Francesca R; Pietropaolo, Susanna

    2015-01-01

    Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases. PMID:25348604

  7. Brain gene expression differences are associated with abnormal tail biting behavior in pigs.

    PubMed

    Brunberg, E; Jensen, P; Isaksson, A; Keeling, L J

    2013-03-01

    Knowledge about gene expression in animals involved in abnormal behaviors can contribute to the understanding of underlying biological mechanisms. This study aimed to explore the motivational background to tail biting, an abnormal injurious behavior and severe welfare problem in pig production. Affymetrix microarrays were used to investigate gene expression differences in the hypothalamus and prefrontal cortex of pigs performing tail biting, pigs receiving bites to the tail and neutral pigs who were not involved in the behavior. In the hypothalamus, 32 transcripts were differentially expressed (P < 0.05) when tail biters were compared with neutral pigs, 130 when comparing receiver pigs with neutrals, and two when tail biters were compared with receivers. In the prefrontal cortex, seven transcripts were differently expressed in tail biters when compared with neutrals, seven in receivers vs. neutrals and none in the tail biters vs. receivers. In total, 19 genes showed a different expression pattern in neutral pigs when compared with both performers and receivers. This implies that the functions of these may provide knowledge about why the neutral pigs are not involved in tail biting behavior as performers or receivers. Among these 19 transcripts were genes associated with production traits in pigs (PDK4), sociality in humans and mice (GTF2I) and novelty seeking in humans (EGF). These are in line with hypotheses linking tail biting with reduced back fat thickness and explorative behavior. PMID:23146156

  8. Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm-/- knockout mice.

    PubMed

    Chen, Ying; Curran, Christine P; Nebert, Daniel W; Patel, Krishna V; Williams, Michael T; Vorhees, Charles V

    2012-07-01

    Enhanced oxidative stress or deficient oxidative stress response in the brain is associated with neurodegenerative disorders and behavioral abnormalities. Previously we generated a knockout mouse line lacking the gene encoding glutamate-cysteine ligase modifier subunit (GCLM). Gclm(-/-) knockout (KO) mice are viable and fertile, yet exhibit only 9-35% of wild-type levels of reduced glutathione (GSH) in tissues, making them a useful model for chronic GSH depletion. Having the global absence of this gene, KO mice--from the time of conception and throughout postnatal life--experience chronic oxidative stress in all tissues, including brain. Between postnatal day (P) 60 and P100, we carried out behavioral phenotyping tests in adults, comparing male and female Gclm(-/-) with Gclm(-/-) wild-type (WT) littermates. Compared with WT, KO mice exhibited: subnormal anxiety in the elevated zero maze; normal overall exploratory open-field activity, but slightly more activity in the peripheral zones; normal acoustic startle and prepulse inhibition reactions; normal novel object recognition with increased time attending to the stimulus objects; slightly reduced latencies to reach a random marked platform in the Morris water maze; normal spatial learning and memory in multiple phases of the Morris water maze; and significantly greater hyperactivity in response to methamphetamine in the open field. These findings are generally in agreement with two prior studies on these mice and suggest that the brain is remarkably resilient to lowered GSH levels, implying significant reserve capacity to regulate reactive oxygen species-but with regional differences such that anxiety and stimulated locomotor control brain regions might be more vulnerable. PMID:22580179

  9. Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm(−/−) knockout mice

    PubMed Central

    Chen, Ying; Curran, Christine P.; Nebert, Daniel W.; Patel, Krishna V.; Williams, Michael T.; Vorhees, Charles V.

    2012-01-01

    Enhanced oxidative stress or deficient oxidative stress response in the brain is associated with neurodegenerative disorders and behavioral abnormalities. Previously we generated a knockout mouse line lacking the gene encoding γ-glutamylcysteine ligase modifier subunit (GCLM). Gclm(−/−) knockout (KO) mice are viable and fertile, yet exhibit only 9–35% of wild-type levels of reduced glutathione (GSH) in tissues, making them a useful model for chronic GSH depletion. Having the global absence of this gene, KO mice—from the time of conception and throughout postnatal life—experience chronic oxidative stress in all tissues, including brain. Between postnatal day (P) 60 and P100, we carried out behavioral phenotyping tests in adults, comparing male and female Gclm(−/−) with Gclm(+/+) wild-type (WT) littermates. Compared with WT, KO mice exhibited: subnormal anxiety in the elevated zero maze; normal overall exploratory open-field activity, but slightly more activity in the peripheral zones; normal acoustic startle and prepulse inhibition reactions; normal novel object recognition with increased time attending to the stimulus objects; slightly reduced latencies to reach a random marked platform in the Morris water maze; normal spatial learning and memory in multiple phases of the Morris water maze; and significantly greater hyperactivity in response to methamphetamine in the open field. These findings are in general agreement with two prior studies on these mice and suggest that the brain is remarkably resilient to lowered GSH levels, implying significant reserve capacity to regulate reactivity oxygen species—but with regional differences such that anxiety and stimulated locomotor control brain regions might be more vulnerable. PMID:22580179

  10. Studies of planning behavior of aircraft pilots in normal, abnormal, and emergency situations

    NASA Technical Reports Server (NTRS)

    Johannsen, G.; Rouse, W. B.; Hillmann, K.

    1981-01-01

    A methodology for the study of human planning behavior in complex dynamic systems is presented and applied to the study of aircraft pilot behavior in normal, abnormal and emergency situations. The method measures the depth of planning, that is the level of detail employed with respect to a specific task, according to responses to a verbal questionnaire, and compares planning depth with variables relating to time, task criticality and the probability of increased task difficulty. In two series of experiments, depth of planning was measured on a five- or ten-point scale during various phases of flight in a HFB-320 simulator under normal flight conditions, abnormal scenarios involving temporary runway closure due to snow removal or temporary CAT-III conditions due to a dense fog, and emergency scenarios involving engine shut-down or hydraulic pressure loss. Results reveal a dichotomy between event-driven and time-driven planning, different effects of automation in abnormal and emergency scenarios and a low correlation between depth of planning and workload or flight performance.

  11. Abnormal animal behavior prior to the Vrancea (Romania) major subcrustal earthquakes

    NASA Astrophysics Data System (ADS)

    Constantin, Angela; Pantea, Aurelian

    2013-04-01

    The goal of this paper is to present some observations about abnormal animal behavior prior and during of some Romanian subcrustal earthquakes. The major Vrancea earthquakes of 4 March 1977 (Mw = 7.4, Imax = IX-X MSK), 30 August 1986 (Mw = 7.1, Io = VIII-IX MSK) and 30 May 1990 (Mw = 6.9, Io = VIII MSK), were preceded by extensive occurrences of anomalous animal behavior. These data were collected immediately after the earthquakes from the areas affected by these. Some species of animals became excited, nervous and panicked before and during the earthquakes, such as: dogs (barking and running in panic), cats, snakes, mice and rats (came into the houses and have lost their fear), birds (hens, geese, parrots), horses, fishes etc. These strange manifestations of the animals were observed on the entire territory of country, especially in the extra-Carpathian area. This unusual behavior was noticed within a few hours to days before the seismic events, but for the most of cases the time of occurrence was within two hours of the quakes. We can hope that maybe one day the abnormal animal behavior will be used as a reliable seismic precursor for the intermediate depth earthquakes.

  12. Antisocial behavior, psychopathic features and abnormalities in reward and punishment processing in youth.

    PubMed

    Byrd, Amy L; Loeber, Rolf; Pardini, Dustin A

    2014-06-01

    A better understanding of what leads youth to initially engage in antisocial behavior (ASB) and more importantly persist with such behaviors into adulthood has significant implications for prevention and intervention efforts. A considerable number of studies using behavioral and neuroimaging techniques have investigated abnormalities in reward and punishment processing as potential causal mechanisms underlying ASB. However, this literature has yet to be critically evaluated, and there are no comprehensive reviews that systematically examine and synthesize these findings. The goal of the present review is twofold. The first aim is to examine the extent to which youth with ASB are characterized by abnormalities in (1) reward processing; (2) punishment processing; or (3) both reward and punishment processing. The second aim is to evaluate whether aberrant reward and/or punishment processing is specific to or most pronounced in a subgroup of antisocial youth with psychopathic features. Studies utilizing behavioral methods are first reviewed, followed by studies using functional magnetic resonance imaging. An integration of theory and research across multiple levels of analysis is presented in order to provide a more comprehensive understanding of reward and punishment processing in antisocial youth. Findings are discussed in terms of developmental and contextual considerations, proposed future directions and implications for intervention. PMID:24357109

  13. 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…

  14. Pharmacological screening of bryophyte extracts that inhibit growth and induce abnormal phenotypes in human HeLa cancer cells.

    PubMed

    Krzaczkowski, Lucie; Wright, Michel; Rebérioux, Delphine; Massiot, Georges; Etiévant, Chantal; Gairin, Jean Edouard

    2009-08-01

    Antitumor activities of substances from natural sources apart from vascular plants and micro-organisms have been poorly investigated. Here we report on a pharmacological screening of a bryophyte extract library using a phenotypic cell-based assay revealing microtubules, centrosomes and DNA. Among the 219 moss extracts tested, we identified 41 extracts acting on cell division with various combinations of significant effects on interphasic and mitotic cells. Seven extracts were further studied using a cell viability assay, cell cycle analysis and the phenotypic assay. Three distinct pharmacological patterns were identified including two unusual phenotypes. PMID:19709324

  15. Who Should Report Abnormal Behavior at Preschool Age? The Case of Behavioral Inhibition

    ERIC Educational Resources Information Center

    Ballespi, Sergi; Jane, Ma Claustre; Riba, Ma Dolors

    2012-01-01

    Children who are behaviorally "inhibited"--a condition at the extreme of the behavioral inhibition dimension--experience distress in uncertain social situations. Although parents and teachers are in the best position to detect this condition, they rarely agree. This study aims to analyze the agreement between parents and teachers and to examine…

  16. Repeated transcranial direct current stimulation prevents abnormal behaviors associated with abstinence from chronic nicotine consumption.

    PubMed

    Pedron, Solène; Monnin, Julie; Haffen, Emmanuel; Sechter, Daniel; Van Waes, Vincent

    2014-03-01

    Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders. PMID:24154668

  17. 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. PMID:26861717

  18. A survey of abnormal repetitive behaviors in North American river otters housed in zoos.

    PubMed

    Morabito, Paige; Bashaw, Meredith J

    2012-01-01

    Stereotypic behaviors, indicating poor welfare and studied in a variety of species (especially carnivores), appear related to characteristics of current and past environments. Although North American river otters (Lontra canadensis) often develop abnormal, repetitive, possibly stereotypic behaviors, no published reports describe otter housing and management or characterize how these variables relate to abnormal repetitive behavior (ARB) occurrence. The first author developed surveys to gather data on housing, individual history, management, and the prevalence of ARBs in otters housed in facilities accredited by the Association of Zoos and Aquariums. Consistent with anecdotal evidence that otters are prone to ARBs, 46% of river otters in the study exhibit them. ARBs were mostly locomotor and often preceded feeding. Exhibits where otters were fed and trained housed a greater percentage of nonhuman animals with ARBs. This study supports the Tarou, Bloomsmith, and Maple (2005) report that more hands-on management is associated with higher levels of ARBs because management efforts are only for animals with ARBs. Escape motivation, breeding season, feeding cues, and ability to forage may affect ARBs in river otters and should be investigated. PMID:22742198

  19. Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors.

    PubMed

    Erbel-Sieler, Claudia; Dudley, Carol; Zhou, Yudong; Wu, Xinle; Estill, Sandi Jo; Han, Tina; Diaz-Arrastia, Ramon; Brunskill, Eric W; Potter, S Steven; McKnight, Steven L

    2004-09-14

    Laboratory mice bearing inactivating mutations in the genes encoding the NPAS1 and NPAS3 transcription factors have been shown to exhibit a spectrum of behavioral and neurochemical abnormalities. Behavioral abnormalities included diminished startle response, as measured by prepulse inhibition, and impaired social recognition. NPAS1/NPAS3-deficient mice also exhibited stereotypic darting behavior at weaning and increased locomotor activity. Immunohistochemical staining assays showed that the NPAS1 and NPAS3 proteins are expressed in inhibitory interneurons and that the viability and anatomical distribution of these neurons are unaffected by the absence of either transcription factor. Adult brain tissues from NPAS3- and NPAS1/NPAS3-deficient mice exhibited a distinct reduction in reelin, a large, secreted protein whose expression has been reported to be attenuated in the postmortem brain tissue of patients with schizophrenia. These observations raise the possibility that a regulatory program controlled in inhibitory interneurons by the NPAS1 and NPAS3 transcription factors may be either substantively or tangentially relevant to psychosis. PMID:15347806

  20. Identifying Behavioral Phenotypes and Heterogeneity in Heart Valve Surface Endothelium.

    PubMed

    Blancas, Alicia A; Balaoing, Liezl R; Acosta, Francisca M; Grande-Allen, K Jane

    2016-01-01

    Heart valvular endothelial cells (VECs) are distinct from vascular endothelial cells (ECs), but have an uncertain context within the spectrum of known endothelial phenotypes, including lymphatic ECs (LECs). Profiling the phenotypes of the heart valve surface VECs would facilitate identification of a proper seeding population for tissue-engineered valves, as well as elucidate mechanisms of valvular disease. Porcine VECs and porcine aortic ECs (AECs) were isolated from pig hearts and characterized to assess known EC and LEC markers. A transwell migration assay determined their propensity to migrate toward vascular endothelial growth factor, an angiogenic stimulus, over 24 h. Compared to AECs, Flt-1 was expressed on almost double the percentage of VECs, measured as 74 versus 38%. The expression of angiogenic EC markers CXCR4 and DLL4 was >90% on AECs, whereas VECs showed only 35% CXCR4+ and 47% DLL4+. AECs demonstrated greater migration (71.5 ± 11.0 cells per image field) than the VECs with 30.0 ± 15.3 cells per image field (p = 0.032). In total, 30% of VECs were positive for LYVE1+/Prox1+, while these markers were absent in AECs. In conclusion, the population of cells on the surface of heart valves is heterogeneous, consisting largely of nonangiogenic VECs and a subset of LECs. Previous studies have indicated the presence of LECs within the interior of the valves; however, this is the first study to demonstrate their presence on the surface. Identification of this unique endothelial mixture is a step forward in the development of engineered valve replacements as a uniform EC seeding population may not be the best option to maximize transplant success. PMID:27144771

  1. Prenatal diagnosis of sub-microscopic partial trisomy 10q using chromosomal microarray analysis in a phenotypically abnormal fetus with normal karyotype.

    PubMed

    Browne, P C; Adam, S; Badr, M; Brooks, C R; Edwards, J; Walker, P; Mohamed, S; Gregg, A R

    2016-05-17

    Partial trisomy of the 10q region was originally reported in 1979 [1]. For 25 years, the diagnosis was made microscopically based on large, visible insertions in the region identified by karyotype analysis. Previous case reports have included both unbalanced translocations and large duplications/insertions in the 10q region [2]. Probands with partial trisomy 10q syndrome often have an abnormal phenotype that may include developmental delay [3-5], craniofacial abnormalities [3, 5], talipes (clubfoot) [2], microcephaly [2-4], or congenital heart disease [2-6]. Prenatal diagnoses by karyotype have been made following ultrasound diagnosis of sacrococcygeal teratoma [7], renal pyelectasis [3, 8-10], and other fetal abnormalities [4]. In this case, we report the first prenatal diagnosis of partial trisomy 10q (10q22.3-10q23.2) with a normal karyotype and an abnormal chromosomal microarray analysis (CMA). This is the smallest copy number variant (CNV) (7.5 Mb) in the 10q22.3-10q23.2 regions yet reported. PMID:27197934

  2. Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.

    PubMed

    van der Crabben, Saskia N; Harakalova, Magdalena; Brilstra, Eva H; van Berkestijn, Frédérique M C; Hofstede, Floris C; van Vught, Adrianus J; Cuppen, Edwin; Kloosterman, Wigard; Ploos van Amstel, Hans Kristian; van Haaften, Gijs; van Haelst, Mieke M

    2014-01-01

    Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family. PMID:24259184

  3. Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

    ERIC Educational Resources Information Center

    Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

    2012-01-01

    The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome;…

  4. Environmental Influences on the Behavioral Phenotype of Angelman Syndrome

    ERIC Educational Resources Information Center

    Horsler, Kate; Oliver, Chris

    2006-01-01

    Using observational methods, we examined the social influences on laughing and smiling behavior in children with Angelman syndrome by systematically manipulating aspects of social interaction. Seven boys and 4 girls who were between 4 and 11 years of age and who had a confirmed maternal deletion of chromosome 15q11-q13 completed the study. Each…

  5. Trichloroethylene exposure aggravates behavioral abnormalities in mice that are deficient in superoxide dismutase.

    PubMed

    Otsuki, Noriyuki; Homma, Takujiro; Fujiwara, Hiroki; Kaneko, Kenya; Hozumi, Yasukazu; Shichiri, Mototada; Takashima, Mizuki; Ito, Junitsu; Konno, Tasuku; Kurahashi, Toshihiro; Yoshida, Yasukazu; Goto, Kaoru; Fujii, Satoshi; Fujii, Junichi

    2016-08-01

    Trichloroethylene (TCE) has been implicated as a causative agent for Parkinson's disease (PD). The administration of TCE to rodents induces neurotoxicity associated with dopaminergic neuron death, and evidence suggests that oxidative stress as a major player in the progression of PD. Here we report on TCE-induced behavioral abnormality in mice that are deficient in superoxide dismutase 1 (SOD1). Wild-type (WT) and SOD1-deficient (Sod1(-/-)) mice were intraperitoneally administered TCE (500 mg/kg) over a period of 4 weeks. Although the TCE-administrated Sod1(-/-) mice showed marked abnormal motor behavior, no significant differences were observed among the experimental groups by biochemical and histopathological analyses. However, treating mouse neuroblastoma-derived NB2a cells with TCE resulted in the down regulation of the SOD1 protein and elevated oxidative stress under conditions where SOD1 production was suppressed. Taken together, these data indicate that SOD1 plays a pivotal role in protecting motor neuron function against TCE toxicity. PMID:27166294

  6. Mice lacking the Parkinson's related GPR37/PAEL receptor show non-motor behavioral phenotypes: age and gender effect.

    PubMed

    Mandillo, S; Golini, E; Marazziti, D; Di Pietro, C; Matteoni, R; Tocchini-Valentini, G P

    2013-06-01

    Non-motor symptoms in Parkinson's disease (PD) have been often described at different stages of the disease but they are poorly understood. We observed specific phenotypes related to these symptoms in mice lacking the PD-associated GPR37/PAEL receptor. GPR37 is an orphan G-protein-coupled receptor highly expressed in the mammalian central nervous system. It is a substrate of parkin and it is involved in the pathogenesis of PD. GPR37 interacts with the dopamine transporter (DAT), modulating nigro-striatal dopaminergic signaling and behavioral responses to amphetamine and cocaine. GPR37 knockout (KO) mice are resistant to MPTP and exhibit several motor behavioral abnormalities related to altered dopaminergic system function. To evaluate non-motor behavioral domains, adult and aged, male and female GPR37 KO mice and their wild-type (WT) littermates were analyzed in a series of cross-sectional studies. Aged GPR37 KO female mice showed mild improvements in olfactory function, while anxiety and depression-like behaviors appeared to be significantly increased. A reduction of the startle response to acoustic stimuli was observed only in adult GPR37 KO mice of both genders. Furthermore, HPLC analysis of major neurotransmitter levels revealed gender differences in the striatum, hippocampus and olfactory bulb of mutant mice. The absence of GPR37 receptor could have a neuroprotective effect in an age and gender-dependent manner, and the study of this receptor could be valuable in the search for novel therapeutic targets. PMID:23574697

  7. Elevated PEM (Phasic Electromyographic Metric) Rates Identify Rapid Eye Movement Behavior Disorder Patients on Nights Without Behavioral Abnormalities

    PubMed Central

    Bliwise, Donald L.; Rye, David B.

    2008-01-01

    Objective: To determine the validity of the phasic electromyographic metric (PEM) to differentiate patients with a history suggestive of rapid eye movement behavior disorder (REMBD) on laboratory nights without overt dream-enactment behavior. Methods: PEM was quantified as the % of 2.5-sec intervals with phasic muscle activity of 100-msec duration with an amplitude of at least 4 times background activity in 11 patients and 31 elderly controls. Data were derived from both REM and NREM sleep from 5 muscle groups (mentalis, left/right anterior tibialis, left/right brachioradialis). Results: Relative to controls, REMBD patients had significantly higher levels of PEM activity in all recordings. The largest differences occurred during REM sleep for the mentalis and brachioradialis channels. Similar results were obtained by limiting quantification of PEM to the final REM period of the night and could be accomplished by individuals with no previous familiarity with polysomnography. Discussion: PEM may be a useful metric to characterize the REM related phasic muscle activity on patients with a history of REMBD, even when no overt dream-enactment behaviors are detected on a laboratory night. Citation: Bliwise DL; Rye DB. Elevated PEM (phasic electromyographic metric) rates identify rapid eye movement behavior disorder patients on nights without behavioral abnormalities. SLEEP 2008;31(6):853–857. PMID:18548830

  8. Neurocognitive Phenotypes and Genetic Dissection of Disorders of Brain and Behavior

    PubMed Central

    Congdon, Eliza; Poldrack, Russell A.; Freimer, Nelson B.

    2014-01-01

    Summary Elucidating the molecular mechanisms underlying quantitative neurocognitive phenotypes will further our understanding of the brain’s structural and functional architecture and advance the diagnosis and treatment of the psychiatric disorders that these traits underlie. Although many neurocognitive traits are highly heritable, little progress has been made in identifying genetic variants unequivocally associated with these phenotypes. A major obstacle to such progress is the difficulty in identifying heritable neurocognitive measures which are precisely defined, systematically assessed and represent unambiguous mental constructs, yet are amenable to the high-throughput phenotyping necessary to obtain adequate power for genetic association studies. In this perspective we compare the current status of genetic investigations of neurocognitive phenotypes to that of other categories of biomedically relevant traits and suggest strategies for genetically dissecting traits that may underlie disorders of brain and behavior. PMID:20955930

  9. Chromosomal Abnormalities and Schizophrenia

    PubMed Central

    BASSETT, ANNE S.; CHOW, EVA W.C.; WEKSBERG, ROSANNA

    2011-01-01

    Schizophrenia is a common and serious psychiatric illness with strong evidence for genetic causation, but no specific loci yet identified. Chromosomal abnormalities associated with schizophrenia may help to understand the genetic complexity of the illness. This paper reviews the evidence for associations between chromosomal abnormalities and schizophrenia and related disorders. The results indicate that 22q11.2 microdeletions detected by fluorescence in-situ hybridization (FISH) are significantly associated with schizophrenia. Sex chromosome abnormalities seem to be increased in schizophrenia but insufficient data are available to indicate whether schizophrenia or related disorders are increased in patients with sex chromosome aneuploidies. Other reports of chromosomal abnormalities associated with schizophrenia have the potential to be important adjuncts to linkage studies in gene localization. Advances in molecular cytogenetic techniques (i.e., FISH) have produced significant increases in rates of identified abnormalities in schizophrenia, particularly in patients with very early age at onset, learning difficulties or mental retardation, or dysmorphic features. The results emphasize the importance of considering behavioral phenotypes, including adult onset psychiatric illnesses, in genetic syndromes and the need for clinicians to actively consider identifying chromosomal abnormalities and genetic syndromes in selected psychiatric patients. PMID:10813803

  10. 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…

  11. Reproductive and behavioral abnormalities in tree swallows with high levels of PCB contamination

    SciTech Connect

    McCarty, J.; Secord, A.; Tillitt, D.

    1995-12-31

    Tree Swallows (Tachycineta bicolor) breeding along the Hudson River forage extensively on PCB contaminated insects that emerge from the river. The authors studied the reproductive ecology and behavior of tree swallows breeding at several sites along the Hudson River. These sites vary in the severity of PCB contamination. PCB levels in both eggs and chicks were found to be among the highest ever reported in this species, with concentrations comparable to those found in aquatic organisms in the Hudson River. In 1994 reproductive success at PCB contaminated sites was significantly impaired, relative to other sites in New York. Reduced reproductive success was largely attributed to high levels of nest abandonment during incubation and reduced hatchability of eggs. Growth and development of nestlings was not significantly impaired. Abnormal nest building behavior was also noted in 1994, and this was studied in detail in 1995. Nests from contaminated areas are significantly smaller than those at a nearby reference site and at other sites in New York. The authors suggest that the reduced reproductive outputs at these sites are, in large part, a result of effects on the behavior of incubating females. The population-level implications of these patterns are unknown.

  12. Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe

    SciTech Connect

    Kenworthy, L.; Charnas, L.

    1995-11-20

    The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Although there is a wide range of intellectual function in affected individuals, it is often compromised by a high prevalence of maladaptive behaviors, including tantrums, stubbornness, and stereotypy. Whether these behaviors simply reflect the multiple disabilities found in some developmentally impaired individuals with or without OCRL, or a specific genetically-determined behavioral phenotype of OCRL, is unknown. Controls were matched for sex, age, visual impairment, and adaptive functioning and compared with OCRL patients on three standardized measures of adaptive/maladaptive behaviors. Forty-three matched pairs of OCRL and control subjects were identified. Both groups were similar in communication, daily living, socialization, and motor skills, in socioeconomic status, and in measures of parental stress. Individuals with OCRL displayed significantly more severe maladaptive behaviors than control boys, as measured by the Vineland Adaptive Behavior Scales (VABS), with 41% of the difference between the two groups attributable to the diagnosis of OCRL. Twelve maladaptive behaviors measured on the VABS appeared more frequently in OCRL than in controls. Five of these 12 behaviors, i.e., temper tantrums, irritability, complex repetitive behaviors (stereotypy)/mannerisms, obsessions/unusual preoccupations, and negativism, were identified by discriminant function analysis to significantly distinguish between controls and OCRL individuals. The diagnosis of OCRL is associated with a behavioral phenotype consisting of temper tantrums, stereotypy, stubbornness, and obsessions/unusual preoccupations. This phenotype cannot be attributed solely to the visual, motor, and intellectual disabilities characteristic of OCRL, and may represent a specific effect of the OCRL gene on the central nervous system. 57 refs., 5 tabs.

  13. Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder.

    PubMed

    Currais, A; Farrokhi, C; Dargusch, R; Goujon-Svrzic, M; Maher, P

    2016-03-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene-environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition. PMID:26055422

  14. Variables influencing the origins of diverse abnormal behaviors in a large sample of captive chimpanzees (Pan troglodytes).

    PubMed

    Nash, L T; Fritz, J; Alford, P A; Brent, L

    1999-01-01

    The developmental origin of abnormal behaviors is generally associated with early rearing environments that lack sufficient physical and sensory stimulation. However, other factors should also be considered. A large sample of captive chimpanzees (128 males and 140 females) was surveyed for the presence or absence of 18 abnormal behaviors. Origin variables included the subject's source (zoo, pet, performer, or laboratory), rearing (mother- or hand-reared), and sex. Animals were assessed while held at the Primate Foundation of Arizona, University of Texas M. D. Anderson Cancer Center, or White Sands Research Center. There was a confound among origin variables; more hand-reared animals than expected were from laboratories. Logistic regression tested the relationship of rearing and source, with sex as a secondary predictor variable, to each of the abnormal behaviors. There was no clear association between any abnormal behavior and source. However, for coprophagy, relative to animals from the laboratory, zoo animals tended to show a higher prevalence, while performers tended to show a lower prevalence (when rearing and sex were controlled). Rocking and self-sucking were significantly more likely in hand-reared animals. Coprophagy and depilation of self were significantly more likely in mother-reared animals. When rearing and source were statistically controlled, the only significant sex difference was a higher prevalence of coprophagy in females and a higher prevalence of rocking in males. In a second, smaller sample of 25 males and 33 females from Southwest Foundation for Biomedical Research, no significant sex association was found for coprophagy, urophagy, rocking, or self-depilation. In this second sample, coprophagy was also significantly more likely in mother-reared than hand-reared subjects. The association of some abnormal behaviors with mother-rearing suggests that some form of social learning may be involved in the origin of some of these behavior patterns

  15. Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene

    PubMed Central

    2013-01-01

    Background Intellectual disability (ID) is often associated with behavioral problems or disorders. Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 – 1% in individuals with ID) associated with EEG and behavioral problems. Methods We assessed five GRIN2B mutation carriers aged between 3 and 14 years clinically and via standardized questionnaires to delineate a detailed behavioral phenotype. Parents and teachers rated problem behavior of their affected children by completing the Developmental Behavior Checklist (DBC) and the Conners’ Rating Scales Revised (CRS-R:L). Results All individuals had mild to severe ID and needed guidance in daily routine. They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span. Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported. Conclusion Our observations provide an initial delineation of the behavioral phenotype of GRIN2B mutation carriers. PMID:23718928

  16. ENU-mutagenesis mice with a non-synonymous mutation in Grin1 exhibit abnormal anxiety-like behaviors, impaired fear memory, and decreased acoustic startle response

    PubMed Central

    2013-01-01

    Background The Grin1 (glutamate receptor, ionotropic, NMDA1) gene expresses a subunit of N-methyl-D-aspartate (NMDA) receptors that is considered to play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. Grin1 is a candidate susceptibility gene for neuropsychiatric disorders, including schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). In our previous study, we examined an N-ethyl-N-nitrosourea (ENU)-generated mutant mouse strain (Grin1Rgsc174/Grin1+) that has a non-synonymous mutation in Grin1. These mutant mice showed hyperactivity, increased novelty-seeking to objects, and abnormal social interactions. Therefore, Grin1Rgsc174/Grin1+ mice may serve as a potential animal model of neuropsychiatric disorders. However, other behavioral characteristics related to these disorders, such as working memory function and sensorimotor gating, have not been fully explored in these mutant mice. In this study, to further investigate the behavioral phenotypes of Grin1Rgsc174/Grin1+ mice, we subjected them to a comprehensive battery of behavioral tests. Results There was no significant difference in nociception between Grin1Rgsc174/Grin1+ and wild-type mice. The mutants did not display any abnormalities in the Porsolt forced swim and tail suspension tests. We confirmed the previous observations that the locomotor activity of these mutant mice increased in the open field and home cage activity tests. They displayed abnormal anxiety-like behaviors in the light/dark transition and the elevated plus maze tests. Both contextual and cued fear memory were severely deficient in the fear conditioning test. The mutant mice exhibited slightly impaired working memory in the eight-arm radial maze test. The startle amplitude was markedly decreased in Grin1Rgsc174/Grin1+ mice, whereas no significant differences between genotypes were detected in the prepulse inhibition (PPI) test. The mutant mice showed no obvious

  17. Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes.

    PubMed

    Ek, Fredrik; Malo, Marcus; Åberg Andersson, Madelene; Wedding, Christoffer; Kronborg, Joel; Svensson, Peder; Waters, Susanna; Petersson, Per; Olsson, Roger

    2016-05-18

    Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D1-D4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D1 and D3 whereas D2 and D4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand-receptor interactions. PMID

  18. Transgenic rats overexpressing the human MrgX3 gene show cataracts and an abnormal skin phenotype

    SciTech Connect

    Kaisho, Yoshihiko . E-mail: Kaisho_Yoshihiko@takeda.co.jp; Watanabe, Takuya; Nakata, Mitsugu; Yano, Takashi; Yasuhara, Yoshitaka; Shimakawa, Kozo; Mori, Ikuo; Sakura, Yasufumi; Terao, Yasuko; Matsui, Hideki; Taketomi, Shigehisa

    2005-05-13

    The human MrgX3 gene, belonging to the mrgs/SNSRs (mass related genes/sensory neuron specific receptors) family, was overexpressed in transgenic rats using the actin promoter. Two animal lines showed cataracts with liquification/degeneration and swelling of the lens fiber cells. The transient epidermal desquamation was observed in line with higher gene expression. Histopathology of the transgenic rats showed acanthosis and focal parakeratosis. In the epidermis, there was an increase in cellular keratin 14, keratin 10, and loricrin, as well as PGP 9.5 in innervating nerve fibers. These phenotypes accompanied an increase in the number of proliferating cells. These results suggest that overexpression of the human MrgX3 gene causes a disturbance of the normal cell-differentiation process.

  19. 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

  20. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities.

    PubMed

    Wöhr, M; Orduz, D; Gregory, P; Moreno, H; Khan, U; Vörckel, K J; Wolfer, D P; Welzl, H; Gall, D; Schiffmann, S N; Schwaller, B

    2015-01-01

    Gene mutations and gene copy number variants are associated with autism spectrum disorders (ASDs). Affected gene products are often part of signaling networks implicated in synapse formation and/or function leading to alterations in the excitation/inhibition (E/I) balance. Although the network of parvalbumin (PV)-expressing interneurons has gained particular attention in ASD, little is known on PV's putative role with respect to ASD. Genetic mouse models represent powerful translational tools for studying the role of genetic and neurobiological factors underlying ASD. Here, we report that PV knockout mice (PV(-/-)) display behavioral phenotypes with relevance to all three core symptoms present in human ASD patients: abnormal reciprocal social interactions, impairments in communication and repetitive and stereotyped patterns of behavior. PV-depleted mice also showed several signs of ASD-associated comorbidities, such as reduced pain sensitivity and startle responses yet increased seizure susceptibility, whereas no evidence for behavioral phenotypes with relevance to anxiety, depression and schizophrenia was obtained. Reduced social interactions and communication were also observed in heterozygous (PV(+/-)) mice characterized by lower PV expression levels, indicating that merely a decrease in PV levels might be sufficient to elicit core ASD-like deficits. Structural magnetic resonance imaging measurements in PV(-/-) and PV(+/-) mice further revealed ASD-associated developmental neuroanatomical changes, including transient cortical hypertrophy and cerebellar hypoplasia. Electrophysiological experiments finally demonstrated that the E/I balance in these mice is altered by modification of both inhibitory and excitatory synaptic transmission. On the basis of the reported changes in PV expression patterns in several, mostly genetic rodent models of ASD, we propose that in these models downregulation of PV might represent one of the points of convergence, thus providing a

  1. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities

    PubMed Central

    Wöhr, M; Orduz, D; Gregory, P; Moreno, H; Khan, U; Vörckel, K J; Wolfer, D P; Welzl, H; Gall, D; Schiffmann, S N; Schwaller, B

    2015-01-01

    Gene mutations and gene copy number variants are associated with autism spectrum disorders (ASDs). Affected gene products are often part of signaling networks implicated in synapse formation and/or function leading to alterations in the excitation/inhibition (E/I) balance. Although the network of parvalbumin (PV)-expressing interneurons has gained particular attention in ASD, little is known on PV's putative role with respect to ASD. Genetic mouse models represent powerful translational tools for studying the role of genetic and neurobiological factors underlying ASD. Here, we report that PV knockout mice (PV−/−) display behavioral phenotypes with relevance to all three core symptoms present in human ASD patients: abnormal reciprocal social interactions, impairments in communication and repetitive and stereotyped patterns of behavior. PV-depleted mice also showed several signs of ASD-associated comorbidities, such as reduced pain sensitivity and startle responses yet increased seizure susceptibility, whereas no evidence for behavioral phenotypes with relevance to anxiety, depression and schizophrenia was obtained. Reduced social interactions and communication were also observed in heterozygous (PV+/−) mice characterized by lower PV expression levels, indicating that merely a decrease in PV levels might be sufficient to elicit core ASD-like deficits. Structural magnetic resonance imaging measurements in PV−/− and PV+/− mice further revealed ASD-associated developmental neuroanatomical changes, including transient cortical hypertrophy and cerebellar hypoplasia. Electrophysiological experiments finally demonstrated that the E/I balance in these mice is altered by modification of both inhibitory and excitatory synaptic transmission. On the basis of the reported changes in PV expression patterns in several, mostly genetic rodent models of ASD, we propose that in these models downregulation of PV might represent one of the points of convergence, thus

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

    PubMed Central

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

    2016-01-01

    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. PMID:27532047

  3. 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. PMID:27532047

  4. Tspyl2 Loss-of-Function Causes Neurodevelopmental Brain and Behavior Abnormalities in Mice.

    PubMed

    Li, Qi; Chan, Siu Yuen; Wong, Kwun K; Wei, Ran; Leung, Yu On; Ding, Abby Y; Hui, Tomy C K; Cheung, Charlton; Chua, Siew E; Sham, Pak C; Wu, Ed X; McAlonan, Grainne M

    2016-07-01

    Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more 'sensitive' to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits. PMID:26826030

  5. Knockout of the two evolutionarily conserved peroxisomal 3-ketoacyl-CoA thiolases in Arabidopsis recapitulates the abnormal inflorescence meristem 1 phenotype.

    PubMed

    Wiszniewski, Andrew A G; Bussell, John D; Long, Rowena L; Smith, Steven M

    2014-12-01

    A specific function for peroxisomal β-oxidation in inflorescence development in Arabidopsis thaliana is suggested by the mutation of the abnormal inflorescence meristem 1 gene, which encodes one of two peroxisomal multifunctional proteins. Therefore, it should be possible to identify other β-oxidation mutants that recapitulate the aim1 phenotype. Three genes encode peroxisomal 3-ketoacyl-CoA thiolase (KAT) in Arabidopsis. KAT2 and KAT5 are present throughout angiosperms whereas KAT1 is a Brassicaceae-specific duplication of KAT2 expressed at low levels in Arabidopsis. KAT2 plays a dominant role in all known aspects of peroxisomal β-oxidation, including that of fatty acids, pro-auxins, jasmonate precursor oxophytodienoic acid, and trans-cinnamic acid. The functions of KAT1 and KAT5 are unknown. Since KAT5 is conserved throughout vascular plants and expressed strongly in flowers, kat2 kat5 double mutants were generated. These were slow growing, had abnormally branched inflorescences, and ectopic organ growth. They made viable pollen, but produced no seed indicating that infertility was due to defective gynaecium function. These phenotypes are strikingly similar to those of aim1. KAT5 in the Brassicaceae encodes both cytosolic and peroxisomal proteins and kat2 kat5 defects could be complemented by the re-introduction of peroxisomal (but not cytosolic) KAT5. It is concluded that peroxisomal KAT2 and KAT5 have partially redundant functions and operate downstream of AIM1 to provide β-oxidation functions essential for inflorescence development and fertility. PMID:25297549

  6. Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.

    PubMed

    Chen, Y; Curran, C P; Nebert, D W; Patel, K V; Williams, M T; Vorhees, C V

    2012-04-01

    Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reactive oxygen species during metabolic processes. Various species--including humans and other primates--suffer mutations in the GULO gene encoding L-gulono-γ-lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo-/- knockout (KO) mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo-/- KO mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo+/+ wild-type littermates, ascorbate-deficient Gulo-/- mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo-/- mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction. PMID:22296218

  7. GABAergic influences on ORX receptor-dependent abnormal motor behaviors and neurodegenerative events in fish

    SciTech Connect

    Facciolo, Rosa Maria; Crudo, Michele; Giusi, Giuseppina; Canonaco, Marcello

    2010-02-15

    At date the major neuroreceptors i.e. gamma-aminobutyric acid{sub A} (GABA{sub A}R) and orexin (ORXR) systems are beginning to be linked to homeostasis, neuroendocrine and emotional states. In this study, intraperitoneal treatment of the marine teleost Thalassoma pavo with the highly selective GABA{sub A}R agonist (muscimol, MUS; 0,1 mug/g body weight) and/or its antagonist bicuculline (BIC; 1 mug/g body weight) have corroborated a GABA{sub A}ergic role on motor behaviors. In particular, MUS induced moderate (p < 0.05) and great (p < 0.01) increases of swimming towards food sources and resting states after 24 (1 dose) and 96 (4 doses) h treatment sessions, respectively, when compared to controls. Conversely, BIC caused a very strong (p < 0.001) reduction of the former behavior and in some cases convulsive swimming. From the correlation of BIC-dependent behavioral changes to neuronal morphological and ORXR transcriptional variations, it appeared that the disinhibitory action of GABA{sub A}R was very likely responsible for very strong and strong ORXR mRNA reductions in cerebellum valvula and torus longitudinalis, respectively. Moreover these effects were linked to evident ultra-structural changes such as shrunken cell membranes and loss of cytoplasmic architecture. In contrast, MUS supplied a very low, if any, argyrophilic reaction in hypothalamic and mesencephalic regions plus a scarce level of ultra-structural damages. Interestingly, combined administrations of MUS + BIC were not related to consistent damages, aside mild neuronal alterations in motor-related areas such as optic tectum. Overall it is tempting to suggest, for the first time, a neuroprotective role of GABA{sub A}R inhibitory actions against the overexcitatory ORXR-dependent neurodegeneration and consequently abnormal swimming events in fish.

  8. Abnormal patterns of equine leucocyte differentiation antigen expression in severe combined immunodeficiency foals suggests the phenotype of normal equine natural killer cells.

    PubMed Central

    Lunn, D P; McClure, J T; Schobert, C S; Holmes, M A

    1995-01-01

    Severe combined immunodeficiency (SCID) is a fatal autosommal disease of Arabian horses that leads to failure of maturation of T- and B-lymphocyte populations, although natural killer (NK) cells are unaffected. Thymic and lymph node tissues from two foals suffering from SCID were examined in an immunohistological study using a panel of monoclonal antibodies recognising equine leucocyte differentiation antigens. In both foals, the majority of cells in lymphoid tissues had an EqCD3-EqCD4-EqCD8+ phenotype, although rare EqCD3+ cells were also detected. The EqCD3-EqCD4-EqCD8+ cells may represent an abnormal lymphocyte differentiation product resulting from the SCID defect, or alternatively may be a normal equine NK cell population. We suggest that the evidence favours the latter proposal, and that equine NK cells in normal horses therefore may be identified by an EqCD3-EqCD8+ phenotype. The implications for the nature of the equine SCID defect are discussed. Images Figure 1 PMID:7751035

  9. Compound Heterozygous Desmoplakin Mutations Result in a Phenotype with a Combination of Myocardial, Skin, Hair, and Enamel Abnormalities

    PubMed Central

    Mahoney, Mỹ G.; Sadowski, Sara; Brennan, Donna; Pikander, Pekka; Saukko, Pekka; Wahl, James; Aho, Heikki; Heikinheimo, Kristiina; Bruckner-Tuderman, Leena; Fertala, Andrzej; Peltonen, Juha; Uitto, Jouni; Peltonen, Sirkku

    2014-01-01

    Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses. PMID:19924139

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

    PubMed Central

    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

  11. Abnormal MicroRNA Expression in Ts65Dn Hippocampus and Whole Blood: Contributions to Down Syndrome Phenotypes

    PubMed Central

    Keck-Wherley, Jennifer; Grover, Deepak; Bhattacharyya, Sharmistha; Xu, Xiufen; Holman, Derek; Lombardini, Eric D.; Verma, Ranjana; Biswas, Roopa; Galdzicki, Zygmunt

    2011-01-01

    Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21. Using ABI TaqMan miRNA arrays, we found a set of miRNAs that were significantly up- or downregulated in the Ts65Dn hippocampus compared to euploid controls. Furthermore, miR-155 and miR-802 showed significant overexpression in the Ts65Dn hippocampus, thereby confirming results of previous studies. Interestingly, miR-155 and miR-802 were also overexpressed in the Ts65Dn whole blood but not in lung tissue. We also found overexpression of the miR-155 precursors, pri- and pre-miR-155 derived from the miR-155 host gene, known as B cell integration cluster, suggesting enhanced biogenesis of miR-155. Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs. We selected some of these potential gene targets and found downregulation of mRNA encoding Ship1, Mecp2 and Ezh2 in Ts65Dn hippocampus. Interestingly, the miR-155 target gene Ship1 (inositol phosphatase) was also downregulated in Ts65Dn whole blood but not in lung tissue. Our findings provide insights into miRNA-mediated gene regulation in Ts65Dn mice and their potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, as well as hemopoietic abnormalities observed in DS. PMID:22042248

  12. 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…

  13. [Effects of Gut Microbiota on Stress Response and Behavioral Phenotype of the Host].

    PubMed

    Sudo, Nobuyuki

    2016-06-01

    Gut microbiota are involved in host patho-physiological functions; however, little is known about whether or not they can affect brain function. Several recent works including ours have shown that gut microbiota play a critical role in the determination of stress response and behavioral phenotype of the host. We here review recent advances in this area, i.e. the interaction between gut microbiota and the brain-gut axis, based on our series of experimental data. PMID:27279157

  14. Loss of prion protein leads to age-dependent behavioral abnormalities and changes in cytoskeletal protein expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cellular prion protein (PrPC) is a multifunctional protein, whose exact physiological role remains elusive. Since previous studies indicated a neuroprotective function of PrPC, we investigated whether Prnp knockout mice(Prnp0/0)display age-dependent behavioral abnormalities. Matched sets of Prnp0/0 ...

  15. Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

    PubMed

    Hoffman, Ellen J; Turner, Katherine J; Fernandez, Joseph M; Cifuentes, Daniel; Ghosh, Marcus; Ijaz, Sundas; Jain, Roshan A; Kubo, Fumi; Bill, Brent R; Baier, Herwig; Granato, Michael; Barresi, Michael J F; Wilson, Stephen W; Rihel, Jason; State, Matthew W; Giraldez, Antonio J

    2016-02-17

    Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism. PMID:26833134

  16. Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice.

