Publications (10)39.5 Total impact
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Article: Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation.
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ABSTRACT: GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents--C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel--Gabra1, Gabrb2, and Gabrg2--and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3' UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4-100 fold differences in mRNA levels.PLoS ONE 01/2012; 7(4):e34586. · 4.09 Impact Factor -
Article: Sex-specific modulation of gene expression networks in murine hypothalamus.
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ABSTRACT: The hypothalamus contains nuclei and cell populations that are critical in reproduction and that differ significantly between the sexes in structure and function. To examine the molecular and genetic basis for these differences, we quantified gene expression in the hypothalamus of 39 pairs of adult male and female mice belonging to the BXD strains. This experimental design enabled us to define hypothalamic gene coexpression networks and provided robust estimates of absolute expression differences. As expected, sex has the strongest effect on the expression of genes on the X and Y chromosomes (e.g., Uty, Xist, Kdm6a). Transcripts associated with the endocrine system and neuropeptide signaling also differ significantly. Sex-differentiated transcripts often have well delimited expression within specific hypothalamic nuclei that have roles in reproduction. For instance, the estrogen receptor (Esr1) and neurokinin B (Tac2) genes have intense expression in the medial preoptic and arcuate nuclei and comparatively high expression in females. Despite the strong effect of sex on single transcripts, the global pattern of covariance among transcripts is well preserved, and consequently, males and females have well matched coexpression modules. However, there are sex-specific hub genes in functionally equivalent modules. For example, only in males is the Y-linked gene, Uty, a highly connected transcript in a network that regulates chromatin modification and gene transcription. In females, the X chromosome paralog, Kdm6a, takes the place of Uty in the same network. We also find significant effect of sex on genetic regulation and the same network in males and females can be associated with markedly different regulatory loci. With the exception of a few sex-specific modules, our analysis reveals a system in which sets of functionally related transcripts are organized into stable sex-independent networks that are controlled at a higher level by sex-specific modulators.Frontiers in Neuroscience 01/2012; 6:63. -
Article: Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
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ABSTRACT: Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.Journal of Neuroscience 04/2010; 30(15):5357-67. · 7.11 Impact Factor -
Article: High-throughput sequencing of the DBA/2J mouse genome.
BMC Bioinformatics. 01/2010; 11:O7. -
Article: Detection, validation, and downstream analysis of allelic variation in gene expression.
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ABSTRACT: Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control-or cis modulation-rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40-50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to approximately 80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.Genetics 11/2009; 184(1):119-28. · 4.01 Impact Factor -
Article: Dissection of a QTL hotspot on mouse distal chromosome 1 that modulates neurobehavioral phenotypes and gene expression.
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ABSTRACT: A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21-q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of approximately 20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes.PLoS Genetics 12/2008; 4(11):e1000260. · 8.69 Impact Factor -
Article: Genetic modulation of striatal volume by loci on Chrs 6 and 17 in BXD recombinant inbred mice.
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ABSTRACT: Natural variation in the absolute and relative size of different parts of the human brain is substantial, with a range that often exceeds a factor of 2. Much of this variation is generated by the cumulative effects of sets of unknown gene variants that modulate the proliferation, growth and death of neurons and glial cells. Discovering and testing the functions of these genes should contribute significantly to our understanding of differences in brain development, behavior and disease susceptibility. We have exploited a large population of genetically well-characterized strains of mice (BXD recombinant inbred strains) to map gene variants that influence the volume of the dorsal striatum (caudate-putamen without nucleus accumbens). We used unbiased methods to estimate volumes bilaterally in a sex-balanced sample taken from the Mouse Brain Library (www.mbl.org). We generated a matched microarray data set to efficiently evaluate candidate genes (www.genenetwork.org). As in humans, volume of the striatum is highly heritable, with greater than twofold differences among strains. We mapped a locus that modulates striatal volume on chromosome (Chr) 6 at 88 +/- 5 Mb. We also uncovered an epistatic interaction between loci on Chr 6 and Chr 17 that modulates striatal volume. Using bioinformatic tools and the corresponding expression database, we have identified positional candidates in these quantitative trait locus intervals.Genes Brain and Behavior 02/2008; 8(3):296-308. · 3.48 Impact Factor -
Article: Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning.
