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1.
Mol Psychiatry ; 21(10): 1417-33, 2016 10.
Article in English | MEDLINE | ID: mdl-26830142

ABSTRACT

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a ß-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the ß-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.


Subject(s)
Stereotypic Movement Disorder/genetics , Stereotypic Movement Disorder/physiopathology , Adaptor Proteins, Signal Transducing/genetics , Animals , Behavior, Animal , Brain/embryology , Brain/metabolism , Brain/physiology , Dishevelled Proteins/genetics , Dishevelled Proteins/metabolism , Humans , Mice , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/physiology , Neural Stem Cells/metabolism , Neurons/metabolism , POU Domain Factors/metabolism , POU Domain Factors/physiology , Phosphoproteins/genetics , Signal Transduction/physiology , Stereotyped Behavior/physiology , T-Box Domain Proteins/metabolism , T-Box Domain Proteins/physiology , Wnt Proteins/metabolism , Wnt Signaling Pathway/genetics , Wnt Signaling Pathway/physiology , beta Catenin/metabolism , beta Catenin/physiology
3.
Mol Psychiatry ; 20(1): 118-25, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25199916

ABSTRACT

Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.


Subject(s)
Autistic Disorder/pathology , Brain/pathology , Disease Models, Animal , Multigene Family/genetics , Animals , Autistic Disorder/genetics , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Mice , Mice, Inbred BALB C , Mice, Transgenic
4.
Phys Rev Lett ; 108(11): 112502, 2012 Mar 16.
Article in English | MEDLINE | ID: mdl-22540469

ABSTRACT

We report the first measurement of the parity-violating asymmetry A(PV) in the elastic scattering of polarized electrons from 208Pb. A(PV) is sensitive to the radius of the neutron distribution (R(n)). The result A(PV)=0.656±0.060(stat)±0.014(syst) ppm corresponds to a difference between the radii of the neutron and proton distributions R(n)-R(p)=0.33(-0.18)(+0.16) fm and provides the first electroweak observation of the neutron skin which is expected in a heavy, neutron-rich nucleus.

5.
Neuroscience ; 179: 80-93, 2011 Apr 14.
Article in English | MEDLINE | ID: mdl-21256192

ABSTRACT

Although the orbitofrontal cortex has been implicated in important aspects of social behavior, few studies have evaluated semi-naturalistic social behavior in nonhuman primates after discrete lesions of this cortical area. In the present report, we evaluated the behavior of adult rhesus monkeys during dyadic social interactions with novel animals following discrete lesions of the orbitofrontal cortex. In a constrained condition, in which animals could engage in only restricted social behaviors, there were no significant differences in social behavior between the lesion group and the sham-operated control group. When the experimental animals could freely interact with partner animals, however, lesioned animals differed from control animals in terms of social interest and fear-related behaviors. These alterations were contingent on the partner with which they interacted. The lesioned animals, when compared to the control animals, had a significantly greater propensity to approach some but not all of their social partners. They also grimaced more towards the partner animal that they did not approach. Behavioral alterations were more apparent during the initial interactions between animals. We discuss these findings in relation to the role of the orbitofrontal cortex in context dependent modulation of social behavior.


Subject(s)
Behavior, Animal/physiology , Frontal Lobe/physiology , Social Behavior , Animals , Frontal Lobe/injuries , Macaca mulatta
6.
Behav Neurosci ; 122(5): 1005-15, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18823158

ABSTRACT

The emergence of stereotypies was examined in juvenile rhesus monkeys (Macaca mulatta) who, at 2 weeks of postnatal age, received selective bilateral ibotenic acid lesions of the amygdala (N = 8) or hippocampus (N = 8). The lesion groups were compared to age-matched control subjects that received a sham surgical procedure (N = 8). All subjects were maternally reared for the first 6 months and provided access to social groups throughout development. Pronounced stereotypies were not observed in any of the experimental groups during the first year of life. However, between 1 to 2 years of age, both amygdala- and hippocampus-lesioned subjects began to exhibit stereotypies. When observed as juveniles, both amygdala- and hippocampus-lesioned subjects consistently produced more stereotypies than the control subjects in a variety of contexts. More interesting, neonatal lesions of either the amygdala or hippocampus resulted in unique repertoires of repetitive behaviors. Amygdala-lesioned subjects exhibited more self-directed stereotypies and the hippocampus-lesioned subjects displayed more head-twisting. We discuss these results in relation to the neurobiological basis of repetitive stereotypies in neurodevelopmental disorders, such as autism.


Subject(s)
Amygdala/injuries , Amygdala/physiology , Hippocampus/injuries , Hippocampus/physiology , Stereotyped Behavior/physiology , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Behavior, Animal , Body Weight , Female , Macaca mulatta , Male
7.
Brain ; 129(Pt 1): 256-71, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16246864

ABSTRACT

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. Mass spectrometric analysis of the entire protein complement of the isolated inclusions, combined with immunohistochemical analysis of both isolated nuclei and tissue sections, has been used to identify inclusion-associated proteins. More than 20 inclusion-associated proteins have been identified on the basis of combined immunohistochemical and mass spectrometric analysis, including a number of neurofilaments and lamin A/C. There is no dominant protein species in the inclusions, and ubiquitinated proteins represent only a minor component; thus, inclusion formation is not likely to reflect a breakdown in proteasomal degradation of nuclear proteins. The list of proteins includes at least two RNA binding proteins, heterogeneous nuclear ribonucleoprotein A2 and muscle blind-like protein 1, which are possible mediators of the RNA gain-of-function in FXTAS.


Subject(s)
Ataxia/metabolism , Fragile X Syndrome/metabolism , Intranuclear Inclusion Bodies/chemistry , Nuclear Proteins/analysis , Tremor/metabolism , Aged , Ataxia/genetics , Base Sequence , Blotting, Western/methods , Brain/ultrastructure , Brain Chemistry , Chromatography, Liquid , Crystallins/analysis , Electrophoresis, Gel, Two-Dimensional , Flow Cytometry , Fluorescent Antibody Technique , Heterogeneous-Nuclear Ribonucleoprotein Group A-B/analysis , Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics , Humans , Laminin/analysis , Male , Molecular Sequence Data , Myelin Basic Protein/analysis , Myelin Basic Protein/genetics , Nuclear Proteins/genetics , Peptide Mapping , RNA-Binding Proteins/analysis , Spectrum Analysis , Tremor/genetics , Ubiquitin/analysis
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