    PubMed

    Villares, Ricardo; Gutiérrez, Julio; Fütterer, Agnes; Trachana, Varvara; Gutiérrez del Burgo, Fernando; Martínez-A, Carlos

    2015-04-14

    Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia. PMID:25825751

  17. Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice

    PubMed Central

    Villares, Ricardo; Gutiérrez, Julio; Fütterer, Agnes; Trachana, Varvara; Gutiérrez del Burgo, Fernando; Martínez-A, Carlos

    2015-01-01

    Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia. PMID:25825751

  18. Periventricular white matter abnormalities and restricted repetitive behavior in autism spectrum disorder

    PubMed Central

    Blackmon, Karen; Ben-Avi, Emma; Wang, Xiuyuan; Pardoe, Heath R.; Di Martino, Adriana; Halgren, Eric; Devinsky, Orrin; Thesen, Thomas; Kuzniecky, Ruben

    2015-01-01

    Malformations of cortical development are found at higher rates in autism spectrum disorder (ASD) than in healthy controls on postmortem neuropathological evaluation but are more variably observed on visual review of in-vivo MRI brain scans. This may be due to the visually elusive nature of many malformations on MRI. Here, we utilize a quantitative approach to determine whether a volumetric measure of heterotopic gray matter in the white matter is elevated in people with ASD, relative to typically developing controls (TDC). Data from a primary sample of 48 children/young adults with ASD and 48 age-, and gender-matched TDCs, selected from the Autism Brain Imaging Data Exchange (ABIDE) open-access database, were analyzed to compare groups on (1) blinded review of high-resolution T1-weighted research sequences; and (2) quantitative measurement of white matter hypointensity (WMH) volume calculated from the same T1-weighted scans. Groupwise WMH volume comparisons were repeated in an independent, multi-site sample (80 ASD/80 TDC), also selected from ABIDE. Visual review resulted in equivalent proportions of imaging abnormalities in the ASD and TDC group. However, quantitative analysis revealed elevated periventricular and deep subcortical WMH volumes in ASD. This finding was replicated in the independent, multi-site sample. Periventricular WMH volume was not associated with age but was associated with greater restricted repetitive behaviors on both parent-reported and clinician-rated assessment inventories. Thus, findings demonstrate that periventricular WMH volume is elevated in ASD and associated with a higher degree of repetitive behaviors and restricted interests. Although the etiology of focal WMH clusters is unknown, the absence of age effects suggests that they may reflect a static anomaly. PMID:26693400

  19. Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish

    PubMed Central

    Grone, Brian P.; Marchese, Maria; Hamling, Kyla R.; Kumar, Maneesh G.; Krasniak, Christopher S.; Sicca, Federico; Santorelli, Filippo M.; Patel, Manisha; Baraban, Scott C.

    2016-01-01

    Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing “dark-flash” visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations. PMID:26963117

  20. The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome).

    PubMed

    Tartaglia, Nicole; Cordeiro, Lisa; Howell, Susan; Wilson, Rebecca; Janusz, Jennifer

    2010-12-01

    The behavioral phenotype of 47,XXY (Klinefelter syndrome) includes increased risks for developmental delays, language-based learning disabilities, executive dysfunction/ADHD, and socialemotional difficulties. However there is significant variability between individuals with 47,XXY, and many children and adolescents have minimal or no behavioral features while others have quite significant involvement. This paper describes behavioral features in a cohort of 57 children and adolescents with 47,XXY, including results on standardized measures of behavior (BASC-2), attention (Conner's Rating Scales), and social skills (Social Responsiveness Scale). A subset was directly assessed for autism spectrum disorders using the ADOS and ADIR. We discuss our results within the context of previous literature, including implications for genetic counseling, recommendations for care, and areas for future research. PMID:21217607

  1. A Constitutively Active Gαi3 Protein Corrects the Abnormal Retinal Pigment Epithelium Phenotype of Oa1−/− mice

    PubMed Central

    Young, Alejandra; Wang, Ying; Ahmedli, Novruz B.; Jiang, Meisheng; Farber, Debora B.

    2013-01-01

    Purpose Ocular Albinism type 1 (OA1) is a disease caused by mutations in the OA1 gene and characterized by the presence of macromelanosomes in the retinal pigment epithelium (RPE) as well as abnormal crossing of the optic axons at the optic chiasm. We showed in our previous studies in mice that Oa1 activates specifically Gαi3 in its signaling pathway and thus, hypothesized that a constitutively active Gαi3 in the RPE of Oa1−/− mice might keep on the Oa1 signaling cascade and prevent the formation of macromelanosomes. To test this hypothesis, we have generated transgenic mice that carry the constitutively active Gαi3 (Q204L) protein in the RPE of Oa1−/− mice and are now reporting the effects that the transgene produced on the Oa1−/− RPE phenotype. Methods Transgenic mice carrying RPE-specific expression of the constitutively active Gαi3 (Q204L) were generated by injecting fertilized eggs of Oa1−/− females with a lentivirus containing the Gαi3 (Q204L) cDNA. PCR, Southern blots, Western blots and confocal microscopy were used to confirm the presence of the transgene in the RPE of positive transgenic mice. Morphometrical analyses were performed using electron microscopy to compare the size and number of melanosomes per RPE area in putative Oa1−/−, Gαi3 (Q204L) transgenic mice with those of wild-type NCrl and Oa1−/− mice. Results We found a correlation between the presence of the constitutively active Gαi3 (Q204L) transgene and the rescue of the normal phenotype of RPE melanosomes in Oa1−/−, Gαi3 (Q204L) mice. These mice have higher density of melanosomes per RPE area and a larger number of small melanosomes than Oa1−/− mice, and their RPE phenotype is similar to that of wild-type mice. Conclusions Our results show that a constitutively active Gαi3 protein can by-pass the lack of Oa1 protein in Oa1−/− mice and consequently rescue the RPE melanosomal phenotype. PMID:24098784

  2. Structural and behavioral correlates of abnormal encoding of money value in the sensorimotor striatum in cocaine addiction

    PubMed Central

    Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo; Parvaz, Muhammad A.; Alia-Klein, Nelly; Volkow, Nora D.; Goldstein, Rita Z.

    2012-01-01

    Abnormalities in frontostriatal systems are thought to be central to the pathophysiology of addiction, and may underlie maladaptive processing of the highly generalizable reinforcer, money. Although abnormal frontostriatal structure and function have been observed in individuals addicted to cocaine, it is less clear how individual variability in brain structure is associated with brain function to influence behavior. Our objective was to examine frontostriatal structure and neural processing of money value in chronic cocaine users and closely matched healthy controls. A reward task that manipulated different levels of money was used to isolate neural activity associated with money value. Gray matter volume measures were used to assess frontostriatal structure. Our results indicated that cocaine users had an abnormal money value signal in the sensorimotor striatum (right putamen/globus pallidus) which was negatively associated with accuracy adjustments to money and was more pronounced in individuals with more severe use. In parallel, group differences were also observed in both function and gray matter volume of the ventromedial prefrontal cortex; in the cocaine users, the former was directly associated with response to money in the striatum. These results provide strong evidence for abnormalities in the neural mechanisms of valuation in addiction and link these functional abnormalities with deficits in brain structure. In addition, as value signals represent acquired associations, their abnormal processing in the sensorimotor striatum, a region centrally implicated in habit formation, could signal disadvantageous associative learning in cocaine addiction. PMID:22775285

  3. Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

    PubMed Central

    Blum, Kenneth; Chen, Amanda L. C.; Oscar-Berman, Marlene; Chen, Thomas J. H.; Lubar, Joel; White, Nancy; Lubar, Judith; Bowirrat, Abdalla; Braverman, Eric; Schoolfield, John; Waite, Roger L.; Downs, Bernard W.; Madigan, Margaret; Comings, David E.; Davis, Caroline; Kerner, Mallory M.; Knopf, Jennifer; Palomo, Tomas; Giordano, John J.; Morse, Siobhan A.; Fornari, Frank; Barh, Debmalya; Femino, John; Bailey, John A.

    2011-01-01

    Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may

  4. The Clinical Phenotype of Idiopathic Rapid Eye Movement Sleep Behavior Disorder at Presentation: A Study in 203 Consecutive Patients

    PubMed Central

    Fernández-Arcos, Ana; Iranzo, Alex; Serradell, Mónica; Gaig, Carles; Santamaria, Joan

    2016-01-01

    Objective: To describe the clinical phenotype of idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) at presentation in a sleep center. Methods: Clinical history review of 203 consecutive patients with IRBD identified between 1990 and 2014. IRBD was diagnosed by clinical history plus video-polysomnographic demonstration of REM sleep with increased electromyographic activity linked to abnormal behaviors. Results: Patients were 80% men with median age at IRBD diagnosis of 68 y (range, 50–85 y). In addition to the already known clinical picture of IRBD, other important features were apparent: 44% of the patients were not aware of their dream-enactment behaviors and 70% reported good sleep quality. In most of these cases bed partners were essential to convince patients to seek medical help. In 11% IRBD was elicited only after specific questioning when patients consulted for other reasons. Seven percent did not recall unpleasant dreams. Leaving the bed occurred occasionally in 24% of subjects in whom dementia with Lewy bodies often developed eventually. For the correct diagnosis of IRBD, video-polysomnography had to be repeated in 16% because of insufficient REM sleep or electromyographic artifacts from coexistent apneas. Some subjects with comorbid obstructive sleep apnea reported partial improvement of RBD symptoms following continuous positive airway pressure therapy. Lack of therapy with clonazepam resulted in an increased risk of sleep related injuries. Synucleinopathy was frequently diagnosed, even in patients with mild severity or uncommon IRBD presentations (e.g., patients who reported sleeping well, onset triggered by a life event, nocturnal ambulation) indicating that the development of a neurodegenerative disease is independent of the clinical presentation of IRBD. Conclusions: We report the largest IRBD cohort observed in a single center to date and highlight frequent features that were not reported or not sufficiently emphasized in previous

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

    PubMed

    Hall, F Scott; Perona, Maria T G

    2012-12-01

    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 is 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

  6. 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

  7. Phenotypic Overlap between Core Diagnostic Features and Emotional/Behavioral Problems in Preschool Children with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Georgiades, Stelios; Szatmari, Peter; Duku, Eric; Zwaigenbaum, Lonnie; Bryson, Susan; Roberts, Wendy; Fombonne, Eric; Mirenda, Pat; Smith, Isabel; Vaillancourt, Tracy; Volden, Joanne; Waddell, Charlotte; Thompson, Ann

    2011-01-01

    This study examined the phenotypic overlap between core diagnostic features and emotional/behavioral problems in a sample of 335 preschool children with autism spectrum disorder (ASD). Results from principal component analysis (2 components; 49.70% variance explained) suggested substantial phenotypic overlap between core diagnostic features and…

  8. Defining the Social Phenotype in Williams Syndrome: A Model for Linking Gene, the Brain, and Behavior

    PubMed Central

    Järvinen-Pasley, Anna; Bellugi, Ursula; Reilly, Judy; Mills, Debra L.; Galaburda, Albert; Reiss, Allan L.; Korenberg, Julie R.

    2010-01-01

    Research into phenotype-genotype correlations in neurodevelopmental disorders has greatly elucidated the contribution of genetic and neurobiological factors to variations in typical and atypical development. Etiologically relatively homogeneous disorders, such as Williams syndrome (WS), provide unique opportunities for elucidating gene-brain-behavior relationships. WS is a neurogenetic disorder, caused by a hemizygous deletion of approximately 25 genes on chromosome 7q11.23. This results in a cascade of physical, cognitive-behavioral, affective, and neurobiological aberrations. WS is associated with a markedly uneven neurocognitive profile, and the mature state cognitive profile of WS is relatively well developed. Although anecdotally, individuals with WS have been frequently described as unusually friendly and sociable, personality remains a considerably less well-studied area. This paper investigates genetic influences, cognitive-behavioral characteristics, aberrations in brain structure and function, and environmental and biological variables that influence the social outcomes of individuals with WS. We bring together a series of findings across multiple levels of scientific enquiry to examine the social phenotype in WS, reflecting the journey from gene to the brain to behavior. Understanding the complex multilevel scientific perspective in WS has implications for understanding typical social development by identifying important developmental events and markers, as well as helping to define the boundaries of psychopathology. PMID:18211726

  9. From Cortical and Subcortical Grey Matter Abnormalities to Neurobehavioral Phenotype of Angelman Syndrome: A Voxel-Based Morphometry Study.

    PubMed

    Aghakhanyan, Gayane; Bonanni, Paolo; Randazzo, Giovanna; Nappi, Sara; Tessarotto, Federica; De Martin, Lara; Frijia, Francesca; De Marchi, Daniele; De Masi, Francesco; Kuppers, Beate; Lombardo, Francesco; Caramella, Davide; Montanaro, Domenico

    2016-01-01

    Angelman syndrome (AS) is a rare neurogenetic disorder due to loss of expression of maternal ubiquitin-protein ligase E3A (UBE3A) gene. It is characterized by severe developmental delay, speech impairment, movement or balance disorder and typical behavioral uniqueness. Affected individuals show normal magnetic resonance imaging (MRI) findings, although mild dysmyelination may be observed. In this study, we adopted a quantitative MRI analysis with voxel-based morphometry (FSL-VBM) method to investigate disease-related changes in the cortical/subcortical grey matter (GM) structures. Since 2006 to 2013 twenty-six AS patients were assessed by our multidisciplinary team. From those, sixteen AS children with confirmed maternal 15q11-q13 deletions (mean age 7.7 ± 3.6 years) and twenty-one age-matched controls were recruited. The developmental delay and motor dysfunction were assessed using Bayley III and Gross Motor Function Measure (GMFM). Principal component analysis (PCA) was applied to the clinical and neuropsychological datasets. High-resolution T1-weighted images were acquired and FSL-VBM approach was applied to investigate differences in the local GM volume and to correlate clinical and neuropsychological changes in the regional distribution of GM. We found bilateral GM volume loss in AS compared to control children in the striatum, limbic structures, insular and orbitofrontal cortices. Voxel-wise correlation analysis with the principal components of the PCA output revealed a strong relationship with GM volume in the superior parietal lobule and precuneus on the left hemisphere. The anatomical distribution of cortical/subcortical GM changes plausibly related to several clinical features of the disease and may provide an important morphological underpinning for clinical and neurobehavioral symptoms in children with AS. PMID:27626634

  10. An unusual phenotype of X-linked developmental delay and extreme behavioral difficulties associated with a mutation in the EBP gene.

    PubMed

    Hartill, Verity L; Tysoe, Carolyn; Manning, Nigel; Dobbie, Angus; Santra, Saikat; Walter, John; Caswell, Richard; Koster, Janet; Waterham, Hans; Hobson, Emma

    2014-04-01

    We report on a family in which four males over three generations are affected with X-linked recessive developmental delay, learning difficulties, severe behavioral difficulties and mild dysmorphic features. Plasma sterol analysis in three of the four affected males demonstrated increased concentrations of 8-dehydrocholesterol (8-DHC) and cholest-8(9)-enol. All four affected males had a novel hemizygous missense mutation, p.W47R (c.139T>C), in EBP. Functional studies showed raised levels of cholest-8(9)-enol in patient's cultured fibroblast cells, which were suppressed when the cells were incubated with simvastatin. EBP encodes 3β-hydroxysteroid-delta8, delta7-isomerase, a key enzyme involved in the cholesterol biosynthesis pathway. Mutations in EBP have previously been associated with Conradi-Hunermann-Happle syndrome (CHH), an X-linked dominant disorder characterized by skeletal dysplasia, skin, and ocular abnormalities, which is usually lethal in males. Four previous reports describe X-linked recessive multiple anomaly syndromes associated with non-mosaic EBP mutations in males, two at the same amino acid position, p.W47C. This phenotype has previously been described as "MEND" syndrome (male EBP disorder with neurological defects). The family reported herein represent either a novel phenotype, or an expansion of the MEND phenotype, characterized by extreme behavioral difficulties and a scarcity of structural anomalies. Simvastatin therapy is being evaluated in two males from this family. PMID:24459067

  11. Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion

    PubMed Central

    Donti, Taraka R.; Stromberger, Carmen; Ge, Ming; Eldin, Karen W.; Craigen, William J.; Graham, Brett H.

    2014-01-01

    ABSTRACT Mutations in subunits of succinyl-CoA synthetase/ligase (SCS), a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA), and mitochondrial DNA (mtDNA) depletion. A FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES) cells for abnormal mitochondrial phenotypes identified a gene trap allele of Sucla2 (Sucla2SAβgeo), which was used to generate transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform of SCS. Sucla2SAβgeo homozygotes exhibited recessive lethality, with most mutants dying late in gestation (e18.5). Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20–60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed. Elevated levels of MMA were observed in embryonic brain. SCS-deficient mouse embryonic fibroblasts (MEFs) demonstrated a 50% reduction in mtDNA content compared with wild-type MEFs. The mtDNA depletion resulted in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies. mtDNA content could be restored by reintroduction of Sucla2. This mouse model of SCS deficiency and mtDNA depletion promises to provide insights into the pathogenesis of mitochondrial diseases with mtDNA depletion and into the biology of mtDNA maintenance. In addition, this report demonstrates the power of a genetic screen that combines gene trap mutagenesis and FACS analysis in mouse ES cells to identify mitochondrial phenotypes and to develop animal models of mitochondrial dysfunction. PMID:24271779

  12. In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD.

    PubMed

    Leuzy, Antoine; Zimmer, Eduardo Rigon; Dubois, Jonathan; Pruessner, Jens; Cooperman, Cory; Soucy, Jean-Paul; Kostikov, Alexey; Schirmaccher, Esther; Désautels, René; Gauthier, Serge; Rosa-Neto, Pedro

    2016-04-01

    Although the pathogenesis underlying behavioral variant frontotemporal dementia (bvFTD) has yet to be fully understood, glutamatergic abnormalities have been hypothesized to play an important role. The aim of the present study was to determine the availability of the metabotropic glutamate receptor type 5 (mGluR5) using a novel positron emission tomography (PET) radiopharmaceutical with high selectivity for mGluR5 ([(11)C]ABP688) in a sample of bvFTD patients. In addition, we sought to determine the overlap between availability of mGluR5 and neurodegeneration, as measured using [(18)F]FDG-PET and voxel-based morphometry (VBM). Availability of mGluR5 and glucose metabolism ([(18)F]FDG) were measured in bvFTD (n = 5) and cognitively normal (CN) subjects (n = 10). [(11)C]ABP688 binding potential maps (BPND) were calculated using the cerebellum as a reference region, with [(18)F]FDG standardized uptake ratio maps (SUVR) normalized to the pons. Grey matter (GM) concentrations were determined using VBM. Voxel-based group differences were obtained using RMINC. BvFTD patients showed widespread decrements in [(11)C]ABP688 BPND throughout frontal, temporal and subcortical areas. These areas were likewise characterized by significant hypometabolism and GM loss, with overlap between reduced [(11)C]ABP688 BPND and hypometabolism superior to that for GM atrophy. Several regions were characterized only by decreased binding of [(11)C]ABP688. The present findings represent the first in vivo report of decreased availability of mGluR5 in bvFTD. This study suggests that glutamate excitotoxicity may play a role in the pathogenesis of bvFTD and that [(11)C]ABP688 may prove a suitable marker of glutamatergic neurotransmission in vivo. PMID:25596865

  13. GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats.

    PubMed

    Sharma, Ajaykumar N; Ligade, Sagar S; Sharma, Jay N; Shukla, Praveen; Elased, Khalid M; Lucot, James B

    2015-04-01

    Mood disorder patients that are on long-term atypical antipsychotics treatment frequently experience metabolic dysfunctions. In addition to this, accumulating evidences points to increased risk of structural abnormalities, brain volume changes, altered neuroplasticity and behavioral depression with long-term antipsychotics use. However, there is paucity of preclinical evidences for long-term antipsychotic associated depression-like behavior. The objectives of the present study were: (1) to evaluate influence of long-term antipsychotic (olanzapine) treatment on rat behavior in forced swim test (FST) as a model for depression and; (2) to examine impact of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide - an antidiabetic medication for type II diabetes, on long-term olanzapine associated metabolic and behavioral changes in rats. Daily olanzapine treatment (0.5 mg/kg; p.o.) for 8-9 weeks significantly increased body weights, food and water intake, plasma cholesterol and triglycerides and immobility time in FST with parallel reduction in plasma HDL cholesterol levels. These results points to development of metabolic abnormalities and depression-like behavior with long-term olanzapine treatment. Acute liraglutide (50 μg/kg; i.p.) and imipramine (10 mg/kg, i. p.) treatment per se significantly decreased duration of immobility in FST compared to vehicle treated rats. Additionally, 3-week liraglutide treatment (50 μg/kg; i.p., daily) partially reversed metabolic abnormalities and depression-like behavior with long-term olanzapine-treatment in rats. None of these treatment regimens affected locomotor behavior of rats. In summary, add-on GLP-1 receptor agonists promise novel alternatives to counteract long-term antipsychotics associated behavioral and metabolic complications. PMID:25023888

  14. Molecular Phenotyping of Immune Cells from Young NOD Mice Reveals Abnormal Metabolic Pathways in the Early Induction Phase of Autoimmune Diabetes

    PubMed Central

    Wu, Jian; Kakoola, Dorothy N.; Lenchik, Nataliya I.; Desiderio, Dominic M.; Marshall, Dana R.; Gerling, Ivan C.

    2012-01-01

    Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse – a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (∼90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes. PMID:23071669

  15. Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes.

    PubMed

    Wu, Jian; Kakoola, Dorothy N; Lenchik, Nataliya I; Desiderio, Dominic M; Marshall, Dana R; Gerling, Ivan C

    2012-01-01

    Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse--a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (~90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes. PMID:23071669

  16. Abnormal sexual behavior during sleep in temporal lobe epilepsy: a case report.

    PubMed

    Pelin, Zerrin; Yazla, Ece

    2012-06-01

    Herein, we describe a case who presented with abnormal sexual behaviour during sleep. Video-electroencephalography monitoring during sleep revealed an abnormality suggesting an epileptic basis. The patient was successfully treated with carbamazepin. The psychiatric symptoms that were thought to be related to abnormal sexual behaviours were controlled with antipsychotic treatment. Our findings strongly emphasize the fact that efforts should be spent to increase awareness of seizure activity at night, which can be misinterpreted as benign parasomnias. Such a misinterpretation may have serious consequences, such as insufficient seizure control, progressive personality changes, and cognitive impairment. PMID:25206999

  17. The Family Context of Autism Spectrum Disorders: Influence on the Behavioral Phenotype and Quality of Life

    PubMed Central

    Smith, Leann E.; Greenberg, Jan; Mailick, Marsha R.

    2013-01-01

    Synopsis In this review, we report the findings from our longitudinal program of research examining the bidirectional influences of the family environment on the behavioral phenotype of autism, and describe a newly developed family psychoeducation program, titled Transitioning Together, designed to reduce family stress, address behavior problems, and improve the overall quality of life of adolescents with autism and their families. In our search for characteristics of the family environment that influence the behavioral phenotype of adolescents and adults with autism, we focus on both positive dimensions of family life, such as warmth and positive remarks that may promote adaptive behavior in individuals with autism, as well as negative dimensions, such as high levels of criticism that may result in an escalation of behavior problems. We find that high levels of maternal warmth and positive remarks are associated with the abatement of behavior problems over time, while high levels of maternal criticism are associated with increasing levels of behavior problems in adolescents and adults with autism. These patterns of relationships have been replicated in a longitudinal study of families of children and adolescents with fragile X syndrome, and are consistent with other studies examining the impact of the family on the behavior of children with developmental disabilities. These findings suggest that the family environment is an important target for interventions not only to reduce family stress but also to improve the behavioral functioning of children, adolescents or adults with ASD. Building upon a well-developed intervention for families of individuals with psychiatric conditions, we report on the development of Transitioning Together, a psychoeducation program targeted to families with adolescents with autism who are approaching high school exit, a difficult transition stage for individuals with autism that is often marked by negative changes in behavior problems

  18. 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

  19. Phenotypic correlates of melanization in two Sceloporus occidentalis (Phrynosomatidae) populations: Behavior, androgens, stress reactivity, and ectoparasites.

    PubMed

    Seddon, Ryan J; Hews, Diana K

    2016-09-01

    Mechanisms underlying production of animal coloration can affect key traits besides coloration. Melanin, and molecules regulating melanin, can directly and indirectly affect other phenotypic traits including aggression, stress-reactivity, and immune function. We studied correlation of melanization with these other traits, comparing within- and between-population differences of adult male western fence lizards, Sceloporus occidentalis. We compared one high- and one low-elevation population in California where individuals are increasingly darker at higher elevations, working during comparable periods of the breeding season at each site (first egg clutch). We measured agonistic behaviors of free-ranging males in response to staged territorial intrusions (STIs). In other sets of males we measured baseline testosterone and corticosterone levels, and hormonal-reactivity to a stress handling paradigm. We counted ectoparasite loads for all males. There were no significant associations between individual variation in melanization and individual variation in any of the variables measured. However, analysis of behavior from the STIs revealed that males in the darker high-elevation population responded with more aggressive behavior compared to males in the lighter low-elevation population. Males in the low-elevation population had significantly higher mean baseline testosterone, but the two populations did not differ in adrenal function (baseline corticosterone or corticosterone after 1-h confinement stress). Males in the darker high-elevation population had higher mean mite loads compared to males in the lighter population. This array of phenotypic differences between the two populations, and the absence of trait associations when assessing individual variation, do not parallel the patterns in other vertebrates. We describe potential differences in selective regimes that could produce these different patterns across vertebrates. These data suggest that hormonal pleiotropy

  20. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

    PubMed

    Brunetti-Pierri, Nicola; Berg, Jonathan S; Scaglia, Fernando; Belmont, John; Bacino, Carlos A; Sahoo, Trilochan; Lalani, Seema R; Graham, Brett; Lee, Brendan; Shinawi, Marwan; Shen, Joseph; Kang, Sung-Hae L; Pursley, Amber; Lotze, Timothy; Kennedy, Gail; Lansky-Shafer, Susan; Weaver, Christine; Roeder, Elizabeth R; Grebe, Theresa A; Arnold, Georgianne L; Hutchison, Terry; Reimschisel, Tyler; Amato, Stephen; Geragthy, Michael T; Innis, Jeffrey W; Obersztyn, Ewa; Nowakowska, Beata; Rosengren, Sally S; Bader, Patricia I; Grange, Dorothy K; Naqvi, Sayed; Garnica, Adolfo D; Bernes, Saunder M; Fong, Chin-To; Summers, Anne; Walters, W David; Lupski, James R; Stankiewicz, Pawel; Cheung, Sau Wai; Patel, Ankita

    2008-12-01

    Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity. PMID:19029900

  1. Is it all the X: familial learning dysfunction and the impact of behavioral aspects of the phenotypic presentation of XXY?

    PubMed

    Samango-Sprouse, Carole A; Stapleton, Emily; Sadeghin, Teresa; Gropman, Andrea L

    2013-02-15

    The behavioral phenotype of children with XXY has not been extensively studied until recently and this research has been confounded by insufficient study populations and ascertainment biases. The aim of the study was to expand the behavioral aspect of the XXY phenotype as well as investigate the role of existing familial learning disabilities (FLD) on behavioral problems. Behavioral phenotype of XXY includes social anxiety, ADHD, social communication, and atypical peer interactions. The Child Behavior Checklist (CBCL), Social Responsiveness Scale (SRS), and Gilliam Autism Rating Scale (GARS) were completed by the parents of 54 boys with XXY who had not received hormonal replacement prior to participation. Our findings suggest fewer behavioral deficits and lower severity in the general 47,XXY population than previously published and found significant differences between the groups with a positive FLD on the behavioral assessments. Findings demonstrate that boys with FLD exhibit an increased incidence and severity of behavioral problems. Our study expands on the findings of Samango-Sprouse et al. [Samango-Sprouse et al. (2012b) J Intellect Disabil Res] and the significant influence that FLD has on not only neurodevelopment, but also behavioral deficits. Our study suggests that part of the XXY phenotypic profile may be modulated by FLD. Further study is underway to examine the interaction between the many salient factors effecting behavioral and neurodevelopmental progression in XXY and variant forms. © 2013 Wiley Periodicals, Inc. PMID:23359595

  2. 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. PMID:16939636

  3. Modeling autism-relevant behavioral phenotypes in rats and mice: Do 'autistic' rodents exist?

    PubMed

    Servadio, Michela; Vanderschuren, Louk J M J; Trezza, Viviana

    2015-09-01

    Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets. PMID:26226143

  4. 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. PMID:26228524

  5. High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains

    PubMed Central

    Philip, V M; Duvvuru, S; Gomero, B; Ansah, T A; Blaha, C D; Cook, M N; Hamre, K M; Lariviere, W R; Matthews, D B; Mittleman, G; Goldowitz, D; Chesler, E J

    2010-01-01

    Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and covariation. 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 the 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 coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4-methylenedioxymethamphetamine; “ecstasy” (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 in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits. PMID:19958391

  6. Behavioral and pharmacological phenotypes of brain-specific diacylglycerol kinase δ-knockout mice.

    PubMed

    Usuki, Takako; Takato, Tamae; Lu, Qiang; Sakai, Hiromichi; Bando, Kana; Kiyonari, Hiroshi; Sakane, Fumio

    2016-10-01

    Diacylglycerol kinase (DGK) is a lipid-metabolizing enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. Previously, we reported that the δ isozyme of DGK was abundantly expressed in the mouse brain. However, the functions of DGKδ in the brain are still unclear. Because conventional DGKδ-knockout (KO) mice die within 24h after birth, we have generated brain-specific conditional DGKδ-KO mice to circumvent the lethality. In the novel object recognition test, the number of contacts in the DGKδ-KO mice to novel and familiar objects was greatly increased compared to the control mice, indicating that the DGKδ-KO mice showed irrational contacts with objects such as compulsive checking. In the marble burying test, which is used for analyzing obsessive-compulsive disorder (OCD)-like phenotypes, the DGKδ-KO mice buried more marbles than the control mice. Additionally, these phenotypes were significantly alleviated by the administration of an OCD remedy, fluoxetine. These results indicate that the DGKδ-KO mice showed OCD-like behaviors. Moreover, the number of long axon/neurites increased in both DGKδ-KO primary cortical neurons and DGKδ-knockdown neuroblastoma Neuro-2a cells compared to control cells. Conversely, overexpression of DGKδ decreased the number of long axon/neurites of Neuro-2a cells. Taken together, these results strongly suggest that a deficiency of DGKδ induces OCD-like behavior through enhancing axon/neurite outgrowth. PMID:27423518

  7. Postanesthetic Effects of Isoflurane on Behavioral Phenotypes of Adult Male C57BL/6J Mice

    PubMed Central

    Asakura, Ayako; Kobayashi, Ayako; Takase, Kenkichi; Goto, Takahisa

    2015-01-01

    Isoflurane was previously the major clinical anesthetic agent but is now mainly used for veterinary anesthesia. Studies have reported widespread sites of action of isoflurane, suggesting a wide array of side effects besides sedation. In the present study, we phenotyped isoflurane-treated mice to investigate the postanesthetic behavioral effects of isoflurane. We applied comprehensive behavioral test batteries comprising sensory test battery, motor test battery, anxiety test battery, depression test battery, sociability test battery, attention test battery, and learning test battery, which were started 7 days after anesthesia with 1.8% isoflurane. In addition to the control group, we included a yoked control group that was exposed to the same stress of handling as the isoflurane-treated animals before being anesthetized. Our comprehensive behavioral test batteries revealed impaired latent inhibition in the isoflurane-treated group, but the concentration of residual isoflurane in the brain was presumably negligible. The yoked control group and isoflurane-treated group exhibited higher anxiety in the elevated plus-maze test and impaired learning function in the cued fear conditioning test. No influences were observed in sensory functions, motor functions, antidepressant behaviors, and social behaviors. A number of papers have reported an effect of isoflurane on animal behaviors, but no systematic investigation has been performed. To the best of our knowledge, this study is the first to systematically investigate the general health, neurological reflexes, sensory functions, motor functions, and higher behavioral functions of mice exposed to isoflurane as adults. Our results suggest that the postanesthetic effect of isoflurane causes attention deficit in mice. Therefore, isoflurane must be used with great care in the clinical setting and veterinary anesthesia. PMID:25806517

  8. Presence of XIST specific sequences and apparent failure of X dosage compensation by inactivation in a patient with a severe Turner phenotype and mosaicism for X chromosome abnormalities

    SciTech Connect

    Bent-Williams, A.H.; Felton, S.M.; Driscoll, D.J.

    1994-09-01

    An XIST FISH analysis and a late replication chromosome study was performed for a 10 year old female with Turner stigmata, mental retardation, multiple congenital anomalies and a cytogenetic mosaicism of 45,X,inv(9)(p11q13)/46,X,del(X)(q22),inv(9)(p11q13)/46,X,+mar,inv(9)(p11q13). The X chromosomes from a cell line in which one was deleted for the distal long arm segment (breakpoint of Xq22), observed in 6% of metaphase cells from peripheral blood and 23.3% of metaphase cells from skin fibroblasts, did not demonstrate an asynchronous or differential staining pattern by BrDU techniques. However, both the normal X chromosome and the deleted X chromosome were demonstrated to contain XIST specific sequences by FISH analysis. A very small marker chromosome, observed in 6% of metaphase cells from peripheral blood and 3.3% of metaphase cells from skin fibroblasts, appeared to consist exclusively of X chromosome alpha satellite centromeric material (DXZ1). This finding was consistent with the morphology of the marker chromosome as observed by conventional G-banding. Due to its small size and low level frequency, analysis by late replication BrDU techniques was not possible. The predominate cell line containing a signal X chromosome was observed in 88% of metaphase cells from peripheral blood and 73.3% of metaphase cells from skin fibroblasts. This case is significant because: (1) it represents another case of an X chromosome abnormality in which XIST is apparently present but not expressed; and (2) the more severe phenotype expressed is probably attributable to the failure of X gene dosage compensation by inactivation.

  9. Superoxide dismutase overexpression protects against glucocorticoid-induced depressive-like behavioral phenotypes in mice.

    PubMed

    Uchihara, Yuki; Tanaka, Ken-ichiro; Asano, Teita; Tamura, Fumiya; Mizushima, Tohru

    2016-01-22

    In the stress response, activation of the hypothalamic-pituitary-adrenal axis, and particularly the release of glucocorticoids, plays a critical role. However, dysregulation of this system and sustained high plasma levels of glucocorticoids can result in depression. Recent studies have suggested the involvement of reactive oxygen species (ROS), such as superoxide anion, in depression. However, direct evidence for a role of ROS in the pathogenesis of this disorder is lacking. In this study, using transgenic mice expressing human Cu/Zn-superoxide dismutase (SOD1), an enzyme that catalyzes the dismutation of superoxide anions, we examined the effect of SOD1 overexpression on depressive-like behavioral phenotypes in mice. Depressive-like behaviors were induced by daily subcutaneous administration of the glucocorticoid corticosterone for 4 weeks, and was monitored with the social interaction test, the sucrose preference test and the forced swim test. These tests revealed that transgenic mice overexpressing SOD1 are more resistant to glucocorticoid-induced depressive-like behavioral disorders than wild-type animals. Furthermore, compared with wild-type mice, transgenic mice showed a reduction in the number of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress)-positive cells in the hippocampal CA3 region following corticosterone administration. These results suggest that overexpression of SOD1 protects mice against glucocorticoid-induced depressive-like behaviors by decreasing cellular ROS levels. PMID:26721432

  10. Defining the behavioral phenotype in children with fetal alcohol spectrum disorders: a review.

    PubMed

    Kodituwakku, P W

    2007-01-01

    While there exists a large body of literature on cognitive functions in children with prenatal alcohol exposure, it remains undetermined if these children exhibit a unique profile of cognitive-behavioral functioning or a behavioral phenotype. Researchers have consistently found that intellectual functioning, as assessed by IQ tests, of children with prenatal alcohol exposure is deficient. There is increasing evidence that prenatal alcohol exposure is associated with slow information processing and attentional problems, in particular inattentiveness. Studies examining specific cognitive abilities such as language, visual perception, and memory in alcohol-affected children have shown performance decrements associated with increased task complexity. Children with prenatal alcohol exposure have also been found to exhibit significant deficits in daily functional skills or adaptive behavior, with deficits in socialization becoming pronounced during adolescence. The above findings point to the conclusion that a generalized deficit in complex information processing constitutes the central cognitive-behavioral characteristic of children with prenatal alcohol exposure. Researchers have consistently documented that specific brain regions are more affected by alcohol than other regions. The problem of mapping focal anomalies of the brain with a generalized pattern of deficits can be solved by taking developmental processes into consideration. PMID:16930704

  11. Unipolar resistance switching and abnormal reset behaviors in Pt/CuO/Pt and Cu/CuO/Pt structures

    NASA Astrophysics Data System (ADS)

    Wu, Liang; Li, Xiaomin; Gao, Xiangdong; Zheng, Renkui; Zhang, Feng; Liu, Xinjun; Wang, Qun

    2012-07-01

    The effects of Pt and Cu top electrodes on resistance switching properties were investigated for CuO thin films with Pt/CuO/Pt and Cu/CuO/Pt sandwich structures. Typical unipolar resistance switching (URS) behaviors and two different kinds of resistance changes in the reset process were observed in both structures. When voltages were applied to the film, the low-resistance state (LRS) with relatively low resistance value (<30 Ω) was switched to the high-resistance state (HRS), exhibiting normal reset behavior. For LRS with relatively high resistance value (>50 Ω), the resistance first decreased then increased to HRS, showing abnormal reset behavior. The former variation of LRS could be ascribed to the decrease in filament size induced by Joule heating, while the latter one could be ascribed to the growth of disconnected filaments induced by high electric fields. This study indicates that the switching modes and the abnormal reset behaviors in CuO thin films are not due to Pt and Cu top electrodes, but the intrinsic properties of CuO film.

  12. Mice Genetically Depleted of Brain Serotonin do not Display a Depression-like Behavioral Phenotype

    PubMed Central

    Angoa-Pérez, Mariana; Kane, Michael J.; Briggs, Denise I.; Herrera-Mundo, Nieves; Sykes, Catherine E.; Francescutti, Dina M.; Kuhn, Donald M.

    2016-01-01

    Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Serotonin selective reuptake inhibitors (SSRIs) are the most common treatment for depression and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their anti-depressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2−/− mice on the sucrose preference test, tail suspension test and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2−/− mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2−/− mouse questions the role of 5HT in depression. Furthermore, the TPH2−/− mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. PMID:25089765

  13. The Relationship between Personality Dimensions and Resiliency to Environmental Stress in Orange-Winged Amazon Parrots (Amazona amazonica), as Indicated by the Development of Abnormal Behaviors.

    PubMed

    Cussen, Victoria A; Mench, Joy A

    2015-01-01

    Parrots are popular companion animals, but are frequently relinquished because of behavioral problems, including abnormal repetitive behaviors like feather damaging behavior and stereotypy. In addition to contributing to pet relinquishment, these behaviors are important as potential indicators of diminished psychological well-being. While abnormal behaviors are common in captive animals, their presence and/or severity varies between animals of the same species that are experiencing the same environmental conditions. Personality differences could contribute to this observed individual variation, as they are known risk factors for stress sensitivity and affective disorders in humans. The goal of this study was to assess the relationship between personality and the development and severity of abnormal behaviors in captive-bred orange-winged Amazon parrots (Amazona amazonica). We monitored between-individual behavioral differences in enrichment-reared parrots of known personality types before, during, and after enrichment deprivation. We predicted that parrots with higher scores for neurotic-like personality traits would be more susceptible to enrichment deprivation and develop more abnormal behaviors. Our results partially supported this hypothesis, but also showed that distinct personality dimensions were related to different forms of abnormal behavior. While neuroticism-like traits were linked to feather damaging behavior, extraversion-like traits were negatively related to stereotypic behavior. More extraverted birds showed resiliency to environmental stress, developing fewer stereotypies during enrichment deprivation and showing lower levels of these behaviors following re-enrichment. Our data, together with the results of the few studies conducted on other species, suggest that, as in humans, certain personality types render individual animals more susceptible or resilient to environmental stress. Further, this susceptibility/resiliency can have a long

  14. The Relationship between Personality Dimensions and Resiliency to Environmental Stress in Orange-Winged Amazon Parrots (Amazona amazonica), as Indicated by the Development of Abnormal Behaviors

    PubMed Central

    Cussen, Victoria A.; Mench, Joy A.

    2015-01-01

    Parrots are popular companion animals, but are frequently relinquished because of behavioral problems, including abnormal repetitive behaviors like feather damaging behavior and stereotypy. In addition to contributing to pet relinquishment, these behaviors are important as potential indicators of diminished psychological well-being. While abnormal behaviors are common in captive animals, their presence and/or severity varies between animals of the same species that are experiencing the same environmental conditions. Personality differences could contribute to this observed individual variation, as they are known risk factors for stress sensitivity and affective disorders in humans. The goal of this study was to assess the relationship between personality and the development and severity of abnormal behaviors in captive-bred orange-winged Amazon parrots (Amazona amazonica). We monitored between-individual behavioral differences in enrichment-reared parrots of known personality types before, during, and after enrichment deprivation. We predicted that parrots with higher scores for neurotic-like personality traits would be more susceptible to enrichment deprivation and develop more abnormal behaviors. Our results partially supported this hypothesis, but also showed that distinct personality dimensions were related to different forms of abnormal behavior. While neuroticism-like traits were linked to feather damaging behavior, extraversion-like traits were negatively related to stereotypic behavior. More extraverted birds showed resiliency to environmental stress, developing fewer stereotypies during enrichment deprivation and showing lower levels of these behaviors following re-enrichment. Our data, together with the results of the few studies conducted on other species, suggest that, as in humans, certain personality types render individual animals more susceptible or resilient to environmental stress. Further, this susceptibility/resiliency can have a long

  15. Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits

    PubMed Central

    Santin, L.J.; Bilbao, A.; Pedraza, C.; Matas-Rico, E.; López-Barroso, D.; Castilla-Ortega, E.; Sánchez-López, J.; Riquelme, R.; Varela-Nieto, I.; de la Villa, P.; Suardíaz, M.; Chun, J.; De Fonseca, F. Rodriguez; Estivill-Torrús, G.

    2016-01-01

    Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have demonstrated a role for this molecule and its LPA1 receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA1 receptor is involved in behavior. Here we studied the phenotype of maLPA1–null mice, which bear a targeted deletion at the lpa1 locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA1-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor coordination was impaired only in the equilibrium and grasping reflexes. The mice also showed impairments in neuromuscular strength and analgesic response. No additional differences were observed in the rest of the tests used to study sensoriomotor orientation, limb reflexes, and coordinated limb use. At behavioral level, maLPA1-null mice showed an impaired exploration in the open field and increased anxiety-like response when exposed to the elevated plus maze. Furthermore, the mice exhibit impaired spatial memory retention and reduced use of spatial strategies in the Morris water maze. We propose that the LPA1 receptor may play a major role in both spatial memory and response to anxiety-like conditions. PMID:19689455

  16. Abnormalities of physics and mechanical properties, behavior of helium and hydrogen in the V-Ti alloys (Overview)

    NASA Astrophysics Data System (ADS)

    Staltsov, M. S.; Chernov, I. I.; Kalin, B. A.; Korchagin, O. N.; Anan'in, V. M.

    2016-04-01

    The paper presents the results of studies of physical and mechanical properties, helium and hydrogen behavior in vanadium-titanium alloys depending on titanium content. In particular, the results of helium swelling research, thermal desorption studies of helium and hydrogen behavior, results of internal friction measurements, measuring amount of hydrogen retained introduced by various methods. It was shown that the addition of titanium to vanadium have nonmonotonic influence on the behavior of implanted helium and hydrogen, as well as on the physical and mechanical and radiation properties known in literature. It is expected that such an abnormal influence of titanium on various properties of vanadium-titanium alloys occurs because of the interaction of vanadium and titanium atoms with atoms of interstitial impurities.

  17. Schizophrenia and abnormal brain network hubs

    PubMed Central

    Rubinov, Mikail; Bullmore, Ed.

    2013-01-01

    Schizophrenia is a heterogeneous psychiatric disorder of unknown cause or characteristic pathology. Clinical neuroscientists increasingly postulate that schizophrenia is a disorder of brain network organization. In this article we discuss the conceptual framework of this dysconnection hypothesis, describe the predominant methodological paradigm for testing this hypothesis, and review recent evidence for disruption of central/hub brain regions, as a promising example of this hypothesis. We summarize studies of brain hubs in large-scale structural and functional brain networks and find strong evidence for network abnormalities of prefrontal hubs, and moderate evidence for network abnormalities of limbic, temporal, and parietal hubs. Future studies are needed to differentiate network dysfunction from previously observed gray- and white-matter abnormalities of these hubs, and to link endogenous network dysfunction phenotypes with perceptual, behavioral, and cognitive clinical phenotypes of schizophrenia. PMID:24174905

  18. Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees.

    PubMed

    Liu, Hui; Robinson, Gene E; Jakobsson, Eric

    2016-06-01

    The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior, the honey bee, revealed distinct brain gene expression patterns in African and European honey bees, and within European honey bees with different behavioral phenotypes. The present work is a computational study of these previous findings in which we analyze, by orthology determination, the extent to which genes that are socially regulated in honey bees are conserved across the Metazoa. We found that the differentially expressed gene sets associated with alarm pheromone response, the difference between old and young bees, and the colony influence on soldier bees, are enriched in widely conserved genes, indicating that these differences have genomic bases shared with many other metazoans. By contrast, the sets of differentially expressed genes associated with the differences between African and European forager and guard bees are depleted in widely conserved genes, indicating that the genomic basis for this social behavior is relatively specific to honey bees. For the alarm pheromone response gene set, we found a particularly high degree of conservation with mammals, even though the alarm pheromone itself is bee-specific. Gene Ontology identification of human orthologs to the strongly conserved honey bee genes associated with the alarm pheromone response shows overrepresentation of protein metabolism, regulation of protein complex formation, and protein folding, perhaps associated with remodeling of critical neural circuits in response to alarm pheromone. We hypothesize that such remodeling may be an adaptation of social animals to process and respond appropriately to the complex patterns of conspecific communication essential for social organization

  19. Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees

    PubMed Central

    Robinson, Gene E.; Jakobsson, Eric

    2016-01-01

    The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior, the honey bee, revealed distinct brain gene expression patterns in African and European honey bees, and within European honey bees with different behavioral phenotypes. The present work is a computational study of these previous findings in which we analyze, by orthology determination, the extent to which genes that are socially regulated in honey bees are conserved across the Metazoa. We found that the differentially expressed gene sets associated with alarm pheromone response, the difference between old and young bees, and the colony influence on soldier bees, are enriched in widely conserved genes, indicating that these differences have genomic bases shared with many other metazoans. By contrast, the sets of differentially expressed genes associated with the differences between African and European forager and guard bees are depleted in widely conserved genes, indicating that the genomic basis for this social behavior is relatively specific to honey bees. For the alarm pheromone response gene set, we found a particularly high degree of conservation with mammals, even though the alarm pheromone itself is bee-specific. Gene Ontology identification of human orthologs to the strongly conserved honey bee genes associated with the alarm pheromone response shows overrepresentation of protein metabolism, regulation of protein complex formation, and protein folding, perhaps associated with remodeling of critical neural circuits in response to alarm pheromone. We hypothesize that such remodeling may be an adaptation of social animals to process and respond appropriately to the complex patterns of conspecific communication essential for social organization

  20. Revealing Behavioral Learning Deficit Phenotypes Subsequent to In Utero Exposure to Benzo(a)pyrene.

    PubMed

    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

  1. The perivascular phenotype and behaviors of dedifferentiated cells derived from human mature adipocytes.

    PubMed

    Song, Ning; Kou, Liang; Lu, Xiao-Wen; Sugawara, Atsunori; Shimizu, Yutaka; Wu, Min-Ke; Du, Li; Wang, Hang; Sato, Soh; Shen, Jie-Fei

    2015-02-13

    Derived from mature adipocytes, dedifferentiated fat (DFAT) cells represent a special group of multipotent cells. However, their phenotype and cellular nature remain unclear. Our study found that human DFAT cells adopted perivascular characteristics and behaviors. Flow cytometry and immunofluorescent staining revealed that human DFAT cells positively expressed markers highly related to perivascular cell lineages, such as CD140b, NG2 and desmin, but were negative for common endothelial markers, including CD31, CD34, and CD309. Furthermore, DFAT cells displayed vascular network formation ability in Matrigel, and they noticeably promoted and stabilized the vessel structures formed by human umbilical vascular endothelial cells (HUVECs) in vitro. These results provide novel evidence on the pericyte nature of human DFAT cells, further supporting the recent model for the perivascular origin of adult stem cells, in which tissue-specific progenitor cells in mesenchymal tissues associate with blood vessels, exhibiting perivascular characteristics and functions. PMID:25603054

  2. Abnormal bipolar resistive switching behavior in a Pt/GaO{sub 1.3}/Pt structure

    SciTech Connect

    Guo, D. Y.; Wu, Z. P.; Zhang, L. J.; Yang, T.; Hu, Q. R.; Lei, M.; Tang, W. H. E-mail: pgli@zstu.edu.cn; Li, P. G. E-mail: pgli@zstu.edu.cn; Li, L. H.

