Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor l-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor... more
Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor l-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor behaviors and molecular alterations in a mouse model of dyskinesia. Transgenic mice overexpressing human COMT (TG) and their wildtype (WT) littermates received unilateral 6-OHDA lesions in the dorsal striatum and were treated chronically with l-DOPA for two weeks. l-DOPA-induced dyskinesia was exacerbated in TG mice without altering l-DOPA motor efficacy as determined by contralateral rotations or motor coordination. Inductions of FosB and phospho-acetylated histone 3 (molecular correlates of dyskinesia) were potentiated in the lesioned striatum of TG mice compared with their WT littermates. The TG mice had lower basal levels of dopamine in the striatum. In mice with lesions, l-DOPA induces a greater increase in the dopamine metabolite 3-methoxytyramine in...
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Abstract Rare genomic variants, termed copy number variants (CNVs), confer unprecedented degrees of risk for schizophrenia, autism spectrum disorders, intellectual disability, and attention deficit hyperactivity disorder. The pleiotropic... more
Abstract Rare genomic variants, termed copy number variants (CNVs), confer unprecedented degrees of risk for schizophrenia, autism spectrum disorders, intellectual disability, and attention deficit hyperactivity disorder. The pleiotropic actions of CNVs on seemingly diverse clinical diagnoses raise the tantalizing possibility that many clinically defined neuropsychiatric disorders share common genetic, molecular, and neuronal mechanisms, but their ultimate phenotypic features diverge under the modulatory influence of factors other than copy number variants. Mouse models of CNVs are being developed, and these studies have provided insights into the precise manner through which CNV-encoded genes contribute to dimensional features of neuropsychiatric disorders. Evidence suggests that individual genes encoded in contiguous deletion or duplication cause quantitative dimensional shifts in cognitive, socioemotional, and motivational domains in a non-contiguous manner and that the phenotypic targets of individual contributory genes are not identical. Thus, quantitative, dimensional profiling of CNV mouse models is a sound alternative to a disease-specific modeling.
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ABSTRACT
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The brain dopaminergic system is a critical modulator of basal ganglia function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor... more
The brain dopaminergic system is a critical modulator of basal ganglia function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor mutant mice. Histological analyses suggested that there are no major changes in general anatomy of the mutant mouse brains, but indicated that the expression of dynorphin is greatly reduced in the striatum and related regions of the basal ganglia. The mutant mice do not respond to the stimulant and suppressive effects of D1 receptor agonists and antagonists, respectively, and they exhibit locomotor hyperactivity. These results suggest that the D1 receptor regulates the neurochemical architecture of the striatum and is critical for the normal expression of motor activity.
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Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability or... more
Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability or attention-deficit/hyperactivity disorder. The unprecedented levels of robust and reproducible penetrance of copy number variants make them one of the most promising and reliable entry points to delve into the mechanistic bases of many mental disorders. However, the precise mechanistic bases of these associations still remain elusive in humans due to the many genes encoded in each copy number variant and the diverse associated phenotypic features. Genetically engineered mice have provided a technical means to ascertain precise genetic mechanisms of association between copy number variants and dimensional aspects of mental illnesses. Molecular, cellular and neuronal phenotypes can be detected as potential mechanistic substrates for various behavioral constructs of mental il...
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Copy number variants (CNVs) have provided a reliable entry point to identify structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however,... more
Copy number variants (CNVs) have provided a reliable entry point to identify structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which numerous genes encoded in this CNV contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in a mouse model. The heterozygosity ofTbx1, a22q11.2 gene, altered the composition of myelinated axons in the fimbria, reduced oligodendrocyte production capacity, and slowed the acquisition of spatial memory and cognitive flexibility. Our findings provide a cellular basis for specific cognitive dysfunctions that occur in patients with loss-of-functionTBX1variants and 22q11.2 hemizygous deletion.TeaserA risk gene for autism alters myelin composition in the hippocampal conn...
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Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is... more
Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute...
