Disruption Of Development Research Articles

Developmental disruption of paracrine hormone regulation in the pathogenesis of germ cell neoplasms

Developmental disruption of paracrine hormone regulation in the pathogenesis of germ cell neoplasms

Molecular responses to 17β-estradiol in early life stage salmonids

Environmental estrogens (EE) are ubiquitous in many aquatic environments and biological responses to EEs in early developmental stages of salmonids are poorly understood compared to juvenile and adult stages. Using 17β-estradiol (E2) as a model estrogen, waterborne exposures were conducted on early life stage rainbow trout (Oncorhynchus mykiss; egg, alevin, swim-up fry) and both molecular and physiological endpoints were measured to quantify the effects of E2. To investigate developmental stage-specific effects, laboratory exposures of 1μg/L E2 were initiated pre-hatching as eyed embryos or post-hatching upon entering the alevin stage. High mortality (∼90%) was observed when E2 exposures were initiated at the eyed embryo stage compared to the alevin stage (∼35% mortality), demonstrating stage-specific sensitivity. Gene expression analyses revealed that vitellogenin was detectable in the liver of swim-up fry, and was highly inducible by 1μg/L E2 (>200-fold higher levels compared to control animals). Experiments also confirmed the induction of vitellogenin protein levels in protein extracts isolated from head and tail regions of swim-up fry after E2 exposure. These findings suggest that induction of vitellogenin, a well-characterized biomarker for estrogenic exposure, can be informative measured at this early life stage. Several other genes of the reproductive endocrine axis (e.g. estrogen receptors and androgen receptors) exhibited decreased expression levels compared to control animals. In addition, chronic exposure to E2 during the eyed embryo and alevin stages resulted in suppressive effects on growth related genes (growth hormone receptors, insulin-like growth factor 1) as well as premature hatching, suggesting that the somatotropic axis is a key target for E2-mediated developmental and growth disruptions. Combining molecular biomarkers with morphological and physiological changes in early life stage salmonids holds considerable promise for further defining estrogen action during development, and for assessing the impacts of endocrine disrupting chemicals in vivo in teleosts.

Dhilirolides E–N, Meroterpenoids Produced in Culture by the Fungus Penicillium purpurogenum Collected in Sri Lanka: Structure Elucidation, Stable Isotope Feeding Studies, and Insecticidal Activity

Extracts of laboratory cultures of the fungus Penicilium purpurogenum obtained from rotting fruit of the tree Averrhoa bilimbi growing in Sri Lanka have yielded 10 new meroterpenoids, dhilirolides E-N (5-14). The structures of the new dhilirolides have been elucidated by analysis of spectroscopic data and a single-crystal X-ray diffraction analysis of dhilirolide L (12). Dhilirolides A-N (1-14) represent the four unprecedented and rearranged dhilirane, isodhilirane, 14,15-dinordhilirane, and 23,24-dinorisodhilirane meroterpenoid carbon skeletons. Stable isotope feeding studies have confirmed the meroterpenoid biogenetic origin of the dhilirolides and provided support for a proposed genesis of the new carbon skeletons. Dhilirolide L (12) showed significant feeding inhibition and sublethal developmental disruption in the cabbage looper Trichoplusia ni, an important agricultural pest, at low concentrations.

Developmental but not adult cannabinoid treatments persistently alter axonal and dendritic morphology within brain regions important for zebra finch vocal learning

Prior work shows developmental cannabinoid exposure alters zebra finch vocal development in a manner associated with altered CNS physiology, including changes in patterns of CB1 receptor immunoreactivity, endocannabinoid concentrations and dendritic spine densities. These results raise questions about the selectivity of developmental cannabinoid effects: are they a consequence of a generalized developmental disruption, or are effects produced through more selective and distinct interactions with biochemical pathways that control receptor, endogenous ligand and dendritic spine dynamics? To begin to address this question we have examined effects of developmental cannabinoid exposure on the pattern and density of expression of proteins critical to dendritic (MAP2) and axonal (Nf-200) structure to determine the extent to which dendritic vs. axonal neuronal morphology may be altered. Results demonstrate developmental, but not adult cannabinoid treatments produce generalized changes in expression of both dendritic and axonal cytoskeletal proteins within brain regions and cells known to express CB1 cannabinoid receptors. Results clearly demonstrate that cannabinoid exposure during a period of sensorimotor development, but not adulthood, produce profound effects upon both dendritic and axonal morphology that persist through at least early adulthood. These findings suggest an ability of exogenous cannabinoids to alter general processes responsible for normal brain development. Results also further implicate the importance of endocannabinoid signaling to peri-pubertal periods of adolescence, and underscore potential consequences of cannabinoid abuse during periods of late-postnatal CNS development.