    2015-07-20

    A stable and repeatable abnormal bipolar resistive switching behavior was observed in a Pt/GaO{sub 1.3}/Pt sandwich structure without an electroforming process. The low resistance state (LRS) and the high resistance state (HRS) of the device can be distinguished clearly and be switched reversibly under a train of the voltage pulses. The LRS exhibits a conduction of electron tunneling, while the HRS shows a conduction of Schottky-type. The observed phenomena are considered to be related to the migration of oxygen vacancies which changes the space charge region width of the metal/semiconductor interface and results in a different electron transport mechanism.

  3. MicroRNAs Classify Different Disease Behavior Phenotypes of Crohn's Disease and May Have Prognostic Utility

    PubMed Central

    Peck, Bailey C. E.; Weiser, Matthew; Lee, Saangyoung E.; Gipson, Gregory R.; Iyer, Vishal B.; Sartor, Ryan B.; Herfarth, Hans H.; Long, Millie D.; Hansen, Jonathan J.; Isaacs, Kim L.; Trembath, Dimitri G.; Rahbar, Reza; Sadiq, Timothy S.

    2015-01-01

    Background: There is a dire need for reliable prognostic markers that can guide effective therapeutic intervention in Crohn's disease (CD). We examined whether different phenotypes in CD can be classified based on colonic microRNA (miRNA) expression and whether miRNAs have prognostic utility for CD. Methods: High-throughput sequencing of small and total RNA isolated from colon tissue from patients with CD and controls without Inflammatory Bowel Disease (non-IBD) was performed. To identify miRNAs associated with specific phenotypes of CD, patients were stratified according to disease behavior (nonstricturing, nonpenetrating; stricturing; penetrating), and miRNA profiles in each subset were compared with those of the non-IBD group. Validation assays were performed using quantitative reverse transcription polymerase chain reaction. These miRNAs were further evaluated by quantitative reverse transcriptase polymerase chain reaction on formalin-fixed, paraffin-embedded tissue (index biopsies) of patients with nonpenetrating CD at the time of diagnosis that either retained the nonpenetrating phenotype or progressed to penetrating/fistulizing CD. Results: We found a suite of miRNAs, including miR-31-5p, miR-215, miR-223-3p, miR-196b-5p, and miR-203 that stratify patients with CD according to disease behavior independent of the effect of inflammation. Furthermore, we also demonstrated that expression levels of miR-215 in index biopsies of patients with CD might predict the likelihood of progression to penetrating/fistulizing CD. Finally, using a novel statistical simulation approach applied to colonic RNA-sequencing data for patients with CD and non-IBD controls, we identified miR-31-5p and miR-203 as candidate master regulators of gene expression profiles associated with CD. Conclusions: miRNAs may serve as clinically useful prognostic markers guiding initial therapy and identifying patients who would benefit most from effective intervention. PMID:26164662

  4. Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse

    PubMed Central

    Yang, S.; Farias, M.; Kapfhamer, D.; Tobias, J.; Grant, G.; Abel, T.; Bućan, M.

    2010-01-01

    Ras-associated binding (Rab) protein 3A is a neuronal guanosine triphosphate (GTP)-binding protein that binds synaptic vesicles and regulates synaptic transmission. A mouse mutant, earlybird (Ebd), with a point mutation in the GTP-binding domain of Rab3A (D77G), exhibits anomalies in circadian behavior and homeostatic response to sleep loss. Here, we show that the D77G substitution in the Ebd allele causes reduced GTP and GDP binding, whereas GTPase activity remains intact, leading to reduced protein levels of both Rab3A and rabphilin3A. Expression profiling of the cortex and hippocampus of Ebd and Rab3a-deficient mice revealed subtle differences between wild-type and mutant mice. Although mice were backcrossed for three generations to a C57BL/6J background, the most robust changes at the transcriptional level between Rab3a−/− and Rab3a+/+ mice were represented by genes from the 129/Sv-derived chromosomal region surrounding the Rab3a gene. These results showed that differences in genetic background have a stronger effect on gene expression than the mutations in the Rab3a gene. In behavioral tests, the Ebd/Ebd mice showed a more pronounced mutant phenotype than the null mice; Ebd/Ebd have reduced anxiety-like behavior in the elevated zero-maze test, reduced response to stress in the forced swim test and a deficit in cued fear conditioning (FC), whereas Rab3a−/− showed only a deficit in cued FC. Our data implicate Rab3A in learning and memory as well as in the regulation of emotion. A combination of forward and reverse genetics has provided multiple alleles of the Rab3a gene; our studies illustrate the power and complexities of the parallel analysis of these alleles at the biochemical, molecular and behavioral levels. PMID:16734774

  5. A Phenotypic Structure and Neural Correlates of Compulsive Behaviors in Adolescents

    PubMed Central

    Montigny, Chantale; Castellanos-Ryan, Natalie; Whelan, Robert; Banaschewski, Tobias; Barker, Gareth J.; Büchel, Christian; Gallinat, Jürgen; Flor, Herta; Mann, Karl; Paillère-Martinot, Marie-Laure; Nees, Frauke; Lathrop, Mark; Loth, Eva; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Schumann, Gunter; Smolka, Michael N.; Struve, Maren; Robbins, Trevor W.; Garavan, Hugh; Conrod, Patricia J.

    2013-01-01

    Background A compulsivity spectrum has been hypothesized to exist across Obsessive-Compulsive disorder (OCD), Eating Disorders (ED), substance abuse (SA) and binge-drinking (BD). The objective was to examine the validity of this compulsivity spectrum, and differentiate it from an externalizing behaviors dimension, but also to look at hypothesized personality and neural correlates. Method A community-sample of adolescents (N=1938; mean age 14.5 years), and their parents were recruited via high-schools in 8 European study sites. Data on adolescents’ psychiatric symptoms, DSM diagnoses (DAWBA) and substance use behaviors (AUDIT and ESPAD) were collected through adolescent- and parent-reported questionnaires and interviews. The phenotypic structure of compulsive behaviors was then tested using structural equation modeling. The model was validated using personality variables (NEO-FFI and TCI), and Voxel-Based Morphometry (VBM) analysis. Results Compulsivity symptoms best fit a higher-order two factor model, with ED and OCD loading onto a compulsivity factor, and BD and SA loading onto an externalizing factor, composed also of ADHD and conduct disorder symptoms. The compulsivity construct correlated with neuroticism (r=0.638; p≤0.001), conscientiousness (r=0.171; p≤0.001), and brain gray matter volume in left and right orbitofrontal cortex, right ventral striatum and right dorsolateral prefrontal cortex. The externalizing factor correlated with extraversion (r=0.201; p≤0.001), novelty-seeking (r=0.451; p≤0.001), and negatively with gray matter volume in the left inferior and middle frontal gyri. Conclusions Results suggest that a compulsivity spectrum exists in an adolescent, preclinical sample and accounts for variance in both OCD and ED, but not substance-related behaviors, and can be differentiated from an externalizing spectrum. PMID:24244633

  6. Uncovering cancer cell behavioral phenotype in 3-D in vitro metastatic landscapes

    NASA Astrophysics Data System (ADS)

    Liu, Liyu; Sun, Bo; Duclos, Guillaume; Kam, Yoonseok; Gatenby, Robert; Stone, Howard; Austin, Robert

    2012-02-01

    One well-known fact is that cancer cell genetics determines cell metastatic potentials. However, from a physics point of view, genetics as cell properties cannot directly act on metastasis. An agent is needed to unscramble the genetics first before generating dynamics for metastasis. Exactly this agent is cell behavioral phenotype, which is rarely studied due to the difficulties of real-time cell tracking in in vivo tissue. Here we have successfully constructed a micro in vitro environment with collagen based Extracellular Matrix (ECM) structures for cell 3-D metastasis. With stable nutrition (glucose) gradient inside, breast cancer cell MDA-MB-231 is able to invade inside the collagen from the nutrition poor site towards the nutrition rich site. Continuous confocal microscopy captures images of the cells every 12 hours and tracks their positions in 3-D space. The micro fluorescent beads pre-mixed inside the ECM demonstrate that invasive cells have altered the structures through mechanics. With the observation and the analysis of cell collective behaviors, we argue that game theory may exist between the pioneering cells and their followers in the metastatic cell group. The cell collaboration may explain the high efficiency of metastasis.

  7. The Sweet Drive Test: refining phenotypic characterization of anhedonic behavior in rodents

    PubMed Central

    Mateus-Pinheiro, António; Patrício, Patrícia; Alves, Nuno D.; Machado-Santos, Ana R.; Morais, Monica; Bessa, João M.; Sousa, Nuno; Pinto, Luisa

    2014-01-01

    Measuring anhedonic behavior in rodents is a challenging task as current methods display only moderate sensitivity to detect anhedonic phenotype and, consequently, results from different labs are frequently incongruent. Herein we present a newly-developed test, the Sweet Drive Test (SDT), which integrates food preference measurement in a non-aversive environment, with ultrasonic vocalizations (USVs) recording. Animals were placed in a soundproofed black arena, under red light illumination, and allowed to choose between regular and sweet food pellets. During the test trials, 50 KHz USVs, previously described to be associated with positive experiences, were recorded. In a first experimental approach, we demonstrate the ability of SDT to accurately characterize anhedonic behavior in animals chronically exposed to stress. In a subsequent set of experiments, we show that this paradigm has high sensitivity to detect mood-improving effects of antidepressants. The combined analysis of both food preference and the number of 50 KHz vocalizations in the SDT provides also a valuable tool to discriminate animals that responded to treatment from non-responder animals. PMID:24639637

  8. Abnormal behavioral responses to fenfluramine in patients with affective and personality disorders. Correlation with increased serotonergic responsivity.

    PubMed

    Myers, J E; Mieczkowski, T; Perel, J; Abbondanza, D; Cooper, T B; Mann, J J

    1994-01-15

    Serotonergic responsivity was assessed in 20 psychiatric patients by the prolactin response to a fenfluramine challenge test. During the fenfluramine challenge 6 of 20 patients (30%) spontaneously reported psychopathologic reactions that included: increased anxiety/agitation, psychotic symptoms, illusions, mood elevation, and anergia. The time of peak behavioral symptoms (2.5 +/- 0.8 hrs) corresponded closely to the time of peak increase in prolactin levels (3.0 +/- 1.1 hr). Abnormal behavioral responders had statistically significant greater increases in prolactin 1 to 4 hr after fenfluramine when compared to normal responders. Patients who developed an abnormal psychopathologic response to fenfluramine were characterized by higher levels of anxiety and agitation at the time of admission to the hospital but otherwise were not distinguishable on the basis of severity of other psychiatric symptoms. This study suggests that increased serotonergic transmission may trigger anxiety, psychosis, and mood elevation in specific vulnerable individuals, whereas other patients with similar psychiatric illnesses are not affected. PMID:8167207

  9. A two-hit model of suicide-trait-related behaviors in the context of a schizophrenia-like phenotype: Distinct effects of lithium chloride and clozapine.

    PubMed

    Deslauriers, Jessica; Belleville, Karine; Beaudet, Nicolas; Sarret, Philippe; Grignon, Sylvain

    2016-03-15

    Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non-schizophrenic population, while clozapine is the antipsychotic with the best-established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia. PMID:26772420

  10. Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model

    PubMed Central

    Takeda, Atsushi; Tamano, Haruna; Nishio, Ryusuke; Murakami, Taku

    2016-01-01

    Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer’s disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency. PMID:27438830

  11. Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model.

    PubMed

    Takeda, Atsushi; Tamano, Haruna; Nishio, Ryusuke; Murakami, Taku

    2016-01-01

    Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer's disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency. PMID:27438830

  12. Coordination of cell decisions and promotion of phenotypic diversity in B. subtilis via pulsed behavior of the phosphorelay.

    PubMed

    Schultz, Daniel

    2016-05-01

    The phosphorelay of Bacillus subtilis, a kinase cascade that activates master regulator Spo0A ∼ P in response to starvation signals, is the core of a large network controlling the cell's decision to differentiate into sporulation and other phenotypes. This article reviews recent advances in understanding the origins and purposes of the complex dynamical behavior of the phosphorelay, which pulses with peaks of activity coordinated with the cell cycle. The transient imbalance in the expression of two critical genes caused by their strategic placement at opposing ends of the chromosome proved to be the key for this pulsed behavior. Feedback control loops in the phosphorelay use these pulses to implement a timer mechanism, which creates several windows of opportunity for phenotypic transitions over multiple generations. This strategy allows the cell to coordinate multiple differentiation programs in a decision process that fosters phenotypic diversity and adapts to current conditions. PMID:26941227

  13. X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities.

    PubMed

    Sikora, Jakub; Leddy, Jennifer; Gulinello, Maria; Walkley, Steven U

    2016-01-01

    Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient

  14. X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities

    PubMed Central

    Sikora, Jakub; Leddy, Jennifer; Gulinello, Maria; Walkley, Steven U.

    2016-01-01

    ABSTRACT Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably

  15. Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1

    PubMed Central

    Ribeiro, Maria J.; Violante, Inês R.; Bernardino, Inês; Edden, Richard A.E.; Castelo-Branco, Miguel

    2016-01-01

    Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and

  16. The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake.

    PubMed

    Godar, Sean C; Bortolato, Marco; Castelli, M Paola; Casti, Alberto; Casu, Angelo; Chen, Kevin; Ennas, M Grazia; Tambaro, Simone; Shih, Jean C

    2014-09-01

    The termination of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is regulated by its uptake by the 5-HT transporter (5-HTT), as well as its degradation by monoamine oxidase (MAO)-A. MAO-A deficiency results in a wide set of behavioral alterations, including perseverative behaviors and social deficits. These anomalies are likely related to 5-HTergic homeostatic imbalances; however, the role of 5-HTT in these abnormalities remains unclear. To ascertain the role of 5-HTT in the behavioral anomalies associated to MAO-A deficiency, we tested the behavioral effects of its blocker fluoxetine on perseverative, social and aggressive behaviors in transgenic animals with hypomorphic or null-allele MAO-A mutations. Acute treatment with the 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-A(Neo) mice. Furthermore, this treatment also reduced perseverative responses (including marble burying and water mist-induced grooming) in both MAO-A mutant genotypes. Both MAO-A mutant lines displayed significant reductions in 5-HTT expression across the prefrontal cortex, amygdala and striatum, as quantified by immunohistochemical detection; however, the down-regulation of 5-HTT in MAO-A(Neo) mice was more pervasive and widespread than in their KO counterparts, possibly indicating a greater ability of the hypomorphic line to enact compensatory mechanisms with respect to 5-HT homeostasis. Collectively, these findings suggest that the behavioral deficits associated with low MAO-A activity may reflect developmental alterations of 5-HTT within 5-HTergic neurons. Furthermore, the translational implications of our results highlight 5-HT reuptake inhibition as an interesting approach for the control of aggressive outbursts in MAO-A deficient individuals. PMID:24882701

  17. Behavioral Phenotype of Fmr1 Knock-Out Mice during Active Phase in an Altered Light/Dark Cycle123

    PubMed Central

    Saré, R. Michelle

    2016-01-01

    Abstract Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability and is a disorder that is also highly associated with autism. FXS occurs as a result of an expanded CGG repeat sequence leading to transcriptional silencing. In an animal model of FXS in which Fmr1 is knocked out (Fmr1 KO), many physical, physiological, and behavioral characteristics of the human disease are recapitulated. Prior characterization of the mouse model was conducted during the day, the inactive phase of the circadian cycle. Circadian rhythms are an important contributor to behavior and may play a role in the study of disease phenotype. Moreover, changes in the parameters of circadian rhythm are known to occur in FXS animal models. We conducted an investigation of key behavioral phenotypes in Fmr1 KO mice during their active phase. We report that phase did not alter the Fmr1 KO phenotype in open field activity, anxiety, and learning and memory. There was a slight effect of phase on social behavior as measured by time in chamber, but not by time spent sniffing. Our data strengthen the existing data characterizing the phenotype of Fmr1 KO mice, indicating that it is independent of circadian phase. PMID:27294193

  18. 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…

  19. Behavioral and neurochemical abnormalities after exposure to low doses of high-energy iron particles.

    PubMed

    Hunt, W A; Joseph, J A; Rabin, B M

    1989-01-01

    Exposure of rats to high-energy iron particles (600 MeV/amu) has been found to alter behavior after doses as low as 10 rads. The performance of a task that measures upper body strength was significantly degraded after irradiation. In addition, an impairment in the regulation of dopamine release in the caudate nucleus (a motor center in the brain), lasting at least 6 months, was also found and correlated with the performance deficits. A general indication of behavioral toxicity and an index of nausea and emesis, the conditioned taste aversion, was also evident. The sensitivity to iron particles was 10-600 times greater than to gamma photons. These results suggest that behavioral and neurobiological damage may be a consequence of exposure to low doses of heavy particles and that this possibility should be extensively studied. PMID:11537313

  20. Behavioral and neurochemical abnormalities after exposure to low doses of high-energy iron particles

    NASA Astrophysics Data System (ADS)

    Hunt, Walter A.; Joseph, James A.; Rabin, Bernard M.

    Exposure of rats to high-energy iron particles (600 MeV/amu) has been found to alter behavior after doses as low as 10 rads. The performance of a task that measures upper body strength was significantly degraded after irradiation. In addition, an impairment in the regulation of dopamine release in the caudate nucleus (a motor center in the brain), lasting at least 6 months, was also found and correlated with the performance deficits. A general indication of behavioral toxicity and an index of nausea and emesis, the conditioned taste aversion, was also evident. The sensitivity to iron particles was 10-600 times greater than to gamma photons. These results suggest that behavioral and neurobiological damage may be a consequence of exposure to low doses of heavy particles and that this possibility should be extensively studied.

  1. Behavioral and neurochemical abnormalities after exposure to low doses of high-energy iron particles

    SciTech Connect

    Hunt, W.A.; Joseph, J.A.; Rabin, B.M.

    1989-01-01

    Exposure of rats to high-energy iron particles (600 MeV/amu) has been found to alter behavior after doses as low as 10 rads. The performance of a task that measures upper body strength was significantly degraded after irradiation. In addition, an impairment in the regulation of dopamine release in the caudate nucleus (a motor center in the brain), lasting at least 6 months, was also found and correlated with the performance deficits. A general indication of behavioral toxicity and an index of nausea and emesis, the conditioned taste aversion, was also evident. The sensitivity to iron particles was 10-600 times greater than to gamma photons. These results suggest that behavioral and neurobiological damage may be a consequence of exposure to low doses of heavy particles and that this possibility should be extensively studied.

  2. LIN-41 inactivation leads to delayed centrosome elimination and abnormal chromosome behavior during female meiosis in Caenorhabditis elegans

    PubMed Central

    Matsuura, Rieko; Ashikawa, Tomoko; Nozaki, Yuka; Kitagawa, Daiju

    2016-01-01

    During oogenesis, two successive meiotic cell divisions occur without functional centrosomes because of the inactivation and subsequent elimination of maternal centrosomes during the diplotene stage of meiosis I. Despite being a conserved phenomenon in most metazoans, the means by which this centrosome behavior is controlled during female meiosis remain elusive. Here, we conducted a targeted RNAi screening in the Caenorhabditis elegans gonad to identify novel regulators of centrosome behavior during oogenesis. We screened 513 genes known to be essential for embryo production and directly visualized GFP–γ-tubulin to monitor centrosome behavior at all stages of oogenesis. In the screening, we found that RNAi-mediated inactivation of 33 genes delayed the elimination of GFP–γ-tubulin at centrosomes during oogenesis, whereas inactivation of nine genes accelerated the process. Depletion of the TRIM-NHL protein LIN-41 led to a significant delay in centrosome elimination and to the separation and reactivation of centrosomes during oogenesis. Upon LIN-41 depletion, meiotic chromosomes were abnormally condensed and pulled toward one of the two spindle poles around late pachytene even though the spindle microtubules emanated from both centrosomes. Overall, our work provides new insights into the regulation of centrosome behavior to ensure critical meiotic events and the generation of intact oocytes. PMID:26764090

  3. Regional brain abnormalities in 22q11.2 deletion syndrome: association with cognitive abilities and behavioral symptoms.

    PubMed

    Bearden, Carrie E; van Erp, Theo G M; Monterosso, John R; Simon, Tony J; Glahn, David C; Saleh, Peter A; Hill, Nicole M; McDonald-McGinn, Donna M; Zackai, Elaine; Emanuel, Beverly S; Cannon, Tyrone D

    2004-06-01

    Children with 22q11.2 microdeletions (Velocardiofacial Syndrome; VCFS) have previously been shown to exhibit learning deficits and elevated rates of psychopathology. The aim of this study was to assess regional brain abnormalities in children with 22q11DS, and to determine the relationship of these measures to neurocognitive and behavioral function. Thirteen children with confirmed deletions and 9 demographically matched comparison subjects were assessed with a neurocognitive battery, behavioral measures, and high-resolution MRI. Twenty-two qllDS children showed a nonsignificant 4.3% global decrease in total brain volume as compared to healthy controls,with differential reduction in white matter, and significantly increased sulcal cerebrospinal fluid (CSF) in temporal and posterior brain regions. In 22q11 DS subjects, but not controls, bilateral temporal gray and white matter volumes were significant predictors of overall cognitive performance. Further, reduced temporal gray matter was associated with elevated Thought Problems score on the CBCL. Results indicate that global alterations in brain volume are common in children with 22q deletions, particularly those with low IQ and/or behavioral disturbance. Although preliminary,these findings suggest a possible underlying pathophysiology of the cognitive deficits seen in this syndrome,and provide insight into complex gene-brain-behavior relationships. PMID:15788257

  4. Behavioral, neurochemical and neuroendocrine effects of abnormal savda munziq in the chronic stress mice.

    PubMed

    Amat, Nurmuhammat; Hoxur, Parida; Ming, Dang; Matsidik, Aynur; Kijjoa, Anake; Upur, Halmurat

    2012-01-01

    Oral administration of Abnormal Savda Munsiq (ASMq), a herbal preparation used in Traditional Uighur Medicine, was found to exert a memory-enhancing effect in the chronic stressed mice, induced by electric foot-shock. The memory improvement of the stressed mice was shown by an increase of the latency time in the step-through test and the decrease of the latency time in the Y-maze test. Treatment with ASMq was found to significantly decrease the serum levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT) and β-endorphin (β-EP) as well as the brain and serum level of norepinephrine (NE). Furthermore, ASMq was able to significantly reverse the chronic stress by decreasing the brain and serum levels of the monoamine neurotransmitters dopamine (DA), 5-hydroxytryptamine (5-HT) and 3,4-dihydroxyphenylalanine (DOPAC). The results obtained from this study suggested that the memory-enhancing effect of ASMq was mediated through regulations of neurochemical and neuroendocrine systems. PMID:22919413

  5. Adults with Chromosome 18 Abnormalities.

    PubMed

    Soileau, Bridgette; Hasi, Minire; Sebold, Courtney; Hill, Annice; O'Donnell, Louise; Hale, Daniel E; Cody, Jannine D

    2015-08-01

    The identification of an underlying chromosome abnormality frequently marks the endpoint of a diagnostic odyssey. However, families are frequently left with more questions than answers as they consider their child's future. In the case of rare chromosome conditions, a lack of longitudinal data often makes it difficult to provide anticipatory guidance to these families. The objective of this study is to describe the lifespan, educational attainment, living situation, and behavioral phenotype of adults with chromosome 18 abnormalities. The Chromosome 18 Clinical Research Center has enrolled 483 individuals with one of the following conditions: 18q-, 18p-, Tetrasomy 18p, and Ring 18. As a part of the ongoing longitudinal study, we collect data on living arrangements, educational level attained, and employment status as well as data on executive functioning and behavioral skills on an annual basis. Within our cohort, 28 of the 483 participants have died, the majority of whom have deletions encompassing the TCF4 gene or who have unbalanced rearrangement involving other chromosomes. Data regarding the cause of and age at death are presented. We also report on the living situation, educational attainment, and behavioral phenotype of the 151 participants over the age of 18. In general, educational level is higher for people with all these conditions than implied by the early literature, including some that received post-high school education. In addition, some individuals are able to live independently, though at this point they represent a minority of patients. Data on executive function and behavioral phenotype are also presented. Taken together, these data provide insight into the long-term outcome for individuals with a chromosome 18 condition. This information is critical in counseling families on the range of potential outcomes for their child. PMID:25403900

  6. Activity Suppression Behavior Phenotype in SULT4A1 Frameshift Mutant Zebrafish.

    PubMed

    Crittenden, Frank; Thomas, Holly R; Parant, John M; Falany, Charles N

    2015-07-01

    Since its identification in 2000, sulfotransferase (SULT) 4A1 has presented an enigma to the field of cytosolic SULT biology. SULT4A1 is exclusively expressed in neural tissue, is highly conserved, and has been identified in every vertebrate studied to date. Despite this singular level of conservation, no substrate or function for SULT4A1 has been identified. Previous studies demonstrated that SULT4A1 does not bind the obligate sulfate donor, 3'-phosphoadenosine-5'-phosphosulfate, yet SULT4A1 is classified as a SULT superfamily member based on sequence and structural similarities to the other SULTs. In this study, transcription activator-like effector nucleases were used to generate heritable mutations in the SULT4A1 gene of zebrafish. The mutation (SULT4A1(Δ8)) consists of an 8-nucleotide deletion within the second exon of the gene, resulting in a frameshift mutation and premature stop codon after 132 AA. During early adulthood, casual observations were made that mutant zebrafish were exhibiting excessively sedentary behavior during the day. These observations were inconsistent with published reports on activity in zebrafish that are largely diurnal organisms and are highly active during the day. Thus, a decrease in activity during the day represents an abnormal behavior and warranted further systematic analysis. EthoVision video tracking software was used to monitor activity levels in wild-type (WT) and SULT4A1(Δ8/Δ8) fish over 48 hours of a normal light/dark cycle. SULT4A1(Δ8/Δ8) fish were shown to exhibit increased inactivity bout length and frequency as well as a general decrease in daytime activity levels when compared with their WT counterparts. PMID:25934576

  7. Activity Suppression Behavior Phenotype in SULT4A1 Frameshift Mutant Zebrafish

    PubMed Central

    Crittenden, Frank; Thomas, Holly R.; Parant, John M.

    2015-01-01

    Since its identification in 2000, sulfotransferase (SULT) 4A1 has presented an enigma to the field of cytosolic SULT biology. SULT4A1 is exclusively expressed in neural tissue, is highly conserved, and has been identified in every vertebrate studied to date. Despite this singular level of conservation, no substrate or function for SULT4A1 has been identified. Previous studies demonstrated that SULT4A1 does not bind the obligate sulfate donor, 3′-phosphoadenosine-5′-phosphosulfate, yet SULT4A1 is classified as a SULT superfamily member based on sequence and structural similarities to the other SULTs. In this study, transcription activator-like effector nucleases were used to generate heritable mutations in the SULT4A1 gene of zebrafish. The mutation (SULT4A1Δ8) consists of an 8-nucleotide deletion within the second exon of the gene, resulting in a frameshift mutation and premature stop codon after 132 AA. During early adulthood, casual observations were made that mutant zebrafish were exhibiting excessively sedentary behavior during the day. These observations were inconsistent with published reports on activity in zebrafish that are largely diurnal organisms and are highly active during the day. Thus, a decrease in activity during the day represents an abnormal behavior and warranted further systematic analysis. EthoVision video tracking software was used to monitor activity levels in wild-type (WT) and SULT4A1Δ8/Δ8 fish over 48 hours of a normal light/dark cycle. SULT4A1Δ8/Δ8 fish were shown to exhibit increased inactivity bout length and frequency as well as a general decrease in daytime activity levels when compared with their WT counterparts. PMID:25934576

  8. Modulation of Serotonin Transporter Function during Fetal Development Causes Dilated Heart Cardiomyopathy and Lifelong Behavioral Abnormalities

    PubMed Central

    Noorlander, Cornelle W.; Ververs, Frederique F. T.; Nikkels, Peter G. J.; van Echteld, Cees J. A.; Visser, Gerard H. A.; Smidt, Marten P.

    2008-01-01

    Background Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI. Methodology/Principal Findings In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring. Conclusions These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher

  9. Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57Bl/6 mice

    PubMed Central

    Tsai, Peter T.; Green-Colozzi, Emily; Goto, June; Anderl, Stefanie; Kwiatkowski, David; Sahin, Mustafa

    2012-01-01

    Mammalian target of rapamycin (mTOR) signaling has been shown to be deregulated in a number of genetic, neurodevelopmental disorders including Tuberous Sclerosis Complex, Neurofibromatosis, Fragile X, and Rett syndromes. As a result, mTOR inhibitors, such as rapamycin and its analogs, offer potential therapeutic avenues for these disorders. Some of these disorders – such as Tuberous Sclerosis Complex – can be diagnosed prenatally. Thus, prenatal administration of these inhibitors could potentially prevent the development of the devastating symptoms associated with these disorders. To assess the possible detrimental effects of prenatal rapamycin treatment, we evaluated both early and late behavioral effects of a single rapamycin treatment at embryonic day 16.5 in wildtype C57Bl/6 mice. This treatment adversely impacted early developmental milestones as well as motor function in adult animals. Rapamycin also resulted in anxiety-like behaviors during both early development and adulthood but did not affect adult social behaviors. Together, these results indicate that a single, prenatal rapamycin treatment not only adversely affects early postnatal development but also results in long lasting negative effects, persisting into adulthood. These findings are of importance in considering prenatal administration of rapamycin and related drugs in the treatment of patients with neurogenetic, neurodevelopmental disorders. PMID:23229624

  10. A latent modeling approach to genotype-phenotype relationships: maternal problem behavior clusters, prenatal smoking, and MAOA genotype.

    PubMed

    McGrath, L M; Mustanski, B; Metzger, A; Pine, D S; Kistner-Griffin, E; Cook, E; Wakschlag, L S

    2012-08-01

    This study illustrates the application of a latent modeling approach to genotype-phenotype relationships and gene × environment interactions, using a novel, multidimensional model of adult female problem behavior, including maternal prenatal smoking. The gene of interest is the monoamine oxidase A (MAOA) gene which has been well studied in relation to antisocial behavior. Participants were adult women (N = 192) who were sampled from a prospective pregnancy cohort of non-Hispanic, white individuals recruited from a neighborhood health clinic. Structural equation modeling was used to model a female problem behavior phenotype, which included conduct problems, substance use, impulsive-sensation seeking, interpersonal aggression, and prenatal smoking. All of the female problem behavior dimensions clustered together strongly, with the exception of prenatal smoking. A main effect of MAOA genotype and a MAOA × physical maltreatment interaction were detected with the Conduct Problems factor. Our phenotypic model showed that prenatal smoking is not simply a marker of other maternal problem behaviors. The risk variant in the MAOA main effect and interaction analyses was the high activity MAOA genotype, which is discrepant from consensus findings in male samples. This result contributes to an emerging literature on sex-specific interaction effects for MAOA. PMID:22610759

  11. Early life seizures in female rats lead to anxiety-related behavior and abnormal social behavior characterized by reduced motivation to novelty and deficit in social discrimination.

    PubMed

    Castelhano, Adelisandra Silva Santos; Ramos, Fabiane Ochai; Scorza, Fulvio Alexandre; Cysneiros, Roberta Monterazzo

    2015-03-01

    Previously, we demonstrated that male Wistar rats submitted to neonatal status epilepticus showed abnormal social behavior characterized by deficit in social discrimination and enhanced emotionality. Taking into account that early insult can produce different biological manifestations in a gender-dependent manner, we aimed to investigate the social behavior and anxiety-like behavior in female Wistar rats following early life seizures. Neonate female Wistar rats at 9 days postnatal were subject to pilocarpine-induced status epilepticus and the control received saline. Behavioral tests started from 60 days postnatal and were carried out only during the diestrus phase of the reproductive cycle. In sociability test experimental animals exhibited reduced motivation for social encounter and deficit in social discrimination. In open field and the elevated plus maze, experimental animals showed enhanced emotionality with no changes in basal locomotor activity. The results showed that female rats submitted to neonatal status epipepticus showed impaired social behavior, characterized by reduced motivation to novelty and deficit in social discrimination in addition to enhanced emotionality. PMID:25139483

  12. Increased apoptosis and abnormal visual behavior by histone modifications with exposure to para-xylene in developing Xenopus.

    PubMed

    Gao, Juanmei; Ruan, Hangze; Qi, Xianjie; Guo, Xia; Zheng, Jingna; Liu, Cong; Fang, Yanxiao; Huang, Minjiao; Xu, Miao; Shen, Wanhua

    2016-09-01

    Xylene and its derivatives are raw materials widely used in industry and known to be toxic to animals. However, the mechanism underlying the neurotoxicity of para-xylene (PX) to the central nervous system (CNS) in vivo is less clear. Here, we exposed Xenopus laevis tadpoles to sub-lethal concentrations of PX during the critical period of brain development to determine the effects of PX on Xenopus development and visual behavior. We found that the abnormality rate was significantly increased with exposure to increasing concentrations of PX. In particular, the number of apoptotic cells in the optic tectum was dramatically increased with exposure to PX at 2mM. Long-term PX exposure also resulted in significant deficits in visually guided avoidance behavior. Strikingly, co-incubation with PX and d-glucuronolactone (GA) decreased the number of apoptotic cells and rescued the avoidance behavior. Furthermore, we found that the acetylation of H4K12 (H4K12ac) and the dimethylation of H3K9 (H3K9me2) in the optic tectum were significantly increased in PX-treated animals, and these effects were suppressed by GA treatment. In particular, the increase in apoptotic cells in PX-treated brains was also inhibited by GA treatment. These effects indicate that epigenetic regulation plays a key role in PX-induced apoptosis and animal behavior. In an effort to characterize the neurotoxic effects of PX on brain development and behavior, these results suggest that the neurotoxicity of PX requires further evaluation regarding the safety of commercial and industrial uses. PMID:27343828

  13. Loss of GSK-3 Causes Abnormal Astrogenesis and Behavior in Mice.

    PubMed

    Jung, Eui-Man; Ka, Minhan; Kim, Woo-Yang

    2016-08-01

    Altered activity of glycogen synthase kinase-3 (GSK-3) is associated with psychiatric diseases and neurodegenerative diseases. GSK-3 is a key regulator in multiple aspects of neuronal differentiation in the brain. However, little is known about the role of GSK-3 in astrocyte development. To examine the role of GSK-3 in astrocytes, we generated a conditional knockout mouse using a glial fibrillary acidic protein (GFAP)-cre driver, in which the GSK-3 alpha and beta genes are deleted in astrocytes. We found that GFAP-cre-mediated GSK-3 deletion led to a larger brain. The number and size of astrocytes were increased in GSK-3 mutant brains. The levels of GFAP and phospho-STAT3, indicators of astrogenesis, were elevated in GSK-3 mutants. Furthermore, we found upregulation of astrocyte regulatory molecules such as phospho-AKT, phospho-S6, and cyclin D in GSK-3 mutant brains. Finally, GSK-3 mutant mice exhibited aberrant anxiety and social behavior. Our results suggest that GSK-3 plays a significant role in astrocyte development and behavioral control in mice. PMID:26179612

  14. Abnormal behavior of midgap electron trap in HB-GaAs during thermal annealing

    NASA Astrophysics Data System (ADS)

    Min, Suk-Ki; Kim, Eun Kyu; Cho, Hoon Young

    1988-05-01

    The behavior of the EL2 family in horizontal Bridgman-(HB) grown GaAs by two thermal annealing methods, furnace annealing and rapid thermal annealing, was studied through deep level transient spectroscopy (DLTS) measurements, and a similar behavior of another group of electron traps was observed. As the annealing time is increased, the EL2 trap (Ec-0.81 eV) is transformed to the new trap, EX2 (Ec-0.73 eV), and finally to the other new trap, EX1 (Ec-0.86 eV). Also the EL6 group (Ec-0.18, 0.22, 0.27, and 0.35 eV) varied similarly to the EL2 family as a trap (Ec-0.27 eV) is transformed to the first trap (Ec-0.18 eV) and then the second trap (Ec-0.22 eV). This result revealed that the EL2 family is related to the EL6 group. From the study of photocapacitance quenching, the existence of metastable states of the EL2 family is identified. These results suggest that the atomic structure of the EL2 trap may be an arsenic antisite with an interstitial arsenic and a double vacancy, such as VAsAsIVGaAsGa or its complex.

  15. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    PubMed Central

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

  16. Behavioral phenotypic properties of a natural occurring rat model of congenital stationary night blindness with Cacna1f mutation.

    PubMed

    An, Jing; Wang, Li; Guo, Qun; Li, Li; Xia, Feng; Zhang, Zuoming

    2012-09-01

    Cacna1f gene mutation could lead to incomplete congenital stationary night blindness (iCSNB) disease. The CSNB-like phenotype rat is a spontaneous rat model caused by Cacna1f gene mutation. The present study explored the phenotypic properties of behavior performance in CSNB rats further. The vision-related behaviors of CSNB rats were assessed with a Morris water maze (MWM), passive avoidance tests, and open-field test. Motor ability was evaluated with a rotarod test and a wire hang test, and mechanical pain and thermalgia were used to evaluate sensory system function. Electroretinograms (ERGs) were recorded to evaluate the function of the retina. The vision-related results showed that longer latencies of escape and reduced probe trial in MWM for CSNB rats. There were more errors in avoidance test; CSNB rats were more active in the open field and presented a different pattern of exploration. The locomotor-related behaviors showed shorter falling latencies in the rotarod test and shorter gripping time in CSNB rats. And mechanical thresholds of pain increased in CSNB rats. The ERGs indicated that both the amplitude and latency of rod and cone systems were impaired in the CSNB rats. In summary, Cacna1f gene mutation changed the performance of various behaviors in the CSNB rat aside from vision-related phenotype. Cacna1f gene might play a role in a wide range of responses in the organism. These results confirm the importance of a comprehensive profile for understanding the behavior phenotype of Cacna1f gene mutation in CSNB rat. PMID:22800190

  17. Deficiency of Schnurri-2, an MHC Enhancer Binding Protein, Induces Mild Chronic Inflammation in the Brain and Confers Molecular, Neuronal, and Behavioral Phenotypes Related to Schizophrenia

    PubMed Central

    Takao, Keizo; Kobayashi, Katsunori; Hagihara, Hideo; Ohira, Koji; Shoji, Hirotaka; Hattori, Satoko; Koshimizu, Hisatsugu; Umemori, Juzoh; Toyama, Keiko; Nakamura, Hironori K; Kuroiwa, Mahomi; Maeda, Jun; Atsuzawa, Kimie; Esaki, Kayoko; Yamaguchi, Shun; Furuya, Shigeki; Takagi, Tsuyoshi; Walton, Noah M; Hayashi, Nobuhiro; Suzuki, Hidenori; Higuchi, Makoto; Usuda, Nobuteru; Suhara, Tetsuya; Nishi, Akinori; Matsumoto, Mitsuyuki; Ishii, Shunsuke; Miyakawa, Tsuyoshi

    2013-01-01

    Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. PMID:23389689

  18. Disruption of Visc-2, a Brain-Expressed Conserved Long Noncoding RNA, Does Not Elicit an Overt Anatomical or Behavioral Phenotype

    PubMed Central

    Oliver, Peter L.; Chodroff, Rebecca A.; Gosal, Amrit; Edwards, Benjamin; Cheung, Amanda F.P.; Gomez-Rodriguez, Julio; Elliot, Gene; Garrett, Lisa J.; Lickiss, Tom; Szele, Francis; Green, Eric D.; Molnár, Zoltán; Ponting, Chris P.

    2015-01-01

    Although long noncoding RNAs (lncRNAs) are proposed to play essential roles in mammalian neurodevelopment, we know little of their functions from their disruption in vivo. Combining evidence for evolutionary constraint and conserved expression data, we previously identified candidate lncRNAs that might play important and conserved roles in brain function. Here, we demonstrate that the sequence and neuronal transcription of lncRNAs transcribed from the previously uncharacterized Visc locus are conserved across diverse mammals. Consequently, one of these lncRNAs, Visc-2, was selected for targeted deletion in the mouse, and knockout animals were subjected to an extremely detailed anatomical and behavioral characterization. Despite a neurodevelopmental expression pattern of Visc-2 that is highly localized to the cortex and sites of neurogenesis, anomalies in neither cytoarchitecture nor neuroproliferation were identified in knockout mice. In addition, no abnormal motor, sensory, anxiety, or cognitive behavioral phenotypes were observed. These results are important because they contribute to a growing body of evidence that lncRNA loci contribute on average far less to brain and biological functions than protein-coding loci. A high-throughput knockout program focussing on lncRNAs, similar to that currently underway for protein-coding genes, will be required to establish the distribution of their organismal functions. PMID:25209608

  19. Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.

    PubMed

    Takao, Keizo; Kobayashi, Katsunori; Hagihara, Hideo; Ohira, Koji; Shoji, Hirotaka; Hattori, Satoko; Koshimizu, Hisatsugu; Umemori, Juzoh; Toyama, Keiko; Nakamura, Hironori K; Kuroiwa, Mahomi; Maeda, Jun; Atsuzawa, Kimie; Esaki, Kayoko; Yamaguchi, Shun; Furuya, Shigeki; Takagi, Tsuyoshi; Walton, Noah M; Hayashi, Nobuhiro; Suzuki, Hidenori; Higuchi, Makoto; Usuda, Nobuteru; Suhara, Tetsuya; Nishi, Akinori; Matsumoto, Mitsuyuki; Ishii, Shunsuke; Miyakawa, Tsuyoshi

    2013-07-01

    Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. PMID:23389689

  20. Consequences of long-term treatment with agomelatine on depressive-like behavior and neurobiological abnormalities in pinealectomized rats.

    PubMed

    Tchekalarova, Jana; Nenchovska, Zlatina; Atanasova, Dimitrina; Atanasova, Milena; Kortenska, Lidia; Stefanova, Miroslava; Alova, Liana; Lazarov, Nikolai

    2016-04-01

    Previous data have shown that the rat model of melatonin deficit can cause a number of neurobiological aberrations. The aim of the present study was to determine whether the antidepressant drug agomelatine, a MT1/MT2 melatoninergic receptor agonist/5-HT2C receptor antagonist is able to prevent some of the behavioral, biochemical and cellular abnormalities induced by pinealectomy. The injection of agomelatine (40 mg/kg, i.p. for 5 weeks)/vehicle started after pinealectomy/sham procedure in Wistar rats. Animals were tested in different behavioral tests for anxiety and depression during the period of agomelatine treatment (chronic effect) and two months later (plastic effect). The effect of agomelatine on KCl-evoked serotonin (5-HT) release from the hippocampus, the activity of the hypothalamic-pituitary-adrenal (HPA) axis and neuronal loss in pinealectomized rats were assessed. Our results showed that agomelatine not only did not prevent the disturbed emotional arousal/anxiety behavior in pinealectomized rats during the treatment but the enhanced motor activity and decreased anxiety state was still observed two months after the discontinuation of treatment. However, the drug corrected a depressive-like behavior (chronic and plastic effect), alleviated the enhanced KCl-evoked 5-HT release in the hippocampus, recovered the suppressed negative feedback inhibition of HPA axis and exerted a neuroprotection in pinealectomized rats. Our findings suggest that pinealectomy can model melancholic depression disorder while the antidepressant action of agomelatine is associated with a correction of 5-HT release in the hippocampus, dysregulated HPA system and neuroprotection in limbic structures. PMID:26779670

  1. Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: association with delayed myelination and behavioral abnormalities.