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Rare gene variants confer a high level of penetrance to neurodevelopmental disorders, but their developmental origin and cellular substrates remain poorly understood. To address this limitation, we explored the role of TBX1, a gene... more
Rare gene variants confer a high level of penetrance to neurodevelopmental disorders, but their developmental origin and cellular substrates remain poorly understood. To address this limitation, we explored the role of TBX1, a gene encoded in a rare copy number variant, in cell and mouse models. Here, we report that neonatal Tbx1 deficiency contributes to defective peripubertal social behavior and impairs the proliferation of neonatal neural stem/progenitor cells. Moreover, TBX1 transcriptionally regulates genes linked to post-embryonic neurogenesis and neurodevelopmental disorders associated with other rare gene variants. Our data indicate a precise time window and cell type through which the social dimension is altered by a gene encoded in a rare CNV and provide a potential common mechanistic basis for a group of neurodevelopmental disorders.One-Sentence SummaryTbx1, a gene affecting neonatal stem cell proliferation, influences peripubertal social behavior.
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Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function;... more
Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1, one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in my...
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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular... more
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a ...
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Copy number variants, such as duplications and hemizygous deletions at chromosomal loci of up to a few million base pairs, are highly associated with psychiatric disorders. Hemizygous deletions at human chromosome 22q11.2 were found to be... more
Copy number variants, such as duplications and hemizygous deletions at chromosomal loci of up to a few million base pairs, are highly associated with psychiatric disorders. Hemizygous deletions at human chromosome 22q11.2 were found to be associated with elevated instances of schizophrenia and autism spectrum disorder in 1992 and 2002, respectively. Following these discoveries, many mouse models have been developed and tested to analyze the effects of gene dose alterations in small chromosomal segments and single genes of 22q11.2. Despite several limitations to modeling mental illness in mice, mouse models have identified several genes on 22q11.2—Tbx1, Dgcr8, Comt, Sept5, and Prodh—that contribute to dimensions of autism spectrum disorder and schizophrenia, including working memory, social communication and interaction, and sensorimotor gating. Mouse studies have identified that heterozygous deletion of Tbx1 results in defective social communication during the neonatal period and so...
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We investigated the involvement of the hippocampal formation and the amygdala in the acquisition and expression of the amphetamine-produced conditioned place preference (CPP). Animals were conditioned in four sessions that included two... more
We investigated the involvement of the hippocampal formation and the amygdala in the acquisition and expression of the amphetamine-produced conditioned place preference (CPP). Animals were conditioned in four sessions that included two pairings of d-amphetamine (2.0 mg/kg, s.c.) with one of two distinct compartments and two pairings of vehicle with the other compartment in a counterbalanced manner. Animals' preferences for the compartments were then tested in the absence of amphetamine. The CPP was attenuated by preconditioning electrolytic or excitotoxic lesions of the lateral nucleus of amygdala, but not by electrolytic lesions of the central or basolateral nucleus of amygdala, endopiriform nucleus, or ventral hippocampus or by radio-frequency lesions of the fornix-fimbria. When the lateral nucleus of amygdala was damaged by electrolytic or excitotoxic lesions after conditioning, animals failed to express an amphetamine-produced CPP. These results demonstrate that expression o...
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Cocaine regulates the transcription factor CREB (adenosine 3′,5′-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the... more
Cocaine regulates the transcription factor CREB (adenosine 3′,5′-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of κ opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade—culminating in gene expression—through which exposure to cocaine modifies subsequent responsiveness to the drug.
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Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD),... more
Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of ...
Research Interests: Neuroscience, Psychology, Intelligence, Neurogenesis, Biology, and 15 moreIntellectual Disability, Medicine, Molecular Psychiatry, Executive Function, Biological Sciences, Neural stem cell, Hippocampus, Childhood, Proliferation, Autism Spectrum Disorder, Cognitive Deficits, Neurosciences, COMT, Hippocampal formation, and Medical and Health Sciences
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Research Interests: Genetics, Psychology, Communication, Autism, Medicine, and 15 moreMolecular Psychiatry, Biological Sciences, Mice, Female, Animals, Male, Phenotype, Autism Spectrum Disorder, Copy Number Variation, Genotype, Maternal Behavior, Risk Factors, Autistic disorder, Psychology and Cognitive Sciences, and Medical and Health Sciences
Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally... more
Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. NMS attenuated neural differentiation of adult neural precur...