Fibroblast growth factor deficiencies impact anxiety-like behavior and the serotonergic system

Serotonergic neurons in the dorsal raphe nucleus (DR) are organized in anatomically distinct subregions that form connections with specific brain structures to modulate diverse behaviors, including anxiety-like behavior. It is unclear if the functional heterogeneity of these neurons is coupled to their developmental heterogeneity, and if abnormal development of specific DR serotonergic subregions can permanently impact anxiety circuits and behavior. The goal of this study was to examine if deficiencies in different components of fibroblast growth factor (Fgf) signaling could preferentially impact the development of specific populations of DR serotonergic neurons to alter anxiety-like behavior in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8, Fgfr1, or both (Fgfr1/Fgf8) were tested in an anxiety-related behavioral battery. Both Fgf8- and Fgfr1/Fgf8-deficient mice display increased anxiety-like behavior as measured in the elevated plus-maze and the open-field tests. Immunohistochemical staining of a serotonergic marker, tryptophan hydroxylase (Tph), revealed reductions in specific populations of serotonergic neurons in the ventral, interfascicular, and ventrolateral/ventrolateral periaqueductal gray subregions of the DR in all Fgf-deficient mice, suggesting a neuroanatomical basis for increased anxiety-like behavior. Overall, this study suggests Fgf signaling selectively modulates the development of different serotonergic neuron subpopulations. Further, it suggests anxiety-like behavior may stem from developmental disruption of these neurons, and individuals with inactivating mutations in Fgf signaling genes may be predisposed to anxiety disorders.

Chemical composition, toxicity and growth inhibitory activities of essential oils of three Achillea species and their nano-emulsions against Tribolium castaneum (Herbst)

Essential oils of Achillea biebersteinii, A. santolina and A. mellifolium were obtained by hydrodistillation, then analyzed using gas chromatography (GC) and GC/mass spectrometry (MS). The obtained oils showed considerable toxic and growth inhibitory activities against the red flour beetle, Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). The time of exposure, the technique used and the stage treated, all were activity-determinant factors, where A. biebersteinii oil showed the strongest insecticidal activity and the adult stage was more susceptible than larvae. Using topical application, LC50 values of A. biebersteinii, A. santolina and A. mellifolium oils after 96h of exposure of larvae were 30.3, 47.8 and 62.3μg/mg insect, respectively. In this case, LC50s against adults were ranged between 21.8 and 50.7μg/mg insects. Using treated filter papers, the LC50 values after 96h of exposure against larvae were ranged between 124.9 and 212.0μL/cm2, while against adults were ranged between 113.0 and 196.8μL/cm2. In the fumigant bioassay, LC50s after 96h of exposure against larvae were between 41.7 and 93.2μL/L air, while against adults were between 36.1 and 80.6μL/L air. When prepared as nano-emulsions and tested as fumigants, toxicity of oils was increased dramatically, where LC50 values after 96h of exposure against larvae and adults were ranged between 11.0 and 27.5μL/L air and 8.8 and 21.3μL/L air, respectively. When exposed as 2nd instar larvae to sub-lethal doses-treated grains, the developmental course, life span and F1 progeny of T. castaneum were significantly affected, where the oil of A. santolina showed the strongest activity. All of these developmental disruptions led to a great reduction in the number of adults that undergo successful emergence.

Longitudinal four-dimensional mapping of subcortical anatomy in human development

Growing access to large-scale longitudinal structural neuroimaging data has fundamentally altered our understanding of cortical development en route to human adulthood, with consequences for basic science, medicine, and public policy. In striking contrast, basic anatomical development of subcortical structures such as the striatum, pallidum, and thalamus has remained poorly described--despite these evolutionarily ancient structures being both intimate working partners of the cortical sheet and critical to diverse developmentally emergent skills and disorders. Here, to begin addressing this disparity, we apply methods for the measurement of subcortical volume and shape to 1,171 longitudinally acquired structural magnetic resonance imaging brain scans from 618 typically developing males and females aged 5-25 y. We show that the striatum, pallidum, and thalamus each follow curvilinear trajectories of volume change, which, for the striatum and thalamus, peak after cortical volume has already begun to decline and show a relative delay in males. Four-dimensional mapping of subcortical shape reveals that (i) striatal, pallidal, and thalamic domains linked to specific fronto-parietal association cortices contract with age whereas other subcortical territories expand, and (ii) each structure harbors hotspots of sexually dimorphic change over adolescence--with relevance for sex-biased mental disorders emerging in youth. By establishing the developmental dynamism, spatial heterochonicity, and sexual dimorphism of human subcortical maturation, these data bring our spatiotemporal understanding of subcortical development closer to that of the cortex--allowing evolutionary, basic, and clinical neuroscience to be conducted within a more comprehensive developmental framework.