    PubMed

    Sawano, Erika; Negishi, Takayuki; Aoki, Tomoyuki; Murakami, Masami; Tashiro, Tomoko

    2013-03-01

    The senescence-accelerated mouse (SAM) strains were established through selective inbreeding of the AKR/J strain based on phenotypic variations of aging and consist of senescence-prone (SAMP) and senescence-resistant (SAMR) strains. Among them, SAMP8 is considered as a model of neurodegeneration displaying age-associated learning and memory impairment and altered emotional status. Because adult hypothyroidism is one of the common causes of cognitive impairment and various psychiatric disorders, we examined the possible involvement of thyroid hormone (TH) signaling in the pathological aging of SAMP8 using the senescence-resistant SAMR1 as control. Although plasma TH levels were similar in both strains, a significant decrease in type 2 deiodinase (D2) gene expression was observed in the SAMP8 hippocampus from 1 to 8 months of age, which led to a 35-50% reductions at the protein level and 20% reduction of its enzyme activity at 1, 3, and 5 months. D2 is responsible for local conversion of thyroxine into transcriptionally active 3,5,3'-triiodothyronine (T3), so the results suggest a reduction in T3 level in the SAMP8 hippocampus. Attenuation of local TH signaling was confirmed by downregulation of TH-dependent genes and by immunohistochemical demonstration of delayed and reduced accumulation of myelin basic protein, the expression of which is highly dependent on TH. Furthermore, we found that hyperactivity and reduced anxiety were not age-associated but were characteristic of young SAMP8 before they start showing impairments in learning and memory. Early alterations in local TH signaling may thus underlie behavioral abnormalities as well as the pathological aging of SAMP8. PMID:23224839

  2. A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders.

    PubMed

    Abdelhedi, Fatma; El Khattabi, Laila; Essid, Nouha; Viot, Geraldine; Letessier, Dominique; Lebbar, Aziza; Dupont, Jean-Michel

    2016-07-01

    Chromosomal microarray analysis has become a powerful diagnostic tool in the investigation of patients with intellectual disability leading to the discovery of dosage sensitive genes implicated in the manifestation of various genomic disorders. Interstitial deletions of the short arm of chromosome 10 represent rare genetic abnormalities, especially those encompassing the chromosomal region 10p11-p12. To date, only 10 postnatal cases with microdeletion of this region have been described, and all patients shared a common phenotype, including intellectual disability, abnormal behavior, distinct dysmorphic features, visual impairment, and cardiac malformations. WAC was suggested to be the main candidate gene for intellectual disability associated with 10 p11-p12 deletion syndrome. Here, we describe a new case of de novo 10p11.23-p12.1 microdeletion in a patient with intellectual disability, abnormal behavior, and distinct dysmorphic features. Our observation allows us to redefine the smallest region of overlap among patients reported so far, with a size of 80 Kb and which contains only the WAC gene. These findings strengthen the hypothesis that haploinsufficency of WAC gene might be likely responsible for intellectual disability and behavior disorders. Our data also led us to propose a clinical pathway for patients with this recognizable genetic syndrome depending on the facial dysmorphisms. © 2016 Wiley Periodicals, Inc. PMID:27119754

  3. A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood.

    PubMed

    Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N; Hudziak, James J; Ducharme, Simon

    2016-01-01

    Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. PMID:26431805

  4. High Fat Diet Produces Brain Insulin Resistance, Synaptodendritic Abnormalities and Altered Behavior in Mice

    PubMed Central

    Arnold, Steven E.; Lucki, Irwin; Brookshire, Bethany R.; Carlson, Gregory C.; Browne, Carolyn A.; Kazi, Hala; Bang, Sookhee; Choi, Bo-Ran; Chen, Yong; McMullen, Mary F.; Kim, Sangwon F.

    2014-01-01

    Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17 days or a moderate high fat diet (HFD, 45% kcal by fat) for 8 weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS616), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors. PMID:24686304

  5. Behavioral abnormalities and Parkinson’s-like histological changes resulting from Id2 inactivation in mice

    PubMed Central

    Havrda, Matthew C.; Paolella, Brenton R.; Ward, Nora M.; Holroyd, Kathryn B.

    2013-01-01

    SUMMARY Characterizing dopaminergic neuronal development and function in novel genetic animal models might uncover strategies for researchers to develop disease-modifying treatments for neurologic disorders. Id2 is a transcription factor expressed in the developing central nervous system. Id2−/− mice have fewer dopaminergic neurons in the olfactory bulb and reduced olfactory discrimination, a pre-clinical marker of Parkinson’s disease. Here, we summarize behavioral, histological and in vitro molecular biological analyses to determine whether midbrain dopaminergic neurons are affected by Id2 loss. Id2−/− mice were hyperactive at 1 and 3 months of age, but by 6 months showed reduced activity. Id2−/− mice showed age-dependent histological alterations in dopaminergic neurons of the substantia nigra pars compacta (SNpC) associated with changes in locomotor activity. Reduced dopamine transporter (DAT) expression was observed at early ages in Id2−/− mice and DAT expression was dependent on Id2 expression in an in vitro dopaminergic differentiation model. Evidence of neurodegeneration, including activated caspase-3 and glial infiltration, were noted in the SNpC of older Id2−/− mice. These findings document a novel role for Id2 in the maintenance of midbrain dopamine neurons. The Id2−/− mouse should provide unique opportunities to study the progression of neurodegenerative disorders involving the dopamine system. PMID:23264561

  6. Surface Structure Evolution and Abnormal Wear Behavior of the TiNiNb Alloy under Impact Load

    NASA Astrophysics Data System (ADS)

    Zhang, Jianjun; Zhu, Jinhua

    2009-05-01

    The TiNiNb alloy exhibits a linear increase in wear with a number of impacts at the low impact energy density E im of 1.6 J/cm2. However, a change in the volume wear occurs on the wear curve when E im is increased to 2.42 J/cm2. In this case, when the number of impacts N is more than 3 × 105 cycles, the wear rate decreases from 5.8 × 10-6 to 1.9 × 10-6 mm3/cycle, which is only one-half of that under low E im (1.6 J/cm2). It is significant for practical applications because impact energy increases while the wear rate decreases. X-ray diffraction (XRD) and transmission electron microscopy (TEM) analyses show that a large number of amorphous structures are produced on the sample surface at high E im , while no new crystalline phases appear. The abnormal wear behavior of the TiNiNb alloy can be attributed to the excellent wear behavior of amorphous structure and the consumption of impact energy during amorphous structure production.

  7. Aberrant IgG isotype generation in mice with abnormal behaviors.

    PubMed

    Kim, So-Nam; Jo, Gwang-Ho; Kim, Hyoung-Ah; Heo, Yong

    2016-01-01

    BTBR T+tf/J (BTBR) mice were recently cited as a suitable animal model for the study of autism because of their behavioral characteristics and immunological changes similar to those reported from autistic subjects. The BTBR mouse was reported to have significantly higher levels of serum IgG, brain IgG deposits and anti-brain IgG than highly social C57BL/6 mice, suggesting involvement of aberrant immune responses in the occurrence of autism. Up-regulation of IgG production was investigated here, with a focus on the pattern of IgG isotype distribution compared with that in FVB/NJ (FVB) mice, another highly social control strain. The results indicated that levels of serum IgG1, IgG2b and IgG3 in post-natal day 21 BTBR mice was significantly higher than FVB mice, regardless of sex, resulting in higher IgG1:IgG2a ratios in BTBR mice than in FVB mice (statistical significance in males). A similar outcome regarding the IgG1:IgG2a ratio was observed in culture supernatants of bone marrow cells from these hosts. A presence of brain-reactive IgG in the sera of BTBR was higher than in FVB mice; levels of brain-reactive IgG against whole brain homogenates were higher in BTBR than in FVB mice, with significant differences seen in the striatum and substantia nigra regions. Levels of IgG1 deposited in the cerebellum, cortex, hippocampus or striatum of both BTBR male and female mice were significantly higher than in FVB counterparts. Overall, these results suggest that alterations in IgG isotype production or deposition in the brain could be implicated in the aberrant immune reactivities of BTBR mice. PMID:25691089

  8. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

    SciTech Connect

    Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert; Volz, Cornelia; Jägle, Herbert; Liebisch, Gerhard; Utermöhlen, Olaf; Langmann, Thomas

    2015-08-21

    Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.

  9. 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. PMID:25152719

  10. Heightened D3 Dopamine Receptor Levels in Cocaine Dependence and Contributions to the Addiction Behavioral Phenotype: A Positron Emission Tomography Study with [11C]-(+)-PHNO

    PubMed Central

    Payer, Doris E; Behzadi, Arian; Kish, Stephen J; Houle, Sylvain; Wilson, Alan A; Rusjan, Pablo M; Tong, Junchao; Selby, Peter; George, Tony P; McCluskey, Tina; Boileau, Isabelle

    2014-01-01

    The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [11C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7–240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [11C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [11C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [11C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [11C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in ⩾2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment. PMID:23921256

  11. Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO.

    PubMed

    Payer, Doris E; Behzadi, Arian; Kish, Stephen J; Houle, Sylvain; Wilson, Alan A; Rusjan, Pablo M; Tong, Junchao; Selby, Peter; George, Tony P; McCluskey, Tina; Boileau, Isabelle

    2014-01-01

    The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment. PMID:23921256

  12. Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders

    PubMed Central

    2010-01-01

    Background It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS) and 'repetitive sensory-motor actions' (RSMA) are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales. Methods A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees. Results Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled. Conclusions The finding that IS and RSMA are linked to different regions that only

  13. X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism

    SciTech Connect

    Brunner, H.G.; Nelen, M.R.; Zandvoort, P. van; Abeling, N.G.G.M.; Gennip, A.H. van; Ropers, H.H.; Oost, B.A. van ); Wolters, E.C.; Kuiper, M.A. )

    1993-06-01

    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. These 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.

  14. Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

    PubMed Central

    Grote, Jessica; Krysciak, Dagmar

    2015-01-01

    Phenotypic heterogeneity describes the occurrence of “nonconformist” cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. PMID:26025903

  15. Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior.

    PubMed

    Grote, Jessica; Krysciak, Dagmar; Streit, Wolfgang R

    2015-08-15

    Phenotypic heterogeneity describes the occurrence of "nonconformist" cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. PMID:26025903

  16. Duplication of the EFNB1 Gene in Familial Hypertelorism: Imbalance in Ephrin-B1 Expression and Abnormal Phenotypes in Humans and Mice

    PubMed Central

    Babbs, Christian; Stewart, Helen S; Williams, Louise J; Connell, Lyndsey; Goriely, Anne; Twigg, Stephen RF; Smith, Kim; Lester, Tracy; Wilkie, Andrew OM

    2011-01-01

    Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc. PMID:21542058

  17. In Nicotiana species, an artificial microRNA corresponding to the virulence modulating region of Potato spindle tuber viroid directs RNA silencing of a soluble inorganic pyrophosphatase gene and the development of abnormal phenotypes.

    PubMed

    Eamens, Andrew L; Smith, Neil A; Dennis, Elizabeth S; Wassenegger, Michael; Wang, Ming-Bo

    2014-02-01

    Potato spindle tuber viroid (PSTVd) is a small non-protein-coding RNA pathogen that can induce disease symptoms in a variety of plant species. How PSTVd induces disease symptoms is a long standing question. It has been suggested that PSTVd-derived small RNAs (sRNAs) could direct RNA silencing of a targeted host gene(s) resulting in symptom development. To test this, we expressed PSTVd sequences as artificial microRNAs (amiRNAs) in Nicotiana tabacum and Nicotiana benthamiana. One amiRNA, amiR46 that corresponds to sequences within the PSTVd virulence modulating region (VMR), induced abnormal phenotypes in both Nicotiana species that closely resemble those displayed by PSTVd infected plants. In N. tabacum amiR46 plants, phenotype severity correlated with amiR46 accumulation and expression down-regulation of the bioinformatically-identified target gene, a Nicotiana soluble inorganic pyrophosphatase (siPPase). Taken together, our phenotypic and molecular analyses suggest that disease symptom development in Nicotiana species following PSTVd infection results from sRNA-directed RNA silencing of the host gene, siPPase. PMID:24503090

  18. Altered Behavioral Phenotypes In Soluble Epoxide Hydrolase Knockout Mice: Effects of Traumatic Brain Injury

    PubMed Central

    Gruzdev, Artiom; Zeldin, Darryl C.

    2014-01-01

    After traumatic brain injury (TBI), arachidonic acid (ArA) is released from damaged cell membranes and metabolized to many bioactive eicosanoids, including several epoxyeicosatrienoic acids (EETs). Soluble epoxide hydrolase (Ephx2, sEH) appears to be the predominant pathway for EET metabolism to less active dihydroxyeicosatrienoates (DHETs). Prior studies indicate that brain levels of EETs increase transiently after TBI and EETs have antiinflammatory and neuroprotective activities which may benefit the injured brain. If the net effect of increased EET levels in the injured brain is beneficial to recovery, then Ephx2 gene disruption would be expected to enhance elevated EET levels and improve recovery in the injured brain. Thus, Ephx2-KO (Ephx2−/− bred onto pure C57Bl/6 background) mice were compared to wild-type controls in a unilateral controlled cortical impact model of TBI. Before injury, animals behaved comparably in open field activity and neurologic reflexes. Interestingly, the Ephx2-KO mice showed improved motor coordination on a beam walk task, yet showed indications of defective learning in a test of working spatial memory. After surgery, brain-injured Ephx2-KO mice again had less of a deficit in the beam walk than wild-type, and the difference in latency (post – pre) showed a trend of protection for Ephx2-KO mice after TBI. Brain-injured mice showed no genotype differences in working memory. Surprisingly, sham-operated Ephx2-KO mice exhibited an injured phenotype for working memory, compared to sham-operated wild-type mice. Brain eicosanoid levels were measured using liquid chromatography with tandem mass spectrometry. Of the 20 eicosanoids evaluated, only 8,9-EET was elevated in the Ephx2-KO cerebral cortex (37d post-surgery, in both sham and injured). Tissue DHET levels were below the limit of quantification. These results reflect a significant contribution of sEH deficiency in coordination of ambulatory movements and working spatial memory in the

  19. Neural correlates of abnormal sensory discrimination in laryngeal dystonia

    PubMed Central

    Termsarasab, Pichet; Ramdhani, Ritesh A.; Battistella, Giovanni; Rubien-Thomas, Estee; Choy, Melissa; Farwell, Ian M.; Velickovic, Miodrag; Blitzer, Andrew; Frucht, Steven J.; Reilly, Richard B.; Hutchinson, Michael; Ozelius, Laurie J.; Simonyan, Kristina

    2015-01-01

    Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder. PMID:26693398

  20. Are There Gender-Specific Pathways from Early Adolescence Psychological Distress Symptoms toward the Development of Substance Use and Abnormal Eating Behavior?

    ERIC Educational Resources Information Center

    Beato-Fernandez, Luis; Rodriguez-Cano, Teresa; Pelayo-Delgado, Esther; Calaf, Myralys

    2007-01-01

    The aim of the present longitudinal community study was to test whether psychological distress at 13 years of age predicted reported substance use problems in boys and abnormal eating behavior in girls 2 years later. The sample consisted of 500 male and 576 female students. The use of substances was evaluated using a semi-structured interview,…

  1. Severe Myoclonic Epilepsy in Infancy - Adult Phenotype with Bradykinesia, Hypomimia, and Perseverative Behavior: Report of Five Cases.

    PubMed

    Martin, P; Rautenstrauβ, B; Abicht, A; Fahrbach, J; Koster, S

    2010-01-01

    Dravet syndrome or severe myoclonic epilepsy in infancy (SMEI) is an epileptic syndrome characterised by refractory epilepsy and intellectual disability, typically presenting with febrile and afebrile generalised and unilateral clonic/tonic-clonic seizures in the first year of life and other types of seizures appearing later in the course of the disease. Five adult patients with SMEI and SCN1A mutations are reported, in which motor and behavioural abnormalities were outstanding symptoms. Bradykinesia, responding with latency, slow speaking with a thin voice, midface hypomimia and perseveration were distinctive features in all cases. These symptoms may be fit to define the adult phenotype of SMEI beyond seizure/epilepsy criteria. The motor and behavioural symptoms are discussed in the context of a possibly underlying frontal lobe/mesofrontal and cerebellar dysfunction. PMID:22140375

  2. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity.

    PubMed

    Sharma, Sorabh; Taliyan, Rajeev; Singh, Sumel

    2015-09-15

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recent studies have investigated the involvement of epigenetic modifications in PD. Histone deacetylase (HDAC) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study was designed to investigate the effect of sodium butyrate, a HDAC inhibitor in 6-hydroxydopamine (6-OHDA) - induced experimental PD like symptoms in rats. To produce motor deficit, 6-OHDA was administered unilaterally in the right medial forebrain bundle. Three weeks after 6-OHDA administration, the rats were challenged with apomorphine. Following this, the animals were treated with sodium butyrate (150 and 300 mg/kg i.p.) once daily for 14 days. Movement abnormalities were assessed by battery of behavioral tests. Biochemically, oxidative stress markers, neuroinflammation and dopamine were measured in striatal brain homogenate. Further, to explore the molecular mechanism(s), we measured the level of global H3 histone acetylation and brain derived neurotrophic factor (BDNF). 6-OHDA administration results in significant motor deficit along with reduction in striatal dopamine level. 6-OHDA treated rats showed elevated oxidative stress and neuroinflammatory markers. Treatment with sodium butyrate results in significant attenuation of motor deficits and increased striatal dopamine level. Moreover, sodium butyrate treatment attenuated the oxidative stress and neuroinflammatory markers. These effects occur concurrently with increased global H3 histone acetylation and BDNF levels. Thus, the observed results of the present study are indicative for the therapeutic potential of HDAC inhibitors in PD. PMID:26048426

  3. Neuropsychological and dimensional behavioral trait profiles in Costa Rican ADHD sib pairs: Potential intermediate phenotypes for genetic studies.

    PubMed

    Peskin, Viviana A; Ordóñez, Anna; Mackin, R Scott; Delucchi, Kevin; Monge, Silvia; McGough, James J; Chavira, Denise A; Berrocal, Monica; Cheung, Erika; Fournier, Eduardo; Badner, Judith A; Herrera, Luis Diego; Mathews, Carol A

    2015-06-01

    Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity. PMID:25832558

  4. Neuropsychological and Dimensional Behavioral Trait Profiles in Costa Rican ADHD Sib Pairs: Potential Intermediate Phenotypes for Genetic Studies

    PubMed Central

    Peskin, Viviana A.; Ordóñez, Anna; Mackin, R. Scott; Delucchi, Kevin; Monge, Silvia; McGough, James J.; Chavira, Denise A.; Berrocal, Monica; Cheung, Erika; Fournier, Eduardo; Badner, Judith A.; Herrera, Luis Diego; Mathews, Carol A.

    2015-01-01

    Introduction Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. Methods We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. Results We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). Conclusions The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70–90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity. PMID:25832558

  5. 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…

  6. Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments

    PubMed Central

    Zumbrennen-Bullough, Kimberly B.; Becker, Lore; Garrett, Lillian; Hölter, Sabine M.; Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia; Racz, Ildiko; Rathkolb, Birgit; Klopstock, Thomas; Wurst, Wolfgang; Zimmer, Andreas; Wolf, Eckhard; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabě; Romney, Steven J.; Leibold, Elizabeth A.

    2014-01-01

    Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2−/− mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2−/− mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments. PMID:24896637

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

    SciTech Connect

    Philip, Vivek M; Ansah, T; Blaha, C,; Cook, Melloni N.; Hamre, Kristin M.; Lariviere, William R; Matthews, Douglas B; Goldowitz, Daniel; Chesler, Elissa J

    2010-01-01

    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 have 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.

  8. Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL.

    PubMed

    D'Avola, Annalisa; Drennan, Samantha; Tracy, Ian; Henderson, Isla; Chiecchio, Laura; Larrayoz, Marta; Rose-Zerilli, Matthew; Strefford, Jonathan; Plass, Christoph; Johnson, Peter W; Steele, Andrew J; Packham, Graham; Stevenson, Freda K; Oakes, Christopher C; Forconi, Francesco

    2016-08-11

    Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) immunoglobulin gene heavy-chain variable region (IGHV) displays different states of anergy, indicated by reduced surface immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca(2+) mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. sIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with +12, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, although the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo, and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset. PMID:27301861

  9. Positive affect: phenotypic and etiologic associations with prosocial behaviors and internalizing problems in toddlers

    PubMed Central

    Wang, Manjie; Saudino, Kimberly J.

    2015-01-01

    Despite evidence for the associations of positive affect to prosocial behaviors and internalizing problems, relatively little is known about the underlying etiology. The sample comprised over 300 twin pairs at age 3. Positive affect, prosocial behaviors, and internalizing problems were assessed using the Toddler Behavior Assessment Questionnaire (Goldsmith, 1996), the Revised Rutter Parent Scale for Preschool Children (Hogg et al., 1997), and the Child Behavior Checklist for ages 1.5–5 (Achenbach, 1991), respectively. Positive affect correlated positively with prosocial behaviors, and negatively with internalizing problems. Prosocial behaviors were negatively associated with internalizing problems. The relations of positive affect to prosocial behaviors and internalizing problems were due to environmental effects (shared and non-shared). In contrast, the link between prosocial behaviors and internalizing problems was entirely explained by genetic effects. The current study has moved beyond prior emphasis on negative affect and elucidated the less understood etiology underlying the associations between positive affect, prosocial behaviors, and internalizing problems. This study could guide the development of programs for promoting prosocial behaviors and alleviating internalizing problems in children. PMID:25914668

  10. IgG (Gm) allotypes and multiple sclerosis in a French population: phenotype distribution and quantitative abnormalities in CSF with respect to sex, disease severity, and presence of intrathecal antibodies.

    PubMed

    Sesboüé, R; Daveau, M; Degos, J D; Martin-Mondiere, C; Goust, J M; Schuller, E; Rivat-Peran, L; Coquerel, A; Dujardin, M; Salier, J P

    1985-11-01

    The association of a given Gm allotype or phenotype with MS susceptibility, as previously described in some Caucasian populations, was not observed in a large French MS group, whether or not considering the possible influence of sex or disease severity. This result could be related to variations in geographical distribution of Gm alleles and MS susceptibility gene(s) or suggests the simultaneous involvement of Gm and other genetic system(s). In contrast, the corresponding CSFs exhibited already known MS-associated abnormalities of IgG1 (G1m) allotype contents, which therefore did not merely result from a Gm-associated MS susceptibility. These quantitative abnormalities were not sex dependent, but may fluctuate with MS severity. The G1m allotype levels in each CSF were not correlated with titers of various intrathecal antibodies but with the number of antibody specificities detected, a picture arguing for a polyclonal, non-antigen-specific activation of G1m allotype-producing B cells present in MS brain. PMID:4042430

  11. Diacylglycerol Lipase α Knockout Mice Demonstrate Metabolic and Behavioral Phenotypes Similar to Those of Cannabinoid Receptor 1 Knockout Mice

    PubMed Central

    Powell, David R.; Gay, Jason P.; Wilganowski, Nathaniel; Doree, Deon; Savelieva, Katerina V.; Lanthorn, Thomas H.; Read, Robert; Vogel, Peter; Hansen, Gwenn M.; Brommage, Robert; Ding, Zhi-Ming; Desai, Urvi; Zambrowicz, Brian

    2015-01-01

    After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) similar to pair-fed WT mice, and adult Dagla KO mice had normal activity and VO2 levels, similar to Cnr1 KO mice. Our Dagla and Cnr1 KO mice also had low fasting insulin, triglyceride, and total cholesterol levels, and after glucose challenge had normal glucose but very low insulin levels. Dagla and Cnr1 KO mice also showed similar responses to a battery of behavioral tests. These data suggest: (1) the lean phenotype of young Dagla and Cnr1 KO mice is mainly due to hypophagia; (2) in pathways where ECs signal through Cnr1 to regulate food intake and other metabolic and behavioral phenotypes observed in Cnr1 KO mice, Dagla alone provides the 2-AG that serves as the EC signal; and (3) small molecule Dagla inhibitors with a pharmacokinetic profile similar to that of Cnr1 inverse agonists are likely to mirror the ability of these Cnr1 inverse agonists to lower BW and improve glycemic control in obese patients with type 2 diabetes, but may also induce undesirable neuropsychiatric side

  12. Diacylglycerol Lipase α Knockout Mice Demonstrate Metabolic and Behavioral Phenotypes Similar to Those of Cannabinoid Receptor 1 Knockout Mice.

    PubMed

    Powell, David R; Gay, Jason P; Wilganowski, Nathaniel; Doree, Deon; Savelieva, Katerina V; Lanthorn, Thomas H; Read, Robert; Vogel, Peter; Hansen, Gwenn M; Brommage, Robert; Ding, Zhi-Ming; Desai, Urvi; Zambrowicz, Brian

    2015-01-01

    After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) similar to pair-fed WT mice, and adult Dagla KO mice had normal activity and VO2 levels, similar to Cnr1 KO mice. Our Dagla and Cnr1 KO mice also had low fasting insulin, triglyceride, and total cholesterol levels, and after glucose challenge had normal glucose but very low insulin levels. Dagla and Cnr1 KO mice also showed similar responses to a battery of behavioral tests. These data suggest: (1) the lean phenotype of young Dagla and Cnr1 KO mice is mainly due to hypophagia; (2) in pathways where ECs signal through Cnr1 to regulate food intake and other metabolic and behavioral phenotypes observed in Cnr1 KO mice, Dagla alone provides the 2-AG that serves as the EC signal; and (3) small molecule Dagla inhibitors with a pharmacokinetic profile similar to that of Cnr1 inverse agonists are likely to mirror the ability of these Cnr1 inverse agonists to lower BW and improve glycemic control in obese patients with type 2 diabetes, but may also induce undesirable neuropsychiatric side

  13. Evidence of a Distinct Behavioral Phenotype in Young Boys with Fragile X Syndrome and Autism

    ERIC Educational Resources Information Center

    Wolff, Jason J.; Bodfish, James W.; Hazlett, Heather C.; Lightbody, Amy A.; Reiss, Allan L.; Piven, Joseph

    2012-01-01

    Objective: How does the behavioral expression of autism in fragile X syndrome (FXS + Aut) compare with idiopathic autism (iAut)? Although social impairments and restricted, repetitive behaviors are common to these variants of autism, closer examination of these symptom domains may reveal meaningful similarities and differences. To this end, the…

  14. Modifying Behavioral Phenotypes in Fmr1 KO Mice: Genetic Background Differences Reveal Autistic-Like Responses

    PubMed Central

    Spencer, Corinne M.; Alekseyenko, Olga; Hamilton, Shannon M.; Thomas, Alexia M.; Serysheva, Ekaterina; Yuva-Paylor, Lisa A.; Paylor, Richard

    2010-01-01

    Scientific Abstract Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in humans. In addition to cognitive impairment, patients may exhibit hyperactivity, attention deficits, social difficulties and anxiety, and autistic-like behaviors. The degree to which patients display these behaviors varies considerably and is influenced by family history, suggesting that genetic modifiers play a role in the expression of behaviors in FXS. Several studies have examined behavior in a mouse model of FXS in which the Fmr1 gene has been ablated. Most of those studies were done in Fmr1 knockout mice on a pure C57BL/6 or FVB strain background. To gain a better understanding of the effects of genetic background on behaviors resulting from the loss of Fmr1 gene expression, we generated F1 hybrid lines from female Fmr1 heterozygous mice on a pure C57BL/6J background bred with male Fmr1 wild-type mice of various background strains (A/J, DBA/2J, FVB/NJ, 129S1/SvImJ and CD-1). Male Fmr1 knockout and wild-type littermates from each line were examined in an extensive behavioral test battery. Results clearly indicate that multiple behavioral responses are dependent on genetic background, including autistic-like traits that are present on limited genetic backgrounds. This approach has allowed us to identify improved models for different behavioral symptoms present in FXS including autistic-like traits. PMID:21268289

  15. 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

  16. The effect of otolith malformation on behavior and cortisol levels in juvenile red drum fish (Sciaenops ocellatus).

    PubMed

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

    2012-08-01

    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

  17. 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 =…

  18. 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…

  19. The α4β2 nicotinic acetylcholine receptor modulates autism-like behavioral and motor abnormalities in pentylenetetrazol-kindled mice.

    PubMed

    Takechi, Kenshi; Suemaru, Katsuya; Kiyoi, Takeshi; Tanaka, Akihiro; Araki, Hiroaki

    2016-03-15

    Epilepsy is associated with several psychiatric disorders, including cognitive impairment, autism and attention deficit/hyperactivity disorder (ADHD). However, the psychopathology of epilepsy is frequently unrecognized and untreated in patients. In the present study, we investigated the effects of ABT-418, a neuronal nicotinic acetylcholine receptor agonist, on pentylenetetrazol (PTZ)-kindled mice with behavioral and motor abnormalities. PTZ-kindled mice displayed impaired motor coordination (in the rotarod test), anxiety (in the elevated plus maze test) and social approach impairment (in the three-chamber social test) compared with control mice. ABT-418 treatment (0.05mg/kg, intraperitoneally) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 nicotinic acetylcholine receptor subunit in the medial habenula was similar in control and PTZ-kindled mice. However, expression was significantly decreased in the piriform cortex in PTZ-kindled mice. In addition, we examined the expression of the synaptic adhesion molecule neuroligin 3 (NLG3). NLG3 expression in the piriform cortex was significantly higher in PTZ-kindled mice compared with control mice. Collectively, our findings suggest that ADHD-like or autistic-like behavioral abnormalities associated with epilepsy are closely related to the downregulation of the α4 nicotinic receptor and the upregulation of NLG3 in the piriform cortex. In summary, this study indicates that ABT-418 might have therapeutic potential for attentional impairment in epileptic patients with psychiatric disorders such as autism and ADHD. PMID:26868186

  20. Stability and change: Stress responses and the shaping of behavioral phenotypes over the life span

    PubMed Central

    2015-01-01

    In mammals, maternal signals conveyed via influences on hypothalamic-pituitary-adrenal (HPA) activity may shape behavior of the young to be better adapted for prevailing environmental conditions. However, the mother's influence extends beyond classic stress response systems. In guinea pigs, several hours (h) of separation from the mother activates not only the HPA axis, but also the innate immune system, which effects immediate behavioral change, as well as modifies behavioral responsiveness in the future. Moreover, the presence of the mother potently suppresses the behavioral consequences of this innate immune activation. These findings raise the possibility that long-term adaptive behavioral change can be mediated by the mother's influence on immune-related activity of her pups. Furthermore, the impact of social partners on physiological stress responses and their behavioral outcomes are not limited to the infantile period. A particularly crucial period for social development in male guinea pigs is that surrounding the attainment of sexual maturation. At this time, social interactions with adults can dramatically affect circulating cortisol concentrations and social behavior in ways that appear to prepare the male to best cope in its likely future social environment. Despite such multiple social influences on the behavior of guinea pigs at different ages, inter-individual differences in the magnitude of the cortisol response remain surprisingly stable over most of the life span. Together, it appears that throughout the life span, physiological stress responses may be regulated by social stimuli. These influences are hypothesized to adjust behavior for predicted environmental conditions. In addition, stable individual differences might provide a means of facilitating adaptation to less predictable conditions. PMID:26816517

  1. Stability and change: Stress responses and the shaping of behavioral phenotypes over the life span.

    PubMed

    Hennessy, Michael B; Kaiser, Sylvia; Tiedtke, Tobias; Sachser, Norbert

    2015-01-01

    In mammals, maternal signals conveyed via influences on hypothalamic-pituitary-adrenal (HPA) activity may shape behavior of the young to be better adapted for prevailing environmental conditions. However, the mother's influence extends beyond classic stress response systems. In guinea pigs, several hours (h) of separation from the mother activates not only the HPA axis, but also the innate immune system, which effects immediate behavioral change, as well as modifies behavioral responsiveness in the future. Moreover, the presence of the mother potently suppresses the behavioral consequences of this innate immune activation. These findings raise the possibility that long-term adaptive behavioral change can be mediated by the mother's influence on immune-related activity of her pups. Furthermore, the impact of social partners on physiological stress responses and their behavioral outcomes are not limited to the infantile period. A particularly crucial period for social development in male guinea pigs is that surrounding the attainment of sexual maturation. At this time, social interactions with adults can dramatically affect circulating cortisol concentrations and social behavior in ways that appear to prepare the male to best cope in its likely future social environment. Despite such multiple social influences on the behavior of guinea pigs at different ages, inter-individual differences in the magnitude of the cortisol response remain surprisingly stable over most of the life span. Together, it appears that throughout the life span, physiological stress responses may be regulated by social stimuli. These influences are hypothesized to adjust behavior for predicted environmental conditions. In addition, stable individual differences might provide a means of facilitating adaptation to less predictable conditions. PMID:26816517

  2. Phenotypic heterogeneity influences the behavior of rat aortic smooth muscle cells in collagen lattice

    SciTech Connect

    Orlandi, Augusto . E-mail: orlandi@uniroma2.it; Ferlosio, Amedeo; Gabbiani, Giulio; Spagnoli, Luigi Giusto; Ehrlich, Paul H.

    2005-12-10

    Phenotypic modulation of vascular smooth muscle cells (SMCs) in atherosclerosis and restenosis involves responses to the surrounding microenvironment. SMCs obtained by enzymatic digestion from tunica media of newborn, young adult (YA) and old rats and from the thickened intima (TI) and underlying media of young adult rat aortas 15 days after ballooning were entrapped in floating populated collagen lattice (PCL). TI-SMCs elongated but were poor at PCL contraction and remodeling and expressed less {alpha}2 integrin compared to other SMCs that appeared more dendritic. During early phases of PCL contraction, SMCs showed a marked decrease in the expression of {alpha}-smooth muscle actin and myosin. SMCs other than TI-SMCs required 7 days to re-express {alpha}-smooth muscle actin and myosin. Only TI-SMCs in PCL were able to divide in 48 h, with a greater proportion in S and G2-M cell cycle phases compared to other SMCs. Anti-{alpha}2 integrin antibody markedly inhibited contraction but not proliferation in YA-SMC-PLCs; anti-{alpha}1 and anti-{alpha}2 integrin antibodies induced a similar slight inhibition in TI-SMC-PCLs. Finally, TI-SMCs rapidly migrated from PCL on plastic reacquiring their epithelioid phenotype. Heterogeneity in proliferation and cytoskeleton as well the capacity to remodel the extracellular matrix are maintained, when SMCs are suspended in PCLs.

  3. The Abnormal Phenotypes of Cartilage and Bone in Calcium-Sensing Receptor Deficient Mice Are Dependent on the Actions of Calcium, Phosphorus, and PTH

    PubMed Central

    Tao, Chunxiang; Ding, Guoxian; Karaplis, Andrew; Brown, Edward; Goltzman, David; Miao, Dengshun

    2011-01-01

    Patients with neonatal severe hyperparathyroidism (NSHPT) are homozygous for the calcium-sensing receptor (CaR) mutation and have very high circulating PTH, abundant parathyroid hyperplasia, and severe life-threatening hypercalcemia. Mice with homozygous deletion of CaR mimic the syndrome of NSHPT. To determine effects of CaR deficiency on skeletal development and interactions between CaR and 1,25(OH)2D3 or PTH on calcium and skeletal homeostasis, we compared the skeletal phenotypes of homozygous CaR–deficient (CaR−/−) mice to those of double homozygous CaR– and 1α(OH)ase–deficient [CaR−/−1α(OH)ase−/−] mice or those of double homozygous CaR– and PTH–deficient [CaR−/−PTH−/−] mice at 2 weeks of age. Compared to wild-type littermates, CaR−/− mice had hypercalcemia, hypophosphatemia, hyperparathyroidism, and severe skeletal growth retardation. Chondrocyte proliferation and PTHrP expression in growth plates were reduced significantly, whereas trabecular volume, osteoblast number, osteocalcin-positive areas, expression of the ALP, type I collagen, osteocalcin genes, and serum ALP levels were increased significantly. Deletion of 1α(OH)ase in CaR−/− mice resulted in a longer lifespan, normocalcemia, lower serum phosphorus, greater elevation in PTH, slight improvement in skeletal growth with increased chondrocyte proliferation and PTHrP expression, and further increases in indices of osteoblastic bone formation. Deletion of PTH in CaR−/− mice resulted in rescue of early lethality, normocalcemia, increased serum phosphorus, undetectable serum PTH, normalization in skeletal growth with normal chondrocyte proliferation and enhanced PTHrP expression, and dramatic decreases in indices of osteoblastic bone formation. Our results indicate that reductions in hypercalcemia play a critical role in preventing the early lethality of CaR−/− mice and that defects in endochondral bone formation in CaR−/− mice result from effects of the

  4. The abnormal phenotypes of cartilage and bone in calcium-sensing receptor deficient mice are dependent on the actions of calcium, phosphorus, and PTH.

    PubMed

    Liu, Jingning; Lv, Fangqiao; Sun, Wen; Tao, Chunxiang; Ding, Guoxian; Karaplis, Andrew; Brown, Edward; Goltzman, David; Miao, Dengshun

    2011-09-01

    Patients with neonatal severe hyperparathyroidism (NSHPT) are homozygous for the calcium-sensing receptor (CaR) mutation and have very high circulating PTH, abundant parathyroid hyperplasia, and severe life-threatening hypercalcemia. Mice with homozygous deletion of CaR mimic the syndrome of NSHPT. To determine effects of CaR deficiency on skeletal development and interactions between CaR and 1,25(OH)(2)D(3) or PTH on calcium and skeletal homeostasis, we compared the skeletal phenotypes of homozygous CaR-deficient (CaR(-/-)) mice to those of double homozygous CaR- and 1α(OH)ase-deficient [CaR(-/-)1α(OH)ase(-/-)] mice or those of double homozygous CaR- and PTH-deficient [CaR(-/-)PTH(-/-)] mice at 2 weeks of age. Compared to wild-type littermates, CaR(-/-) mice had hypercalcemia, hypophosphatemia, hyperparathyroidism, and severe skeletal growth retardation. Chondrocyte proliferation and PTHrP expression in growth plates were reduced significantly, whereas trabecular volume, osteoblast number, osteocalcin-positive areas, expression of the ALP, type I collagen, osteocalcin genes, and serum ALP levels were increased significantly. Deletion of 1α(OH)ase in CaR(-/-) mice resulted in a longer lifespan, normocalcemia, lower serum phosphorus, greater elevation in PTH, slight improvement in skeletal growth with increased chondrocyte proliferation and PTHrP expression, and further increases in indices of osteoblastic bone formation. Deletion of PTH in CaR(-/-) mice resulted in rescue of early lethality, normocalcemia, increased serum phosphorus, undetectable serum PTH, normalization in skeletal growth with normal chondrocyte proliferation and enhanced PTHrP expression, and dramatic decreases in indices of osteoblastic bone formation. Our results indicate that reductions in hypercalcemia play a critical role in preventing the early lethality of CaR(-/-) mice and that defects in endochondral bone formation in CaR(-/-) mice result from effects of the marked elevation in serum

  5. Motor and behavioral phenotype in conditional mutants with targeted ablation of cortical D1 dopamine receptor-expressing cells.

    PubMed

    Jiang, Luning; O'Leary, Claire; Kim, Hyun Ah; Parish, Clare L; Massalas, Jim; Waddington, John L; Ehrlich, Michelle E; Schütz, Günter; Gantois, Ilse; Lawrence, Andrew J; Drago, John

    2015-04-01

    D1-dopamine receptors (Drd1a) are highly expressed in the deep layers of the cerebral cortex and the striatum. A number of human diseases such as Huntington disease and schizophrenia are known to have cortical pathology involving dopamine receptor expressing neurons. To illuminate their functional role, we exploited a Cre/Lox molecular paradigm to generate Emx-1(tox) MUT mice, a transgenic line in which cortical Drd1a-expressing pyramidal neurons were selectively ablated. Emx-1(tox) MUT mice displayed prominent forelimb dystonia, hyperkinesia, ataxia on rotarod testing, heightened anxiety-like behavior, and age-dependent abnormalities in a test of social interaction. The latter occurred in the context of normal working memory on testing in the Y-maze and for novel object recognition. Some motor and behavioral abnormalities in Emx-1(tox) MUT mice overlapped with those in CamKIIα(tox) MUT transgenic mice, a line in which both striatal and cortical Drd1a-expressing cells were ablated. Although Emx-1(tox) MUT mice had normal striatal anatomy, both Emx-1(tox) MUT and CamKIIα(tox) MUT mice displayed selective neuronal loss in cortical layers V and VI. This study shows that loss of cortical Drd1a-expressing cells is sufficient to produce deficits in multiple motor and behavioral domains, independent of striatal mechanisms. Primary cortical changes in the D1 dopamine receptor compartment are therefore likely to model a number of core clinical features in disorders such as Huntington disease and schizophrenia. PMID:25684539

  6. Abnormal Eu behavior at formation of H2O- and Cl-bearing fluids during degassing of granite magmas

    NASA Astrophysics Data System (ADS)

    Lukanin, Oleg

    2010-05-01

    melt. The abnormal behavior of Eu shows itself the stronger, the lower fO2and, accordingly, the more fraction of Eu2+is present in melt. The work is supported of the Geosciences Department of the Russian Academy of Science (the program 2- 2010) and RFBR (grant 08-05-00022). References [1] Reed M.J., Candela Ph.A., Piccoli Ph.M. Contrib. Mineral. Petrol. 2000. V. 140. P. 251-262. [2] Lukanin O.A., Dernov-Pegarev V.F. Vestnik Otd. Nauk Zemle RAN, No 1(25)'2007 URL: http://www.scgis.ru/russian/cp1251/h_dgggms/1-2007/informbul-1_2007/term-30e.pdf [3] Drake M.J. Geochim. Cosmochim. Acta. 1975. V. 39. P. 55-64. [4] Wilke M. Behrens H. Contrib. Mineral. Petrol. 1999. V. 137. P. 102-114. [5] Lukanin O.A. Vestnik Otd. Nauk o Zemle RAN, No 1(26)'2008. URL: http://www.scgis.ru/russian/cp1251/h_dgggms/1-2008/informbul-1_2008/magm-20e.pdf [6] Lukanin O.A., Dernov-Pegarev V.F. Geochemistry International, 2010 (in press)

  7. Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features

    PubMed Central

    Ross, J. L.; Tartaglia, N.; Merry, D. E.; Dalva, M.; Zinn, A. R.

    2016-01-01

    The male sex chromosome disorder, 47,XYY syndrome (XYY), is associated with increased risk for social-emotional difficulties, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes. We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression and autistic behaviors (from questionnaires) in boys with XYY. The XYY cohort had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners’ DSM-IV inattention and hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY vs. typically developing controls was increased twofold in the XYY group. Results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Males with XYY have social phenotypes that include increased risk for autism-related behaviors and ADHD. Expression of NLGN4Y , a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted. PMID:25558953

  8. Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features.

    PubMed

    Ross, J L; Tartaglia, N; Merry, D E; Dalva, M; Zinn, A R

    2015-02-01

    The male sex chromosome disorder, 47,XYY syndrome (XYY), is associated with increased risk for social-emotional difficulties, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes. We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression and autistic behaviors (from questionnaires) in boys with XYY. The XYY cohort had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY vs. typically developing controls was increased twofold in the XYY group. Results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Males with XYY have social phenotypes that include increased risk for autism-related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted. PMID:25558953

  9. Positive effects of early androgen therapy on the behavioral phenotype of boys with 47,XXY.

    PubMed

    Samango-Sprouse, Carole; Stapleton, Emily J; Lawson, Patrick; Mitchell, Francie; Sadeghin, Teresa; Powell, Sherida; Gropman, Andrea L

    2015-06-01

    47, XXY occurs in up to 1 in 650 male births and is associated with androgen deficiency, neurodevelopmental delays, and atypical social-behaviors. Previously, we showed that young boys with 47, XXY who received early hormonal therapy (EHT) had significantly improved neurodevelopment. The objective of this follow-up study was to examine the effects of EHT on social behavior in boys with 47, XXY. The study consisted of boys prenatally diagnosed with 47, XXY who were referred for evaluations. Twenty-nine boys received three injections of 25 mg testosterone enanthate and 57 controls did not receive EHT. Behavioral functioning was assessed using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, 2nd Ed., and the Child Behavior Checklist for Ages 6-18. The hypothesis that EHT may affect behavior was formulated prior to data collection. Questionnaire data was prospectively obtained and analyzed to test for significance between two groups. Significant differences were identified between group's scores over time in Social Communication (P=0.007), Social Cognition (P=0.006), and Total T-score (P=0.001) on the SRS-2; Initiation (P=0.05) on the BRIEF; and Externalizing Problems (P=0.024), Affective Problems (P=0.05), and Aggressive Behaviors (P=0.031) on the CBCL. This is the third study revealing positive effects of EHT on boys with XXY. There was a significant improvements associated with the 47, XXY genotype in boys who received EHT. Research is underway on the neurobiological mechanisms, and later developmental effects of EHT. PMID:25939399

  10. Continuity of aggressive antisocial behavior from childhood to adulthood: The question of phenotype definition.

    PubMed

    Hofvander, Björn; Ossowski, Daniel; Lundström, Sebastian; Anckarsäter, Henrik

    2009-01-01

    Aiming to clarify the adult phenotype of antisocial personality disorder (ASPD), the empirical literature on its childhood background among the disruptive behaviour disorders, such as attention deficit/hyperactivity disorder (AD/HD), oppositional defiant disorder (ODD), conduct disorder (CD), or hyperkinetic conduct disorder (HKCD), was reviewed according to the Robins and Guze criteria for nosological validity. At least half of hyperactive children develop ODD and about a third CD (i.e. AD/HD+CD or HKCD) before puberty. About half of children with this combined problem constellation develop antisocial personality disorder (ASPD) in adulthood. Family and adoption/twin studies indicate that AD/HD and CD share a high heritability and that, in addition, there may be specific environmental effects for criminal behaviours. "Zones of rarity" delineating the disorders from each other, or from the normal variation, have not been identified. Neurophysiology, brain imaging, neurochemistry, neurocognition, or molecular genetics have not provided "external validity" for any of the diagnostic categories used today. Deficient mental functions, such as inattention, poor executive functions, poor verbal learning, and impaired social interaction (empathy), seem to form unspecific susceptibility factors. As none of today's proposed syndromes (e.g. AD/HD or psychopathy) seems to describe a natural category, a dimensional behavioural phenotype reflecting aggressive antisocial behaviours assessed by numbers of behaviours, the severity of their consequences and how early is their age at onset, which will be closely related to childhood hyperactivity, would bring conceptual clarity, and may form the basis for further probing into mental, cognitive, biological and treatment-related co-varying features. PMID:19428109

  11. A Cross-Sectional Study of Major Repeaters: A Distinct Phenotype of Suicidal Behavior

    PubMed Central

    Jaussent, Isabelle; Olié, Emilie; Béziat, Severine; Guillaume, Sebastien; Artieda-Urrutia, Paula; Baca-Garcia, Enrique; de Leon, Jose; Courtet, Philippe

    2014-01-01

    Objective: The characterization of major repeaters (individuals with ≥ 5 lifetime suicide attempts) is a neglected area of research. Our aim was to establish whether or not major repeaters are a distinctive suicidal phenotype, taking into account a wide range of potential competing risks including sociodemographic characteristics, personal and familial history, psychiatric diagnoses, and personality traits. Method: This cross-sectional study included 372 suicide attempters admitted to a specialized unit for suicide attempters in Montpellier University Hospital, Montpellier, France, between October 12, 2000, and June 10, 2010. Logistic regression models controlling for potential confounders were used. Results: When compared with subjects who attempted suicide < 5 times, major repeaters were more likely to be female (odds ratio [OR] = 5.54; 95% CI, 1.41–21.81), to have a lower educational level (OR = 5.1; 95% CI, 1.55–17.2), to have lifetime diagnoses of anorexia nervosa (OR = 3.45; 95% CI, 1.10–10.84) and substance dependence (OR = 5.00; 95% CI, 1.37–18.27), and to have lower levels of anger expressed outward (OR = 0.17; 95% CI, 0.06–0.47) and higher levels of trait anger (OR = 2.82; 95% CI, 1.18–6.75). Major repeaters had significantly higher suicide risk (lethality) scores (OR = 2.14; 95% CI, 1.08–4.23). Conclusion: Major repeaters are a distinctive suicidal phenotype characterized by a distinctive sociodemographic (ie, female gender, low education) and clinical profile (ie, trait anger, substance dependence, anorexia nervosa). If our results are replicated, specific preventive plans should be tailored to major repeaters. PMID:25664212

  12. Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice

    PubMed Central

    Tanda, Koichi; Nishi, Akinori; Matsuo, Naoki; Nakanishi, Kazuo; Yamasaki, Nobuyuki; Sugimoto, Tohru; Toyama, Keiko; Takao, Keizo; Miyakawa, Tsuyoshi

    2009-01-01

    Background Neuronal nitric oxide synthase (nNOS) is involved in the regulation of a diverse population of intracellular messenger systems in the brain. In humans, abnormal NOS/nitric oxide metabolism is suggested to contribute to the pathogenesis and pathophysiology of some neuropsychiatric disorders, such as schizophrenia and bipolar disorder. Mice with targeted disruption of the nNOS gene exhibit abnormal behaviors. Here, we subjected nNOS knockout (KO) mice to a battery of behavioral tests to further investigate the role of nNOS in neuropsychiatric functions. We also examined the role of nNOS in dopamine/DARPP-32 signaling in striatal slices from nNOS KO mice and the effects of the administration of a dopamine D1 receptor agonist on behavior in nNOS KO mice. Results nNOS KO mice showed hyperlocomotor activity in a novel environment, increased social interaction in their home cage, decreased depression-related behavior, and impaired spatial memory retention. In striatal slices from nNOS KO mice, the effects of a dopamine D1 receptor agonist, SKF81297, on the phosphorylation of DARPP-32 and AMPA receptor subunit GluR1 at protein kinase A sites were enhanced. Consistent with the biochemical results, intraperitoneal injection of a low dose of SKF81297 significantly decreased prepulse inhibition in nNOS KO mice, but not in wild-type mice. Conclusion These findings indicate that nNOS KO upregulates dopamine D1 receptor signaling, and induces abnormal social behavior, hyperactivity and impaired remote spatial memory. nNOS KO mice may serve as a unique animal model of psychiatric disorders. PMID:19538708

  13. An open-source toolbox for automated phenotyping of mice in behavioral tasks.

    PubMed

    Patel, Tapan P; Gullotti, David M; Hernandez, Pepe; O'Brien, W Timothy; Capehart, Bruce P; Morrison, Barclay; Bass, Cameron; Eberwine, James E; Abel, Ted; Meaney, David F

    2014-01-01

    Classifying behavior patterns in mouse models of neurological, psychiatric and neurodevelopmental disorders is critical for understanding disease causality and treatment. However, complete characterization of behavior is time-intensive, prone to subjective scoring, and often requires specialized equipment. Although several reports describe automated home-cage monitoring and individual task scoring methods, we report the first open source, comprehensive toolbox for automating the scoring of several common behavior tasks used by the neuroscience community. We show this new toolbox is robust and achieves equal or better consistency when compared to manual scoring methods. We use this toolbox to study the alterations in behavior that occur following blast-induced traumatic brain injury (bTBI), and study if these behavior patterns are altered following genetic deletion of the transcription factor Ets-like kinase 1 (Elk-1). Due to the role of Elk-1 in neuronal survival and proposed role in synaptic plasticity, we hypothesized that Elk-1 deletion would improve some neurobehavioral deficits, while impairing others, following blast exposure. In Elk-1 knockout (KO) animals, deficits in open field, spatial object recognition (SOR) and elevated zero maze performance after blast exposure disappeared, while new significant deficits appeared in spatial and associative memory. These are the first data suggesting a molecular mediator of anxiety deficits following bTBI, and represent the utility of the broad screening tool we developed. More broadly, we envision this open-source toolbox will provide a more consistent and rapid analysis of behavior across many neurological diseases, promoting the rapid discovery of novel pathways mediating disease progression and treatment. PMID:25339878

  14. An open-source toolbox for automated phenotyping of mice in behavioral tasks

    PubMed Central

    Patel, Tapan P.; Gullotti, David M.; Hernandez, Pepe; O'Brien, W. Timothy; Capehart, Bruce P.; Morrison, Barclay; Bass, Cameron; Eberwine, James E.; Abel, Ted; Meaney, David F.