Research Interests: Neurogenesis, Biology, Adult neurogenesis, Medicine, Biological Sciences, and 15 moreBiological Psychiatry, Neural stem cell, Female, Animals, Male, DNA methylation, Neurons, Dentate Gyrus, Rats, Neural Stem Cells, Maternal Separation, Maternal Deprivation, Hippocampal formation, Psychology and Cognitive Sciences, and Medical and Health Sciences
Copy number variation (CNV) of human chromosome 22q11.2 is associated with an elevated rate of autism spectrum disorder (ASD) and represents one of syndromic ASDs with rare genetic variants. However, the precise genetic basis of this... more
Copy number variation (CNV) of human chromosome 22q11.2 is associated with an elevated rate of autism spectrum disorder (ASD) and represents one of syndromic ASDs with rare genetic variants. However, the precise genetic basis of this association remains unclear due to its relatively large hemizygous and duplication region, including more than 30 genes. Previous studies using genetic mouse models suggested that although not all 22q11.2 genes contribute to ASD symptomatology, more than one 22q11.2 genes have distinct phenotypic targets for ASD symptoms. Our data show that deficiency of the two 22q11.2 genesTbx1 and Sept5 causes distinct phenotypic sets of ASD symptoms.
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Research Interests: Autism, Schizophrenia, Epilepsy, Biology, Intellectual Disability, and 15 moreMedicine, Biological Sciences, Biological Psychiatry, Brain, Humans, Mice, Female, Animals, Male, Copy Number Variation, Seizures, Chromosome Disorders, Psychology and Cognitive Sciences, Chromosome deletion, and Medical and Health Sciences
Research Interests: Psychology, Psychopharmacology, Schizophrenia, Behavioral Medicine, Medicine, and 14 moreMolecular Psychiatry, Biological Sciences, Humans, Smoking, Nicotine, Animals, Nicotine Dependence, Phenotype, Genetic Susceptibility, Knockout Mice, Monoamine oxidase, Psychology and Cognitive Sciences, Tobacco use disorder, and Medical and Health Sciences
Research Interests: Genetics, Psychology, Addiction, Animal Studies, Behavioral Medicine, and 15 moreMedicine, Comorbidity, Molecular Psychiatry, Antisocial Personality Disorder, Biological Sciences, Humans, Animals, Novelty, Antisocial Behavior, Genetic variation, Exploratory Behavior, Genetic Predisposition, Genetic Susceptibility, Novelty Seeking, and Medical and Health Sciences
Research Interests: Biology, Immunohistochemistry, Cell Biology, Medicine, Hearing, and 15 moreMice, Animals, Medical Physiology, Phenotype, Clinical Sciences, Genotype, Auditory Threshold, Septins, organ of Corti, Cochlea, Knockout Mice, Neurosciences, Gene Expression Regulation, Acoustic Stimulation, and reverse transcriptase polymerase chain reaction
Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric/behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are... more
Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric/behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an approximately 200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an approximately 200-kb region of human 22q11.2, containing CDCrel, GP1Bbeta, TBX1, and WDR14, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although Tbx1 has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency, Tbx1 heterozygous mice did not display these behavioral abnormalities. Our results show that the approximately 200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnorm...
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To directly address whether regulating mRNA localization can influence animal behavior, we created transgenic mice that conditionally express Zipcode Binding Protein 1 (ZBP1) in a subset of neurons in the brain. ZBP1 is an RNA-binding... more
To directly address whether regulating mRNA localization can influence animal behavior, we created transgenic mice that conditionally express Zipcode Binding Protein 1 (ZBP1) in a subset of neurons in the brain. ZBP1 is an RNA-binding protein that regulates the localization, as well as translation and stability of target mRNAs in the cytoplasm. We took advantage of the absence of ZBP1 expression in the mature brain to examine the effect of expressing ZBP1 on animal behavior. We constructed a transgene conditionally expressing a GFP-ZBP1 fusion protein in a subset of forebrain neurons and compared cocaine-cued place conditioning in these mice versus noninduced littermates. Transgenic ZBP1 expression resulted in impaired place conditioning relative to nonexpressing littermates, and acutely repressing expression of the transgene restored normal cocaine conditioning. To gain insight into the molecular changes that accounted for this change in behavior, we identified mRNAs that specifica...