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ABSTRACT: A wealth of research identifies the amygdala as a key brain region mediating negative affect, and implicates amygdala dysfunction in the pathophysiology of anxiety disorders. Although there is a strong genetic component to anxiety disorders such as posttraumatic stress disorder (PTSD) there remains debate about whether abnormalities in amygdala function predispose to these disorders. In the present study, groups of C57BL/6 x DBA/2 (B x D) recombinant inbred strains of mice were selected for differences in volume of the basolateral amygdala complex (BLA). Strains with relatively small, medium, or large BLA volumes were compared for Pavlovian fear learning and memory, anxiety-related behaviors, depression-related behavior, and glucocorticoid responses to stress. Strains with relatively small BLA exhibited stronger conditioned fear responses to both auditory tone and contextual stimuli, as compared to groups with larger BLA. The small BLA group also showed significantly greater corticosterone responses to stress than the larger BLA groups. BLA volume did not predict clear differences in measures of anxiety-like behavior or depression-related behavior, other than greater locomotor inhibition to novelty in strains with smaller BLA. Neither striatal, hippocampal nor cerebellar volumes correlated significantly with any behavioral measure. The present data demonstrate a phenotype of enhanced fear conditioning and exaggerated glucocorticoid responses to stress associated with small BLA volume. This profile is reminiscent of the increased fear processing and stress reactivity that is associated with amygdala excitability and reduced amygdala volume in humans carrying loss of function polymorphisms in the serotonin transporter and monoamine oxidase A genes. Our study provides a unique example of how natural variation in amygdala volume associates with specific fear- and stress-related phenotypes in rodents, and further supports the role of amygdala dysfunction in anxiety disorders such as PTSD.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2008; 33(11):2595-604. · 6.99 Impact Factor -
Article: Genetic and structural analysis of the basolateral amygdala complex in BXD recombinant inbred mice.
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ABSTRACT: The amygdala integrates and coordinates emotional and autonomic responses. The genetics that underlie variation in amygdala structure may be coupled to variation in levels of aggression, fear, anxiety, and affiliated behaviors. We systematically quantified the volume and cell populations of the basolateral amygdala complex (BLAc) across 35 BXD recombinant inbred (RI) lines, the parental strains--C57BL/6J (B6) and DBA/2J (D2)--and F1 hybrids (n cases=199, bilateral analysis). Neuron number and volume vary 1.7- to 2-fold among strains (e.g., neuron number ranged from 88,000 to 170,000). Glial and endothelial populations ranged more widely (5- to 8-fold), in part because of higher technical error. A quantitative trait locus (QTL) for the BLAc size is located on chromosome (Chr) 8 near the Large gene. This locus may also influence volume of other regions including hippocampus and cerebellum. Cell populations in the BLAc appear to be modulated more weakly by loci on Chrs 11 and 13. Candidate genes were selected on the basis of correlation with BLAc traits, chromosomal location, single nucleotide polymorphism (SNP) density, and expression patterns in the Allen Brain Atlas. Neurod2, a gene shown to be significant for the formation of the BLAc by knockout studies, is among the candidates genes. Other candidates include Large, and Thra. Responses to drugs of abuse and locomotor activity were the most notable behavioral correlates of the BLAc traits.Behavior Genetics 02/2007; 37(1):223-43. · 2.52 Impact Factor -
Article: Differential covariation in taste responsiveness to bitter stimuli in rats.
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ABSTRACT: Variation exists in the sensitivity of individual rodents and humans to different bitter tastants. An absence of uniform correlation in responsiveness to different bitter substances across individuals within a species suggests heterogeneity in the mechanisms underlying stimulus processing within this taste modality. Here, we examined taste responsiveness of individual rats to three bitter compounds (quinine hydrochloride, denatonium benzoate, and cycloheximide) in short-term lick tests to determine the magnitude of covariation among responses to these stimuli and infer commonalities in their receptor and neural mechanisms. Rats were tested with a given pair of bitter stimuli during three sessions comprising randomized trial blocks of six concentrations of each stimulus + deionized water. Psychophysical functions were generated for individual rats for respective stimulus pairs, and concentrations of each stimulus that produced equivalent lick suppression relative to water were correlated across animals. Behavioral taste responsiveness to quinine hydrochloride strongly covaried with responsiveness to denatonium benzoate (r = +0.82). Lick responsiveness to quinine was less robustly correlated with that to cycloheximide (r = +0.44), and denatonium and cycloheximide responses failed to correlate. These results imply substantial overlap in the bitter taste coding mechanisms for quinine and denatonium but some degree of independence in the mechanisms responsible for gustatory processing of cycloheximide. More generally, these data reinforce the notion that bitter taste processing is not a homogeneous event.Chemical Senses 12/2005; 30(9):793-9. · 2.60 Impact Factor
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- Behavior Genetics (1)
- Chemical Senses (1)
- Journal of Neuroscience (1)
- PLoS Genetics (1)
- Genes Brain and Behavior (1)
Institutions
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2007–2012
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The University of Tennessee Health Science Center
- Department of Anatomy and Neurobiology
Memphis, TN, USA
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