    2014-01-01

    Classifying behavior patterns in mouse models of neurological, psychiatric and neurodevelopmental disorders is critical for understanding disease causality and treatment. However, complete characterization of behavior is time-intensive, prone to subjective scoring, and often requires specialized equipment. Although several reports describe automated home-cage monitoring and individual task scoring methods, we report the first open source, comprehensive toolbox for automating the scoring of several common behavior tasks used by the neuroscience community. We show this new toolbox is robust and achieves equal or better consistency when compared to manual scoring methods. We use this toolbox to study the alterations in behavior that occur following blast-induced traumatic brain injury (bTBI), and study if these behavior patterns are altered following genetic deletion of the transcription factor Ets-like kinase 1 (Elk-1). Due to the role of Elk-1 in neuronal survival and proposed role in synaptic plasticity, we hypothesized that Elk-1 deletion would improve some neurobehavioral deficits, while impairing others, following blast exposure. In Elk-1 knockout (KO) animals, deficits in open field, spatial object recognition (SOR) and elevated zero maze performance after blast exposure disappeared, while new significant deficits appeared in spatial and associative memory. These are the first data suggesting a molecular mediator of anxiety deficits following bTBI, and represent the utility of the broad screening tool we developed. More broadly, we envision this open-source toolbox will provide a more consistent and rapid analysis of behavior across many neurological diseases, promoting the rapid discovery of novel pathways mediating disease progression and treatment. PMID:25339878

  15. Adiposity and Insufficient MVPA Predict Cardiometabolic Abnormalities in Adults

    PubMed Central

    Peterson, Mark D.; Snih, Soham Al; Stoddard, Jonathan; McClain, James; Lee, IMin

    2014-01-01

    Objectives To compare the extent to which different combinations of objectively measured sedentary behavior (SB) and physical activity contribute to cardiometabolic health. Design and Methods A population representative sample of 5,268 individuals, aged 20-85 years, was included from the combined 2003-2006 NHANES datasets. Activity categories were created on the combined basis of objectively measured SB and moderate-to-vigorous physical activity (MVPA) tertiles. Cardiometabolic abnormalities included elevated blood pressure, levels of triglycerides, fasting plasma glucose, C-reactive protein, homeostasis model assessment (HOMA) of insulin resistance value, and low HDL-cholesterol level. BMI, and DXA-derived percent body fat (% BF) and android adiposity were also compared across groups. Predictors for a metabolically abnormal phenotype (≥3 cardiometabolic abnormalities, or insulin resistance) were determined. Results Adults with the least SB and greatest MVPA exhibited the healthiest cardiometabolic profiles, whereas adults with the greatest SB and lowest MVPA were older and had elevated risk. Time spent in SB was not a predictor of the metabolically abnormal phenotype when MVPA was accounted for. Adults with the highest MVPA across SB tertiles did not differ markedly in prevalence of obesity, adiposity, and/or serum cardiometabolic risk factors; however, less MVPA was associated with substantial elevations of obesity and cardiometabolic risk. Android adiposity (per kilogram) was independently associated with the metabolically abnormal phenotype in both men (OR: 2.36 [95% CI, 1.76-3.17], p<0.001) and women (OR: 2.00 [95% CI, 1.63-2.45], p<0.001). Among women, greater SB, and less lifestyle moderate activity and MVPA were each independently associated with the metabolically abnormal phenotype, whereas only less MVPA was associated with it in men. Conclusions MVPA is a strong predictor of cardiometabolic health among adults, independent of time spent in SB. PMID

  16. Increased expression of receptor phosphotyrosine phosphatase-β/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes

    PubMed Central

    Takahashi, N; Sakurai, T; Bozdagi-Gunal, O; Dorr, N P; Moy, J; Krug, L; Gama-Sosa, M; Elder, G A; Koch, R J; Walker, R H; Hof, P R; Davis, K L; Buxbaum, J D

    2011-01-01

    Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-β/ζ (RPTP β/ζ) and that the gene encoding RPTPβ/ζ (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTPβ/ζ in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTPβ/ζ (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTPβ/ζ signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTPβ/ζ as a therapeutic target in schizophrenia. PMID:22832403

  17. No delayed behavioral and phenotypic responses to experimental early-life lead exposure in great tits (Parus major).

    PubMed

    Ruuskanen, Suvi; Eeva, Tapio; Kotitalo, Päivi; Stauffer, Janina; Rainio, Miia

    2015-02-01

    Early-life exposure to pollutants, such as lead, may have long-lasting consequences on health, behavior, and cognition. However, experiments on delayed effects of specific pollutants are very rare in wild animals. We experimentally exposed wild nestling great tits (Parus major) to dietary lead (high, low, or control group) in levels relevant to exposure levels of wild populations in Europe and studied delayed effects on phenotypic and behavioral traits in captivity. We also included a group of birds from a vicinity of a copper smelter, exposed to a mixture of toxic metals and altered food supply during development. This experimental setup allowed us to compare the strength of direct (exposure to lead per se) and indirect (pollution-related changes in diet) effects of pollutants. Our experimental lead treatment significantly increased lead levels in bone and feces compared with controls. However, we found no carry-over effect of early-life dietary lead on morphology, plumage coloration, or heat shock proteins. Treatment did not affect activity, exploration, neophobia, or success in learning and spatial memory task. We conclude that with the exposure levels and relatively short exposure period used, delayed effects on the measured traits were not found. However, it is important to further study other types of behavioral traits and ultimately fitness effects. PMID:25194842

  18. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders

    PubMed Central

    Ku, Katherine M.; Weir, Ruth K.; Silverman, Jill L.; Berman, Robert F.; Bauman, Melissa D.

    2016-01-01

    The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26–56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions. PMID:27351457

  19. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

    PubMed

    Ku, Katherine M; Weir, Ruth K; Silverman, Jill L; Berman, Robert F; Bauman, Melissa D

    2016-01-01

    The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions. PMID:27351457

  20. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

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

    PubMed

    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

    2015-08-01

    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 syndrome would increase children's learning of phonological awareness, letter sounds, and words. Five children with Down syndrome, ages 6 to 8 years, participated in a multiple baseline across participants single case design experiment in which response to an adapted phonological awareness intervention was compared with response to the nonadapted program. Results indicate a functional relation between the adapted program and phonological awareness. Suggestions for future research and implications for practice are provided. PMID:26214557

  2. Theory of mind mediates the prospective relationship between abnormal social brain network morphology and chronic behavior problems after pediatric traumatic brain injury.

    PubMed

    Ryan, Nicholas P; Catroppa, Cathy; Beare, Richard; Silk, Timothy J; Crossley, Louise; Beauchamp, Miriam H; Yeates, Keith Owen; Anderson, Vicki A

    2016-04-01

    Childhood and adolescence coincide with rapid maturation and synaptic reorganization of distributed neural networks that underlie complex cognitive-affective behaviors. These regions, referred to collectively as the 'social brain network' (SBN) are commonly vulnerable to disruption from pediatric traumatic brain injury (TBI); however, the mechanisms that link morphological changes in the SBN to behavior problems in this population remain unclear. In 98 children and adolescents with mild to severe TBI, we acquired 3D T1-weighted MRIs at 2-8 weeks post-injury. For comparison, 33 typically developing controls of similar age, sex and education were scanned. All participants were assessed on measures of Theory of Mind (ToM) at 6 months post-injury and parents provided ratings of behavior problems at 24-months post-injury. Severe TBI was associated with volumetric reductions in the overall SBN package, as well as regional gray matter structural change in multiple component regions of the SBN. When compared with TD controls and children with milder injuries, the severe TBI group had significantly poorer ToM, which was associated with more frequent behavior problems and abnormal SBN morphology. Mediation analysis indicated that impaired theory of mind mediated the prospective relationship between abnormal SBN morphology and more frequent chronic behavior problems. Our findings suggest that sub-acute alterations in SBN morphology indirectly contribute to long-term behavior problems via their influence on ToM. Volumetric change in the SBN and its putative hub regions may represent useful imaging biomarkers for prediction of post-acute social cognitive impairment, which may in turn elevate risk for chronic behavior problems. PMID:26796967

  3. An Allele of Sequoia Dominantly Enhances a Trio Mutant Phenotype to Influence Drosophila Larval Behavior

    PubMed Central

    Liebl, Eric C.

    2013-01-01

    The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency. PMID:24376789

  4. Differential rates of phenotypic introgression are associated with male behavioral responses to multiple signals.

    PubMed

    Greig, Emma I; Baldassarre, Daniel T; Webster, Michael S

    2015-10-01

    Sexual selection on multiple signals may lead to differential rates of signal introgression across hybrid zones if some signals contribute to reproductive isolation but others facilitate gene flow. Competition among males is one powerful form of sexual selection, but male behavioral responses to multiple traits have not been considered in a system where traits have introgressed differentially. Using playbacks, mounts, and a reciprocal experimental design, we tested the hypothesis that male responses to song and plumage in two subspecies of red-backed fairy-wren (Malurus melanocephalus) explain patterns of differential signal introgression (song has not introgressed, whereas plumage color has introgressed asymmetrically). We found that males of both subspecies discriminated symmetrically between subspecies' songs at a long range, but at a close range, we found that aggression was equal for both subspecies' plumage and songs. Taken together, our results suggest that male behavioral responses hinder the introgression of song, but allow for the observed asymmetrical introgression of plumage. Our results highlight how behavioral responses are a key component of signal evolution when recently divergent taxa come together, and how differential responses to multiple signals may lead to differential signal introgression and novel trait combinations. PMID:26292844

  5. Cause and Consequence: Mitochondrial Dysfunction Initiates and Propagates Neuronal Dysfunction, Neuronal Death and Behavioral Abnormalities in Age Associated Neurodegenerative Diseases

    PubMed Central

    Gibson, Gary E.; Starkov, Anatoly; Blass, John P.; Ratan, Rajiv R.; Beal, M. Flint

    2009-01-01

    SUMMARY Age-related neurodegenerative diseases are associated with mild impairment of oxidative metabolism and accumulation of abnormal proteins. Within the cell, the mitochondria appears to be a dominant site for initiation and propagation of disease processes. Shifts in metabolism in response to mild metabolic perturbations may decrease the threshold for irreversible injury in response to ordinarily sub lethal metabolic insults. Mild impairment of metabolism accrue from and lead to increased reactive oxygen species (ROS). Increased ROS change cell signaling via post transcriptional and transcriptional changes. The cause and consequences of mild impairment of mitochondrial metabolism is one focus of this review. Many experiments in tissues from humans support the notion that oxidative modification of the α-ketoglutarate dehydrogenase complex (KGDHC) compromises neuronal energy metabolism and enhance ROS production in Alzheimer’s Disease (AD). These data suggest that cognitive decline in AD derives from the selective tricarboxylic acid (TCA) cycle abnormalities. By contrast in Huntington’s Disease (HD), a movement disorder with cognitive features distinct form AD, complex II + III abnormalities may dominate. These distinct mitochondrial abnormalities culminate in oxidative stress, energy dysfunction, and aberrant homeostasis of cytosolic calcium. Cytosolic calcium, elevations even only transiently, leads to hyperactivity of a number of enzymes. One calcium activated enzyme with demonstrated pathophysiological import in HD and AD is transglutaminase (TGase). TGase is a cross linking enzymes that can modulate transcrption, inactivate metabolic enzymes, and cause aggregation of critical proteins. Recent data indicate that TGase can silence expression of genes involved in compensating for metabolic stress. Altogether, our results suggest that increasing KGDHC via inhibition of TGase or via a host of other strategies to be described would be effective therapeutic

  6. Epithelial-Mesenchymal Transition Phenotype Is Associated with Clinicopathological Factors That Indicate Aggressive Biological Behavior and Poor Clinical Outcomes in Invasive Breast Cancer

    PubMed Central

    Choi, Jung Eun; Kang, Su Hwan; Lee, Soo Jung

    2015-01-01

    Purpose Cancer tissue may display a wide spectrum of expression phenotypes of epithelial-mesenchymal transition (EMT)-related proteins. The purpose of this study was to investigate the clinical significance of EMT phenotypes in breast cancer. Methods We evaluated the expression pattern of the EMT-related proteins E-cadherin and fibronectin in samples from 1,495 patients with invasive breast carcinoma (IBC) on tissue microarrays using immunohistochemistry to investigate the clinical significance of EMT phenotypes in IBC. EMT phenotypes were divided into complete type (E-cadherin-negative/fibronectin-positive), incomplete type (hybrid type, E-cadherinpositive/fibronectin-positive; null type, E-cadherin-negative/fibronectin-negative), and wild-type (E-cadherin-positive/fibronectin-negative). We analyzed the correlation of EMT phenotype with clinicopathological factors and patient survival. Results Loss of E-cadherin was observed in 302 patients (20.2%), and fibronectin was expressed in the cancer cells of 354 patients (23.7%). In total, 64 (4.3%), 290 (19.4%), 238 (15.9%), and 903 (60.4%) samples were categorized as complete, hybrid, null, and wild-type, respectively. The complete EMT phenotype exhibited significant associations with young age (p=0.017), advanced pT (p<0.001) and pN (p<0.001) stages, higher histological grade (p<0.001), lymphovascular invasion (p<0.001), and triple negativity (p<0.001). Patients with complete and hybrid EMT phenotypes had poorer overall survival (OS) and disease-free survival (DFS) than those with the wild-type phenotype (OS, p=0.001; DFS, p<0.001). In multivariate analysis, the hybrid EMT phenotype was an independent prognostic factor for DFS in patients with IBC (p=0.032). Conclusion EMT phenotypes exhibited significant associations with clinicopathological factors indicating aggressive biologic behavior and poor outcome in patients with IBC. PMID:26472976

  7. Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson's disease.

    PubMed

    Rial, Daniel; Castro, Adalberto A; Machado, Nuno; Garção, Pedro; Gonçalves, Francisco Q; Silva, Henrique B; Tomé, Angelo R; Köfalvi, Attila; Corti, Olga; Raisman-Vozari, Rita; Cunha, Rodrigo A; Prediger, Rui D

    2014-01-01

    There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin-/-) to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin-/- mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination), anxiety (elevated plus-maze), depressive-like behavior (forced swimming and tail suspension) and motor function (rotarod, grasping strength and pole). However, parkin-/- mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP). These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin-/- mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD. PMID:25486126

  8. Abnormal chromosome behavior during meiosis in the allotetraploid of Carassius auratus red var. (♀) × Megalobrama amblycephala (♂)

    PubMed Central

    2014-01-01

    Background Allopolyploids generally undergo bivalent pairing at meiosis because only homologous chromosomes pair up. On the other hand, several studies have documented abnormal chromosome behavior during mitosis and meiosis in allopolyploids plants leading to the production of gametes with complete paternal or maternal chromosomes. Polyploidy is relatively rare in animals compared with plants; thus, chromosome behavior at meiosis in the allopolyploid animals is poorly understood. Results Tetraploid hybrids (abbreviated as 4nRB) (4n = 148, RRBB) of Carassius auratus red var. (abbreviated as RCC) (2n = 100, RR) (♀) × Megalobrama amblycephala (abbreviated as BSB) (2n = 48, BB) (♂) generated gametes of different size. To test the genetic composition of these gametes, the gynogenetic offspring and backcross progenies of 4nRB were produced, and their genetic composition were examined by chromosome analysis and FISH. Our results suggest that 4nRB can produce several types of gametes with different genetic compositions, including allotetraploid (RRBB), autotriploid (RRR), autodiploid (RR), and haploid (R) gametes. Conclusions This study provides direct evidence of abnormal chromosome behavior during meiosis in an allotetraploid fish. PMID:25178799

  9. Congenital Abnormalities

    MedlinePlus

    ... serious health problems (e.g. Down syndrome ). Single-Gene Abnormalities Sometimes the chromosomes are normal in number, ... blood flow to the fetus impair fetal growth. Alcohol consumption and certain drugs during pregnancy significantly increase ...

  10. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  11. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  12. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  13. Nail abnormalities

    MedlinePlus

    Nail abnormalities are problems with the color, shape, texture, or thickness of the fingernails or toenails. ... Fungus or yeast cause changes in the color, texture, and shape of the nails. Bacterial infection may ...

  14. High sucrose consumption during pregnancy induced ADHD-like behavioral phenotypes in mice offspring.

    PubMed

    Choi, Chang Soon; Kim, Pitna; Park, Jin Hee; Gonzales, Edson Luck T; Kim, Ki Chan; Cho, Kyu Suk; Ko, Mee Jung; Yang, Sung Min; Seung, Hana; Han, Seol-Heui; Ryu, Jong Hoon; Cheong, Jae Hoon; Shin, Chan Young

    2015-12-01

    In recent years, the average consumption of sugar in humans from all ages has remarkably increased, exceeding the recommended limit. Pregnancy is a critical time for the global development of offsprings who are vulnerable to the deleterious effects of environmental factors. In this study, we investigated whether high sucrose consumption during pregnancy could affect the attention-deficit hyperactivity disorder (ADHD)-like neurobehavioral outcomes in offspring mice. Pregnant mice were randomly grouped and orally administered with either water as control (Con) or 30% wt/vol sucrose diluted in water at 6 (Suc6) or 9 (Suc9) g/kg dosage per day from gestational days 6 to 15. After the weaning period, offspring mice underwent a series of behavioral testing for locomotor activity, attention, and impulsivity. Although there is no obvious difference in gross development of offspring mice such as weight gain, high sucrose-exposed offspring mice showed a significantly increased locomotor activity. Moreover, these mice exhibited a dose-dependent decrease in attention and increase in impulsivity. In the striatum, a significantly increased dopamine transporter (DAT) mRNA expression was found in the Suc9 group along with dose-dependent decreases in the Drd1, Drd2 and Drd4 dopamine receptor subtypes. Furthermore, synaptosomal DAT protein expression was increased about twofold in the Suc9 group. Prenatal fructose exposure also induced hyperactive behavior in offspring mice suggesting the essential role of fructose in the dysregulated neurobehavioral development. These findings suggest prenatal sucrose consumption as a new risk factor for ADHD, which may need further attention and investigation in humans. PMID:26452319

  15. Differentiation of rodent behavioral phenotypes and methylphenidate action in sustained and flexible attention tasks.

    PubMed

    Chu, Richard; Shumsky, Jed; Waterhouse, Barry D

    2016-06-15

    Methyphenidate (MPH) is the primary drug treatment of choice for ADHD. It is also frequently used off-label as a cognitive enhancer by otherwise healthy individuals from all age groups and walks of life. Military personnel, students, and health professionals use MPH illicitly to increase attention and improve workplace performance over extended periods of work activity. Despite the frequency of its use, the efficacy of MPH to enhance cognitive function across individuals and in a variety of circumstances is not well characterized. We sought to better understand MPH׳s cognitive enhancing properties in two different rodent models of attention. We found that MPH could enhance performance in a sustained attention task, but that its effects in this test were subject dependent. More specifically, MPH increased attention in low baseline performing rats but had little to no effect on high performing rats. MPH exerted a similar subject specific effect in a test of flexible attention, i.e. the attention set shifting task. In this test MPH increased behavioral flexibility in animals with poor flexibility but impaired performance in more flexible animals. Overall, our results indicate that the effects of MPH are subject-specific and depend on the baseline level of performance. Furthermore, good performance in in the sustained attention task was correlated with good performance in the flexible attention task; i.e. animals with better vigilance exhibited greater behavioral flexibility. The findings are discussed in terms of potential neurobiological substrates, in particular noradrenergic mechanisms, that might underlie subject specific performance and subject specific responses to MPH. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26688113

  16. Recognition in a social symbiosis: chemical phenotypes and nestmate recognition behaviors of neotropical parabiotic ants.

    PubMed

    Emery, Virginia J; Tsutsui, Neil D

    2013-01-01

    Social organisms rank among the most abundant and ecologically dominant species on Earth, in part due to exclusive recognition systems that allow cooperators to be distinguished from exploiters. Exploiters, such as social parasites, manipulate their hosts' recognition systems, whereas cooperators are expected to minimize interference with their partner's recognition abilities. Despite our wealth of knowledge about recognition in single-species social nests, less is known of the recognition systems in multi-species nests, particularly involving cooperators. One uncommon type of nesting symbiosis, called parabiosis, involves two species of ants sharing a nest and foraging trails in ostensible cooperation. Here, we investigated recognition cues (cuticular hydrocarbons) and recognition behaviors in the parabiotic mixed-species ant nests of Camponotus femoratus and Crematogaster levior in North-Eastern Amazonia. We found two sympatric, cryptic Cr. levior chemotypes in the population, with one type in each parabiotic colony. Although they share a nest, very few hydrocarbons were shared between Ca. femoratus and either Cr. levior chemotype. The Ca. femoratus hydrocarbons were also unusually long-chained branched alkenes and dienes, compounds not commonly found amongst ants. Despite minimal overlap in hydrocarbon profile, there was evidence of potential interspecific nestmate recognition -Cr. levior ants were more aggressive toward Ca. femoratus non-nestmates than Ca. femoratus nestmates. In contrast to the prediction that sharing a nest could weaken conspecific recognition, each parabiotic species also maintains its own aggressive recognition behaviors to exclude conspecific non-nestmates. This suggests that, despite cohabitation, parabiotic ants maintain their own species-specific colony odors and recognition mechanisms. It is possible that such social symbioses are enabled by the two species each using their own separate recognition cues, and that interspecific nestmate

  17. Birds, primates, and spoken language origins: behavioral phenotypes and neurobiological substrates

    PubMed Central

    Petkov, Christopher I.; Jarvis, Erich D.

    2012-01-01

    Vocal learners such as humans and songbirds can learn to produce elaborate patterns of structurally organized vocalizations, whereas many other vertebrates such as non-human primates and most other bird groups either cannot or do so to a very limited degree. To explain the similarities among humans and vocal-learning birds and the differences with other species, various theories have been proposed. One set of theories are motor theories, which underscore the role of the motor system as an evolutionary substrate for vocal production learning. For instance, the motor theory of speech and song perception proposes enhanced auditory perceptual learning of speech in humans and song in birds, which suggests a considerable level of neurobiological specialization. Another, a motor theory of vocal learning origin, proposes that the brain pathways that control the learning and production of song and speech were derived from adjacent motor brain pathways. Another set of theories are cognitive theories, which address the interface between cognition and the auditory-vocal domains to support language learning in humans. Here we critically review the behavioral and neurobiological evidence for parallels and differences between the so-called vocal learners and vocal non-learners in the context of motor and cognitive theories. In doing so, we note that behaviorally vocal-production learning abilities are more distributed than categorical, as are the auditory-learning abilities of animals. We propose testable hypotheses on the extent of the specializations and cross-species correspondences suggested by motor and cognitive theories. We believe that determining how spoken language evolved is likely to become clearer with concerted efforts in testing comparative data from many non-human animal species. PMID:22912615

  18. The Social Behavioral Phenotype in Boys and Girls with an Extra X Chromosome (Klinefelter Syndrome and Trisomy X): A Comparison with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    van Rijn, Sophie; Stockmann, Lex; Borghgraef, Martine; Bruining, Hilgo; van Ravenswaaij-Arts, Conny; Govaerts, Lutgarde; Hansson, Kerstin; Swaab, Hanna

    2014-01-01

    The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106…

  19. 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;…

  20. Lithium prevents parkinsonian behavioral and striatal phenotypes in an aged parkin mutant transgenic mouse model.

    PubMed

    Lieu, Christopher A; Dewey, Colleen M; Chinta, Shankar J; Rane, Anand; Rajagopalan, Subramanian; Batir, Sean; Kim, Yong-Hwan; Andersen, Julie K

    2014-12-01

    Lithium has long been used as a treatment for the psychiatric disease bipolar disorder. However, previous studies suggest that lithium provides neuroprotective effects in neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease. The exact mechanism by which lithium exerts these effects still remains unclear. In the present study, we evaluated the effects of low-dose lithium treatment in an aged mouse model expressing a parkin mutation within dopaminergic neurons. We found that low-dose lithium treatment prevented motor impairment as demonstrated by the open field test, pole test, and rearing behavior. Furthermore, lithium prevented dopaminergic striatal degeneration in parkin animals. We also found that parkin-induced striatal astrogliosis and microglial activation were prevented by lithium treatment. Our results further corroborate the use of this parkin mutant transgenic mouse line as a model for PD for testing novel therapeutics. The findings of the present study also provide further validation that lithium could be re-purposed as a therapy for PD and suggest that anti-inflammatory effects may contribute to its neuroprotective mechanisms. PMID:25452026

  1. A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome

    PubMed Central

    Kron, Miriam; Lang, Min; Adams, Ian T.; Sceniak, Michael; Longo, Frank; Katz, David M.

    2014-01-01

    Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal

  2. Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

    PubMed

    Esclassan, Frederic; Francois, Jennifer; Phillips, Keith G; Loomis, Sally; Gilmour, Gary

    2015-02-01

    Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies. PMID:25420124

  3. Genetic damage and the expression of behavioral abnormalities in the progeny of male rats exposed to ionizing radiation

    SciTech Connect

    Lowery, M.C.

    1987-01-01

    To determine the possible genetic nature of behavioral anomalies, an identifiable genetic endpoint, inherited chromosome translocations in the offspring, was selected to evaluate the relationship to behavior. Young adult male Fischer 344 rats were exposed to 50-300 rads of ionizing radiation. Two weeks following their irradiation, the males were mated with four virgin females for one week. During this time, fertilizing sperm were derived from post-meiotic spermatids, the stage of the spermatogenic cycle most sensitive to the mutagenic effects of radiation. Behavioral analyses of the resulting 390 offspring consisted of both motor reflex and motor coordination measurements as well as learning and retention parameters. Significant differences in performance were seen in several of the motor reflex measurements in progeny of males exposed to some of the higher doses of irradiation. A similar phenomenon was observed in the performance of a single learned behavior.

  4. Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease.

    PubMed

    Galeano, Pablo; Martino Adami, Pamela V; Do Carmo, Sonia; Blanco, Eduardo; Rotondaro, Cecilia; Capani, Francisco; Castaño, Eduardo M; Cuello, A Claudio; Morelli, Laura

    2014-01-01

    Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg(+/-)) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg(+/-) rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg(+/-) rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in

  5. Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease

    PubMed Central

    Galeano, Pablo; Martino Adami, Pamela V.; Do Carmo, Sonia; Blanco, Eduardo; Rotondaro, Cecilia; Capani, Francisco; Castaño, Eduardo M.; Cuello, A. Claudio; Morelli, Laura

    2014-01-01

    Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg+/− rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg+/− rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in

  6. Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy

    PubMed Central

    Robinson, Caleb R.; Zhang, Hongmei; Dougherty, Patrick M.

    2014-01-01

    Bortezomib is a first generation proteasome inhibitor that is the frontline chemotherapy for multiple myeloma with the chief dose-limiting side effect of painful peripheral neuropathy. The goal of this study was to define the behavioral phenotype in a preclinical model of bortezomib chemotherapy-induced peripheral neuropathy (CIPN) and to test whether this is matched by changes in the physiological responses of spinal wide dynamic range neurons. Sprague-Dawley rats were treated with four injections of bortezomib at four doses, 0.05mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, or equal volume of saline. All doses of bortezomib above 0.05mg/kg produced showed significant dose-dependent mechanical hyperalgesia that was fully established at 30 days after treatment and that recovered to baseline levels by day 69 after treatment. Thermal, cold, and motor testing were all unaffected by treatment with bortezomib. Spinal wide dynamic range (WDR) neurons in rats with confirmed bortzomib-related CIPN showed an increase in number of evoked discharges to mechanical stimuli and exaggerated after-discharges in rats with bortezomib CIPN. PMID:24949562

  7. Chronic exposure to environmentally-relevant concentrations of fluoxetine (Prozac) decreases survival, increases abnormal behaviors, and delays predator escape responses in guppies.

    PubMed

    Pelli, Marco; Connaughton, Victoria P

    2015-11-01

    This study evaluates the impact of fluoxetine, an antidepressant drug and common pollutant in aquatic environments, on growth, survival, and behavior in juvenile guppies and on predator escape responses in adult guppies (Poecilia reticulata). In juveniles, the effects of acute (4d) and chronic (35d) exposure on growth and survival were examined, and behavioral changes were noted throughout the chronic experiment. In adults, escape responses to a mock predator during chronic (28d) fluoxetine exposure were videotaped to determine the overall speed of response in treated vs. control fish. The effects of fish gender and the presence of a group/school on escape responses were also determined. Our results show that acute exposure to nominal concentrations of 0.03 and 0.5μg/L, levels within the environment, did not adversely impact juvenile guppy survival. However, chronic exposure significantly reduced weight, length, and belly width/girth measurements compared to controls. Chronic exposure also resulted in abnormal swimming behavior and reduced survival in juveniles. In adults, fluoxetine exposure significantly delayed predator escape responses in both males and females. Escape responses were also reduced when adults were tested either individually or in a group, with significantly more delayed responses seen in individually tested fish. Taken together, these findings suggest that fluoxetine can impact guppy populations, during both juvenile and adult stages, with chronic exposure resulting in decreased survival and growth and altered behavioral responses. PMID:26126230

  8. Alzheimer Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior

    PubMed Central

    Dubey, Sonam; Yeung, Sharon; Hough, Olivia; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

    2014-01-01

    Purpose To validate whether repeated magnetic resonance (MR) imaging–guided focused ultrasound treatments targeted to the hippocampus, a brain structure relevant for Alzheimer disease (ADAlzheimer disease), could modulate pathologic abnormalities, plasticity, and behavior in a mouse model. Materials and Methods All animal procedures were approved by the Animal Care Committee and are in accordance with the Canadian Council on Animal Care. Seven-month-old transgenic (TgCRND8) (Tg) mice and their nontransgenic (non-Tg) littermates were entered in the study. Mice were treated weekly with MR imaging–guided focused ultrasound in the bilateral hippocampus (1.68 MHz, 10-msec bursts, 1-Hz burst repetition frequency, 120-second total duration). After 1 month, spatial memory was tested in the Y maze with the novel arm prior to sacrifice and immunohistochemical analysis. The data were compared by using unpaired t tests and analysis of variance with Tukey post hoc analysis. Results Untreated Tg mice spent 61% less time than untreated non-Tg mice exploring the novel arm of the Y maze because of spatial memory impairments (P < .05). Following MR imaging–guided focused ultrasound, Tg mice spent 99% more time exploring the novel arm, performing as well as their non-Tg littermates. Changes in behavior were correlated with a reduction of the number and size of amyloid plaques in the MR imaging–guided focused ultrasound–treated animals (P < .01). Further, after MR imaging–guided focused ultrasound treatment, there was a 250% increase in the number of newborn neurons in the hippocampus (P < .01). The newborn neurons had longer dendrites and more arborization after MR imaging–guided focused ultrasound, as well (P < .01). Conclusion Repeated MR imaging–guided focused ultrasound treatments led to spatial memory improvement in a Tg mouse model of ADAlzheimer disease. The behavior changes may be mediated by decreased amyloid pathologic abnormalities and increased neuronal

  9. Variability in Post-Error Behavioral Adjustment Is Associated with Functional Abnormalities in the Temporal Cortex in Children with ADHD

    ERIC Educational Resources Information Center

    Spinelli, Simona; Vasa, Roma A.; Joel, Suresh; Nelson, Tess E.; Pekar, James J.; Mostofsky, Stewart H.

    2011-01-01

    Background: Error processing is reflected, behaviorally, by slower reaction times (RT) on trials immediately following an error (post-error). Children with attention-deficit hyperactivity disorder (ADHD) fail to show RT slowing and demonstrate increased intra-subject variability (ISV) on post-error trials. The neural correlates of these behavioral…

  10. Abnormal Pre-Attentive Arousal in Young Children with Autism Spectrum Disorder Contributes to Their Atypical Auditory Behavior: An ERP Study

    PubMed Central

    Stroganova, Tatiana A.; Kozunov, Vladimir V.; Posikera, Irina N.; Galuta, Ilia A.; Gratchev, Vitaliy V.; Orekhova, Elena V.

    2013-01-01

    Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks (‘S1’ and ‘S2’) separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the ‘tangential’ P100 component was rightward lateralized in TD children, whereas the ‘radial’ N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward-lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD. PMID:23935931

  11. Abnormal pre-attentive arousal in young children with autism spectrum disorder contributes to their atypical auditory behavior: an ERP study.

    PubMed

    Stroganova, Tatiana A; Kozunov, Vladimir V; Posikera, Irina N; Galuta, Ilia A; Gratchev, Vitaliy V; Orekhova, Elena V

    2013-01-01

    Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks ('S1' and 'S2') separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the 'tangential' P100 component was rightward lateralized in TD children, whereas the 'radial' N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward-lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD. PMID:23935931

  12. Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders

    PubMed Central

    Sakai, Kaori; Shoji, Hirotaka; Kohno, Takao; Miyakawa, Tsuyoshi; Hattori, Mitsuharu

    2016-01-01

    The secreted glycoprotein Reelin is believed to play critical roles in the pathogenesis of several neuropsychiatric disorders. The highly basic C-terminal region (CTR) of Reelin is necessary for efficient activation of its downstream signaling, and the brain structure of knock-in mice that lack the CTR (ΔC-KI mice) is impaired. Here, we performed a comprehensive behavioral test battery on ΔC-KI mice, in order to evaluate the effects of partial loss-of-function of Reelin on brain functions. The ΔC-KI mice were hyperactive and exhibited reduced anxiety-like and social behaviors. The working memory in ΔC-KI mice was impaired in a T-maze test. There was little difference in spatial reference memory, depression-like behavior, prepulse inhibition, or fear memory between ΔC-KI and wild-type mice. These results suggest that CTR-dependent Reelin functions are required for some specific normal brain functions and that ΔC-KI mice recapitulate some aspects of neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder. PMID:27346785

  13. Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders.

    PubMed

    Sakai, Kaori; Shoji, Hirotaka; Kohno, Takao; Miyakawa, Tsuyoshi; Hattori, Mitsuharu

    2016-01-01

    The secreted glycoprotein Reelin is believed to play critical roles in the pathogenesis of several neuropsychiatric disorders. The highly basic C-terminal region (CTR) of Reelin is necessary for efficient activation of its downstream signaling, and the brain structure of knock-in mice that lack the CTR (ΔC-KI mice) is impaired. Here, we performed a comprehensive behavioral test battery on ΔC-KI mice, in order to evaluate the effects of partial loss-of-function of Reelin on brain functions. The ΔC-KI mice were hyperactive and exhibited reduced anxiety-like and social behaviors. The working memory in ΔC-KI mice was impaired in a T-maze test. There was little difference in spatial reference memory, depression-like behavior, prepulse inhibition, or fear memory between ΔC-KI and wild-type mice. These results suggest that CTR-dependent Reelin functions are required for some specific normal brain functions and that ΔC-KI mice recapitulate some aspects of neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder. PMID:27346785

  14. Commentary: behavioral phenotype.

    PubMed

    Oitzl, Melly S

    2008-01-01

    PTSD arises by definition as a direct consequence of the experience of an acute severe stressor. The formation of traumatic memory and its extinction, sympathetic and adrenocortical stress systems activity in relation to individual vulnerability form the core of animal models for PTSD. PMID:18037010

  15. Are there gender-specific pathways from early adolescence psychological distress symptoms toward the development of substance use and abnormal eating behavior?

    PubMed

    Beato-Fernández, Luis; Rodríguez-Cano, Teresa; Pelayo-Delgado, Esther; Calaf, Myralys

    2007-02-01

    The aim of the present longitudinal community study was to test whether psychological distress at 13 years of age predicted reported substance use problems in boys and abnormal eating behavior in girls 2 years later. The sample consisted of 500 male and 576 female students. The use of substances was evaluated using a semi-structured interview, psychological distress with the General Health Questionnaire (GHQ) and eating psychopathology with the Eating Attitudes Test (EAT-40), and the Bulimic Investigatory Test Edinburgh (BITE). Controlling the effect of initial substance use problems, psychological distress predicted later reported substance use problems in males. Girls with an initial score above the cut-off point on the GHQ were two times more likely to be at risk of having an eating disorder 2 years later. Therefore, psychological distress might take different developmental pathways in males and females, leading toward eating problems in the latter versus substance use in the former. PMID:17001526

  16. CamKII inhibitors reduce mitotic instability, connexon anomalies and progression of the in vivo behavioral phenotype in transgenic animals expressing a mutated Gjb1 gene

    PubMed Central

    Mones, Saleh; Bordignon, Benoit; Peiretti, Franck; Landrier, Jean F.; Gess, Burkhardt; Bourguignon, Jean J.; Bihel, Frédéric; Fontés, Michel

    2014-01-01

    Mutation in the Gjb1 gene, coding for a connexin (Cx32), is associated with an inherited peripheral neuropathic disorder (X-linked Charcot-Marie-Tooth, CMTX). Our previous work reported that transgenic animals expressing a human Gjb1 transgene present polyploidy and abnormal over-duplication of the centrosome, suggesting a role for Gjb1 in mitotic stability. In this article, we propose mechanisms by which mutations in Gjb1 induce mitotic instability and discuss its potential relation with the CMTX phenotype. We showed that transgenic cells exhibit CamKII over-stimulation, a phenomenon that has been linked to mitotic instability (polyploidy, nuclear volume and centrosome over-duplication), that is reversed by CamKII inhibitors. We also demonstrate that connexon activity is partially restored in transgenic cells with CamKII inhibitors. Our model supports the role for Pim1, a kinase that has been associated with genomic instability in cancers, in genomic instability in Cx32 mutations. Regarding in vivo phenotype, we showed that degradation on the rotarod test in our transgenic mice is significantly lowered by treatment with a CamKII inhibitor (KN93). This effect was seen in two lines with different point mutations in GJB1, and stopping the treatment led to degradation of the phenotype. PMID:24982612

  17. Prenatal and Early Postnatal Exposure to Cigarette Smoke Decreases BDNF/TrkB Signaling and Increases Abnormal Behaviors Later in Life

    PubMed Central

    Xiao, Lan; Kish, Vincent L.; Benders, Katherine M.

    2016-01-01

    Background: Cigarette smoke exposure during prenatal and early postnatal periods increases the incidence of a variety of abnormal behaviors later in life. The purpose of this study was to identify the possible critical period of susceptibility to cigarette smoke exposure and evaluate the possibe effects of cigarette smoke during early life on brain-derived neurotrophic factor/neurotrophic tyrosine kinase receptor B signaling in the brain. Methods: Three different age of imprinting control region mice were exposed to cigarette smoke or filtered air for 10 consecutive days beginning on either gestational day 7 by maternal exposure, or postnatal days 2 or 21 by direct inhalation. A series of behavioral profiles and neurotrophins in brain were measured 24 hours after mice received acute restraint stress for 1 hour on postnatal day 59. Results: Cigarette smoke exposure in gestational day 7 and postnatal day 2 produced depression-like behaviors as evidenced by significantly increased immobility in both tail suspension and forced-swim test. Increased entry latencies, but not ambulation in the open field test, were also observed in the gestational day 7 and postnatal day 2 cigarette smoke exposure groups. Genetic analysis showed that gestational day 7 cigarette smoke exposure significantly altered mRNA level of brain-derived neurotrophic factor/tyrosine kinase receptor B in the hippocampus. However, behavioral profiles and brain-derived neurotrophic factor/tyrosine kinase receptor B signaling were not significantly changed in PND21 cigarette smoke exposure group compared with FA group. Conclusions: These results suggest that a critical period of susceptibility to cigarette smoke exposure exists in the prenatal and early postnatal period, which results a downregulation in brain-derived neurotrophic factor/tyrosine kinase receptor B signaling in the hippocampus and enhances depression-like behaviors later in life. PMID:26503133

  18. An Interval of the Obesity QTL Nob3.38 within a QTL Hotspot on Chromosome 1 Modulates Behavioral Phenotypes

    PubMed Central

    Vogel, Heike; Montag, Dirk; Kanzleiter, Timo; Jonas, Wenke; Matzke, Daniela; Scherneck, Stephan; Chadt, Alexandra; Töle, Jonas; Kluge, Reinhart; Joost, Hans-Georg; Schürmann, Annette

    2013-01-01

    A region on mouse distal chromosome 1 (Chr. 1) that is highly enriched in quantitative trait loci (QTLs) controlling neural and behavioral phenotypes overlaps with the peak region of a major obesity QTL (Nob3.38), which we identified in an intercross of New Zealand Obese (NZO) mice with C57BL/6J (B6). By positional cloning we recently identified a microdeletion within this locus causing the disruption of Ifi202b that protects from adiposity by suppressing expression of 11β-Hsd1. Here we show that the Nob3.38 segment also corresponds with the QTL rich region (Qrr1) on Chr. 1 and associates with increased voluntary running wheel activity, Rota-rod performance, decreased grip strength, and anxiety-related traits. The characterization of a subcongenic line carrying 14.2 Mbp of Nob3.38 with a polymorphic region of 4.4 Mbp indicates that the microdeletion and/or other polymorphisms in its proximity alter body weight, voluntary activity, and exploration. Since 27 out of 32 QTL were identified in crosses with B6, we hypothesized that the microdeletion and or adjacent SNPs are unique for B6 mice and responsible for some of the complex Qrr1-mediated effects. Indeed, a phylogenic study of 28 mouse strains revealed a NZO-like genotype for 22 and a B6-like genotype for NZW/LacJ and 4 other C57BL strains. Thus, we suggest that a Nob3.38 interval (173.0–177.4 Mbp) does not only modify adiposity but also neurobehavioral traits by a haplotype segregating with C57BL strains. PMID:23308133

  19. Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden.

    PubMed

    Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Kannan, Geetha; Viscidi, Raphael P; Pletnikov, Mikhail V; Yolken, Robert H

    2016-04-01

    There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human. PMID:27124472

  20. Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden

    PubMed Central

    Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Kannan, Geetha; Viscidi, Raphael P.; Pletnikov, Mikhail V.; Yolken, Robert H.