Research Interests: Genetics, Biology, Medicine, Biological Sciences, Brain, and 15 moreMice, Cues, Animals, Cocaine, Male, Comparative Analysis, Cognitive processes, Immunoprecipitation, Microarray Analysis, Conditioning, Doxycycline, DNA binding proteins, Gene Expression Regulation, Forebrain, and Medical and Health Sciences
Deletion or duplication of the human chromosome 22q11.2 is associated with many behavioral traits and neuropsychiatric disorders, including autism spectrum disorders and schizophrenia. However, why phenotypes vary widely among individuals... more
Deletion or duplication of the human chromosome 22q11.2 is associated with many behavioral traits and neuropsychiatric disorders, including autism spectrum disorders and schizophrenia. However, why phenotypes vary widely among individuals with identical deletions or duplications of 22q11.2 and which specific 22q11.2 genes contribute to these phenotypes are still poorly understood. Previous studies have identified a approximately 200 kb 22q11.2 region that contributes to behavioral phenotypes in mice. We tested the role of Septin 5 (Sept5), a gene encoded in the approximately 200 kb region, in affective behaviors, cognitive capacities and motor activity. To evaluate the impact of genetic backgrounds on behavioral phenotypes of Sept5 deficiency, we used mice on two genetic backgrounds. Our data show that Sept5 deficiency decreased affiliative active social interaction, but this phenotypic expression was influenced by genetic backgrounds. In contrast, Sept5 deficiency decreased anxiety...
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Although twin studies indicate clear genetic bases of autism spectrum disorder (ASD), the precise mechanisms through which genetic variations causally result in ASD are poorly understood. Individuals with 3 Mb and nested 1.5 Mb... more
Although twin studies indicate clear genetic bases of autism spectrum disorder (ASD), the precise mechanisms through which genetic variations causally result in ASD are poorly understood. Individuals with 3 Mb and nested 1.5 Mb hemizygosity of the chromosome 22q11.2 represent genetically identifiable cases of ASD. However, because more than 30 genes are deleted even in the minimal deletion cases of 22q11.2 deficiency, the individual 22q11.2 gene(s) responsible for ASD remain elusive. Here, we examined the impact of constitutive heterozygosity of Tbx1, a 22q11.2 gene, on the behavioral phenotypes of ASD and characterized the regional and cellular expression of its mRNA and protein in mice. Congenic Tbx1 heterozygous (HT) mice were impaired in social interaction, ultrasonic vocalization, memory-based behavioral alternation, working memory and thigmotaxis, compared with wild-type (WT) mice. These phenotypes were not due to non-specific alterations in olfactory function, exploratory beh...
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Research Interests: Addiction, Medicine, Learning, Biological Sciences, Biological Psychiatry, and 15 moreClassical Conditioning, Mice, Cues, Nicotine, Animals, Male, Pavlovian conditioning, Extinction, Abstinence, Incentive, Mecamylamine, Choice Behavior, Nicotine withdrawal, Conditioned place preference, and Medical and Health Sciences
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Local infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) can prevent and reverse the ability of chronic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) in this brain region. The... more
Local infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) can prevent and reverse the ability of chronic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) in this brain region. The present study examined a possible role for extracellular signal regulated kinases (ERKs), the major effector for BDNF and related neurotrophins, in morphine and cocaine action in the VTA. Chronic, but not acute, administration of morphine or cocaine increased ERK catalytic activity specifically in the VTA. This increase in ERK activity reflected an increase in the state of phosphorylation of ERK, with no change in levels of total ERK immunoreactivity. Chronic infusions of BDNF into the VTA reduced total ERK immunoreactivity with no change in ERK activity, and also blocked the morphine-induced increase in ERK activity. These results suggest that chronic BDNF elicits a compensatory increase in the phosphorylation of the remaining ERK molecules and thereb...