Nutritional status and dietary habits of young people

Objective. Poor nutrition due to insufficient or unbalanced food intake often leads to poor growth and developmental disruption, as well as to the development of diet-related diseases. Our physiological needs provide the basic determinants of food choice. which varies from individual to individual, and these determinants include꞉ cultural, social, economic, and psychological lifestyle factors. Assessing nutritional status and related factors among children and young people can serve as a predictor of their future health. The aim of the present study is to assess the adolescents' nutritional status and healthy dietary habits adjusted for gender and school-age, as well as to assess the need for improved health education in schools. Methods. The research was conducted using cross-sectional study. A total of 307 students of School of Nursing in Novi Sad were surveyed, including students from first through fourth grades. Results. The results obtained show there was statistically significant difference between the first and fourth grade students in terms of whether they were well informed about good nutrition. The percentage of young people with excess amount of body weight among those being investigated was 10%, while 12% of students were undernourished. A higher consumption of sweets and snacks was observed among students, and most of them did not have a set amount of meals per day. Conclusion. Based on our data, we may conclude that the majority of high school students have poor eating habits and that this study has only been a useful starting point for initiating dietary change in poor eating habits among young people.

Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress

BackgroundThe experience of early life stress is a consistently identified risk factor for the development of mood and anxiety disorders. Preclinical research employing animal models of early life stress has made inroads in understanding this association and suggests that the negative sequelae of early life stress may be mediated by developmental disruption of corticolimbic structures supporting stress responsiveness. Work in humans has corroborated this idea, as childhood adversity has been associated with alterations in gray matter volumes of the hippocampus, amygdala, and medial prefrontal cortex. Yet, missing from this body of research is a full understanding of how these neurobiological vulnerabilities may mechanistically contribute to the reported link between adverse childhood experiences and later affective psychopathology.ResultsAnalyses revealed that self-reported childhood maltreatment was associated with reduced gray matter volumes within the medial prefrontal cortex and left hippocampus. Furthermore, reduced left hippocampal and medial prefrontal gray matter volume mediated the relationship between childhood maltreatment and trait anxiety. Additionally, individual differences in corticolimbic gray matter volume within these same structures predicted the anxious symptoms as a function of life stress 1 year after initial assessment.ConclusionsCollectively, these findings provide novel evidence that reductions in corticolimbic gray matter, particularly within the hippocampus and medial prefrontal cortex, are associated with reported childhood maltreatment and individual differences in adult trait anxiety. Furthermore, our results suggest that these structural alterations contribute to increased affective sensitivity to stress later in life in those that have experienced early adversity. More broadly, the findings contribute to an emerging literature highlighting the critical importance of early stress on the development of corticolimbic structures supporting adaptive functioning later in life.

Morphometric characteristics of craniofacial features in patients with schizophrenia

Background: High incidence of craniofacial dysmorphology in patients with schizophrenia confirms the developmental disruptions during embryonic period. Anthropometry of head and face can give us several clues regarding the maldevelopment of brain. The aim of this study was to assess various dimensions of skull in Schizophrenics. Methods: One hundred and one (101) male and female patients that have been diagnosed with chronic schizophrenia were selected from a psychiatric hospital and 101 healthy controls, which were mostly the paramedical staff of another hospital, were included in the study. The age for both the groups was between 20 to 60 years. The head length, width and height and coronal, axial and sagittal arc lengths, and also body height and weight and BMI of participants were measured. Results: Mean anthropometric measurements of head length, width and height were 18.92, 14.08 and 12.69 in patients and 18.90, 13.89 and 13.38 centimeter in control, also axial, coronal and sagittal arc lengths were 55.85, 35.21 and 33.00 in patients and 55.70, 34.54 and 32.19 centimeter in control group, respectively. Compared to controls the patients had significantly increased coronal (P< 0.022) and Sagittal (P< 0.001) arc lengths. The patients also showed significantly lesser head height (P< 0.001) as compared with controls. Conclusion: The linear measurements of skull in patients with Schizophrenia do not significantly differ from normal populations and/or have slightly differences. Future studies may investigate whether head can be an anatomical marker for patients with schizophrenia.