    2016-01-01

    There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human. PMID:27124472

  1. Hierarchical representation and machine learning from faulty jet engine behavioral examples to detect real time abnormal conditions

    NASA Technical Reports Server (NTRS)

    Gupta, U. K.; Ali, M.

    1988-01-01

    The theoretical basis and operation of LEBEX, a machine-learning system for jet-engine performance monitoring, are described. The behavior of the engine is modeled in terms of four parameters (the rotational speeds of the high- and low-speed sections and the exhaust and combustion temperatures), and parameter variations indicating malfunction are transformed into structural representations involving instances and events. LEBEX extracts descriptors from a set of training data on normal and faulty engines, represents them hierarchically in a knowledge base, and uses them to diagnose and predict faults on a real-time basis. Diagrams of the system architecture and printouts of typical results are shown.

  2. Deletion in the N-terminal Half of Olfactomedin 1 Modifies Its Interaction with Synaptic Proteins and Causes Brain Dystrophy and Abnormal Behavior in Mice

    PubMed Central

    Nakaya, Naoki; Sultana, Afia; Munasinghe, Jeeva; Cheng, Aiwu; Mattson, Mark P.; Tomarev, Stanislav I.

    2013-01-01

    Olfactomedin 1 (Olfm1) is a secreted glycoprotein that is preferentially expressed in neuronal tissues. Here we show that deletion of exons 4 and 5 from the Olfm1 gene, which encodes a 52 amino acid long region in the N-terminal part of the protein, increased neonatal death and reduced body weight of surviving homozygous mice. Magnetic resonance imaging analyses revealed reduced brain volume and attenuated size of white matter tracts such as the anterior commissure, corpus callosum, and optic nerve. Adult Olfm1 mutant mice demonstrated abnormal behavior in several tests including reduced marble digging, elevated plus maze test, nesting activity and latency on balance beam tests as compared with their wild-type littermates. The olfactory system was both structurally and functionally disturbed by the mutation in the Olfm1 gene as shown by functional magnetic resonance imaging analysis and a smell test. Deficiencies of the olfactory system may contribute to the neonatal death and loss of body weight of Olfm1 mutant. Shotgun proteomics revealed 59 candidate proteins that co-precipitated with wild-type or mutant Olfm1 proteins in postnatal day 1 brain. Olfm1-binding targets included GluR2, Cav2.1, Teneurin-4 and Kidins220. Modified interaction of Olfm1 with binding targets led to an increase in intracellular Ca2+ concentration and activation of ERK1/2, MEK1 and CaMKII in the hippocampus and olfactory bulb of Olfm1 mutant mice compared with their wild-type littermates. Excessive activation of the CaMKII and Ras-ERK pathways in the Olfm1 mutant olfactory bulb and hippocampus by elevated intracellular calcium may contribute to the abnormal behavior and olfactory activity of Olfm1 mutant mice. PMID:24095980

  3. Deletion in the N-terminal half of olfactomedin 1 modifies its interaction with synaptic proteins and causes brain dystrophy and abnormal behavior in mice.

    PubMed

    Nakaya, Naoki; Sultana, Afia; Munasinghe, Jeeva; Cheng, Aiwu; Mattson, Mark P; Tomarev, Stanislav I

    2013-12-01

    Olfactomedin 1 (Olfm1) is a secreted glycoprotein that is preferentially expressed in neuronal tissues. Here we show that deletion of exons 4 and 5 from the Olfm1 gene, which encodes a 52 amino acid long region in the N-terminal part of the protein, increased neonatal death and reduced body weight of surviving homozygous mice. Magnetic resonance imaging analyses revealed reduced brain volume and attenuated size of white matter tracts such as the anterior commissure, corpus callosum, and optic nerve. Adult Olfm1 mutant mice demonstrated abnormal behavior in several tests including reduced marble digging, elevated plus maze test, nesting activity and latency on balance beam tests as compared with their wild-type littermates. The olfactory system was both structurally and functionally disturbed by the mutation in the Olfm1 gene as shown by functional magnetic resonance imaging analysis and a smell test. Deficiencies of the olfactory system may contribute to the neonatal death and loss of body weight of Olfm1 mutant. Shotgun proteomics revealed 59 candidate proteins that co-precipitated with wild-type or mutant Olfm1 proteins in postnatal day 1 brain. Olfm1-binding targets included GluR2, Cav2.1, teneurin-4 and Kidins220. Modified interaction of Olfm1 with binding targets led to an increase in intracellular Ca(2+) concentration and activation of ERK1/2, MEK1 and CaMKII in the hippocampus and olfactory bulb of Olfm1 mutant mice compared with their wild-type littermates. Excessive activation of the CaMKII and Ras-ERK pathways in the Olfm1 mutant olfactory bulb and hippocampus by elevated intracellular calcium may contribute to the abnormal behavior and olfactory activity of Olfm1 mutant mice. PMID:24095980

  4. Sleep and Sex: What Can Go Wrong? A Review of the Literature on Sleep Related Disorders and Abnormal Sexual Behaviors and Experiences

    PubMed Central

    Schenck, Carlos H.; Arnulf, Isabelle; Mahowald, Mark W.

    2007-01-01

    Study Objectives: To formulate the first classification of sleep related disorders and abnormal sexual behaviors and experiences. Design: A computerized literature search was conducted, and other sources, such as textbooks, were searched. Results: Many categories of sleep related disorders were represented in the classification: parasomnias (confusional arousals/sleepwalking, with or without obstructive sleep apnea; REM sleep behavior disorder); sleep related seizures; Kleine-Levin syndrome (KLS); severe chronic insomnia; restless legs syndrome; narcolepsy; sleep exacerbation of persistent sexual arousal syndrome; sleep related painful erections; sleep related dissociative disorders; nocturnal psychotic disorders; miscellaneous states. Kleine-Levin syndrome (78 cases) and parasomnias (31 cases) were most frequently reported. Parasomnias and sleep related seizures had overlapping and divergent clinical features. Thirty-one cases of parasomnias (25 males; mean age, 32 years) and 7 cases of sleep related seizures (4 males; mean age, 38 years) were identified. A full range of sleep related sexual behaviors with self and/or bed partners or others were reported, including masturbation, sexual vocalizations, fondling, sexual intercourse with climax, sexual assault/rape, ictal sexual hyperarousal, ictal orgasm, and ictal automatism. Adverse physical and/or psychosocial effects from the sleepsex were present in all parasomnia and sleep related seizure cases, but pleasurable effects were reported by 5 bed partners and by 3 patients with sleep related seizures. Forensic consequences were common, occurring in 35.5% (11/31) of parasomnia cases, with most (9/11) involving minors. All parasomnias cases reported amnesia for the sleepsex, in contrast to 28.6% (2/7) of sleep related seizure cases. Polysomnography (without penile tumescence monitoring), performed in 26 of 31 parasomnia cases, documented sexual moaning from slow wave sleep in 3 cases and sexual intercourse during

  5. Abnormal Osmotic Avoidance Behavior in C. elegans Is Associated with Increased Hypertonic Stress Resistance and Improved Proteostasis

    PubMed Central

    Lee, Elaine C.; Kim, Heejung; Ditano, Jennifer; Manion, Dacie; King, Benjamin L.; Strange, Kevin

    2016-01-01

    Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that mutations in osm-9 and osm-12 that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons are associated with enhanced survival during hypertonic stress. Improved survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, we find that osm-9(ok1677) mutant and osm-9(RNAi) worms exhibit reductions in hypertonicity induced protein damage in non-neuronal cells suggesting that enhanced proteostasis capacity may account for improved hypertonic stress resistance in worms with defects in osmotic avoidance behavior. RNA-seq analysis revealed that genes that play roles in managing protein damage are upregulated in osm-9(ok1677) worms. Our findings are consistent with a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. PMID:27111894

  6. Long-term recovery from hippocampal-related behavioral and biochemical abnormalities induced by noise exposure during brain development. Evaluation of auditory pathway integrity.

    PubMed

    Uran, S L; Gómez-Casati, M E; Guelman, L R

    2014-10-01

    Sound is an important part of man's contact with the environment and has served as critical means for survival throughout his evolution. As a result of exposure to noise, physiological functions such as those involving structures of the auditory and non-auditory systems might be damaged. We have previously reported that noise-exposed developing rats elicited hippocampal-related histological, biochemical and behavioral changes. However, no data about the time lapse of these changes were reported. Moreover, measurements of auditory pathway function were not performed in exposed animals. Therefore, with the present work, we aim to test the onset and the persistence of the different extra-auditory abnormalities observed in noise-exposed rats and to evaluate auditory pathway integrity. Male Wistar rats of 15 days were exposed to moderate noise levels (95-97 dB SPL, 2 h a day) during one day (acute noise exposure, ANE) or during 15 days (sub-acute noise exposure, SANE). Hippocampal biochemical determinations as well as short (ST) and long term (LT) behavioral assessments were performed. In addition, histological and functional evaluations of the auditory pathway were carried out in exposed animals. Our results show that hippocampal-related behavioral and biochemical changes (impairments in habituation, recognition and associative memories as well as distortion of anxiety-related behavior, decreases in reactive oxygen species (ROS) levels and increases in antioxidant enzymes activities) induced by noise exposure were almost completely restored by PND 90. In addition, auditory evaluation shows that increased cochlear thresholds observed in exposed rats were re-established at PND 90, although with a remarkable supra-threshold amplitude reduction. These data suggest that noise-induced hippocampal and auditory-related alterations are mostly transient and that the effects of noise on the hippocampus might be, at least in part, mediated by the damage on the auditory pathway

  7. 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

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

    PubMed

    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

    2015-07-15

    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

  9. Feeding behavior, ruminal fermentation, and performance of pregnant beef cows differing in phenotypic residual feed intake offered grass silage.

    PubMed

    Fitzsimons, C; Kenny, D A; Fahey, A G; McGee, M

    2014-05-01

    This study examined the relationship of residual feed intake (RFI) and performance with feeding behavior and ruminal fermentation variables in pregnant beef cows offered a grass silage diet. Individual grass silage DMI (dry matter digestibility = 666 g/kg) was recorded on 47 gestating (mean gestation d 166, SD = 26 d) Simmental and Simmental × Holstein-Friesian beef cows for a period of 80 d. Cow BW, BCS, skeletal measurements, ultrasonically scanned muscle and fat depth, visual muscular score, ruminal fermentation, blood metabolites, and feeding behavior were measured. Phenotypic RFI was calculated as actual DMI minus expected DMI. Expected DMI was computed for each animal by regressing DMI on conceptus-adjusted mean BW(0.75) and ADG over an 80-d period. Within breed, cows were ranked by RFI into low (efficient), medium, or high groups. Overall mean (SD) values for DMI (kg/d), RFI, initial conceptus-adjusted BW, and conceptus-adjusted ADG were 8.41 (1.09) kg/d, 0.01 (0.13) kg/d, 646 (70) kg, and -0.07 (0.32) kg, respectively. High-RFI cows ate 25% and 8% more than low- and medium-RFI cows, respectively. Live weight and ADG were not correlated (P > 0.05), and DMI was positively correlated (r = 0.80; P < 0.001) with RFI. The low- and high-RFI groups had similar (P > 0.05) BW, ADG, BCS, visual muscular scores, skeletal measurements, blood metabolites, calf birth weight, and calving difficulty scores. All ultrasonic fat and muscle depth measurements were similar (P > 0.05) for low- and high-RFI cows except for back fat thickness change, where low-RFI cows gained less fat (P < 0.05) than high-RFI cows. Low-RFI cows had greater pH and lower ammonia concentrations in ruminal fluid compared to their high-RFI contemporaries. Low-RFI cows had fewer (P < 0.001) daily feeding events, but these were of longer (P < 0.001) duration (min·feed event(-1)·d(-1)). Despite this, total daily duration of feeding was shorter (P < 0.001; min/d) for low- compared to high-RFI cows. High

  10. Transplantation of melanocytes obtained from the skin ameliorates apomorphine-induced abnormal behavior in rodent hemi-parkinsonian models.

    PubMed

    Asanuma, Masato; Miyazaki, Ikuko; Diaz-Corrales, Francisco J; Higashi, Youichirou; Namba, Masayoshi; Ogawa, Norio

    2013-01-01

    Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson's disease. PMID:23776585

  11. Early Behavioral Abnormalities and Perinatal Alterations of PTEN/AKT Pathway in Valproic Acid Autism Model Mice

    PubMed Central

    Yang, Eun-Jeong; Ahn, Sangzin; Lee, Kihwan; Mahmood, Usman; Kim, Hye-Sun

    2016-01-01

    Exposure to valproic acid (VPA) during pregnancy has been linked with increased incidence of autism, and has repeatedly been demonstrated as a useful autism mouse model. We examined the early behavioral and anatomical changes as well as molecular changes in mice prenatally exposed to VPA (VPA mice). In this study, we first showed that VPA mice showed developmental delays as assessed with self-righting, eye opening tests and impaired social recognition. In addition, we provide the first evidence that primary cultured neurons from VPA-treated embryos present an increase in dendritic spines, compared with those from control mice. Mutations in phosphatase and tensin homolog (PTEN) gene are also known to be associated with autism, and mice with PTEN knockout show autistic characteristics. Protein expression of PTEN was decreased and the ratio of p-AKT/AKT was increased in the cerebral cortex and the hippocampus, and a distinctive anatomical change in the CA1 region of the hippocampus was observed. Taken together, our study suggests that prenatal exposure to VPA induces developmental delays and neuroanatomical changes via the reduction of PTEN level and these changes were detectable in the early days of life. PMID:27071011

  12. Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection

    PubMed Central

    Hermes, Gretchen; Ajioka, James W; Kelly, Krystyna A; Mui, Ernest; Roberts, Fiona; Kasza, Kristen; Mayr, Thomas; Kirisits, Michael J; Wollmann, Robert; Ferguson, David JP; Roberts, Craig W; Hwang, Jong-Hee; Trendler, Toria; Kennan, Richard P; Suzuki, Yasuhiro; Reardon, Catherine; Hickey, William F; Chen, Lieping; McLeod, Rima

    2008-01-01

    Background Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. Methods To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5–12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied. Results Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus

  13. Behavioral phenotyping of heterozygous acetylcholinesterase knockout (AChE+/-) mice showed no memory enhancement but hyposensitivity to amnesic drugs.

    PubMed

    Espallergues, Julie; Galvan, Laurie; Sabatier, Florence; Rana-Poussine, Vanessa; Maurice, Tangui; Chatonnet, Arnaud

    2010-01-20

    Decrease in the expression or activity of acetylcholinesterase (AChE) enzymatic activity results in increased cholinergic tonus in the brain and periphery, with concomitant regulations of nicotinic and muscarinic receptors expression. We generated AChE knockout mice and characterized the behavioral phenotype of heterozygous animals, focusing on learning and memory functions. Male and female, AChE+/- and AChE+/+ littermate controls (129 sv strain) were tested at 5-9 weeks of age. AChE activity was significantly decreased in the hippocampus and cortex of AChE+/- mice, but butyrylcholinesterase activity was preserved. AChE+/- mice failed to show any difference in terms of locomotion, exploration and anxiety parameters in the open-field test. Animals were then tested for place learning in the water-maze. They were trained using a 'sustained acquisition' protocol (3 swim trials per day) or a 'mild acquisition' protocol (2 swim trials per day) to locate an invisible platform in fixed position (reference memory procedure). Then, during 3 days, they were trained to locate the platform in a variable position (working memory procedure). Learning profiles and probe test performances were similar for AChE+/- and AChE+/+ mice. Mice were then treated with the muscarinic receptor antagonist scopolamine (0.5, 5 mg/kg) 20 min before each training session. Scopolamine impaired learning at both doses in AChE+/+ mice, but only at the highest dose in AChE+/- mice. Moreover, the intracerebroventricular injection of amyloid-beta25-35 peptide, 9 nmol, 7 days before water-maze acquisition, failed to induce learning deficits in AChE+/- mice, but impaired learning in AChE+/+ controls. The peptide failed to be toxic in forebrain structures of AChE+/- mice, since an increase in lipid peroxidation levels was measured in the hippocampus of AChE+/+ but not AChE+/- mice. We conclude that the increase in cholinergic tonus observed in AChE+/- mice did not result in increased memory functions but

  14. 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

  15. Attentive, Affective, and Adaptive Behavior in the Cat: Sensory deprivation of the forebrain by lesions in the brain stem results in striking behavioral abnormalities.

    PubMed

    Sprague, J M; Chambers, W W; Stellar, E

    1961-01-20

    Lesions of the lateral portion of the upper midbrain, involving medial, lateral, spinal, and trigeminal lemnisci primarily, result in a consistent syndrome of symptoms in the cat. (i) There is a marked sensory deficit, characterized mainly by sensory inattention and poor localization in the tactile, proprioceptive, auditory, gustatory, and nociceptive modalities, where direct pathways are interrupted. Similar defectsappear in vision and olfaction where no known direct or primary paths are interrupted. (ii) These cats are characterized by a lack of affect, showing little or no defensive and aggressive reaction to noxious and aversive situations and no response to pleasurable stimulation or solicitation of affection or petting. The animals are mute, lack facial expression, and show minimal autonomic responses. (iii) They show a hyperexploratory activity characterized by incessant, stereotyped wandering, sniffing, and visual searching, as though hallucinating. This behavior appears to be centrally directed and is very difficult to interrupt with environmental stimuli. (iv) They also demonstrate exaggerated oral activities: they snap in response to tactile stimulation of the lips, seizing and swallowing small objects even if inedible; they overeat; they hold objects too large to swallow (a mouse, a catnip ball) firmly clamped in the mouth for long periods of time; they mount and seize other animals (rat, cat, dog, monkey) by the back or the neck; they lick and chew the hair and skin of the back or tail incessantly when confined in a cage. In interpreting these results we emphasize the view that the syndrome is due chiefly to the extensive, specific, sensory deprivation produced by interruption of the lemnisci at the rostral midbrain. The relation of these findings to the effects of sensory isolation in man and animals, to the effects of midbrain lesions and neodecortication, to parietal lobe syndrome in primates, and to the behavior of autistic children is discussed

  16. Working Memory and Response Inhibition as One Integral Phenotype of Adult ADHD? A Behavioral and Imaging Correlational Investigation

    ERIC Educational Resources Information Center

    Schecklmann, Martin; Ehlis, Ann-Christine; Plichta, Michael M.; Dresler, Thomas; Heine, Monika; Boreatti-Hummer, Andrea; Romanos, Marcel; Jacob, Christian; Pauli, Paul; Fallgatter, Andreas J.

    2013-01-01

    Objective: It is an open question whether working memory (WM) and response inhibition (RI) constitute one integral phenotype in attention deficit hyperactivity disorder (ADHD). Method: The authors investigated 45 adult ADHD patients and 41 controls comparable for age, gender, intelligence, and education during a letter n-back and a stop-signal…

  17. Molecular abnormalities in Ewing's sarcoma.

    PubMed

    Burchill, Susan Ann

    2008-10-01

    Ewing's sarcoma is one of the few solid tumors for which the underlying molecular genetic abnormality has been described: rearrangement of the EWS gene on chromosome 22q12 with an ETS gene family member. These translocations define the Ewing's sarcoma family of tumors (ESFT) and provide a valuable tool for their accurate and unequivocal diagnosis. They also represent ideal targets for the development of tumor-specific therapeutics. Although secondary abnormalities occur in over 80% of primary ESFT the clinical utility of these is currently unclear. However, abnormalities in genes that regulate the G(1)/S checkpoint are frequently described and may be important in predicting outcome and response. Increased understanding of the molecular events that arise in ESFT and their role in the development and maintenance of the malignant phenotype will inform the improved stratification of patients for therapy and identify targets and pathways for the design of more effective cancer therapeutics. PMID:18925858

  18. Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease.

    PubMed

    Sotgia, Federica; Woodman, Scott E; Bonuccelli, Gloria; Capozza, Franco; Minetti, Carlo; Scherer, Philipp E; Lisanti, Michael P

    2003-11-01

    Four different phenotypes have been associated with CAV3 mutations: limb girdle muscular dystrophy-1C (LGMD-1C), rippling muscle disease (RMD), and distal myopathy (DM), as well as idiopathic and familial hyperCKemia (HCK). Detailed molecular characterization of two caveolin-3 mutations (P104L and DeltaTFT), associated with LGMD-1C, shows them to impart a dominant-negative effect on wild-type caveolin-3, rendering it dysfunctional through sequestration in the Golgi complex. Interestingly, substitution of glutamine for arginine at amino acid position 26 (R26Q) of caveolin-3 is associated not only with RMD but also with DM and HCK. However, the phenotypic behavior of the caveolin-3 R26Q mutation has never been evaluated in cultured cells. Thus we characterized the cellular and molecular properties of the R26Q mutant protein to better understand how this mutation can manifest as such distinct disease phenotypes. Here, we show that the caveolin-3 R26Q mutant is mostly retained at the level of the Golgi complex. The caveolin-3 R26Q mutant formed oligomers of a much larger size than wild-type caveolin-3 and was excluded from caveolae-enriched membranes. However, caveolin-3 R26Q did not behave in a dominant-negative fashion when coexpressed with wild-type caveolin-3. Thus the R26Q mutation behaves differently from other caveolin-3 mutations (P104L and DeltaTFT) that have been previously characterized. These data provide a possible explanation for the scope of the various disease phenotypes associated with the caveolin-3 R26Q mutation. We propose a haploinsufficiency model in which reduced levels of wild-type caveolin-3, although not rendered dysfunctional due to the caveolin-3 R26Q mutant protein, are insufficient for normal muscle cell function. PMID:12839838

  19. Detection of Structural Abnormalities Using Neural Nets

    NASA Technical Reports Server (NTRS)

    Zak, M.; Maccalla, A.; Daggumati, V.; Gulati, S.; Toomarian, N.

    1996-01-01

    This paper describes a feed-forward neural net approach for detection of abnormal system behavior based upon sensor data analyses. A new dynamical invariant representing structural parameters of the system is introduced in such a way that any structural abnormalities in the system behavior are detected from the corresponding changes to the invariant.

  20. Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice.

    PubMed

    Stroh, Matthew A; Winter, Michelle K; Swerdlow, Russell H; McCarson, Kenneth E; Zhu, Hao

    2016-08-01

    Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. (59)Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain. PMID:27188291

  1. Impact of global warming at the range margins: phenotypic plasticity and behavioral thermoregulation will buffer an endemic amphibian

    PubMed Central

    Ruiz-Aravena, Manuel; Gonzalez-Mendez, Avia; Estay, Sergio A; Gaitán-Espitia, Juan D; Barria-Oyarzo, Ismael; Bartheld, José L; Bacigalupe, Leonardo D

    2014-01-01

    When dispersal is not an option to evade warming temperatures, compensation through behavior, plasticity, or evolutionary adaptation is essential to prevent extinction. In this work, we evaluated whether there is physiological plasticity in the thermal performance curve (TPC) of maximum jumping speed in individuals acclimated to current and projected temperatures and whether there is an opportunity for behavioral thermoregulation in the desert landscape where inhabits the northernmost population of the endemic frog Pleurodema thaul. Our results indicate that individuals acclimated to 20°C and 25°C increased the breath of their TPCs by shifting their upper limits with respect to when they were acclimated at 10°C. In addition, even when dispersal is not possible for this population, the landscape is heterogeneous enough to offer opportunities for behavioral thermoregulation. In particular, under current climatic conditions, behavioral thermoregulation is not compulsory as available operative temperatures are encompassed within the population TPC limits. However, for severe projected temperatures under climate change, behavioral thermoregulation will be required in the sunny patches. In overall, our results suggest that this population of Pleurodema thaul will be able to endure the worst projected scenario of climate warming as it has not only the physiological capacities but also the environmental opportunities to regulate its body temperature behaviorally. PMID:25512843

  2. Impact of global warming at the range margins: phenotypic plasticity and behavioral thermoregulation will buffer an endemic amphibian.

    PubMed

    Ruiz-Aravena, Manuel; Gonzalez-Mendez, Avia; Estay, Sergio A; Gaitán-Espitia, Juan D; Barria-Oyarzo, Ismael; Bartheld, José L; Bacigalupe, Leonardo D

    2014-12-01

    When dispersal is not an option to evade warming temperatures, compensation through behavior, plasticity, or evolutionary adaptation is essential to prevent extinction. In this work, we evaluated whether there is physiological plasticity in the thermal performance curve (TPC) of maximum jumping speed in individuals acclimated to current and projected temperatures and whether there is an opportunity for behavioral thermoregulation in the desert landscape where inhabits the northernmost population of the endemic frog Pleurodema thaul. Our results indicate that individuals acclimated to 20°C and 25°C increased the breath of their TPCs by shifting their upper limits with respect to when they were acclimated at 10°C. In addition, even when dispersal is not possible for this population, the landscape is heterogeneous enough to offer opportunities for behavioral thermoregulation. In particular, under current climatic conditions, behavioral thermoregulation is not compulsory as available operative temperatures are encompassed within the population TPC limits. However, for severe projected temperatures under climate change, behavioral thermoregulation will be required in the sunny patches. In overall, our results suggest that this population of Pleurodema thaul will be able to endure the worst projected scenario of climate warming as it has not only the physiological capacities but also the environmental opportunities to regulate its body temperature behaviorally. PMID:25512843

  3. 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

  4. Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

    PubMed Central

    Anastasio, Noelle C; Stutz, Sonja J; Fox, Robert G; Sears, Robert M; Emeson, Ronald B; DiLeone, Ralph J; O'Neil, Richard T; Fink, Latham H; Li, Dingge; Green, Thomas A; Gerard Moeller, F; Cunningham, Kathryn A

    2014-01-01

    Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues (‘cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. PMID:23939424

  5. The role of the area postrema in the anorectic effects of amylin and salmon calcitonin: behavioral and neuronal phenotyping.

    PubMed

    Braegger, Fiona E; Asarian, Lori; Dahl, Kirsten; Lutz, Thomas A; Boyle, Christina N

    2014-10-01

    Amylin reduces meal size by activating noradrenergic neurons in the area postrema (AP). Neurons in the AP also mediate the eating-inhibitory effects of salmon calcitonin (sCT), a potent amylin agonist, but the phenotypes of the neurons mediating its effect are unknown. Here we investigated whether sCT activates similar neuronal populations to amylin, and if its anorectic properties also depend on AP function. Male rats underwent AP lesion (APX) or sham surgery. Meal patterns were analysed under ad libitum and post-deprivation conditions. The importance of the AP in mediating the anorectic action of sCT was examined in feeding experiments of dose-response effects of sCT in APX vs. sham rats. The effect of sCT to induce Fos expression was compared between surgery groups, and relative to amylin. The phenotype of Fos-expressing neurons in the brainstem was examined by testing for the co-expression of dopamine beta hydroxylase (DBH) or tryptophan hydroxylase (TPH). By measuring the apposition of vesicular glutamate transporter-2 (VGLUT2)-positive boutons, potential glutamatergic input to amylin- and sCT-activated AP neurons was compared. Similar to amylin, an intact AP was necessary for sCT to reduce eating. Further, co-expression between Fos activation and DBH after amylin or sCT did not differ markedly, while co-localization of Fos and TPH was minor. Approximately 95% of neurons expressing Fos and DBH after amylin or sCT treatment were closely apposed to VGLUT2-positive boutons. Our study suggests that the hindbrain pathways engaged by amylin and sCT share many similarities, including the mediation by AP neurons. PMID:25040689

  6. Phenotypic mapping and clinical ideology

    SciTech Connect

    Lurie, I.W.; Opitz, J.M.

    1995-07-17

    Scientists have been trying to determine whether the main clinical findings in the 4p deletion syndrome are due to a deletion of one small critical segment, or whether deletions of some particular segments of 4p are responsible for different phenotypic manifestations. This is the basic issue for the whole group of autosomal deletion syndromes, as well as for our understanding of mechanisms of the origin of the abnormal phenotype. All circumstances need to be taken into consideration when trying to apply molecular methods for the mapping of phenotypic findings in the 4p deletion or in any other autosomal deletion syndrome. 8 refs.

  7. Daily oral intake of theanine prevents the decline of 5-bromo-2'-deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress.

    PubMed

    Takarada, Takeshi; Nakamichi, Noritaka; Kakuda, Takami; Nakazato, Ryota; Kokubo, Hiroshi; Ikeno, Shinsuke; Nakamura, Saki; Hinoi, Eiichi; Yoneda, Yukio

    2015-03-01

    Posttraumatic stress disorder is a long-lasting psychiatric disease with the consequence of hippocampal atrophy in humans exposed to severe fatal stress. We demonstrated a positive correlation between the transient decline of 5-bromo-2'-deoxyuridine (BrdU) incorporation in the hippocampal dentate gyrus (DG) and long-lasting behavioral abnormalities in mice with traumatic stress. Here, we investigated pharmacological properties of theanine on the declined BrdU incorporation and abnormal behaviors in mice with traumatic stress. Prior daily oral administration of theanine at 50-500 mg/kg for 5 days significantly prevented the decline of BrdU incorporation, while theanine significantly prevented the decline in the DG even when administered for 5 days after stress. Consecutive daily administration of theanine significantly inhibited the prolonged immobility in mice with stress in forced swimming test seen 14 days later. Although traumatic stress significantly increased spontaneous locomotor activity over 30 min even when determined 14 days later, the increased total locomotion was significantly ameliorated following the administration of theanine at 50 mg/kg for 14 days after stress. These results suggest that theanine alleviates behavioral abnormalities together with prevention of the transient decline of BrdU incorporation in the hippocampal DG in adult mice with severe traumatic stress. PMID:25837925

  8. The social behavioral phenotype in boys and girls with an extra X chromosome (Klinefelter syndrome and Trisomy X): a comparison with autism spectrum disorder.

    PubMed

    van Rijn, Sophie; Stockmann, Lex; Borghgraef, Martine; Bruining, Hilgo; van Ravenswaaij-Arts, Conny; Govaerts, Lutgarde; Hansson, Kerstin; Swaab, Hanna

    2014-02-01

    The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106 controls, aged 9 to 18 years. We used the Autism Diagnostic Interview, Social Responsiveness Scale, Social Anxiety Scale and Social Skills Rating System. In the extra X group, levels of social dysfunction and autism symptoms were increased, being in between controls and ASD. In contrast to the ASD group, the extra X group showed increased social anxiety. The effects were similar for boys and girls with an extra X chromosome. PMID:23824705

  9. 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.

    PubMed

    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; nASD = 364) completed an online survey with an autism trait questionnaire and an FFM personality questionnaire. FFM facets accounted for 70 % of variance in autism trait scores. Neuroticism positively correlated with autism symptom severity, while extraversion, openness to experience, agreeableness, and conscientiousness negatively correlated with autism symptom severity. Four FFM subtypes emerged within adults with ASD, with three subtypes characterized by high neuroticism and none characterized by lower-than-average neuroticism. PMID:26319256

  10. Winter Day Lengths Enhance T Lymphocyte Phenotypes, Inhibit Cytokine Responses, and Attenuate Behavioral Symptoms of Infection in Laboratory Rats

    PubMed Central

    Prendergast, Brian J.; Kampf-Lassin, August; Yee, Jason R.; Galang, Jerome; McMaster, Nicholas; Kay, Leslie M.

    2009-01-01

    Annual variations in day length (photoperiod) trigger changes in the immune and reproductive system of seasonally-breeding animals. The purpose of this study was to determine whether photoperiodic changes in immunity depend on concurrent photoperiodic responses in the reproductive system, or whether immunological responses to photoperiod occur independent of reproductive responses. Here we report photoperiodic changes in enumerative, functional, and behavioral aspects of the immune system, and in immunomodulatory glucocorticoid secretion, in reproductively non-photoperiodic Wistar rats. T-cell numbers (CD3+, CD8+, CD8+CD25+, CD4+CD25+) were higher in the blood of rats housed in short as opposed to long day lengths for 10 weeks. Following a simulated bacterial infection (E. coli LPS; 125 μg/kg) the severity of several acute-phase sickness behaviors (anorexia, cachexia, neophobia, and social withdrawal) were attenuated in short days. LPS-stimulated IL-1β and IL-6 production were comparable between photoperiods, but plasma TNFα was higher in long-day relative to short-day rats. In addition, corticosterone concentrations were higher in short-day relative to long-day rats. The data are consistent with the hypothesis that photoperiodic regulation of the immune system can occur entirely independently of photoperiodic regulation of the reproductive system. In the absence of concurrent reproductive responses, short days increase the numbers of leukocytes capable of immunosurveillance and inhibition of inflammatory responses, increase proinflammatory cytokine production, increase immunomodulatory glucocorticoid secretion, and ultimately attenuate behavioral responses to infection. Seasonal changes in the host immune system, endocrine system, and behavior may contribute to the seasonal variability in disease outcomes, even in reproductively non-photoperiodic mammals. PMID:17728099

  11. Stress-induced behavioral and metabolic adaptations lead to an obesity-prone phenotype in ewes with elevated cortisol responses.

    PubMed

    Lee, T Kevin; Lee, Caroline; Bischof, Robert; Lambert, Gavin W; Clarke, Iain J; Henry, Belinda A

    2014-09-01

    The underlying cause of predisposition to obesity is complex but one marker is cortisol responsiveness. Selection of sheep for high (HR) or low (LR) cortisol responses to adrenocorticotropin shows that HR are more likely to become obese. Increased propensity to obesity is associated with reduced skeletal muscle thermogenesis. We sought to determine whether metabolic or behavioral responses to stress also contribute to altered propensity to obesity in LR and HR. Animals (n=5-10/group) were exposed to 3 stressors and we measured food intake and thermogenesis (recorded with dataloggers implanted into muscle). Stressors were hypoglycaemia (0.125 units/kg insulin, IV), a barking dog and immune challenge (200 ng/kg lipopolysaccharide--LPS, IV). LR animals showed a greater catabolic state in response to both immune and psychosocial stressors. LPS reduced (P<0.01) food intake in both groups but LR showed a greater (P<0.05) reduction in food intake and a more substantial (P<0.05) rise in muscle temperature. Introduction of the barking dog reduced (P<0.05) food intake in LR only. These metabolic differences coincided with differences in cortisol responsiveness, where HR animals had increased (P<0.05) cortisol in response to both immune and psychosocial stressors. We also assessed behavior in the following paradigms: 1, isolation in the open field test; 2, response to a human intruder; and 3, food competition. LR had greater (P<0.05) activity, reduced fearfulness and displayed a proactive coping style of behavior. Thus we demonstrate that high cortisol responsiveness identifies animals with stress-induced metabolic and behavioral traits that may contribute to susceptibility to obesity. PMID:25001966

  12. Phenotypic switching in bacteria

    NASA Astrophysics Data System (ADS)

    Merrin, Jack

    Living matter is a non-equilibrium system in which many components work in parallel to perpetuate themselves through a fluctuating environment. Physiological states or functionalities revealed by a particular environment are called phenotypes. Transitions between phenotypes may occur either spontaneously or via interaction with the environment. Even in the same environment, genetically identical bacteria can exhibit different phenotypes of a continuous or discrete nature. In this thesis, we pursued three lines of investigation into discrete phenotypic heterogeneity in bacterial populations: the quantitative characterization of the so-called bacterial persistence, a theoretical model of phenotypic switching based on those measurements, and the design of artificial genetic networks which implement this model. Persistence is the phenotype of a subpopulation of bacteria with a reduced sensitivity to antibiotics. We developed a microfluidic apparatus, which allowed us to monitor the growth rates of individual cells while applying repeated cycles of antibiotic treatments. We were able to identify distinct phenotypes (normal and persistent) and characterize the stochastic transitions between them. We also found that phenotypic heterogeneity was present prior to any environmental cue such as antibiotic exposure. Motivated by the experiments with persisters, we formulated a theoretical model describing the dynamic behavior of several discrete phenotypes in a periodically varying environment. This theoretical framework allowed us to quantitatively predict the fitness of dynamic populations and to compare survival strategies according to environmental time-symmetries. These calculations suggested that persistence is a strategy used by bacterial populations to adapt to fluctuating environments. Knowledge of the phenotypic transition rates for persistence may provide statistical information about the typical environments of bacteria. We also describe a design of artificial

  13. Bioimaging for quantitative phenotype analysis.

    PubMed

    Chen, Weiyang; Xia, Xian; Huang, Yi; Chen, Xingwei; Han, Jing-Dong J

    2016-06-01

    With the development of bio-imaging techniques, an increasing number of studies apply these techniques to generate a myriad of image data. Its applications range from quantification of cellular, tissue, organismal and behavioral phenotypes of model organisms, to human facial phenotypes. The bio-imaging approaches to automatically detect, quantify, and profile phenotypic changes related to specific biological questions open new doors to studying phenotype-genotype associations and to precisely evaluating molecular changes associated with quantitative phenotypes. Here, we review major applications of bioimage-based quantitative phenotype analysis. Specifically, we describe the biological questions and experimental needs addressable by these analyses, computational techniques and tools that are available in these contexts, and the new perspectives on phenotype-genotype association uncovered by such analyses. PMID:26850283

  14. Making chromosome abnormalities treatable conditions.

    PubMed

    Cody, Jannine DeMars; Hale, Daniel Esten

    2015-09-01

    Individuals affected by the classic chromosome deletion syndromes which were first identified at the beginning of the genetic age, are now positioned to benefit from genomic advances. This issue highlights five of these conditions (4p-, 5p-, 11q-, 18p-, and 18q-). It focuses on the increased in understanding of the molecular underpinnings and envisions how these can be transformed into effective treatments. While it is scientifically exciting to see the phenotypic manifestations of hemizygosity being increasingly understood at the molecular and cellular level, it is even more amazing to consider that we are now on the road to making chromosome abnormalities treatable conditions. PMID:26351122

  15. [The effect of bromantane on the behavior of inbred mouse strains with different phenotypes of emotional stress reaction].

    PubMed

    Seredenin, S B; Miramedova, A G; Kozlovskaia, M M

    1999-01-01

    Per os administration of bromantan (2-[n-bromphenyl]-aminoadamantan) in doses of 40-50 mg/kg prevents the fixed posture reaction and reduces the level of defecation in Balb/c mice in the "open field" test and activates their behavior in the "elevated plus maze" test. It increases the motor activity of C57B1/c mice in both tests. It is concluded that an anxiolytic effect is present in the spectrum of pharmacological properties of bromantan. PMID:10439937

  16. The neurobehavioral and molecular phenotype of Angelman Syndrome.

    PubMed

    Wink, Logan K; Fitzpatrick, Sarah; Shaffer, Rebecca; Melnyk, Sophia; Begtrup, Amber H; Fox, Emma; Schaefer, Tori L; Mathieu-Frasier, Lauren; Ray, Balmiki; Lahiri, Debomoy; Horn, Paul A; Erickson, Craig A

    2015-11-01

    Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research. PMID:26219744

  17. Distinct behavioral phenotypes in novel "fast" kindling-susceptible and "slow" kindling-resistant rat strains selected by stimulation of the hippocampal perforant path.

    PubMed

    Langberg, Tomer; Dashek, Ryan; Mulvey, Bernard; Miller, Kimberly A; Osting, Susan; Stafstrom, Carl E; Sutula, Thomas P

    2016-01-01

    Kindling is a phenomenon of activity-dependent neural circuit plasticity induced by repeated seizures that results in progressive permanent increases in susceptibility to epilepsy. As the permanent structural and functional modifications induced by kindling include a diverse range of molecular, cellular, and functional alterations in neural circuits, it is of interest to determine if genetic background associated with seizure-induced plasticity might also influence plasticity in neural circuitry underlying other behaviors. Outbred Sprague-Dawley (SD) rats were selected and bred for ~15 generations for "fast' or "slow" rates of kindling development in response to stimulation of the perforant path input to the hippocampus. After 7-8 generations of selection and breeding, consistent phenotypes of "fast" and "slow" kindling rates were observed. By the 15th generation "fast" kindling rats referred to as Perforant Path Kindling Susceptible (PPKS) rats demonstrated a kindling rate of 10.7 ± 1.1 afterdischarges (ADs) to the milestone of the first secondary generalized (Class V) seizure, which differed significantly from "slow" kindling Perforant Path Kindling Resistant (PPKR) rats requiring 25.5 ± 2.0 ADs, and outbred SD rats requiring 16.8 ± 2.5 ADs (p<0.001, ANOVA). Seizure-naïve adult PPKS and PPKR rats from offspring of this generation and age-matched adult outbred SD rats were compared in validated behavioral measures including the open field test as a measure of exploratory activity, the Morris water maze as a measure of hippocampal spatial memory, and fear conditioning as a behavioral paradigm of associative fear learning. The PPKS ("fast" kindling) strain with increased susceptibility to seizure-induced plasticity demonstrated statistically significant increases in motor exploratory activity in the open field test and reduced spatial learning the Morris water maze, but demonstrated normal fear conditioned learning comparable to outbred SD rats and the "slow

  18. Genotype vs. Phenotype and the Rise of Non-Communicable Diseases: The Importance of Lifestyle Behaviors During Childhood

    PubMed Central

    Skidmore, Paula M; Orta, Olivia R; Faulkner, James; Lambrick, Danielle; Signal, Leigh; Williams, Michelle A; Stoner, Lee

    2016-01-01

    Despite continued research and growing public awareness, the incidence of non-communicable diseases (NCD) continues to accelerate. While a person may have a genetic predisposition to certain NCDs, the rapidly changing epidemiology of NCDs points to the importance of environmental, social, and behavioural determinants of health. Specifically, three lifestyle behaviours expose children to important environmental cues and stressors: physical activity, nutritional intake, and sleep behaviour. Failure to expose children to proper gene-environment interactions, through the aforementioned lifestyle behaviours, can and will predispose children to the development of NCDs. Reengineering the environments of children can induce a paradigm shift, from a predominantly biomedical health model of treating symptomology, to a more holistic model based on encouraging appropriate behavioral decisions and optimal health. PMID:26918226

  19. Just how happy is the happy puppet? An emotion signaling and kinship theory perspective on the behavioral phenotype of children with Angelman syndrome.

    PubMed

    Brown, William M; Consedine, Nathan S

    2004-01-01

    The favored level of parental investment in a child may differ for genes of maternal and paternal origin in the child. This conflict can be expressed in the phenomenon of genomic imprinting that refers to situations in which the same gene is differentially expressed depending on its parent of origin. Two disorders that show the effects of genomic imprinting--both at 15q11-q13--are Angelman Syndrome (AS) which is due to the absence of expression of maternally-inherited genes and Prader-Willi syndromes (PWS) which is due to the absence of expression of paternally-inherited genes. However, although both disorders can arise from the deletion of the same genetic region, the gustatory, behavioral, and affective characteristics of AS and PWS children are remarkably distinct. Recent research inspired by kinship theory has suggested the origins of these phenotypic differences may lie in the differential investment of each parent's genome in the AS or PWS child. Specifically, it is thought that each set of parental genes have different 'ideas' regarding how the child should behave towards the mother and how much investment they should look to extract. In normal cases, the trade-off between the competing parental genomes produces a behavioral equilibrium in the child. However, in pathological instances, particularly where gene expression is one-sided, the evolved behavioral strategies favored by the contributing genome will dominate the child's behavior. To date, research in the area of genomic conflict in AS and PWS children has primarily focusing on differences in post-natal nutrition-related behaviors. The current paper extends this framework by offering an emotion and evolutionary signaling interpretation of the affective characteristics of AS children. A review of the affective characteristics of the two syndromes (PWS and AS) is presented before kinship and emotions theory are used to examine the functions that differential affect expression may serve in altering

  20. Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium.

    PubMed

    Basilico, Nicoletta; Magnetto, Chiara; D'Alessandro, Sarah; Panariti, Alice; Rivolta, Ilaria; Genova, Tullio; Khadjavi, Amina; Gulino, Giulia Rossana; Argenziano, Monica; Soster, Marco; Cavalli, Roberta; Giribaldi, Giuliana; Guiot, Caterina; Prato, Mauro

    2015-11-01

    In chronic wounds, hypoxia seriously undermines tissue repair processes by altering the balances between pro-angiogenic proteolytic enzymes (matrix metalloproteinases, MMPs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) released from surrounding cells. Recently, we have shown that in human monocytes hypoxia reduces MMP-9 and increases TIMP-1 without affecting TIMP-2 secretion, whereas in human keratinocytes it reduces MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. Provided that the phenotype of the cellular environment is better understood, chronic wounds might be targeted by new oxygenating compounds such as chitosan- or dextran-shelled and 2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets (OLNs). Here, we investigated the effects of hypoxia and dextran-shelled OLNs on the pro-angiogenic phenotype and behavior of human dermal microvascular endothelium (HMEC-1 cell line), another cell population playing key roles during wound healing. Normoxic HMEC-1 constitutively released MMP-2, TIMP-1 and TIMP-2 proteins, but not MMP-9. Hypoxia enhanced MMP-2 and reduced TIMP-1 secretion, without affecting TIMP-2 levels, and compromised cell ability to migrate and invade the extracellular matrix. When taken up by HMEC-1, nontoxic OLNs abrogated the effects of hypoxia, restoring normoxic MMP/TIMP levels and promoting cell migration, matrix invasion, and formation of microvessels. These effects were specifically dependent on time-sustained oxygen diffusion from OLN core, since they were not achieved by oxygen-free nanodroplets or oxygen-saturated solution. Collectively, these data provide new information on the effects of hypoxia on dermal endothelium and support the hypothesis that OLNs might be used as effective adjuvant tools to promote chronic wound healing processes. PMID:26276311

  1. Neurobehavioral phenotyping of Gαq knockout mice reveals impairments in motor functions and spatial working memory without changes in anxiety or behavioral despair

    PubMed Central

    Frederick, Aliya L.; Saborido, Tommy P.; Stanwood, Gregg D.

    2012-01-01

    Many neurotransmitters, hormones, and sensory stimuli elicit their cellular responses through the targeted activation of receptors coupled to the Gαq family of heterotrimeric G proteins. Nevertheless, we still understand little about the consequences of loss of this signaling activity on brain function. We therefore examined the effects of genetic inactivation of Gnaq, the gene that encode for Gαq, on responsiveness in a battery of behavioral tests in order to assess the contribution of Gαq signaling capacity in the brain circuits mediating expression of affective behaviors (anxiety and behavioral despair), spatial working memory, and locomotor output (coordination, strength, spontaneous activity, and drug-induced responses). First, we replicated and extended findings showing clear motor deficits in Gαq knockout mice as assessed on an accelerating rotarod and the inverted screen test. We then assessed the contribution of the basal ganglia motor loops to these impairments, using open field testing and analysis of drug-induced locomotor responses to the psychostimulant cocaine, the benzazepine D1 receptor agonists SKF83822 and SKF83959, and the NMDA receptor antagonist MK-801. We observed significant increases in drug-induced locomotor activity in Gαq knockout mice from the dopaminergic agonists but not MK-801, indicating that basal ganglia locomotor circuitry is largely intact in the absence of Gαq. Additionally, we observed normal phenotypes in both the elevated zero maze and the forced swim test indicating that anxiety and depression-related circuitry appears to be largely intact after loss of Gnaq expression. Lastly, use of the Y-maze revealed spatial memory deficits in Gαq knockout mice, indicating that receptors signaling through Gαq are necessary in these circuits for proficiency in this task. PMID:22723772

  2. In tribute to Bob Blanchard: Divergent behavioral phenotypes of 16p11.2 deletion mice reared in same-genotype versus mixed-genotype cages.

