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1.  Revealing a latent variable: Individual differences in affective response to repeated injections 
Behavioral neuroscience  2015;129(5):679-682.
Latent variables may exist in experimental designs and may interfere with reproducibility of findings. The present study reveals one such variable, the individual differences in affective response to chronic injection stress, by using the novelty-seeking phenotype as a model of differential emotional reactivity. The phenotype is identified by exposing a population of experimentally-naïve outbred rats to the mild stress of a novel environment and classifying them as high responders (HR; upper 1/3rd) and low responders (LR; lower 1/3rd) based on their locomotor reactivity. Research has shown that HR/LR animals differ in their basal levels of anxiety- and depressive-like behavior, as well as in their response to environmental and pharmacological challenges; suggesting validity of this model in studying individual differences in stress reactivity. The present data showed that 14 daily, intraperitoneal saline injections did not alter the phenotypic differences in social behavior observed basally in HR/LR rats. However, injections significantly increased time spent immobile in the forced swim test in LRs, while the identical regimen significantly decreased the same measure in HRs, compared to handled-controls. These data indicate that individual differences in stress reactivity can have a significant impact on the depressive-like responses to repeated intraperitoneal injections in rats. Given that such underlying emotional variability exists within standard, outbred rat populations, this study highlights the importance of accounting for such variability in any study investigating the effects of repeated drug administration on depressive-like behavior for reliability and replicability of findings. Thus, we recommend including an uninjected control group in all studies.
doi:10.1037/bne0000084
PMCID: PMC4586401  PMID: 26191946
Replication of findings; stress reactivity; depressive-like behavior; repeated injection stress; individual differences
2.  Lesions of the paraventricular nucleus of the thalamus differentially affect sign- and goal-tracking conditioned responses 
The European journal of neuroscience  2015;42(7):2478-2488.
Recently evidence has emerged suggesting a role for the paraventricular nucleus of the thalamus (PVT) in the processing of reward-associated cues. However, the specific role of the PVT in these processes has yet to be elucidated. Here we use an animal model that captures individual variation in response to discrete reward-associated cues to further assess the role of the PVT in stimulus-reward learning. When rats are exposed to a Pavlovian conditioning paradigm, wherein a discrete cue predicts food reward, two distinct conditioned responses emerge. Some rats, termed sign-trackers, approach and manipulate the cue; whereas others, termed goal-trackers, approach the location of reward delivery upon cue presentation. For both sign- and goal-trackers the cue is a predictor; but only for sign-trackers is it also an incentive stimulus. We investigated the role of the PVT in the acquisition and expression of these conditioned responses using an excitotoxic lesion. Results indicate that PVT lesions prior to acquisition amplify the differences between phenotypes—increasing sign-tracking and attenuating goal-tracking behavior. Lesions of the PVT after rats had acquired their respective conditioned responses also attenuated the expression of the goal-tracking response, and increased the sign-tracking response, but did so selectively in goal-trackers. These results suggest that the PVT acts to suppress the attribution of incentive salience to reward cues, as disruption of the functional activity within this structure enhances the tendency to sign-track.
doi:10.1111/ejn.13031
PMCID: PMC4596770  PMID: 26228683
Pavlovian Conditioning; Motivation; PVT; Incentive Salience; Rats
3.  Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity 
Neuropsychopharmacology  2015;40(9):2113-2123.