Research Interests: Neuroscience, Chemistry, Medicine, Signal Transduction, Dopamine, and 13 moreGlutamate, Tyrosine Hydroxylase, Antisense Oligonucleotide Drugs, Ventral Tegmental Area, Drug Effects, Neurotrophic Factors, Extracellular, Catalytic Activity, Nucleotides, Glutamate Receptor, Brain-derived neurotrophic factor (BDNF), Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Neuroscience, Biology, Immunohistochemistry, Medicine, Dopamine, and 15 moreBrain, Animals, Cocaine, Male, Protein Tyrosine Kinase, DNA binding, Limbic System, Locomotor Activity, DNA binding proteins, Ciliary Neurotrophic Factor, dopaminergic, janus kinase, Psychology and Cognitive Sciences, Protein tyrosine kinases, and Medical and Health Sciences
Neonatal vocalization is structurally altered in mouse models of autism spectrum disorder (ASD). Our published data showed that pup vocalization, under conditions of maternal separation, contains sequences whose alterations in a genetic... more
Neonatal vocalization is structurally altered in mouse models of autism spectrum disorder (ASD). Our published data showed that pup vocalization, under conditions of maternal separation, contains sequences whose alterations in a genetic mouse model of ASD impair social communication between pups and mothers. We describe details of a method which reveals the statistical structure of call sequences that are functionally critical for optimal maternal care. Entropy analysis determines the degree of non-random call sequencing. A Markov model determines the actual call sequences used by pups. Sparse partial least squares discriminant analysis (sPLS-DA) identifies call sequences that differentiate groups and reveals the degrees of individual variability in call sequences between groups. These three sets of analyses can be used to identify the otherwise hidden call structure that is altered in mouse models of developmental neuropsychiatric disorders, including not only autism but also schiz...
Research Interests: Autism, Computational Biology, Biology, Medicine, Markov chains, and 3 moreMice, Animals, and Tape Recording
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Several human chromosomal regions have been identified as candidate regions that play a role in schizophrenia. Deletion or duplication of chromosome 22q11 is associated with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), a... more
Several human chromosomal regions have been identified as candidate regions that play a role in schizophrenia. Deletion or duplication of chromosome 22q11 is associated with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), a disorder associated with high rates of schizophrenia as well as physical abnormalities (i.e., cardiovascular, parathyroid, thymic and craniofacial abnormalities). Recent mouse studies have identified several candidate genes for VCFS/DGS within the mouse homologue chromosome 16. Deletion of Tbx1, Prodh and Comt within mouse chromosome 16 causes several physical and behavioral features of VCFS/DGS. As VCFS/DGS is likely to represent a genetic subtype of schizophrenia, pinpointing the genetic basis for this specific subtype will contribute to a better understanding of this neuropsychiatric disorder.
Research Interests: Genetics, Schizophrenia, Biology, Medicine, Humans, and 5 moreMice, Animals, Gene Duplication, Chromosome, and DiGeorge Syndrome
Previous work has shown that c-Fos and several Fos-like proteins or Fras (Fos-related antigens) are induced acutely in brain in response to a wide variety of stimuli. In contrast, several stimuli induce apparently distinct Fos-like... more
Previous work has shown that c-Fos and several Fos-like proteins or Fras (Fos-related antigens) are induced acutely in brain in response to a wide variety of stimuli. In contrast, several stimuli induce apparently distinct Fos-like proteins, termed chronic Fras, after chronic administration. We show that delta FosB, a truncated splice variant of FosB, responds like the other acute Fras: it is induced rapidly and transiently in cerebral cortex after acute electroconvulsive seizure (ECS) and in striatum after acute cocaine but does not accumulate after chronic ECS or cocaine treatment. Although the chronic Fras are immunochemically related to delta FosB, they can be distinguished from delta FosB based on their temporal properties in that they are induced after chronic ECS and cocaine treatments only. Moreover, the chronic Fras and delta FosB can be distinguished by their migration patterns on one- and two-dimensional gel electrophoresis. The chronic Fras, therefore, appear to be novel...
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Notch signaling regulates the development of a novel type of Thy1-expressing dendritic cell in the thymus Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor Two opposing roles of RBP-J in Notch signaling RBP-J promotes neuronal differentiation and ...more
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) required for T-cell activation and are classified into several subtypes by phenotypic and functional characteristics. However, it remains unclear if distinct... more
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) required for T-cell activation and are classified into several subtypes by phenotypic and functional characteristics. However, it remains unclear if distinct transcription factors control the development of each DC subpopulation. In this report, we demonstrate that Notch signaling controls the development of a novel DC subtype that expresses Thy1 (Thy1(+) DCs). Overstimulation of bone marrow cells with the Notch ligand Delta-like 1 promoted the development of Thy1(+) DCs. Thy1(+) DCs are characterized as CD11c(+) MHC class II(+) NK1.1(-) B220(-) CD8alpha(+) , and are present in the thymus but not in the spleen and lymph nodes. Thymic Thy1(+) DCs are able to capture exogenous proteins and delete CD4(+) CD8(+) T cells. Transplantation experiments demonstrated that CD44(+) CD25(-) and CD44(+) CD25(+) thymocytes can differentiate into Thy1(+) DCs. Recombination signal binding protein for immunoglobulin kappa J region ...
Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of... more
Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine.
Research Interests: Endocrinology, Psychology, Cognitive Science, Animal Behavior, Medicine, and 15 moreNucleus Accumbens, Dopamine, Internal Medicine, Animals, Cocaine, Male, Rats, Glial Fibrillary Acidic Protein, Species Specificity, Neurosciences, Gtp Binding Proteins, Sniffing, Motor activity, Stereotyped behavior, and Stereotypy
Whereas acute administration of many types of stimuli induces c‐Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region‐specific accumulation of novel Fos‐like proteins of 35–37 kD. These... more
Whereas acute administration of many types of stimuli induces c‐Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region‐specific accumulation of novel Fos‐like proteins of 35–37 kD. These proteins, termed chronic FRAs (Fos‐related antigens), have recently been shown to be isoforms of ΔFosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsychotic drugs (APDs) on induction of Fos‐like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these ΔFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces ΔFosB in caudate–putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of ΔFosB in any of the three brain regions, and even tended to reduce ΔFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of ΔFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of ΔFosB in CP and NAc is most dependent on antagonism of D2–D3 dopamine receptors, with antagonism of D1‐like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of ΔFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration of APDs results in the induction of long‐lasting Fos‐like transcription factors that could mediate some of the persistent and region‐specific changes in brain function associated with chronic drug exposure. Synapse 33:118–128, 1999. © 1999 Wiley‐Liss, Inc.
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Histological sections of the mammalian striatum reveal a “matrix” that is histochemically distinguishable from patches, or “striosomes”. The latter are cross sections of a compartment that consists primarily of tube-shaped structures... more
Histological sections of the mammalian striatum reveal a “matrix” that is histochemically distinguishable from patches, or “striosomes”. The latter are cross sections of a compartment that consists primarily of tube-shaped structures radiating through the matrix. As a test of the hypothesis that the function of the striosome/patch compartment includes the mediation of behaviors related to reward, the present study examined electrical self-stimulation of the caudoputamen in rats with electrodes in either of the two compartments. Rats acquired and maintained bar-pressing responses that were contingent on stimulation through electrodes making contact with striosomes/patches more reliably than animals with electrodes terminating exclusively in the matrix. The results provide in vivo evidence that the striosome/patch compartment is functionally differentiated from the matrix compartment: Stimulation centered in or around the striosome/patch compartment but not in the matrix led to rapid ...
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Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We... more
Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-related proteins of 35–37 kDa are induced in the striatum by chronic cocaine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using fos B mutant mice. The striatum of these mice completely lacked basal levels of the 35- to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration. This deficiency was associated with enhanced behavioral responses to cocaine: fos B mutant mice showed exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related...
Research Interests:
Research Interests:
Research Interests: Neuroscience, Psychology, Cognitive Science, Addiction, Biology, and 15 moreMedicine, Nucleus Accumbens, Reward, Brain Mapping, Animals, Male, Amphetamine, Rats, Globus Pallidus, Analysis of Variance, Conditioning, Operant Conditioning, Neurosciences, Dextroamphetamine, and Conditioned place preference
Research Interests:
Research Interests:
Nicotine is thought to act on brain monoamine systems that normally mediate diverse motivational behaviors. How monoamine-related genes contribute to behavioral traits (e.g. responses to novel stimuli) comorbid with the susceptibility to... more
Nicotine is thought to act on brain monoamine systems that normally mediate diverse motivational behaviors. How monoamine-related genes contribute to behavioral traits (e.g. responses to novel stimuli) comorbid with the susceptibility to nicotine addiction is still poorly understood. We examined the impact of constitutive monoamine oxidase A (MAOA) deficiency in mice on nicotine reward and responses to novel stimuli. Age-matched, male Maoa-knockout (KO) mice and wild-type (WT) littermates were tested for nicotine-induced conditioned place preference (CPP); voluntary oral nicotine preference/intake; spontaneous locomotor activity in a novel, inescapable open field; and novelty place preference. Nicotine preference in WT mice was reduced in Maoa-KO mice in the CPP and oral preference/intake tests. Control experiments showed that these phenotypes were not due to abnormalities in nicotine metabolism, fluid intake or response to taste. In contrast, Maoa-KO mice were normal in their behav...