    PubMed

    Yang, Mu; Lewis, Freeman; Foley, Gillian; Crawley, Jacqueline N

    2015-07-01

    mutants together in one group cage, and only wildtype littermates together in another group cage after weaning. 16p11.2 deletion presented a particularly good model organism to investigate this question, because the heterozygotes are smaller than their wildtype littermates, and may therefore become subordinate to their larger cagemates.Wildtype and heterozygotes were housed with cagemates of the same genotype (same-genotype cage) or with cagemates of the opposite genotype (mixed-genotype cage). Current results replicated social vocalization and object recognition deficits that we previously found in heterozygotes living in mixed-genotype cages. In contrast, heterozygotes that lived in same-genotype cages emitted normal numbers of vocalizations during male–female interactions, and displayed normal novel object recognition, indicating that the deletion per se was not sufficient to cause cognitive or social deficits. Social approach, same-sex social interaction, anxiety-related behavior, depression-related behavior, and open field exploration were not different between genotypes, and were not affected by housing in mixed versus in same-genotype cages. These findings suggest that elements of the home cage social environment could interact with genotype to impact aspects of disease phenotypes. Current findings are discussed as potentially reflecting behavioral deficits resulted from social stress, as inspired by a seminal paper by Bob and Caroline Blanchard [1]. PMID:26066718

  3. Capturing phenotypes for precision medicine.

    PubMed

    Robinson, Peter N; Mungall, Christopher J; Haendel, Melissa

    2015-10-01

    Deep phenotyping followed by integrated computational analysis of genotype and phenotype is becoming ever more important for many areas of genomic diagnostics and translational research. The overwhelming majority of clinical descriptions in the medical literature are available only as natural language text, meaning that searching, analysis, and integration of medically relevant information in databases such as PubMed is challenging. The new journal Cold Spring Harbor Molecular Case Studies will require authors to select Human Phenotype Ontology terms for research papers that will be displayed alongside the manuscript, thereby providing a foundation for ontology-based indexing and searching of articles that contain descriptions of phenotypic abnormalities-an important step toward improving the ability of researchers and clinicians to get biomedical information that is critical for clinical care or translational research. PMID:27148566

  4. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  5. Urine - abnormal color

    MedlinePlus

    ... straw-yellow. Abnormally colored urine may be cloudy, dark, or blood-colored. Causes Abnormal urine color may ... red blood cells, or mucus in the urine. Dark brown but clear urine is a sign of ...

  6. Is There a Relationship between Restricted, Repetitive, Stereotyped Behaviors and Interests and Abnormal Sensory Response in Children with Autism Spectrum Disorders?

    ERIC Educational Resources Information Center

    Gabriels, Robin L.; Agnew, John A.; Miller, Lucy Jane; Gralla, Jane; Pan, Zhaoxing; Goldson, Edward; Ledbetter, James C.; Dinkins, Juliet P.; Hooks, Elizabeth

    2008-01-01

    This study examined the relation between restricted, repetitive, and stereotyped behaviors and interests (RBs) and sensory responses in a group of 70 children and adolescents diagnosed with an autism spectrum disorder (ASD). Caregivers completed the Repetitive Behavior Scale-Revised (RBS-R) and the Sensory Profile. Controlling for IQ and age,…

  7. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring.

    PubMed

    Choi, Gloria B; Yim, Yeong S; Wong, Helen; Kim, Sangdoo; Kim, Hyunju; Kim, Sangwon V; Hoeffer, Charles A; Littman, Dan R; Huh, Jun R

    2016-02-26

    Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt)-dependent effector T lymphocytes [for example, T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes. PMID:26822608

  8. The maternal interleukin-17a pathway in mice promotes autismlike phenotypes in offspring

    PubMed Central

    Choi, Gloria B.; Yim, Yeong S.; Wong, Helen; Kim, Sangdoo; Kim, Hyunju; Kim, Sangwon V.; Hoeffer, Charles A.; Littman, Dan R.; Huh, Jun R.

    2016-01-01

    Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor–related orphan nuclear receptor γt (RORγt)–dependent effector T lymphocytes [e.g., T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes PMID:26822608

  9. Chronic reparative changes in medium-sized vessels in a case of primary cutaneous anaplastic large-cell lymphoma with angioinvasive features and cytotoxic phenotype: new histopathological findings in line with indolent clinical behavior.

    PubMed

    Macarenco, Ricardo S; de Oliveira, Deilson Elgui

    2015-05-01

    Angioinvasion/angiodestruction has been reported in a small subset of primary cutaneous anaplastic large-cell lymphomas (PCALCL). Recently, PCALCL with angioinvasive features and cytotoxic phenotype has been characterized as a variant associated with good clinical outcomes despite worrisome histopathologic features. We report a case of PCALCL with angioinvasive features and cytotoxic phenotype associated with reparative changes on the wall of medium-sized vessels involved by the neoplasm, including intimal fibroblastic proliferation and luminal obliteration. This vascular pattern, although previously unreported in PCALCL, is in accordance with the indolent behavior observed in this entity and provides a further link with lymphomatoid papulosis type E. PMID:25365499

  10. 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. PMID:24838000

  11. In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice

    PubMed Central

    Sano, Kazuhiro; Isobe, Tomohiko; Yang, Jiaxin; Win-Shwe, Tin-Tin; Yoshikane, Mitsuha; Nakayama, Shoji F.; Kawashima, Takaharu; Suzuki, Go; Hashimoto, Shunji; Nohara, Keiko; Tohyama, Chiharu; Maekawa, Fumihiko

    2016-01-01

    Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically. PMID:27375407

  12. In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice.

    PubMed

    Sano, Kazuhiro; Isobe, Tomohiko; Yang, Jiaxin; Win-Shwe, Tin-Tin; Yoshikane, Mitsuha; Nakayama, Shoji F; Kawashima, Takaharu; Suzuki, Go; Hashimoto, Shunji; Nohara, Keiko; Tohyama, Chiharu; Maekawa, Fumihiko

    2016-01-01

    Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically. PMID:27375407

  13. Abnormal Neural Activation to Faces in the Parents of Children with Autism.

    PubMed

    Yucel, G H; Belger, A; Bizzell, J; Parlier, M; Adolphs, R; Piven, J

    2015-12-01

    Parents of children with an autism spectrum disorder (ASD) show subtle deficits in aspects of social behavior and face processing, which resemble those seen in ASD, referred to as the "Broad Autism Phenotype " (BAP). While abnormal activation in ASD has been reported in several brain structures linked to social cognition, little is known regarding patterns in the BAP. We compared autism parents with control parents with no family history of ASD using 2 well-validated face-processing tasks. Results indicated increased activation in the autism parents to faces in the amygdala (AMY) and the fusiform gyrus (FG), 2 core face-processing regions. Exploratory analyses revealed hyper-activation of lateral occipital cortex (LOC) bilaterally in autism parents with aloof personality ("BAP+"). Findings suggest that abnormalities of the AMY and FG are related to underlying genetic liability for ASD, whereas abnormalities in the LOC and right FG are more specific to behavioral features of the BAP. Results extend our knowledge of neural circuitry underlying abnormal face processing beyond those previously reported in ASD to individuals with shared genetic liability for autism and a subset of genetically related individuals with the BAP. PMID:25056573

  14. Phenotypic variation in LADD syndrome.

    PubMed Central

    Thompson, E; Pembrey, M; Graham, J M

    1985-01-01

    A mother and son are reported with chronic dacrocystitis, cup shaped ears, hearing loss, abnormal teeth, and poor formation of saliva and tears. They are similar to previously reported cases of lacrimo-auriculo-dento-digital (LADD) syndrome. The variability of expression of this autosomal dominant syndrome is discussed, and it is suggested that poor saliva and tear formation be added to the phenotype. Images PMID:4078868

  15. Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia.

    PubMed

    Managò, Francesca; Mereu, Maddalena; Mastwal, Surjeet; Mastrogiacomo, Rosa; Scheggia, Diego; Emanuele, Marco; De Luca, Maria A; Weinberger, Daniel R; Wang, Kuan Hong; Papaleo, Francesco

    2016-08-23

    Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton-associated protein (Arc) complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia. PMID:27524619

  16. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... The appearance of normal teeth varies, especially the molars. ... conditions. Specific diseases can affect tooth shape, tooth ...

  17. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... from many different conditions. Specific diseases can affect tooth shape, tooth color, time of appearance, or absence ...

  18. Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention

    PubMed Central

    Deckersbach, T; Das, S K; Urban, L E; Salinardi, T; Batra, P; Rodman, A M; Arulpragasam, A R; Dougherty, D D; Roberts, S B

    2014-01-01

    Objectives: Obesity is associated with hyperactivation of the reward system for high-calorie (HC) versus low-calorie (LC) food cues, which encourages unhealthy food selection and overeating. However, the extent to which this hyperactivation can be reversed is uncertain, and to date there has been no demonstration of changes by behavioral intervention. Subjects and methods: We used functional magnetic resonance imaging to measure changes in activation of the striatum for food images at baseline and 6 months in a pilot study of 13 overweight or obese adults randomized to a control group or a novel weight-loss intervention. Results: Compared to controls, intervention participants achieved significant weight loss (−6.3±1.0 kg versus +2.1±1.1 kg, P<0.001) and had increased activation for LC food images with a composition consistent with that recommended in the behavioral intervention at 6 months versus baseline in the right ventral putamen (P=0.04), decreased activation for HC images of typically consumed foods in the left dorsal putamen (P=0.01). There was also a large significant shift in relative activation favoring LC versus HC foods in both regions (P<0.04). Conclusions: This study provides the first demonstration of a positive shift in activation of the reward system toward healthy versus unhealthy food cues in a behavioral intervention, suggesting new avenues to enhance behavioral treatments of obesity. PMID:25177910

  19. Abnormal behavior of threshold voltage shift in bias-stressed a-Si:H thin film transistor under extremely high intensity illumination.

    PubMed

    Han, Sang Youn; Park, Kyung Tea; Kim, Cheolkyu; Jeon, Sanghyun; Yang, Sung-Hoon; Kong, Hyang-Shik

    2015-07-22

    We report on the unusual behavior of threshold voltage turnaround in a hydrogenated amorphous silicon (a-Si:H) thin film transistor (TFT) when biased under extremely high intensity illumination. The threshold voltage shift changes from negative to positive gate bias direction after ∼30 min of bias stress even when the negative gate bias stress is applied under high intensity illumination (>400 000 Cd/cm(2)), which has not been observed in low intensity (∼6000 Cd/cm(2)). This behavior is more pronounced in a low work function gate metal structure (Al: 4.1-4.3 eV), compared to the high work function of Cu (4.5-5.1 eV). Also this is mainly observed in shorter wavelength of high photon energy illumination. However, this behavior is effectively prohibited by embedding the high energy band gap (∼8.6 eV) of SiOx in the gate insulator layer. These imply that this behavior could be originated from the injection of electrons from gate electrode, transported and trapped in the electron trap sites of the SiNx/a-Si:H interface, which causes the shift of threshold voltage toward positive gate bias direction. The results reported here can be applicable to the large-sized outdoor displays which are usually exposed to the extremely high intensity illumination. PMID:26132513

  20. Neurological phenotypes for Down syndrome across the life span

    PubMed Central

    Lott, Ira T.

    2012-01-01

    This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations. PMID:22541290

  1. Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test.

    PubMed

    Arrant, A E; Filiano, A J; Warmus, B A; Hall, A M; Roberson, E D

    2016-07-01

    Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), a neurodegenerative disorder in which social behavior is disrupted. Progranulin-insufficient mice, both Grn(+/-) and Grn(-/-) , are used as models of FTD due to GRN mutations, with Grn(+/-) mice mimicking the progranulin haploinsufficiency of FTD patients with GRN mutations. Grn(+/-) mice have increased social dominance in the tube test at 6 months of age, although this phenotype has not been reported in Grn(-/-) mice. In this study, we investigated how the tube test phenotype of progranulin-insufficient mice changes with age, determined its robustness under several testing conditions, and explored the associated cellular mechanisms. We observed biphasic social dominance abnormalities in Grn(+/-) mice: at 6-8 months, Grn(+/-) mice were more dominant than wild-type littermates, while after 9 months of age, Grn(+/-) mice were less dominant. In contrast, Grn(-/-) mice did not exhibit abnormal social dominance, suggesting that progranulin haploinsufficiency has distinct effects from complete progranulin deficiency. The biphasic tube test phenotype of Grn(+/-) mice was associated with abnormal cellular signaling and neuronal morphology in the amygdala and prefrontal cortex. At 6-9 months, Grn(+/-) mice exhibited increased mTORC2/Akt signaling in the amygdala and enhanced dendritic arbors in the basomedial amygdala, and at 9-16 months Grn(+/-) mice exhibited diminished basal dendritic arbors in the prelimbic cortex. These data show a progressive change in tube test dominance in Grn(+/-) mice and highlight potential underlying mechanisms by which progranulin insufficiency may disrupt social behavior. PMID:27213486

  2. A phenotype survey of 36 mutant mouse strains with gene-targeted defects in glycosyltransferases or glycan-binding proteins

    PubMed Central

    Orr, Sally L; Le, Dzung; Long, Jeffrey M; Sobieszczuk, Peter; Ma, Bo; Tian, Hua; Fang, Xiaoqun; Paulson, James C; Marth, Jamey D; Varki, Nissi

    2013-01-01

    The consortium for functional glycomics (CFG) was a large research initiative providing networking and resources for investigators studying the role of glycans and glycan-binding proteins in health and disease. Starting in 2001, six scientific cores were established to generate data, materials and new technologies. By the end of funding in 2011, the mouse phenotype core (MPC) submitted data to a website from the phenotype screen of 36 mutant mouse strains deficient in a gene for either a glycan-binding protein (GBP) or glycosyltransferase (GT). Each mutant strain was allotted three months for analysis and screened by standard phenotype assays used in the fields of immunology, histology, hematology, coagulation, serum chemistry, metabolism and behavior. Twenty of the deficient mouse strains had been studied in other laboratories, and additional tests were performed on these strains to confirm previous observations and discover new data. The CFG constructed 16 new homozygous mutant mouse strains and completed the initial phenotype screen of the majority of these new mutant strains. In total, >300 phenotype changes were observed, but considering the over 100 assays performed on each strain, most of the phenotypes were unchanged. Phenotype differences include abnormal testis morphology in GlcNAcT9- and Siglec-H-deficient mice and lethality in Pomgnt1-deficient mice. The numerous altered phenotypes discovered, along with the consideration of the significant findings of normality, will provide a platform for future characterization to understand the important roles of glycans and GBPs in the mechanisms of health and disease. PMID:23118208

  3. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  4. Repeated stress-induced expression pattern alterations of the hippocampal chloride transporters KCC2 and NKCC1 associated with behavioral abnormalities in female mice.

    PubMed

    Tsukahara, Takao; Masuhara, Masaaki; Iwai, Haruki; Sonomura, Takahiro; Sato, Tomoaki

    2015-09-11

    The balance of cation-chloride co-transporters, particularly KCC2 and NKCC1, is critical for GABAergic inhibitory signaling. However, KCC2/NKCC1 balance is disrupted in many neurodegenerative diseases. Moreover, correlations between chronic stress, KCC2 and NKCC1 in the hippocampus remain poorly understood. Despite the fact that emotional disorders in humans are far more prevalent in women, there have been relatively few studies about female subjects. Here we investigated behaviors and expression patterns of KCC2 and NKCC1 in the hippocampi of female mice under chronic stress. Repeated stress (RS) was induced in experimental mice by repeated forced water administration. Then, expression patterns of GABAergic signaling molecules were identified by immunohistochemical analysis and performance was assessed using several behavioral tests. The results of semi-quantitative analysis showed that RS decreased KCC2 expression and increased NKCC1 expression in membranes of granular and pyramidal cells in the hippocampus. The novel object recognition (NOR) test and sociability test revealed that RS induced cognitive and sociability deficits, whereas RS increased the time spent in the open arms of the elevated plus maze test and induced attention deficits in other tests. In summary, RS induced alterations in membrane KCC2/NKCC1 balance in the hippocampus of female mice, which may contribute to GABAergic disinhibition associated with cognitional, sociability and attention deficits. PMID:26239662

  5. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  6. Abnormal Uterine Bleeding

    MedlinePlus

    ... Abnormal uterine bleeding is any bleeding from the uterus (through your vagina) other than your normal monthly ... or fibroids (small and large growths) in the uterus can also cause bleeding. Rarely, a thyroid problem, ...

  7. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... as cancer of the uterus, cervix, or vagina • Polycystic ovary syndrome How is abnormal bleeding diagnosed? Your health care ... before the fetus can survive outside the uterus. Polycystic Ovary Syndrome: A condition characterized by two of the following ...

  8. 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. PMID:26836322

  9. Intragenic CAMTA1 deletions are associated with a spectrum of neurobehavioral phenotypes.

    PubMed

    Shinawi, M; Coorg, R; Shimony, J S; Grange, D K; Al-Kateb, H

    2015-05-01

    Intragenic copy number variations involving the CAMTA1 (calmodulin-binding transcription activator 1) gene have recently been reported in four unrelated families with intellectual disability (ID), ataxia, behavioral- and cerebellar-abnormalities. We report a detailed phenotypic and molecular characterization of three individuals with novel intragenic CAMTA1 deletions from two unrelated families and compare the findings to those of previously reported patients. Our patients had deletions of exons 6-11 and presented with ID, developmental delay (DD), attention deficit hyperactivity disorder (ADHD) and constipation. Two individuals from one family had also unsteady gait. Consistent phenotypes associated with CAMTA1 intragenic rearrangements include ID, speech problems and some dysmorphic features whereas neurobehavioral abnormalities are variable. We did not observe obvious phenotypic differences between patients with in-frame and those with frameshift rearrangements. There is an increased evidence that CAMTA1 has a role in brain and cerebellar function. CAMTA1 should be added to the growing list of genes associated with ID/DD, especially when behavioral problems, cerebellar signs, and/or dysmorphism are also present. PMID:24738973

  10. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior.

    PubMed

    Baek, Jean-Ha; Schmidt, Eva; Viceconte, Nikenza; Strandgren, Charlotte; Pernold, Karin; Richard, Thibaud J C; Van Leeuwen, Fred W; Dantuma, Nico P; Damberg, Peter; Hultenby, Kjell; Ulfhake, Brun; Mugnaini, Enrico; Rozell, Björn; Eriksson, Maria

    2015-03-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation in brain, skin, bone and heart to investigate how the mutation affects these organs. Ultrastructural analysis of neuronal nuclei after 70 weeks of expression of the LMNA c.1824C>T mutation showed severe distortion with multiple lobulations and irregular extensions. Despite severe distortions in the nuclei of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology. Our results suggest that certain tissues are protected from functional deleterious effects of progerin. PMID:25343989

  11. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior

    PubMed Central

    Baek, Jean-Ha; Schmidt, Eva; Viceconte, Nikenza; Strandgren, Charlotte; Pernold, Karin; Richard, Thibaud J. C.; Van Leeuwen, Fred W.; Dantuma, Nico P.; Damberg, Peter; Hultenby, Kjell; Ulfhake, Brun; Mugnaini, Enrico; Rozell, Björn; Eriksson, Maria

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation in brain, skin, bone and heart to investigate how the mutation affects these organs. Ultrastructural analysis of neuronal nuclei after 70 weeks of expression of the LMNA c.1824C>T mutation showed severe distortion with multiple lobulations and irregular extensions. Despite severe distortions in the nuclei of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology. Our results suggest that certain tissues are protected from functional deleterious effects of progerin. PMID:25343989

  12. Mapping Pathological Phenotypes in Reelin Mutant Mice

    PubMed Central

    Michetti, Caterina; Romano, Emilia; Altabella, Luisa; Caruso, Angela; Castelluccio, Paolo; Bedse, Gaurav; Gaetani, Silvana; Canese, Rossella; Laviola, Giovanni; Scattoni, Maria Luisa

    2014-01-01

    Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with multifactorial origin characterized by social communication deficits and the presence of repetitive behaviors/interests. Several studies showed an association between the reelin gene mutation and increased risk of ASD and a reduced reelin expression in some brain regions of ASD subjects, suggesting a role for reelin deficiency in ASD etiology. Reelin is a large extracellular matrix glycoprotein playing important roles during development of the central nervous system. To deeply investigate the role of reelin dysfunction as vulnerability factor in ASD, we assessed the behavioral, neurochemical, and brain morphological features of reeler male mice. We recently reported a genotype-dependent deviation in the ultrasonic vocal repertoire and a general delay in motor development of reeler pups. We now report that adult male heterozygous (Het) reeler mice did not show social behavior and communication deficits during male–female social interactions. Wildtype and Het mice showed a typical light/dark locomotor activity profile, with a peak during the central interval of the dark phase. However, when faced with a mild stressful stimulus (a saline injection) only Het mice showed an over response to stress. In addition to the behavioral studies, we conducted high performance liquid chromatography and magnetic resonance imaging and spectroscopy to investigate whether reelin mutation influences brain monoamine and metabolites levels in regions involved in ASD. Low levels of dopamine in cortex and high levels of glutamate and taurine in hippocampus were detected in Het mice, in line with clinical data collected on ASD children. Altogether, our data detected subtle but relevant neurochemical abnormalities in reeler mice supporting this mutant line, particularly male subjects, as a valid experimental model to estimate the contribution played by reelin deficiency in the global ASD neurobehavioral phenotype. PMID

  13. PRIMARY CILIARY DYSKINESIA: DIAGNOSTIC AND PHENOTYPIC FEATURES

    EPA Science Inventory

    Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. We hypothesized that the major clinical and biologic phenotypic markers of the disease could be evaluated by studying a cohort of subjects suspected of having PCD. ...

  14. Targeted mutations in the Na,K-ATPase α 2 isoform confer ouabain resistance and result in abnormal behavior in mice.

    PubMed

    Schaefer, Tori L; Lingrel, Jerry B; Moseley, Amy E; Vorhees, Charles V; Williams, Michael T

    2011-06-01

    Sodium and potassium-activated adenosine triphosphatases (Na,K-ATPase) are ubiquitous, participate in osmotic balance and membrane potential, and are composed of α, β, and γ subunits. The α subunit is required for the catalytic and transport properties of the enzyme and contains binding sites for cations, ATP, and digitalis-like compounds including ouabain. There are four known α isoforms; three that are expressed in the CNS in a regional and cell-specific manner. The α2 isoform is most commonly found in astrocytes, pyramidal cells of the hippocampus in adults, and developmentally in several other neuronal types. Ouabain-like compounds are thought to be produced endogenously in mammals, bind the Na,K-ATPase, and function as a stress-related hormone, however, the impact of the Na,K-ATPase ouabain binding site on neurobehavioral function is largely unknown. To determine if the ouabain binding site of the α2 isoform plays a physiological role in CNS function, we examined knock-in mice in which the normally ouabain-sensitive α2 isoform was made resistant (α2(R/R) ) while still retaining basal Na,K-ATPase enzymatic function. Egocentric learning (Cincinnati water maze) was impaired in adult α2(R/R) mice compared to wild type (WT) mice. They also exhibited decreased locomotor activity in a novel environment and increased responsiveness to a challenge with an indirect sympathomimetic agonist (methamphetamine) relative to WT mice. The α2(R/R) mice also demonstrated a blunted acoustic startle reflex and a failure to habituate to repeated acoustic stimuli. The α2(R/R) mice showed no evidence of altered anxiety (elevated zero maze) nor were they impaired in spatial learning or memory in the Morris water maze and neither group could learn in a large Morris maze. These results suggest that the ouabain binding site is involved in specific types of learning and the modulation of dopamine-mediated locomotor behavior. PMID:20936682

  15. Targeted Mutations in the Na,K-ATPase Alpha 2 Isoform Confer Ouabain Resistance and Result in Abnormal Behavior in Mice

    PubMed Central

    Schaefer, Tori L.; Lingrel, Jerry B; Moseley, Amy E.; Vorhees, Charles V.; Williams, Michael T.

    2011-01-01

    Sodium and potassium-activated adenosine triphosphatases (Na,K-ATPase) are ubiquitous, participate in osmotic balance and membrane potential, and are composed of α, β, and γ subunits. The α subunit is required for the catalytic and transport properties of the enzyme and contains binding sites for cations, ATP, and digitalis-like compounds including ouabain. There are four known α isoforms; three that are expressed in the CNS in a regional and cell-specific manner. The α2 isoform is most commonly found in astrocytes, pyramidal cells of the hippocampus in adults, and developmentally in several other neuronal types. Ouabain-like compounds are thought to be produced endogenously in mammals, bind the Na,K-ATPase, and function as a stress-related hormone, however, the impact of the Na,K-ATPase ouabain binding site on neurobehavioral function is largely unknown. To determine if the ouabain binding site of the α2 isoform plays a physiological role in CNS function, we examined knock-in mice in which the normally ouabain-sensitive α2 isoform was made resistant (α2R/R) while still retaining basal Na,K-ATPase enzymatic function. Egocentric learning (Cincinnati water maze) was impaired in adult α2R/R mice compared to wild type (WT) mice. They also exhibited decreased locomotor activity in a novel environment and increased responsiveness to a challenge with an indirect sympathomimetic agonist (methamphetamine) relative to WT mice. The α2R/R mice also demonstrated a blunted acoustic startle reflex and a failure to habituate to repeated acoustic stimuli. The α2R/R mice showed no evidence of altered anxiety (elevated zero maze) nor were they impaired in spatial learning or memory in the Morris water maze and neither group could learn in a large Morris maze. These results suggest that the ouabain binding site is involved in specific types of learning and the modulation of dopamine-mediated locomotor behavior. PMID:20936682

  16. Behavioral Phenotypes and Special Education: Parent Report of Educational Issues for Children with Down Syndrome, Prader-Willi Syndrome, and Williams Syndrome.

    ERIC Educational Resources Information Center

    Fidler, Deborah J.; Hodapp, Robert M.; Dykens, Elizabeth M.

    2002-01-01

    A study examined the degree to which parents are informed about syndrome-based behaviors in children with Down syndrome (n=21), Prader-Willi syndrome (n=25), and Williams syndrome (n=21). Parents were informed about blatant behavioral features, especially maladaptive behaviors, but were less informed about certain subtle syndrome-based cognitive…

  17. Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders.

    PubMed

    Wurzman, Rachel; Forcelli, Patrick A; Griffey, Christopher J; Kromer, Lawrence F

    2015-02-01

    EphA receptors and ephrin-A ligands play important roles in neural development and synaptic plasticity in brain regions where expression persists into adulthood. Recently, EPHA3 and EPHA7 gene mutations were linked with Autism Spectrum Disorders (ASDs) and developmental neurological delays, respectively. Furthermore, deletions of ephrin-A2 or ephrin-A3, which exhibit high binding affinity for EphA3 and EphA7 receptors, are associated with subtle deficits in learning and memory behavior and abnormalities in dendritic spine morphology in the cortex and hippocampus in mice. To better characterize a potential role for these ligands in ASDs, we performed a comprehensive behavioral characterization of anxiety-like, sensorimotor, learning, and social behaviors in ephrin-A2/-A3 double knockout (DKO) mice. The predominant phenotype in DKO mice was repetitive and self-injurious grooming behaviors such as have been associated with corticostriatal circuit abnormalities in other rodent models of neuropsychiatric disorders. Consistent with ASDs specifically, DKO mice exhibited decreased preference for social interaction in the social approach assay, decreased locomotor activity in the open field, increased prepulse inhibition of acoustic startle, and a shift towards self-directed activity (e.g., grooming) in novel environments, such as marble burying. Although there were no gross deficits in cognitive assays, subtle differences in performance on fear conditioning and in the Morris water maze resembled traits observed in other rodent models of ASD. We therefore conclude that ephrin-A2/-A3 DKO mice have utility as a novel ASD model with an emphasis on sensory abnormalities and restricted, repetitive behavioral symptoms. PMID:25281279

  18. Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders

    PubMed Central

    Wurzman, Rachel; Forcelli, Patrick A.; Griffey, Christopher J.; Kromer, Lawrence F.

    2014-01-01

    EphA receptors and ephrin-A ligands play important roles in neural development and synaptic plasticity in brain regions where expression persists into adulthood. Recently, EPHA3 and EPHA7 gene mutations were linked with Autism Spectrum Disorders (ASDs) and developmental neurological delays, respectively. Furthermore, deletions of ephrin-A2 or ephrin-A3, which exhibit high binding affinity for EphA3 and EphA7 receptors, are associated with subtle deficits in learning and memory behavior and abnormalities in dendritic spine morphology in the cortex and hippocampus in mice. To better characterize a potential role for these ligands in ASDs, we performed a comprehensive behavioral characterization of anxiety-like, sensorimotor, learning, and social behaviors in ephrin-A2/-A3 double knockout (DKO) mice. The predominant phenotype in DKO mice was repetitive and self-injurious grooming behaviors such as have been associated with corticostriatal circuit abnormalities in other rodent models of neuropsychiatric disorders. Consistent with ASDs specifically, DKO mice exhibited decreased preference for social interaction in the social approach assay, decreased locomotor activity in the open field, increased prepulse inhibition of acoustic startle, and a shift towards self-directed activity (e.g., grooming) in novel environments, such as marble burying. Although there were no gross deficits in cognitive assays, subtle differences in performance on fear conditioning and in the Morris water maze resembled traits observed in other rodent models of ASD. We therefore conclude that ephrin-A2/-A3 DKO mice have utility as a novel ASD model with an emphasis on sensory abnormalities and restricted, repetitive behavioral symptoms. PMID:25281279

  19. Copy number variants (CNVs) analysis in a deeply phenotyped cohort of individuals with intellectual disability (ID)

    PubMed Central

    2014-01-01

    Background DNA copy number variants (CNVs) are found in 15% of subjects with ID but their association with phenotypic abnormalities has been predominantly studied in smaller cohorts of subjects with detailed yet non-systematically categorized phenotypes, or larger cohorts (thousands of cases) with smaller number of generalized phenotypes. Methods We evaluated the association of de novo, familial and common CNVs detected in 78 ID subjects with phenotypic abnormalities classified using the Winter-Baraitser Dysmorphology Database (WBDD) (formerly the London Dysmorphology Database). Terminology for 34 primary (coarse) and 169 secondary (fine) phenotype features were used to categorize the abnormal phenotypes and determine the prevalence of each phenotype in patients grouped by the type of CNV they had. Results In our cohort more than 50% of cases had abnormalities in primary categories related to head (cranium, forehead, ears, eye globes, eye associated structures, nose) as well as hands and feet. The median number of primary and secondary abnormalities was 12 and 18 per subject, respectively, indicating that the cohort consisted of subjects with a high number of phenotypic abnormalities (median De Vries score for the cohort was 5). The prevalence of each phenotypic abnormality was comparable in patients with de novo or familial CNVs in comparison to those with only common CNVs, although a trend for increased frequency of cranial and forehead abnormalities was noted in subjects with rare de novo and familial CNVs. Two clusters of subjects were identified based on the prevalence of each fine phenotypic feature, with an average of 28.3 and 13.5 abnormal phenotypes/subject in the two clusters respectively (P < 0.05). Conclusions Our study is a rare example of using standardized, deep morphologic phenotype clustering with phenotype/CNV correlation in a cohort of subjects with ID. The composition of the cohort inevitably influences the phenotype/genotype association

  20. The XXXXY Sex Chromosome Abnormality

    PubMed Central

    Barr, M. L.; Carr, D. H.; Pozsonyi, J.; Wilson, R. A.; Dunn, H. G.; Jacobson, T. S.; Miller, J. R.; Chown, B.

    1962-01-01

    The most common sex chromosome complex in sex chromatin-positive males with Klinefelter's syndrome is XXY. When the complex is XXYY or XXXY, the clinical findings do not seem to differ materially from those seen in XXY subjects, although more patients with these intersexual chromosome complements need to be studied to establish possible phenotypical expressions of the chromosomal variants. Two male children with an XXXXY sex chromosome abnormality are described. The data obtained from the study of these cases and five others described in the literature suggest that the XXXXY patient is likely to have congenital defects not usually seen in the common form of the Klinefelter syndrome. These include a triad of (1) skeletal anomalies (including radioulnar synostosis), (2) hypogenitalism (hypoplasia of penis and scrotum, incomplete descent of testes and defective prepubertal development of seminiferous tubules), and (3) greater risk of severe mental deficiency. That the conclusions are based on data from a small number of patients is emphasized, together with the need for a cytogenetic survey of a large control or unselected population. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10 PMID:13969480

  1. Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

    PubMed Central

    Jacobs, A

    1985-01-01

    The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities. PMID:2999194

  2. Autistic Traits and Abnormal Sensory Experiences in Adults

    ERIC Educational Resources Information Center

    Horder, Jamie; Wilson, C. Ellie; Mendez, M. Andreina; Murphy, Declan G.

    2014-01-01

    Sensory processing abnormalities are common in autism spectrum disorders (ASD), and now form part of the "Diagnostic and Statistical Manual 5th Edition" (DSM-5) diagnostic criteria, but it is unclear whether they characterize the "broader phenotype" of the disorder. We recruited adults (n = 772) with and without an ASD and…

  3. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.

    PubMed

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Israelyan, Narek; Anderson, George M; Snyder, Isaac; Veenstra-VanderWeele, Jeremy; Blakely, Randy D; Gershon, Michael D

    2016-06-01

    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

  4. 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

  5. Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation

    PubMed Central

    Kato, Kumiko; Aguirre-Hernández, Jesús; Tokuriki, Tsuyoshi; Morimoto, Kyohei; Busse, Claudia; Barnett, Keith; Holmes, Nigel; Ogawa, Hiroyuki; Sasaki, Nobuo; Mellersh, Cathryn S.; Sargan, David R.

    2009-01-01

    Purpose Previously, a 44 bp insertion in exon 2 of retinitis pigmentosa GTPase interacting protein 1 (RPGRIP1) was identified as the cause of cone-rod dystrophy 1 (cord1), a recessive form of progressive retinal atrophy (PRA) in the Miniature Longhaired Dachshund (MLHD), a dog model for Leber congenital amaurosis. The cord1 locus was mapped using MLHDs from an inbred colony with a homogeneous early onset disease phenotype. In this paper, the MLHD pet population was studied to investigate phenotypic variation and genotype-phenotype correlation. Further, the cord1 locus was fine-mapped using PRA cases from the MLHD pet population to narrow the critical region. Other dog breeds were also screened for the RGPRIP1 insertion. Methods This study examined phenotypic variation in an MLHD pet population that included 59 sporadic PRA cases and 18 members of an extended family with shared environment and having six PRA cases. Ophthalmologic evaluations included behavioral abnormalities, responses to menace and light, fundoscopy, and electroretinography (ERG). The RPGRIP1 insertion was screened for in all cases and 200 apparently normal control MLHDs and in 510 dogs from 66 other breed. To fine-map the cord1 locus in the MLHD, 74 PRA cases and 86 controls aged 4 years or more were genotyped for 24 polymorphic markers within the previously mapped cord1 critical region of 14.15 Mb. Results Among sporadic PRA cases from the MLHD pet population, the age of onset varied from 4 months to 15 years old; MLHDs from the extended family also showed variable onset and rate of progression. Screening for the insertion in RPGRIP1 identified substantial genotype-phenotype discordance: 16% of controls were homozygous for the insertion (RPGRIP1−/−), while 20% of PRA cases were not homozygous for it. Four other breeds were identified to carry the insertion including English Springer Spaniels and Beagles with insertion homozygotes. The former breed included both controls and PRA cases, yet in

  6. A Case of ADHD and a Major Y Chromosome Abnormality

    ERIC Educational Resources Information Center

    Mulligan, Aisling; Gill, Michael; Fitzgerald, Michael

    2008-01-01

    Background: ADHD is a common, heritable disorder of childhood. Sex chromosome abnormalities are relatively rare conditions that are sometimes associated with behavioral disorders. Method: The authors present a male child with ADHD and a major de-novo Y chromosome abnormality consisting of deletion of the long arm and duplication of the short arm.…

  7. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed. PMID:25903257

  8. Chromosome abnormalities in glioma

    SciTech Connect

    Li, Y.S.; Ramsay, D.A.; Fan, Y.S.

    1994-09-01

    Cytogenetic studies were performed in 25 patients with gliomas. An interesting finding was a seemingly identical abnormality, an extra band on the tip of the short arm of chromosome 1, add(1)(p36), in two cases. The abnormality was present in all cells from a patient with a glioblastoma and in 27% of the tumor cells from a patient with a recurrent irradiated anaplastic astrocytoma; in the latter case, 7 unrelated abnormal clones were identified except 4 of those clones shared a common change, -Y. Three similar cases have been described previously. In a patient with pleomorphic astrocytoma, the band 1q42 in both homologues of chromosome 1 was involved in two different rearrangements. A review of the literature revealed that deletion of the long arm of chromosome 1 including 1q42 often occurs in glioma. This may indicate a possible tumor suppressor gene in this region. Cytogenetic follow-up studies were carried out in two patients and emergence of unrelated clones were noted in both. A total of 124 clonal breakpoints were identified in the 25 patients. The breakpoints which occurred three times or more were: 1p36, 1p22, 1q21, 1q25, 3q21, 7q32, 8q22, 9q22, 16q22, and 22q13.

  9. [Congenital foot abnormalities].

    PubMed

    Delpont, M; Lafosse, T; Bachy, M; Mary, P; Alves, A; Vialle, R

    2015-03-01

    The foot may be the site of birth defects. These abnormalities are sometimes suspected prenatally. Final diagnosis depends on clinical examination at birth. These deformations can be simple malpositions: metatarsus adductus, talipes calcaneovalgus and pes supinatus. The prognosis is excellent spontaneously or with a simple orthopedic treatment. Surgery remains outstanding. The use of a pediatric orthopedist will be considered if malposition does not relax after several weeks. Malformations (clubfoot, vertical talus and skew foot) require specialized care early. Clubfoot is characterized by an equine and varus hindfoot, an adducted and supine forefoot, not reducible. Vertical talus combines equine hindfoot and dorsiflexion of the forefoot, which is performed in the midfoot instead of the ankle. Skew foot is suspected when a metatarsus adductus is resistant to conservative treatment. Early treatment is primarily orthopedic at birth. Surgical treatment begins to be considered after walking age. Keep in mind that an abnormality of the foot may be associated with other conditions: malposition with congenital hip, malformations with syndromes, neurological and genetic abnormalities. PMID:25524290

  10. Complex motivated behaviors for natural rewards following a binge-like regimen of morphine administration: mixed phenotypes of anhedonia and craving after short-term withdrawal

    PubMed Central

    Bai, Yunjing; Li, Yingying; Lv, Yaodi; Liu, Zhengkui; Zheng, Xigeng

    2014-01-01

    The anhedonia-like behaviors following about 1-week withdrawal from morphine were examined in the present study. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. Three types of natural reward were used, food reward (2.5, 4, 15, 30, 40, and 60% sucrose solutions), social reward (male rat) and sexual reward (estrous female rat). For each type of natural stimulus, consummatory behavior and motivational behaviors under varied testing conditions were investigated. The results showed that the morphine-treated rats significantly reduced their consumption of 2.5% sucrose solution during the 1-h consumption testing and their operant responding for 15, 30, and 40% sucrose solutions under a fixed ratio 1 (FR1) schedule. However, performance under a progressive ratio (PR) schedule increased in morphine-treated rats reinforced with 60% sucrose solution, but not in those reinforced with sucrose concentrations lower than 60%. Pretreatment with morphine significantly decreased the male rats' ejaculation frequency (EF) during the 1-h copulation testing, and impaired the maintenance of appetitive motivations to sexual and social stimuli under a free-approach condition. Moreover, the morphine-treated rats demonstrated a diminished motivation to approach social stimulus in the effort-based appetitive behavior test but showed a remarkable increase in motivation to approach sexual stimulus in the risky appetitive behavior test. These results demonstrated some complex motivated behaviors following about 1 week of morphine withdrawal: (1) The anhedonia-like behavior was consistently found in animals withdrawn from morphine. However, for a given reward, there was often a dissociation of the consummatory behaviors from the motivational behaviors, and whether the consummatory or the motivational anhedonia-like behaviors could be discovered heavily depended on the type and magnitude of the reward and the type of testing task; (2) These

  11. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  12. A vestibular phenotype for Waardenburg syndrome?

    NASA Technical Reports Server (NTRS)

    Black, F. O.; Pesznecker, S. C.; Allen, K.; Gianna, C.

    2001-01-01

    OBJECTIVE: To investigate vestibular abnormalities in subjects with Waardenburg syndrome. STUDY DESIGN: Retrospective record review. SETTING: Tertiary referral neurotology clinic. SUBJECTS: Twenty-two adult white subjects with clinical diagnosis of Waardenburg syndrome (10 type I and 12 type II). INTERVENTIONS: Evaluation for Waardenburg phenotype, history of vestibular and auditory symptoms, tests of vestibular and auditory function. MAIN OUTCOME MEASURES: Results of phenotyping, results of vestibular and auditory symptom review (history), results of vestibular and auditory function testing. RESULTS: Seventeen subjects were women, and 5 were men. Their ages ranged from 21 to 58 years (mean, 38 years). Sixteen of the 22 subjects sought treatment for vertigo, dizziness, or imbalance. For subjects with vestibular symptoms, the results of vestibuloocular tests (calorics, vestibular autorotation, and/or pseudorandom rotation) were abnormal in 77%, and the results of vestibulospinal function tests (computerized dynamic posturography, EquiTest) were abnormal in 57%, but there were no specific patterns of abnormality. Six had objective sensorineural hearing loss. Thirteen had an elevated summating/action potential (>0.40) on electrocochleography. All subjects except those with severe hearing loss (n = 3) had normal auditory brainstem response results. CONCLUSION: Patients with Waardenburg syndrome may experience primarily vestibular symptoms without hearing loss. Electrocochleography and vestibular function tests appear to be the most sensitive measures of otologic abnormalities in such patients.

  13. An Introduction to Ethological Approaches With Abnormal Populations.

    ERIC Educational Resources Information Center

    Zabel, Robert H.; Zabel, Mary Kay

    The paper presents an overview of an ethological approach to the study of abnormal human behavior and a review of research using ethological approaches (with an emphasis on autism research). Ethology is defined as the study of behavior as it occurs in its natural habitat. The four types of questions ethologists ask about behavior, such as what is…

  14. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  15. Hippocampal Y2 receptor-mediated mossy fiber plasticity is implicated in nicotine abstinence-related social anxiety-like behavior in an outbred rat model of the novelty-seeking phenotype

    PubMed Central

    Aydin, Cigdem; Oztan, Ozge; Isgor, Ceylan

    2014-01-01

    Experimentally naïve outbred rats display varying rates of locomotor reactivity in response to the mild stress of a novel environment. Namely, some display high rates (HR) whereas some display low rates (LR) of locomotor reactivity. Previous reports from our laboratory show that HRs, but not LRs, develop locomotor sensitization to a low dose nicotine challenge and exhibit increased social anxiety-like behavior following chronic intermittent nicotine training. Moreover, the hippocampus, specifically hippocampal Y2 receptor (Y2R)-mediated neuropeptide Y signaling is implicated in these nicotine-induced behavioral effects observed in HRs. The present study examines the structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR hippocampi. Our data showed that the expression of locomotor sensitization to the low dose nicotine challenge and the increase in social anxiety-like behavior were accompanied by an increase in mossy fiber terminal field size, as well as an increase in spinophilin mRNA levels in the hippocampus in nicotine pre-trained HRs compared to saline pre-trained controls. Furthermore, a novel, selective Y2R antagonist administered systemically during 1 wk of abstinence reversed the behavioral, molecular and neuromorphological effects observed in nicotine-exposed HRs. These results suggest that nicotine-induced neuroplasticity within the hippocampus may regulate abstinence-related negative affect in HRs, and implicate hippocampal Y2R in vulnerability to the behavioral and neuroplastic effects of nicotine in the novelty-seeking phenotype. PMID:25158103

  16. Hippocampal Y2 receptor-mediated mossy fiber plasticity is implicated in nicotine abstinence-related social anxiety-like behavior in an outbred rat model of the novelty-seeking phenotype.