Pavlovian cues associated with junk-foods (caloric, highly sweet, and/or fatty foods), like the smell of brownies, can elicit craving to eat and increase the amount of food consumed. People who are more susceptible to these motivational effects of food cues may have a higher risk for becoming obese. Further, overconsumption of junk-foods leading to the development of obesity may itself heighten attraction to food cues. Here, we used a model of individual susceptibility to junk-foods diet-induced obesity to determine whether there are pre-existing and/or diet-induced increases in attraction to and motivation for sucrose-paired cues (ie, incentive salience or ‘wanting'). We also assessed diet- vs obesity-associated alterations in mesolimbic function and receptor expression. We found that rats susceptible to diet-induced obesity displayed heightened conditioned approach prior to the development of obesity. In addition, after junk-food diet exposure, those rats that developed obesity also showed increased willingness to gain access to a sucrose cue. Heightened ‘wanting' was not due to individual differences in the hedonic impact (‘liking') of sucrose. Neurobiologically, Mu opioid receptor mRNA expression was lower in striatal ‘hot-spots' that generate eating or hedonic impact only in those rats that became obese. In contrast, prolonged exposure to junk-food resulted in cross-sensitization to amphetamine-induced locomotion and downregulation of striatal D2R mRNA regardless of the development of obesity. Together these data shed light on individual differences in behavioral and neurobiological consequences of exposure to junk-food diets and the potential contribution of incentive sensitization in susceptible individuals to greater food cue-triggered motivation.
doi:10.1038/npp.2015.71
PMCID: PMC4613617  PMID: 25761571
4.  Protective Effects of Chronic Mild Stress during Adolescence in the Low Novelty Responder Rat 
Stress (Amsterdam, Netherlands)  2015;19(1):133-138.
Stress-elicited behavioral and physiologic responses vary widely across individuals and depend on a combination of environmental and genetic factors. Adolescence is an important developmental period when neural circuits that guide emotional behavior and stress reactivity are still maturing. A critical question is whether stress exposure elicits contrasting effects when it occurs during adolescence versus adulthood. We previously found that Sprague Dawley rats selectively-bred for low behavioral response to novelty (bred Low Responders; bLRs) are particularly sensitive to chronic unpredictable mild stress (CMS) exposure in adulthood, which exacerbates their typically high levels of spontaneous depressive- and anxiety- like behavior. Given developmental processes known to occur during adolescence, we sought to determine whether the impact of CMS on bLR rats is equivalent when they are exposed to it during adolescence as compared to adulthood. Young bLR rats were either exposed to CMS or control condition from postnatal day 35-60. As adults we found that CMS-exposed bLRs maintained high levels of sucrose preference and exhibited increased social exploration along with decreased immobility on the forced swim test compared to bLR controls. These data indicate a protective effect of CMS exposure during adolescence in bLR rats.
doi:10.3109/10253890.2015.1108304
PMCID: PMC4903024  PMID: 26473581
adolescence; rat; chronic stress; depression; anxiety; social interaction
5.  Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders 
Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.
doi:10.3390/microarrays5010006
PMCID: PMC4795482  PMID: 26998349
expression quantitative trait locus; major histocompatibility locus II; exon array; alternative splicing
6.  Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety 
Developmental neuroscience  2015;37:203-214.
The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high vs. low behavioral response to novelty and found that high reactive (bHR) rats display greater risk-taking, impulsivity, and aggression relative to low reactive (bLR) rats, which show high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior on bLR offspring’s brain development and emotional behavior. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine effects on: 1) developmental gene expression in the hippocampus and amygdala; and 2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain’s developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations.
doi:10.1159/000374108
PMCID: PMC4485591  PMID: 25791846
social interaction; open field test; amygdala; hippocampus; microarray; cross-foster
7.  Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders 
Microarrays  2016;5(1):6.
Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.
doi:10.3390/microarrays5010006
PMCID: PMC4795482  PMID: 26998349
expression quantitative trait locus; major histocompatibility locus II; exon array; alternative splicing
8.  Early-life Exposure to the SSRI Paroxetine Exacerbates Depression-like Behavior in Anxiety/Depression-prone rats 
Neuroscience  2014;0:775-797.
Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10–20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children’s developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers’ anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively-bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10 mg/kg/day p.o.) to examine its effects on offspring’s emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams’ pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7–21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.
doi:10.1016/j.neuroscience.2014.10.044
PMCID: PMC4267992  PMID: 25451292
depression; anxiety; neurodevelopment; hippocampus; amygdala; antidepressant
9.  Mitochondrial Mutations in Subjects with Psychiatric Disorders 
PLoS ONE  2015;10(5):e0127280.
A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.
doi:10.1371/journal.pone.0127280
PMCID: PMC4444211  PMID: 26011537
10.  Fibroblast Growth Factor-2: An Endogenous Antidepressant and Anxiolytic Molecule? 
Biological psychiatry  2012;72(4):254-255.
doi:10.1016/j.biopsych.2012.05.025
PMCID: PMC4417938  PMID: 22840947
prefrontal cortex; hippocampus; neurogenesis; stress; anxiety; depression
11.  ANTECEDENTS AND CONSEQUENCES OF DRUG ABUSE IN RATS SELECTIVELY BRED FOR HIGH AND LOW RESPONSE TO NOVELTY 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.04.033.
Human genetic and epidemiological studies provide evidence that only a subset of individuals who experiment with potentially addictive drugs become addicts. What renders some individuals susceptible to addiction remains to be determined, but most would agree that there is no single trait underlying the disorder. However, there is evidence in humans that addiction liability has a genetic component, and that certain personality characteristics related to temperament (e.g. the sensation-seeking trait) are associated with individual differences in addiction liability. Consequently, we have used a selective breeding strategy based on locomotor response to a novel environment to generate two lines of rats with distinct behavioral characteristics. We have found that the resulting phenotypes differ on a number of neurobehavioral dimensions relevant to addiction. Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats exhibit increased exploratory behavior, are more impulsive, more aggressive, seek stimuli associated with rewards, and show a greater tendency to relapse. We therefore utilize this unique animal model to parse the genetic, neural and environmental factors that contribute to addiction liability. Our work shows that the glucocorticoid receptor (GR), dopaminergic molecules, and members of the fibroblast growth factor family are among the neurotransmitters and neuromodulators that play a role in both the initial susceptibility to addiction as well as the altered neural responses that follow chronic drug exposure. Moreover, our findings suggest that the hippocampus plays a major role in mediating vulnerability to addiction. It is hoped that this work will emphasize the importance of personalized treatment strategies and identify novel therapeutic targets for humans suffering from addictive disorders.
doi:10.1016/j.neuropharm.2013.04.033
PMCID: PMC3766490  PMID: 23639434
addiction; selectively bred; dopamine; fibroblast growth factor (FGF); cocaine; novelty-seeking; high-responder; low-responder
12.  Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex 
Schizophrenia research  2013;152(1):111-116.
The rs1344706, an intronic SNP within the zinc-finger protein 804A gene (ZNF804A), was identified as one of the most compelling risk SNPs for schizophrenia (SZ) and bipolar disorder (BD). It is however not clear by which molecular mechanisms ZNF804A increases disease risk. We evaluated the role of ZNF804A in SZ and BD by genotyping the originally associated rs1344706 SNP and an exonic SNP (rs12476147) located in exon four of ZNF804A in a sample of 428 SZ, 385 BD, and 578 controls from the isolated population of the Costa Rica Central Valley. We also investigated the rs1344706 SNP for allelic specific expression (ASE) imbalance in the dorsolateral prefrontal cortex (DLPFC) of 46 heterozygous postmortem brains.
While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p =0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value = 0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value = 0.02, for heterozygous subjects vs. genomic DNA).
In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subjects design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex.
doi:10.1016/j.schres.2013.11.021
PMCID: PMC3947280  PMID: 24315717
schizophrenia; bipolar disorder; ZNF804A; association study; rs1344706; allelic-specific expression
13.  INTERACTION BETWEEN CHOLECYSTOKININ AND THE FIBROBLAST GROWTH FACTOR SYSTEM IN THE VENTRAL TEGMENTAL AREA OF SELECTIVELY BRED HIGH- AND LOW-RESPONDER RATS 
Neuroscience  2013;255:10.1016/j.neuroscience.2013.09.063.