Inducible gene deletion in the entire cardiac conduction system using Hcn4‐CreERT2 BAC transgenic mice

Developmental defects and disruption of molecular pathways of the cardiac conduction system (CCS) can cause life-threatening cardiac arrhythmias. Despite decades of effort, knowledge about the development and molecular control of the CCS remains primitive. Mouse genetics, complementary to other approaches such as human genetics, has become a key tool for exploring the developmental processes of various organs and associated diseases. Genetic analysis using mouse models will likely provide great insights about the development of the CCS, which can facilitate the development of novel therapeutic strategies to treat arrhythmias. To enable genetic studies of the CCS, CCS-associated Cre mouse models are essential. However, existing mouse models with Cre activity reported in the CCS have various limitations such as Cre leak, haploinsufficiency, and inadequate specificity of the Cre activity. To circumvent those limitations, we successfully generated Hcn4-CreERT2 bacterial artificial chromosome (BAC) transgenic mice using BAC recombineering in which Cre activity was specifically detected in the entire CCS after tamoxifen induction. Our Hcn4-CreERT2 BAC transgenic line will be an invaluable genetic tool with which to dissect the developmental control of CCS and arrhythmias.

Germline Exome Sequencing From MLL-Negative Infant AML Patients Reveals Compound Heterozygosity For Novel, Non-Synonymous Alleles Of MLL3: A Report From The Children's Oncology Group (COG)

IntroductionMixed Lineage Leukemia-negative (MLL-) infant leukemia (IL) is an extremely rare, sporadic, and often fatal form of leukemia in children less than one year of age with overall survival <50%. Approximately two-thirds of these cases possess a translocation in the MLL gene. The incidence rate of IL is increasing (Linabery, Cancer 2008) in the US, but cannot be solely attributed to somatic mutations (Andersson A, Cancer Res 2012) or environmental exposures (Ross, Epidemiol Rev 1994). Maternal prenatal exposure to topoisomerase II inhibitors has been associated with infant AML onset in a model similar to therapy-related AML (Spector, Cancer Epidemiol Biomarkers Prev 2006). While there has been extensive research on the impact of MLL-rearrangements, very little work on the genetics of MLL- IL has been reported. Given the absence of chromosomal rearrangements or somatic mutations, we hypothesized that the onset of MLL- IL requires heritable or de novo deleterious germline variants, which would mitigate the requirement for acquired genetic lesions and allow early leukemic transformation. MethodsWe completed germline exome sequencing of 13 pairs of Caucasian mothers and their infants with MLL- AML collected from the COG “Epidemiology of Infant Leukemia” study and 25 Caucasian children without cancer. Our cohort consisted of six boys and seven girls with an average age at diagnosis of 5.3 months (range 1.6-11.4). Average maternal age was 33.4 years (range 25.4-41.8). DNA was collected from buccal cells either via mouthwash (mothers) or cytobrush (infants). Sequencing was performed at Washington University on the Illumina HiSeq 2000 platform and analyzed using our laboratory's published and validated bioinformatic pipeline (Ramos, BMC Genomics, 2012). We focused on sequence variants within 655 AML-associated genes (defined by COSMIC) that were novel (not in dbSNP, 1000 Genomes or the Exome Variant Server), non-synonymous and predicted to be damaging according to six prediction algorithms in the Annovar software package. We prioritized genes with a compound heterozygous genotype. ResultsCompared to their mothers and unaffected controls, infants with AML demonstrated a 2.7 and 7.9-fold excess, respectively, of novel, non-synonymous and predicted deleterious germline variants in 655 genes associated with somatic mutation in AML. Per exome within these candidate genes, this correlated to an average of 121 variants (range 31-124) for AML infants, 31 (range 0-41) for mothers and 11 (range 6-14) for unaffected controls. Hypergeometric analysis confirmed that this enrichment was significant (P = 2.7 e-41) compared to 100,000 randomly chosen sets of 655 genes from within the same exomes. There was no correlation between gene size and the number of variants identified (r2 = 0.15). To further prioritize genes that may be relevant to infant AML, we looked for any gene with a compound heterozygous genotype. Interestingly, every infant AML patient only possessed two compound heterozygotes: ANKRD36 and MLL3. ANKRD36 was not in our candidate gene list and a connection to leukemia is unclear, but MLL3 has an established history in cancer biology. DiscussionMLL3, a homolog of MLL, is a H3K4 histone methyltransferase and dimerizes with p53 as a tumor suppressor (Lee J, PNAS 2009). Mll3 knockout mice develop urogenital tumors, and somatic mutation has been linked to carcinoma of the stomach, gallbladder, bladder and liver in humans. More recently, a germline frameshift in MLL3 was identified in a pedigree with adult-onset AML and colorectal cancer (Li WD, Blood 2013). Our results provide evidence for a germline mechanism of developmental disruption of essential epigenetic regulatory mechanisms in infant AML, secondary to MLL3 dysfunction, that may be analogous to the consequences of MLL-rearrangement observed in the majority of IL cases and MLL+ therapy-related AML. These results also suggest that a combination of inherited variation from each parent is necessary to create a genetic background amenable to leukemic transformation, and are compatible with an influence from environmental exposures and the in utero establishment of leukemic clones in IL. Functional studies to determine if MLL3 dysfunction alone is sufficient for early onset AML or requires additive cooperativity with other congenital or acquired genetic lesions or specific exposures (e.g. topoisomerase II inhibitors) are necessary. Disclosures:No relevant conflicts of interest to declare.

Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner

Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2Rα-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.

Endogenous Subventricular Zone Neural Progenitors Contribute to the Formation and Hyperexcitability of Experimental Model of Focal Microgyria

Microgyria is associated with epilepsy and due to developmental disruption of neuronal migration. However, the role of endogenous subventricular zone-derived neural progenitors (SDNPs) in formation and hyperexcitability has not been fully elucidated. Here, we establish a neonatal cortex freeze-lesion (FL) model, which was considered as a model for focal microgyria, and simultaneously label SDNPs by CM-DiI. Morphological investigation showed that SDNPs migrated into FL and differentiated into neuronal and glia cell types, suggesting the involvement of endogenous SDNPs in the formation of FL-induced microgyria. Patch-clamp recordings in CM-DiI positive (CM-DiI(+)) pyramidal neurons within FL indicated an increase in frequency of spontaneous action potentials, while the resting membrane potential did not differ from the controls. We also found that spontaneous excitatory postsynaptic currents (EPSCs) increased in frequency but not in amplitude compared with controls. The evoked EPSCs showed a significant increase of 10-90% in rise time and decay time in the CM-DiI(+) neurons. Moreover, paired-pulse facilitation was dramatically larger in CM-DiI(+) pyramidal neurons. Western blotting data showed that AMPA and NMDA receptors were increased to some extent in the FL cortex compared with controls, and the NMDA/AMPA ratio of eEPSCs at CM-DiI(+) pyramidal neurons was significantly increased. Taken together, our findings provide novel evidence for the contribution of endogenous SDNPs in the formation and epileptogenicity of FL-induced focal microgyria.

P.1.j.003 Abnormal reward processing in the methylazoxymethanol (MAM) model of schizophrenia: neural and behavioural evidence

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus.

Developmental disruption by binge-eating disorder and bulimia nervosa: critical windows for detection and intervention

Developmental disruption by binge-eating disorder and bulimia nervosa: critical windows for detection and intervention

Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia

A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced “noise” in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbitofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the “signal-to-noise” ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input.

Morphological and Molecular Characterization of Dietary-Induced Pseudo-Albinism during Post-Embryonic Development of Solea senegalensis (Kaup, 1858)

The appearance of the pseudo-albino phenotype was investigated in developing Senegalese sole (Solea senegalensis, Kaup 1858) larvae at morphological and molecular levels. In order to induce the development of pseudo-albinos, Senegalese sole larvae were fed Artemia enriched with high levels of arachidonic acid (ARA). The development of their skin pigmentation was compared to that of a control group fed Artemia enriched with a reference commercial product. The relative amount of skin melanophores, xanthophores and iridophores revealed that larval pigmentation developed similarly in both groups. However, results from different relative proportions, allocation patterns, shapes and sizes of skin chromatophores revealed changes in the pigmentation pattern between ARA and control groups from 33 days post hatching onwards. The new populations of chromatophores that should appear at post-metamorphosis were not formed in the ARA group. Further, spatial patterns of distribution between the already present larval xanthophores and melanophores were suggestive of short-range interaction that seemed to be implicated in the degradation of these chromatophores, leading to the appearance of the pseudo-albino phenotype. The expression profile of several key pigmentation-related genes revealed that melanophore development was promoted in pseudo-albinos without a sufficient degree of terminal differentiation, thus preventing melanogenesis. Present results suggest the potential roles of asip1 and slc24a5 genes on the down-regulation of trp1 expression, leading to defects in melanin production. Moreover, gene expression data supports the involvement of pax3, mitf and asip1 genes in the developmental disruption of the new post-metamorphic populations of melanophores, xanthophores and iridophores.

Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

Chronic Disabling Fatigue in Adolescents

Chronic Disabling Fatigue in Adolescents