    PubMed

    Aydin, Cigdem; Oztan, Ozge; Isgor, Ceylan

    2014-10-01

    Experimentally naïve outbred rats display varying rates of locomotor reactivity in response to the mild stress of a novel environment. Namely, some display high rates (HR) whereas some display low rates (LR) of locomotor reactivity. Previous reports from our laboratory show that HRs, but not LRs, develop locomotor sensitization to a low dose nicotine challenge and exhibit increased social anxiety-like behavior following chronic intermittent nicotine training. Moreover, the hippocampus, specifically hippocampal Y2 receptor (Y2R)-mediated neuropeptide Y signaling is implicated in these nicotine-induced behavioral effects observed in HRs. The present study examines the structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR hippocampi. Our data showed that the expression of locomotor sensitization to the low dose nicotine challenge and the increase in social anxiety-like behavior were accompanied by an increase in mossy fiber terminal field size, as well as an increase in spinophilin mRNA levels in the hippocampus in nicotine pre-trained HRs compared to saline pre-trained controls. Furthermore, a novel, selective Y2R antagonist administered systemically during 1 wk of abstinence reversed the behavioral, molecular and neuromorphological effects observed in nicotine-exposed HRs. These results suggest that nicotine-induced neuroplasticity within the hippocampus may regulate abstinence-related negative affect in HRs, and implicate hippocampal Y2R in vulnerability to the behavioral and neuroplastic effects of nicotine in the novelty-seeking phenotype. PMID:25158103

  17. Abnormalities in Hippocampal Functioning with Persistent Pain

    PubMed Central

    Mutso, Amelia A.; Radzicki, Daniel; Baliki, Marwan N.; Huang, Lejian; Banisadr, Ghazal; Centeno, Maria Virginia; Radulovic, Jelena; Martina, Marco; Miller, Richard J.; Apkarian, A. Vania

    2012-01-01

    Chronic pain patients exhibit increased anxiety, depression, and deficits in learning and memory. Yet how persistent pain affects the key brain area regulating these behaviors, the hippocampus, has remained minimally explored. In this study we investigated the impact of spared nerve injury (SNI) neuropathic pain in mice on hippocampal-dependent behavior and underlying cellular and molecular changes. In parallel, we measured the hippocampal volume of three groups of chronic pain patients. We found that SNI animals were unable to extinguish to contextual fear and showed increased anxiety-like behavior. Additionally, SNI mice in comparison to sham animals exhibited hippocampal 1) reduced extracellular signal-regulated kinase (ERK) expression and phosphorylation, 2) decreased neurogenesis and 3) altered short-term synaptic plasticity. In order to relate the observed hippocampal abnormalities with human chronic pain, we measured the volume of human hippocampus in chronic back pain (CBP), complex regional pain syndrome (CRPS), and osteoarthritis patients (OA). Compared to controls, CBP and CRPS, but not OA, had significantly less bilateral hippocampal volume. These results indicate that hippocampus-mediated behavior, synaptic plasticity and neurogenesis are abnormal in neuropathic rodents. The changes may be related to the reduction in hippocampal volume we see in chronic pain patients, and these abnormalities may underlie learning and emotional deficits commonly observed in such patients. PMID:22539837

  18. Cornelia de Lange syndrome: Correlation of brain MRI findings with behavioral assessment.

    PubMed

    Roshan Lal, Tamanna R; Kliewer, Mark A; Lopes, Thelma; Rebsamen, Susan L; O'Connor, Julia; Grados, Marco A; Kimball, Amy; Clemens, Julia; Kline, Antonie D

    2016-06-01

    Neurobehavioral and developmental issues with a broad range of deficits are prominent features of Cornelia de Lange syndrome (CdLS), a disorder due to disruption of the cohesin protein complex. The etiologic relationship of these clinical findings to anatomic abnormalities on neuro-imaging studies has not, however, been established. Anatomic abnormalities in the brain and central nervous system specific to CdLS have been observed, including changes in the white matter, brainstem, and cerebellum. We hypothesize that location and severity of brain abnormalities correlate with clinical phenotype in CdLS, as seen in other developmental disorders. In this study, we retrospectively evaluated brain MRI studies of 15 individuals with CdLS and compared these findings to behavior at the time of the scan. Behavior was assessed using the Aberrant Behavior Checklist (ABC), a validated behavioral assessment tool with several clinical features. Ten of fifteen (67%) of CdLS patients had abnormal findings on brain MRI, including cerebral atrophy, white matter changes, cerebellar hypoplasia, and enlarged ventricles. Other findings included pituitary tumors or cysts, Chiari I malformation and gliosis. Abnormal behavioral scores in more than one behavioral area were seen in all but one patient. All 5 of the 15 (33%) patients with normal structural MRI studies had abnormal ABC scores. All normal ABC scores were noted in only one patient and this was correlated with moderately abnormal MRI changes. Although our cohort is small, our results suggest that abnormal behaviors can exist in individuals with CdLS in the setting of relatively normal structural brain findings. © 2016 Wiley Periodicals, Inc. PMID:27164360

  19. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  20. Characterization of the Statistical Signatures of Micro-Movements Underlying Natural Gait Patterns in Children with Phelan McDermid Syndrome: Towards Precision-Phenotyping of Behavior in ASD

    PubMed Central

    Torres, Elizabeth B.; Nguyen, Jillian; Mistry, Sejal; Whyatt, Caroline; Kalampratsidou, Vilelmini; Kolevzon, Alexander

    2016-01-01

    Background: There is a critical need for precision phenotyping across neurodevelopmental disorders, especially in individuals who receive a clinical diagnosis of autism spectrum disorder (ASD). Phelan-McDermid deletion syndrome (PMS) is one such example, as it has a high penetrance of ASD. At present, no biometric characterization of the behavioral phenotype within PMS exists. Methods: We introduce a data-type and statistical framework that permits the personalized profiling of naturalistic behaviors. Walking patterns were assessed in 30 participants (16 PMS, 3 idiopathic-ASD and 11 age- and sex-matched controls). Each individual's micro-movement signatures were recorded at 240 Hz. We empirically estimated the parameters of the continuous Gamma family of probability distributions and calculated their ranges. These estimated stochastic signatures were then mapped on the Gamma plane to obtain several statistical indexes for each child. To help visualize complex patterns across the cohort, we introduce new tools that enable the assessment of connectivity and modularity indexes across the peripheral network of rotational joints. Results: Typical walking signatures are absent in all children with PMS as well as in the children with idiopathic-ASD (iASD). Underlying these patterns are atypical leg rotational acceleration signatures that render participants with PMS unstable with rotations that are much faster than controls. The median values of the estimated Gamma parameters serve as a cutoff to automatically separate children with PMS 5–7 years old from adolescents with PMS 12–16 years old, the former displaying more randomness and larger noise. The fluctuations in the arm's motions during the walking also have atypical statistics that separate males from females in PMS and show higher rates of noise accumulation in idiopathic ASD (iASD) children. Despite high heterogeneity, all iASD children have excess noise, a narrow range of probability-distribution shapes

  1. Abnormal Magnetic Field Effects on Electrogenerated Chemiluminescence

    NASA Astrophysics Data System (ADS)

    Pan, Haiping; Shen, Yan; Wang, Hongfeng; He, Lei; Hu, Bin

    2015-03-01

    We report abnormal magnetic field effects on electrogenerated chemiluminescence (MFEECL) based on triplet emission from the Ru(bpy)3Cl2-TPrA electrochemical system: the appearance of MFEECL after magnetic field ceases. In early studies the normal MFEECL have been observed from electrochemical systems during the application of magnetic field. Here, the abnormal MFEECL suggest that the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes may become magnetized in magnetic field and experience a long magnetic relaxation after removing magnetic field. Our analysis indicates that the magnetic relaxation can gradually increase the density of charge-transfer complexes within reaction region due to decayed magnetic interactions, leading to a positive component in the abnormal MFEECL. On the other hand, the magnetic relaxation facilitates an inverse conversion from triplets to singlets within charge-transfer complexes. The inverse triplet --> singlet conversion reduces the density of triplet light-emitting states through charge-transfer complexes and gives rise to a negative component in the abnormal MFEECL. The combination of positive and negative components can essentially lead to a non-monotonic profile in the abnormal MFEECL after ceasing magnetic field. Nevertheless, our experimental studies may reveal un-usual magnetic behaviors with long magnetic relaxation from the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes in solution at room temperature.

  2. Abnormal magnetic field effects on electrogenerated chemiluminescence.

    PubMed

    Pan, Haiping; Shen, Yan; Wang, Hongfeng; He, Lei; Hu, Bin

    2015-01-01

    We report abnormal magnetic field effects on electrogenerated chemiluminescence (MFEECL) based on triplet emission from the Ru(bpy)3Cl2-TPrA electrochemical system: the appearance of MFEECL after magnetic field ceases. In early studies the normal MFEECL have been observed from electrochemical systems during the application of magnetic field. Here, the abnormal MFEECL suggest that the activated charge-transfer [Ru(bpy)3(3+) … TPrA(•)] complexes may become magnetized in magnetic field and experience a long magnetic relaxation after removing magnetic field. Our analysis indicates that the magnetic relaxation can gradually increase the density of charge-transfer complexes within reaction region due to decayed magnetic interactions, leading to a positive component in the abnormal MFEECL. On the other hand, the magnetic relaxation facilitates an inverse conversion from triplets to singlets within charge-transfer complexes. The inverse triplet → singlet conversion reduces the density of triplet light-emitting states through charge-transfer complexes and gives rise to a negative component in the abnormal MFEECL. The combination of positive and negative components can essentially lead to a non-monotonic profile in the abnormal MFEECL after ceasing magnetic field. Nevertheless, our experimental studies may reveal un-usual magnetic behaviors with long magnetic relaxation from the activated charge-transfer [Ru(bpy)3(3+) … TPrA(•)] complexes in solution at room temperature. PMID:25772580

  3. Abnormal Magnetic Field Effects on Electrogenerated Chemiluminescence

    PubMed Central

    Pan, Haiping; Shen, Yan; Wang, Hongfeng; He, Lei; Hu, Bin

    2015-01-01

    We report abnormal magnetic field effects on electrogenerated chemiluminescence (MFEECL) based on triplet emission from the Ru(bpy)3Cl2-TPrA electrochemical system: the appearance of MFEECL after magnetic field ceases. In early studies the normal MFEECL have been observed from electrochemical systems during the application of magnetic field. Here, the abnormal MFEECL suggest that the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes may become magnetized in magnetic field and experience a long magnetic relaxation after removing magnetic field. Our analysis indicates that the magnetic relaxation can gradually increase the density of charge-transfer complexes within reaction region due to decayed magnetic interactions, leading to a positive component in the abnormal MFEECL. On the other hand, the magnetic relaxation facilitates an inverse conversion from triplets to singlets within charge-transfer complexes. The inverse triplet → singlet conversion reduces the density of triplet light-emitting states through charge-transfer complexes and gives rise to a negative component in the abnormal MFEECL. The combination of positive and negative components can essentially lead to a non-monotonic profile in the abnormal MFEECL after ceasing magnetic field. Nevertheless, our experimental studies may reveal un-usual magnetic behaviors with long magnetic relaxation from the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes in solution at room temperature. PMID:25772580

  4. Phenotypic deconstruction of gene circuitry

    NASA Astrophysics Data System (ADS)

    Lomnitz, Jason G.; Savageau, Michael A.

    2013-06-01

    It remains a challenge to obtain a global perspective on the behavioral repertoire of complex nonlinear gene circuits. In this paper, we describe a method for deconstructing complex systems into nonlinear sub-systems, based on mathematically defined phenotypes, which are then represented within a system design space that allows the repertoire of qualitatively distinct phenotypes of the complex system to be identified, enumerated, and analyzed. This method efficiently characterizes large regions of system design space and quickly generates alternative hypotheses for experimental testing. We describe the motivation and strategy in general terms, illustrate its use with a detailed example involving a two-gene circuit with a rich repertoire of dynamic behavior, and discuss experimental means of navigating the system design space.

  5. Parsing abnormal grain growth in specialty aluminas

    NASA Astrophysics Data System (ADS)

    Lawrence, Abigail Kremer

    Grain growth in alumina is strongly affected by the impurities present in the material. Certain impurity elements are known to have characteristic effects on abnormal grain growth in alumina. Specialty alumina powders contain multiple impurity species including MgO, CaO, SiO2, and Na 2O. In this work, sintered samples made from alumina powders containing various amounts of the impurities in question were characterized by their grain size and aspect ratio distributions. Multiple quantitative methods were used to characterize and classify samples with varying microstructures. The grain size distributions were used to partition the grain size population into subpopulations depending on the observed deviation from normal behavior. Using both grain size and aspect ratio a new visual representation for a microstructure was introduced called a morphology frequency map that gives a fingerprint for the material. The number of subpopulations within a sample and the shape of the distribution on the morphology map provided the basis for a classification scheme for different types of microstructures. Also using the two parameters a series of five metrics were calculated that describe the character of the abnormal grains in the sample, these were called abnormal character values. The abnormal character values describe the fraction of grains that are considered abnormal, the average magnitude of abnormality (including both grain size and aspect ratio), the average size, and variance in size. The final metric is the correlation between grain size and aspect ratio for the entire population of grains. The abnormal character values give a sense of how different from "normal" the sample is, given the assumption that a normal sample has a lognormal distribution of grain size and a Gaussian distribution of aspect ratios. In the second part of the work the quantified measures of abnormality were correlated with processing parameters such as composition and heat treatment conditions. A

  6. Spirometric abnormalities among welders

    SciTech Connect

    Rastogi, S.K.; Gupta, B.N.; Husain, T.; Mathur, N.; Srivastava, S. )

    1991-10-01

    A group of manual welders age group 13-60 years having a mean exposure period of 12.4 {plus minus} 1.12 years were subjected to spirometry to evaluate the prevalence of spirometric abnormalities. The welders showed a significantly higher prevalence of respiratory impairment than that observed among the unexposed controls as a result of exposure to welding gases which comprised fine particles of lead, zinc, chromium, and manganese. This occurred despite the lower concentration of the pollutants at the work place. In the expose group, the smoking welders showed a prevalence of respiratory impairment significantly higher than that observed in the nonsmoking welders. The results of the pulmonary function tests showed a predominantly restrictive type of pulmonary impairment followed by a mixed ventilatory defect among the welders. The effect of age on pulmonary impairment was not discernible. Welders exposed for over 10 years showed a prevalence of respiratory abnormalities significantly higher than those exposed for less than 10 years. Smoking also had a contributory role.

  7. The high-throughput phenotyping of the viscoelastic behavior of whole mouse intervertebral discs using a novel method of dynamic mechanical testing.

    PubMed

    Liu, Jennifer W; Abraham, Adam C; Tang, Simon Y

    2015-07-16

    Intervertebral disc (IVD) degeneration is highly correlated with lower back pain, and thus understanding the mechanisms of IVD degeneration is critical for the treatment of this disease. Utilizing mouse models to probe the mechanisms of degeneration is especially attractive due to the ease of manipulating mouse models and the availability of transgenics. Yet characterizing the mechanical behavior of mice IVDs remain challenging due to their minute size (approximately 540 μm in height and 1080 μm(2) in cross sectional area). We have thus developed a simple method to dynamically characterize the mechanical properties of intact mouse IVDs. The IVDs were dissected with the endplates intact, and dynamically compressed in the axial direction at 1% and 5% peak strains at 1 Hz. Utilizing this novel approach, we examined the effects of in vitro ribosylation and trypsin digestion for 24 or 72 h on the viscoelastic behavior of the whole murine IVD. Trypsin treatment resulted in a decrease of proteoglycans and loss of disc height, while ribosylation had no effect on structure or proteoglycan composition. The 72 h ribosylation group exhibited a stiffening of the disc, and both treatments significantly reduced viscous behavior of the IVDs, with the effects being more pronounced at 5% strain. Here we demonstrate a novel high-throughput method to mechanically characterize murine IVDs and detect strain-dependent differences in the elastic and the viscous behavior of the treated IVDs due to ribose and trypsin treatments. PMID:26004435

  8. Recurrent duplications of 17q12 associated with variable phenotypes.

    PubMed

    Mitchell, Elyse; Douglas, Andrew; Kjaegaard, Susanne; Callewaert, Bert; Vanlander, Arnaud; Janssens, Sandra; Yuen, Amy Lawson; Skinner, Cindy; Failla, Pinella; Alberti, Antonino; Avola, Emanuela; Fichera, Marco; Kibaek, Maria; Digilio, Maria C; Hannibal, Mark C; den Hollander, Nicolette S; Bizzarri, Veronica; Renieri, Alessandra; Mencarelli, Maria Antonietta; Fitzgerald, Tomas; Piazzolla, Serena; van Oudenhove, Elke; Romano, Corrado; Schwartz, Charles; Eichler, Evan E; Slavotinek, Anne; Escobar, Luis; Rajan, Diana; Crolla, John; Carter, Nigel; Hodge, Jennelle C; Mefford, Heather C

    2015-12-01

    The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi-institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability. PMID:26420380

  9. Chromosomal abnormalities in a psychiatric population

    SciTech Connect

    Lewis, K.E.; Lubetsky, M.J.; Wenger, S.L.; Steele, M.W.

    1995-02-27

    Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance. 5 refs., 1 fig., 2 tabs.

  10. Phenotypic differences on the outcome of the host-parasite relationship: behavior of mice of the CBi stock in natural and experimental infections.

    PubMed

    Vasconi, M D; Malfante, P; Bassi, A; Giudici, C; Revelli, S; Di Masso, R; Font, M T; Hinrichsen, L

    2008-05-01

    Investigation of defined animal models may help to elucidate the role of the host genetic background in the development and establishment of a parasitic infection. Four lines of mice obtained by disruptive selection for body conformation (CBi+, CBi-, CBi/C and CBi/L) and the unselected control line CBi were examined in their response to different parasites to assess whether these distinct genotypes showed differences in their resistance to natural and experimental parasitosis. Protozoans (Trichomonas muris and Spironucleus muris) and nemathelminths (Syphacia obvelata and Aspiculurus tetraptera) were found naturally parasitizing the mice's intestines. CBi/C and CBi were the only genotypes in which T. muris was found. CBi- was least resistant to S. muris. The helminth parasitic burden showed differences between sexes within genotypes (males had a higher burden than females) and among genotypes (CBi/L males had the lowest burden). CBi/L animals were also most resistant to experimental challenge with Heligmosomoides polygyrus and Trypanosoma cruzi. Since all the animals examined shared a common habitat throughout the study and were equally exposed to infection, the phenotypic differences in the natural enteroparasitism herein described evince genetic differences among lines in the host-parasite relationship. This interpretation is further supported by the differences in the response to the experimental challenge to H. polygyrus and T. cruzi. PMID:18304738

  11. [Intermediate phenotype studies in psychiatric disorder].

    PubMed

    Hashimoto, Ryota

    2016-02-01

    The concept of intermediate phenotype was proposed by Dr. Weinberger of the National Institute of Mental Health (NIMH). The risk genes for mental disorders define intermediate phenotypes, neurobiological characteristics observed in psychiatric disorders, and intermediate phenotypes increase the risk of mental disorders. The author worked at Dr. Weinberger's laboratory, and after returning home, introduced the concept to Japan, creating a term "Chukanhyogengata" to translate "intermediate phenotype". Intermediate phenotype has been proposed as a tool for the identification of risk genes for mental disorders, spreading the concept as a biomarker for the bridging between genes and behaviors. Intermediate phenotype studies later became one of the main pillars of psychiatric research. As a large number of data and samples are needed for intermediate phenotype research, we built a research resource database that combines the brain phenotype and bioresources. We performed genome-wide association analysis of cognitive decline in schizophrenia and identified the DEGS2 gene using this sample. This research resource database was developed for a multicenter study by COCORO (Cognitive Genetics Collaborative Research Organization). COCORO carried out genome-wide association analysis of the gray matter volume of the superior temporal gyrus and identified genome-wide significant loci. In this paper, we introduce the concept and history of intermediate phenotype study of mental illness and the latest trends. We hope to contribute to the future development of mental illness research through translational research. PMID:27044135

  12. Behaviorism

    ERIC Educational Resources Information Center

    Moore, J.

    2011-01-01

    Early forms of psychology assumed that mental life was the appropriate subject matter for psychology, and introspection was an appropriate method to engage that subject matter. In 1913, John B. Watson proposed an alternative: classical S-R behaviorism. According to Watson, behavior was a subject matter in its own right, to be studied by the…

  13. Eye movement abnormalities.

    PubMed

    Moncayo, Jorge; Bogousslavsky, Julien

    2012-01-01

    Generation and control of eye movements requires the participation of the cortex, basal ganglia, cerebellum and brainstem. The signals of this complex neural network finally converge on the ocular motoneurons of the brainstem. Infarct or hemorrhage at any level of the oculomotor system (though more frequent in the brain-stem) may give rise to a broad spectrum of eye movement abnormalities (EMAs). Consequently, neurologists and particularly stroke neurologists are routinely confronted with EMAs, some of which may be overlooked in the acute stroke setting and others that, when recognized, may have a high localizing value. The most complex EMAs are due to midbrain stroke. Horizontal gaze disorders, some of them manifesting unusual patterns, may occur in pontine stroke. Distinct varieties of nystagmus occur in cerebellar and medullary stroke. This review summarizes the most representative EMAs from the supratentorial level to the brainstem. PMID:22377853

  14. The broad autism phenotype predicts relationship outcomes in newly formed college roommates.

    PubMed

    Faso, Daniel J; Corretti, Conrad A; Ackerman, Robert A; Sasson, Noah J

    2016-05-01

    Although previous studies have reported that the broad autism phenotype is associated with reduced relationship quality within established relationships, understanding how this association emerges requires assessment prior to relationship development. In the present longitudinal study, college roommates with minimal familiarity prior to cohabitation (N = 162) completed the broad autism phenotype questionnaire and intermittently reported on their relationship quality and interpersonal behaviors toward their roommate over their first 10 weeks of living together. Actor-Partner Interdependence Models demonstrated that roommates mismatched on aloofness (one high and one low) had lower relationship satisfaction than those matched on it, with the interpersonal behavior of warmth mediating this association. Because relationship satisfaction remained high when both roommates were aloof, satisfaction does not appear predicated upon the presence of aloofness generally but rather reflects a product of dissimilarity in aloof profiles between roommates. In contrast, although participants reported less relationship satisfaction and commitment with roommates higher on pragmatic language abnormalities, mismatches on this broad autism phenotype trait, and on rigid personality, were less consequential. In sum, these findings suggest that complementary profiles of social motivation may facilitate relationship quality during the early course of relationship development. PMID:26014840

  15. Genetic Analysis of Olfactory Behavior in Drosophila: A New Screen Yields the Ota Mutants

    PubMed Central

    Woodard, C.; Huang, T.; Sun, H.; Helfand, S. L.; Carlson, J.

    1989-01-01

    A simple means of measuring Drosophila olfactory response is described, and the behavior which it measures is characterized. The assay was used to screen for X-linked mutants defective in olfactory function. Six ota mutants were isolated and characterized (ota = olfactory trap abnormal). Four of the mutants were found to be abnormal in another chemosensory behavior as well. Two of the mutant phenotypes extend to include another sensory system: they are defective in visual system physiology. All were normal, however, in a test of giant fiber system physiology. Two of the mutations are dominant, and the recessive mutations define two complementation groups. Mutations representing each complementation group, as well as one of the dominant mutations, were mapped. For the mutants with defective visual system physiology, the visual defects were shown to cosegregate with olfactory phenotypes. PMID:2511068

  16. Large-scale objective phenotyping of 3D facial morphology

    PubMed Central

    Hammond, Peter; Suttie, Michael

    2012-01-01

    Abnormal phenotypes have played significant roles in the discovery of gene function, but organized collection of phenotype data has been overshadowed by developments in sequencing technology. In order to study phenotypes systematically, large-scale projects with standardized objective assessment across populations are considered necessary. The report of the 2006 Human Variome Project meeting recommended documentation of phenotypes through electronic means by collaborative groups of computational scientists and clinicians using standard, structured descriptions of disease-specific phenotypes. In this report, we describe progress over the past decade in 3D digital imaging and shape analysis of the face, and future prospects for large-scale facial phenotyping. Illustrative examples are given throughout using a collection of 1107 3D face images of healthy controls and individuals with a range of genetic conditions involving facial dysmorphism. PMID:22434506

  17. Different strategies of exploration and phenotypic variability of the locomotor behavior in new environment: Comparative study of the laboratory opossum (Monodelphis domestica) and Wistar rat (Rattus norvegicus).

    PubMed

    Klejbor, Ilona; Turlejski, Krzysztof

    2012-01-01

    Spontaneous locomotor activity of opossums and Wistar rats during a two-hour session in the open field has been recorded, assessed and behavior of individuals of the two species compared. Afterwards, groups of highly active (HA) and low active (LA) opossums and rats were selected on the basis of the distance traveled in the test. Differences between the selected groups were evaluated. Opossums were generally more active, moving faster and covering longer distance. They spent more time in the central part of the open field and traveled across the center more times than rats, therefore they showed also a lower level of anxiety. These data confirm our previous results indicating that opossums preferentially use the risky exploration strategy while rats mainly rely on the defensive behavior. Opossums showed a higher variability of the volume of locomotor activity than rats. Comparison of the HA and LA groups of opossums and rats showed that in each species they differed on another principle: the level of anxiety in Wistar rats and level of locomotor activity in opossums. Therefore results of the open field test might measure different parameters in different species. PMID:23377274

  18. Pseudoloma neurophilia: a retrospective and descriptive study of nervous system and muscle infections, with new implications for pathogenesis and behavioral phenotypes.

    PubMed

    Spagnoli, Sean Thomas; Xue, Lan; Murray, Katrina N; Chow, Fidelis; Kent, Michael L

    2015-04-01

    Pseudoloma neurophilia is a microsporidium of zebrafish (Danio rerio) that preferentially infects neural tissue. It is one of the most common pathogens of zebrafish in research laboratories based on diagnostic data from the Zebrafish International Resource Center diagnostic service (Eugene, OR). Five hundred fifty-nine zebrafish infected with P. neurophilia submitted to ZIRC from 86 laboratories between the years 2000 and 2013 were examined via histopathology to develop a retrospective study of the features of neural microsporidiosis. Parasite clusters (PCs) occurred in distinct axonal swellings, frequently with no associated inflammation. Inflammation was observed in viable cell bodies distant from PCs. Multiple PCs occasionally occurred within a single axon, suggesting axonal transport. PCs occurred most frequently in the spinal cord ventral white matter (40.3% of all PCs) and the spinal nerve roots (25.6%). Within the rhombencephalon, PCs were most common in the primary descending white matter tracts. Within the rhombencephalon gray matter, PCs occurred most frequently in the reticular formation and the griseum centrale (61% and 39%, respectively). High numbers of PCs within brain and spinal cord structures mediating startle responses and anxiety suggest that related behaviors could be altered by neural microsporidiosis. Infection could, therefore, introduce unacceptable variation in studies utilizing these behaviors. PMID:25789546

  19. Association of coexisting morphological umbilical cord abnormality and clinical cord compromise with hypoxic and thrombotic placental histology.

    PubMed

    Stanek, Jerzy

    2016-06-01

    To assess the usefulness and limitations of placental histology when morphological umbilical cord (UC) abnormality coexists with clinical UC compromise, 5634 consecutive placentas were divided into four groups and statistically compared: group 1-182 placentas from pregnancies with clinical features of UC compromise (variable decelerations, UC entanglement, prolapse, or true knot at delivery); group 2-1355 placentas with abnormal UC morphology or insertion; group 3-152 placentas with at least one phenotype from group 1 and one from group 2; group 4-3945 placentas with no clinical or morphological UC-related phenotypes (control group).Differences were analyzed by ANOVA or χ (2). Of 68 phenotypes studied, 13 clinical and 18 placental phenotypes were statistically significant. In group 1, 2 phenotypes were most common (oligohydramnios and abnormal fetal heart rate tracing). In group 2, 6 phenotypes were most common, including 4 clinical (abnormal umbilical artery Dopplers, nonmacerated stillbirth, multiple pregnancy, and fetal growth restriction) and 2 placental. In group 3, 23 phenotypes were most common, including 7 clinical (gestational hypertension, polyhydramnios, induction of labor, cesarean section, macerated stillbirth, congenital malformations, and abnormal 3rd stage of labor) and 16 placental. The existence of clinical signs of UC compromise alone was associated with the absence of pathomorphological placental abnormalities. However, the coexistence of clinical and abnormal morphological UC phenotypes was statistically significantly associated with placental histological signs of decreased fetal blood flow, hypoxia (acute and chronic post uterine), shallow placental implantation, and/or amnion nodosum. Thus, confirmation of clinical UC compromise should not be expected on placental examination if no morphological UC abnormality or abnormal UC insertion has been found. PMID:26983702

  20. Reversing song behavior phenotype: testosterone driven induction of singing and measures of song quality in adult male and female canaries (Serinus canaria)

    PubMed Central

    Madison, Farrah N.; Rouse, Melvin L.; Balthazart, Jacques; Ball, Gregory F

    2014-01-01

    In songbirds, such as canaries (Serinus canaria), the song control circuit has been shown to undergo a remarkable change in morphology in response to exogenous testosterone (T). It is also well established that HVC, a telencephalic nucleus involved in song production, is significantly larger in males than in females. T regulates seasonal changes in HVC volume in males and exposure to exogenous T in adult females increases HVC volume and singing activity such that their song becomes more male-like in frequency and structure. However, whether there are sex differences in the ability of T to modulate changes in the song system and song behavior has not been investigated in canaries. In this study, we compared the effects of increasing doses of T on singing and song control nuclei volumes in adult male and female American Singer canaries exposed to identical environmental conditions. Males were castrated and all birds were placed on short days (8L:16D) for 8 weeks. Males and females were implanted either with a 2, 6 or 12 mm long Silastic™ implant filled with crystalline T or an empty 12 mm implant as control. Birds were then housed individually in sound attenuated chambers. Brains were collected from six birds from each group after 1 week or 3 weeks of treatment. Testosterone was not equally effective in increasing singing activity in both males and females. Changes in song quality and occurrence rate took place after a shorter latency in males than in females however, females did undergo marked changes in a number of measures of song behavior if given sufficient time. Males responded with an increase in HVC volume at all three doses. In females, T-induced changes in HVC volume only had limited amplitude and these volumes never reached male-typical levels a suggesting that there are sex differences in the neural substrate that responds to T. PMID:25260250

  1. Ictal Cardiac Ryhthym Abnormalities

    PubMed Central

    Ali, Rushna

    2016-01-01

    Cardiac rhythm abnormalities in the context of epilepsy are a well-known phenomenon. However, they are under-recognized and often missed. The pathophysiology of these events is unclear. Bradycardia and asystole are preceded by seizure onset suggesting ictal propagation into the cortex impacting cardiac autonomic function, and the insula and amygdala being possible culprits. Sudden unexpected death in epilepsy (SUDEP) refers to the unanticipated death of a patient with epilepsy not related to status epilepticus, trauma, drowning, or suicide. Frequent refractory generalized tonic-clonic seizures, anti-epileptic polytherapy, and prolonged duration of epilepsy are some of the commonly identified risk factors for SUDEP. However, the most consistent risk factor out of these is an increased frequency of generalized tonic–clonic seizures (GTC). Prevention of SUDEP is extremely important in patients with chronic, generalized epilepsy. Since increased frequency of GTCS is the most consistently reported risk factor for SUDEP, effective seizure control is the most important preventive strategy. PMID:27347227

  2. Abnormal uterine bleeding.

    PubMed

    Whitaker, Lucy; Critchley, Hilary O D

    2016-07-01

    Abnormal uterine bleeding (AUB) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the relationship between the two remains incompletely understood and in many women the identification of fibroids may be incidental to a menstrual bleeding complaint. A structured approach for establishing the cause using the Fédération International de Gynécologie et d'Obstétrique (FIGO) PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for the underlying cause. Increased availability of medical options has expanded the choice for women and many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of AUB in order to achieve improved quality of life. PMID:26803558

  3. Novel BAC mouse model of Huntington’s disease with 225 CAG repeats exhibits an early widespread and stable degenerative phenotype

    PubMed Central

    Wegrzynowicz, Michal; Bichell, Terry Jo; Soares, Barbara D.; Loth, Meredith K.; McGlothan, Jennifer L.; Alikhan, Fatima S.; Hua, Kegang; Coughlin, Jennifer M.; Holt, Hunter K.; Jetter, Christopher S.; Mori, Susumu; Pomper, Martin G.; Osmand, Alexander P.; Guilarte, Tomás R.; Bowman, Aaron B.

    2015-01-01

    BACKGROUND Unusually large CAG repeat expansions (>60) in exon one of Huntingtin (HTT) are invariably associated with a juvenile-onset form of Huntington’s disease (HD), characterized by a more extensive and rapidly progressing neuropathology than the more prevalent adult-onset form. However, existing mouse models of HD that express the full-length Htt gene with CAG repeat lengths associated with juvenile HD (ranging between ~75 to ~150 repeats in published models) exhibit selective neurodegenerative phenotypes more consistent with adult-onset HD. OBJECTIVE To determine if a very large CAG repeat (>200) in full-length Htt elicits neurodegenerative phenotypes consistent with juvenile HD. METHODS Using a bacterial artificial chromosome (BAC) system, we generated mice expressing full-length mouse Htt with ~225 CAG repeats under control of the mouse Htt promoter. Mice were characterized using behavioral, neuropathological, biochemical and brain imaging methods. RESULTS BAC-225Q mice exhibit phenotypes consistent with a subset of features seen in juvenile-onset HD: very early motor behavior abnormalities, reduced body weight, widespread and progressive increase in Htt aggregates, gliosis, and neurodegeneration. Early striatal pathology was observed, including reactive gliosis and loss of dopamine receptors, prior to detectable volume loss. HD-related blood markers of impaired energy metabolism and systemic inflammation were also increased. Aside from an age-dependent progression of diffuse nuclear aggregates at 6 months of age to abundant neuropil aggregates at 12 months of age, other pathological and motor phenotypes showed little to no progression. CONCLUSIONS The HD phenotypes present in animals 3 to 12 months of age make the BAC-225Q mice a unique and stable model of full-length mutant Htt associated phenotypes, including body weight loss, behavioral impairment and HD-like neurodegenerative phenotypes characteristic of juvenile-onset HD and/or late-stage adult

  4. Normal values for morphological abnormalities in school children.

    PubMed

    Merks, Johannes H M; Ozgen, Heval M; Cluitmans, Theresia L M; van der Burg-van Rijn, Jaqueline M; Cobben, Jan Maarten; van Leeuwen, Flora E; Hennekam, Raoul C M

    2006-10-01

    Clinical morphology has proven to be a strong tool in the delineation of many syndromes and a helpful instrument in molecular studies. Numerous studies have been performed investigating the prevalence of minor anomalies in various disorders; all concluding that minor anomalies can well be utilized as indicators of altered embryonic differentiation. However, for adequate evaluation, normal values for phenotypic abnormalities are essential. So far, only few studies on the frequency of phenotypic abnormalities in the normal population have been done having one thing in common: all were performed in newborn infants. We studied morphological characteristics in a group of 1,007 school children, representative for the Dutch population, through a body surface examination using detailed definitions for all morphological findings. The region of study and distribution of children over various school types was chosen in such a way that it represented the general Dutch population. The median age of the studied children was 11 years (range 8-14 years), sex ratio (M:F) was 0.93. Nine hundred twenty-three children were of Caucasian descent, 84 others of mixed ethnic backgrounds. The reliability of the examinations was tested by independent scoring of 111 children by two observers, showing a kappa score of 0.85. Normal values for the morphological findings are presented together with their age-adjusted classification. These normal values provide a valuable source for validation of classifications of phenotypic abnormalities, especially those that are depending on frequency, that is, minor anomalies and common variants. Furthermore, they will allow a proper evaluation of patterns of phenotypic abnormalities found in patient groups with specific disorders. PMID:16838341

  5. Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations.

    PubMed

    Lo-Castro, Adriana; Brancati, Francesco; Digilio, Maria Cristina; Garaci, Francesco Giuseppe; Bollero, Patrizio; Alfieri, Paolo; Curatolo, Paolo

    2013-01-01

    KBG syndrome is a rare disease characterized by typical facial dysmorphism, macrodontia of upper central incisors, skeletal abnormalities, and developmental delay. Recently, mutations in ANKRD11 gene have been identified in a subset of patients with KBG syndrome, while a contiguous gene deletion syndrome involving 16q24.3 region (including ANKRD11) was delineated in patients with facial dysmorphism, autism, intellectual disability, and brain abnormalities. Although numerous evidences point to a central causative role of ANKRD11 in the neurologic features of these patients, their neurocognitive and behavior phenotypes are still poorly characterized. Herein, we report the complete neurological and psychiatric features observed in two patients with KBG syndrome due to ANKRD11 mutations. Both patients show intellectual disabilities, severe impairment in communication skills, deficits in several aspects of executive functions and working memory and anxious traits. Their features are compared with those of previously reported patients with KBG syndrome aiding in the delineation of neurocognitive phenotype associated to ANKRD11 mutations. PMID:23184435

  6. Abnormal grain growth in TD-nickel.

    NASA Technical Reports Server (NTRS)

    Petrovic, J. J.; Ebert, L. J.

    1972-01-01

    Characteristics of the coarse grain transformation occurring in TD-nickel 1 in. bar under certain conditions of deformation and annealing were examined. The transformation exhibits Avrami-type kinetics, with an activation energy of 250 kcal per mole. Characteristics of untransformed regions are like those of the as-received state. The transformed grain size increases with increasing deformation and decreasing annealing temperature. The coarse grain transformation is significantly different from primary recrystallization in pure nickel. Its characteristics cannot be rationalized in terms of primary recrystallization concepts, but may be explained in terms of an abnormal grain growth description. The coarse grain transformation in TD-nickel is abnormal grain growth rather than primary recrystallization. The analysis suggests an explanation for the effect of thermomechanical history on the deformation and annealing behavior of TD-nickel.

  7. Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington's Disease Mice.

    PubMed

    Lebreton, Fanny; Cayzac, Sebastien; Pietropaolo, Susanna; Jeantet, Yannick; Cho, Yoon H

    2015-01-01

    In hereditary neurodegenerative Huntington's disease (HD), there exists a growing consideration that sleep and circadian dysregulations may be important symptoms. It is not known, however, whether sleep abnormalities contribute to other behavioral deficits in HD patients and mouse models. To determine the precise chronology for sleep physiology alterations and other sensory, motor, psychiatric and cognitive symptoms of HD, the same R6/1 HD transgenics and their wild-type littermates were recorded monthly for sleep electroencephalogram (EEG) together with a wide range of behavioral tests according to a longitudinal plan. We found an early and progressive deterioration of both sleep architecture and EEG brain rhythms in R6/1 mice, which are correlated timely with their spatial working memory impairments. Sleep fragmentation and memory impairments were accompanied by the loss of delta (1-4 Hz) power in the transgenic mice, the magnitude of which increased with age and disease progression. These precocious sleep and cognitive impairments were followed by deficits in social behavior, sensory and motor abilities. Our data confirm the existence and importance of sleep physiology alterations in the widely used R6/1 mouse line and highlight their precedence over other plethoric phenotypic changes. The brainwave abnormalities, may represent a novel biomarker and point to innovative therapeutic interventions against HD. PMID:25966356

  8. Electrocardiograph abnormalities revealed during laparoscopy

    PubMed Central

    Nijjer, Sukhjinder; Dubrey, Simon William

    2010-01-01

    This brief case presents a well patient in whom an electrocardiograph abnormality consistent with an accessory pathway was found during a routine procedure. We present the electrocardiographs, explain the underlying condition, and consider why the abnormality was revealed in this manner. PMID:22419949

  9. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  10. Haem degradation in abnormal haemoglobins.

    PubMed Central

    Brown, S B; Docherty, J C

    1978-01-01

    The coupled oxidation of certain abnormal haemoglobins leads to different bile-pigment isomer distributions from that of normal haemoglobin. The isomer pattern may be correlated with the structure of the abnormal haemoglobin in the neighbourhood of the haem pocket. This is support for haem degradation by an intramolecular reaction. PMID:708385

  11. In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients.

    PubMed

    Geisler, C H; Philip, P; Christensen, B E; Hou-Jensen, K; Pedersen, N T; Jensen, O M; Thorling, K; Andersen, E; Birgens, H S; Drivsholm, A; Ellegaard, J; Larsen, J K; Plesner, T; Brown, P; Andersen, P K; Hansen, M M

    1997-01-01

    Of 560 consecutive, newly diagnosed untreated patients with B CLL submitted for chromosome study, G-banded karyotypes could be obtained in 480 cases (86%). Of these, 345 (72%) had normal karyotypes and 135 (28%) had clonal chromosome abnormalities: trisomy 12 (+12) was found in 40 cases, 20 as +12 alone (+12single), 20 as +12 with additional abnormalities (+12complex). Other frequent findings included abnormalities of 14q, chromosome 17, 13q and 6q. The immunophenotype was typical for CLL in 358 patients (CD5+, Slg(weak), mainly FMC7-) and atypical for CLL in 122 patients (25%) (CD5-, or Slg(strong) or FMC7+). Chromosome abnormalities were found significantly more often in patients with atypical (48%) than in patients with typical CLL phenotype (22%) (P < 0.00005). Also +12complex, 14q+, del6q, and abnormalities of chromosome 17 were significantly more frequent in patients with atypical CLL phenotype, whereas +12single was found equally often in patients with typical and atypical CLL phenotype. The cytomorphology of most of the +12 patients was that of classical CLL irrespective of phenotype. In univariate survival analysis the following cytogenetic findings were significantly correlated to a poor prognosis: chromosome 17 abnormalities, 14q+, an abnormal karyotype, +12complex, more than one cytogenetic event, and the relative number of abnormal mitoses. In multivariate survival analysis chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. We conclude that in patients with typical CLL immunophenotype, chromosome abnormalities are somewhat less frequent at the time of diagnosis than hitherto believed. +12single is compatible with classical CLL, and has no prognostic influence whereas chromosome 17 abnormalities signify a poor prognosis. In patients with an atypical CLL immunophenotype, chromosome abnormalities including +12complex, 14q+, del 6q and chromosome 17 are found in about 50% of the

  12. Genetic abnormalities associated with acute lymphoblastic leukemia.

    PubMed

    Yokota, Takafumi; Kanakura, Yuzuru

    2016-06-01

    Acute lymphoblastic leukemia (ALL) occurs with high frequency in childhood and is associated with high mortality in adults. Recent technical advances in next-generation sequencing have shed light on genetic abnormalities in hematopoietic stem/progenitor cells as the precursor to ALL pathogenesis. Based on these genetic abnormalities, ALL is now being reclassified into newly identified subtypes. Philadelphia chromosome-like B-lineage ALL is one of the new high-risk subtypes characterized by genetic alterations that activate various signaling pathways, including those involving cytokine receptors, tyrosine kinases, and epigenetic modifiers. Philadelphia chromosome-like ALL is essentially heterogeneous; however, deletion mutations in the IKZF1 gene encoding the transcription factor IKAROS underlie many cases as a key factor inducing aggressive phenotypes and poor treatment responses. Whole-genome sequencing studies of ALL patients and ethnically matched controls also identified inherited genetic variations in lymphoid neoplasm-related genes, which are likely to increase ALL susceptibility. These findings are directly relevant to clinical hematology, and further studies on this aspect could contribute to accurate diagnosis, effective monitoring of residual disease, and patient-oriented therapies. PMID:26991355

  13. [Classification and genetic abnormalities of multiple myeloma].

    PubMed

    Hanamura, Ichiro; Iida, Shinsuke

    2015-01-01

    Multiple myeloma (MM) is a malignancy of plasma cells which develops through genetic aberrations, epigenetic changes and the bone marrow microenvironment interaction. Despite recent tremendous progress in treatments for MM, a complete cure remains elusive. Further development of more effective therapeutic strategies is needed. The International Staging System (ISS) reported in 2005 has been used widely as the most simple and powerful prognostic classification in MM, but genetic abnormalities affecting prognosis were not considered in this model. In the past decade, non-random chromosomal aberrations such as t(4;14), t(14;16), t(14;20), amp1q21 and del17p have shown to be poor prognostic value, and moreover, recent progress in genome-wide deep sequencing studies has revealed novel mutations and intra-tumor subclonal heterogeneity which may explain clinical phenotype and therapeutic resistance. Here we review the current understanding of genetic abnormalities in MM for developing better prognostic classification and molecular targeted therapies leading to the stratified or personalized medicine. PMID:25626298

  14. Understanding COPD: A vision on phenotypes, comorbidities and treatment approach.

    PubMed

    Fragoso, E; André, S; Boleo-Tomé, J P; Areias, V; Munhá, J; Cardoso, J

    2016-01-01

    Chronic Obstructive Pulmonary Disease (COPD) phenotypes have become increasingly recognized as important for grouping patients with similar presentation and/or behavior, within the heterogeneity of the disease. The primary aim of identifying phenotypes is to provide patients with the best health care possible, tailoring the therapeutic approach to each patient. However, the identification of specific phenotypes has been hindered by several factors such as which specific attributes are relevant, which discriminant features should be used for assigning patients to specific phenotypes, and how relevant are they to the therapeutic approach, prognostic and clinical outcome. Moreover, the definition of phenotype is still not consensual. Comorbidities, risk factors, modifiable risk factors and disease severity, although not phenotypes, have impact across all COPD phenotypes. Although there are some identified phenotypes that are fairly consensual, many others have been proposed, but currently lack validation. The on-going debate about which instruments and tests should be used in the identification and definition of phenotypes has contributed to this uncertainty. In this paper, the authors review present knowledge regarding COPD phenotyping, discuss the role of phenotypes and comorbidities on the severity of COPD, propose new phenotypes and suggest a phenotype-based pharmacological therapeutic approach. The authors conclude that a patient-tailored treatment approach, which takes into account each patient's specific attributes and specificities, should be pursued. PMID:26827246

  15. Peripheral blood lymphocyte phenotype and function in multiple sclerosis.

    PubMed Central

    Hughes, P J; Compston, D A

    1988-01-01

    T suppressor cell function and phenotype are abnormal in patients with multiple sclerosis, especially during the chronic progressive phase but the sub-populations defined by mitogen stimulation and serological methods may not be identical. In this study, involving 45 patients with multiple sclerosis and 33 controls, there was no correlation between T suppressor function and CD8 cell phenotype in patients with multiple sclerosis or in controls. These phenotypic and functional studies cannot therefore be used interchangeably in the assessment of patients with multiple sclerosis since they provide different information about lymphocyte subpopulations. PMID:2976082

  16. A method for analysis of phenotypic change for phenotypes described by high-dimensional data.

    PubMed

    Collyer, M L; Sekora, D J; Adams, D C

    2015-10-01

    The analysis of phenotypic change is important for several evolutionary biology disciplines, including phenotypic plasticity, evolutionary developmental biology, morphological evolution, physiological evolution, evolutionary ecology and behavioral evolution. It is common for researchers in these disciplines to work with multivariate phenotypic data. When phenotypic variables exceed the number of research subjects--data called 'high-dimensional data'--researchers are confronted with analytical challenges. Parametric tests that require high observation to variable ratios present a paradox for researchers, as eliminating variables potentially reduces effect sizes for comparative analyses, yet test statistics require more observations than variables. This problem is exacerbated with data that describe 'multidimensional' phenotypes, whereby a description of phenotype requires high-dimensional data. For example, landmark-based geometric morphometric data use the Cartesian coordinates of (potentially) many anatomical landmarks to describe organismal shape. Collectively such shape variables describe organism shape, although the analysis of each variable, independently, offers little benefit for addressing biological questions. Here we present a nonparametric method of evaluating effect size that is not constrained by the number of phenotypic variables, and motivate its use with example analyses of phenotypic change using geometric morphometric data. Our examples contrast different characterizations of body shape for a desert fish species, associated with measuring and comparing sexual dimorphism between two populations. We demonstrate that using more phenotypic variables can increase effect sizes, and allow for stronger inferences. PMID:25204302