Individual differences in the locomotor response to novelty have been linked to basal differences in dopaminergic neurotransmission. Mesolimbic dopaminergic outputs are regulated by cholecystokinin (CCK), a neuropeptide implicated in anxiety. In turn, CCK expression is regulated by fibroblast growth factor-2 (FGF2), which has recently been identified as an endogenous regulator of anxiety. FGF2 binds to the high-affinity fibroblast growth factor receptor-1 (FGF-R1) to regulate the development and maintenance of dopamine neurons in the ventral tegmental area (VTA). However, the relationship between the FGF and CCK systems in the VTA is not well understood. Therefore, we utilized the selectively-bred low-responder (bLR; high-anxiety) and high-responder (bHR; low-anxiety) rats to examine the effects of repeated (21-day) FGF2 treatment on CCK and FGF-R1 mRNA in the rostral VTA (VTAr). In vehicle-treated controls, both CCK and FGF-R1 mRNA levels were increased in the VTAr of bLR rats relative to bHR rats. Following FGF2 treatment, however, bHR-bLR differences in CCK and FGF-R1 mRNA expression were eliminated, due to decreased CCK mRNA levels in the VTAr of bLR rats and increased FGF-R1 expression in bHR rats. Differences after FGF2 treatment may denote distinct interactions between the CCK and FGF systems in the VTAr of bHR vs. bLR rats. Indeed, significant correlations between CCK and FGF-R1 mRNA expression were found in bHR, but not bLR rats. Colocalization studies suggest that CCK and FGF-R1 are coexpressed in some VTAr neurons. Taken together, our findings suggest that the FGF system is poised to modulate both CCK and FGF-R1 expression in the VTAr, which may be associated with individual differences in mesolimbic pathways associated with anxietylike behavior.
doi:10.1016/j.neuroscience.2013.09.063
PMCID: PMC3855030  PMID: 24121132
Fibroblast growth factor-2; fibroblast growth factor receptor-1; novelty response; in situ hybridization; colocalization; individual differences
14.  Glucocorticoid and Mineralocorticoid Receptor Expression in the Human Hippocampus in Major Depressive Disorder 
Journal of psychiatric research  2012;47(3):307-314.
Approximately 50% of mood disorder patients exhibit hypercortisolism. Cortisol normally exerts its functions in the CNS via binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Both MR and GR are highly expressed in human hippocampus and several studies have suggested that alterations in the levels of MR or GR within this region may contribute to the dysregulation in major depressive disorder (MDD). Studies have also shown functional heterogeneity across the hippocampus, with posterior hippocampus preferentially involved in cognitive processes and anterior hippocampus involved in stress, emotion and affect. We therefore hypothesize that GR and MR expression in hippocampus of control and MDD patients may vary not only with disease, but also with regional specificity along the anterior/posterior axis. Student’s t-test analysis showed decreased expression of MR in the MDD group compared to controls in the anterior, but not the posterior hippocampus, with no significant changes in GR. Linear regression analysis showed a marked difference in MR:GR correlation between suicide and non-suicide patients in the posterior hippocampus. Our findings are consistent with previous reports of hippocampal corticosteroid receptor dysregulation in mood disorders, but extend those findings by analysis across the anterior/posterior axis of the hippocampus. A decrease in MR in the anterior but not posterior hippocampus of MDD patients emphasizes the important functional role of the anterior hippocampus in neuroendocrine regulation in humans.
doi:10.1016/j.jpsychires.2012.11.002
PMCID: PMC4248661  PMID: 23219281
15.  Differential impact of a complex environment on positive affect in an animal model of individual differences in emotionality 
Neuroscience  2013;0:436-447.
Anhedonia, or the inability to experience positive feelings is a hallmark of depression. However, few animal models have relied on decreased positive affect as an index of susceptibility to depression. Rats emit frequency modulated ultrasonic vocalizations (USVs), designated as “positive” calls in the 50kHz range. USVs have been associated with pharmacological activation of motivational reward circuits. Here we utilized selectively-bred rats differing in “emotionality” to ask whether there are associated differences in USVs. Rats bred based on locomotor response to novelty and classified as bred high-responders (bHRs) or bred low-responder (bLRs) exhibit inborn differences in response to environmental cues, stress responsiveness, and depression-like behavior. These animals also exhibit differences in anxiety-like behavior, which are reversed by exposure to environmental complexity (EC). Finally, these animals exhibit unique profiles of responsiveness to rewarding stimuli accompanied with distinct patterns of dopamine regulation. We investigated whether acute and chronic environmental manipulations impacted USVs in bHRs and bLRs. We found that, relative to bLRs, bHRs emitted significantly more 50 kHz USVs. However, if a bLR is accompanied by another bLR, there is a significant increase in 50kHZ USVs emitted by this phenotype. bHRs emitted increases in 50kHZ UVSs upon first exposure to EC, whereas bLRs showed a similar increase only after repeated exposure. bLRs’ increase in positive affect after chronic EC was coupled with significant positive correlations between corticosterone levels and c-fos mRNA in the accumbens. Conversely, a decline in the rate of positive calls in bHRs after chronic EC was associated with a negative correlation between corticosterone and accumbens c-fos mRNA. These studies demonstrate that inborn differences in emotionality interact with the environment to influence positive affect and underscore the potential interaction between glucocorticoids and the mesolimbic reward circuitry in modulating 50 kHz calls.
doi:10.1016/j.neuroscience.2013.06.015
PMCID: PMC3841231  PMID: 23806722
Ultrasonic vocalization; Affect; Emotionality; Individual Differences
16.  LONG-TERM EFFECTS OF COCAINE EXPERIENCE ON NEUROPLASTICITY IN THE NUCLEUS ACCUMBENS CORE OF ADDICTION-PRONE RATS 
Neuroscience  2013;0:571-584.
Repeated exposure to drugs of abuse is associated with structural plasticity in brain reward pathways. Rats selectively bred for locomotor response to novelty differ on a number of neurobehavioral dimensions relevant to addiction. This unique genetic animal model was used here to examine both pre-existing differences and long-term consequences of repeated cocaine treatment on structural plasticity. Selectively bred high-responder (bHR) and low-responder (bLR) rats received repeated saline or cocaine injections for 9 consecutive days. Escalating doses of cocaine (7.5, 15 and 30 mg/kg) were administered on the first (day 1) and last (day 9) days of treatment and a single injection of the intermediate dose (15 mg/kg) was given on days 2-8. Motor activity in response to escalating doses of cocaine was compared on the first and last days of treatment to assess the acute and sensitized response to the drug. Following prolonged cocaine abstinence (28 days), spine density was examined on terminal dendrites of medium spiny neurons in the nucleus accumbens core. Relative to bLRs, bHRs exhibited increased psychomotor activation in response to both the acute and repeated effects of cocaine. There were no differences in spine density between bHR and bLR rats under basal conditions or following repeated saline treatment. However, spine density differed markedly between these two lines following prolonged cocaine abstinence. All spine types were decreased in cocaine-treated bHRs, while only mushroom spines were decreased in bLRs that received cocaine. Changes in spine density occurred specifically near the branch point of terminal dendrites. These findings indicate that structural plasticity associated with prolonged cocaine abstinence varies markedly in two selected strains of rats that vary on numerous traits relevant to addiction. Thus, genetic factors that contribute to individual variation in the behavioral response to cocaine also influence cocaine-induced structural plasticity.
doi:10.1016/j.neuroscience.2013.06.042
PMCID: PMC3859827  PMID: 23811073
cocaine; psychomotor sensitization; dendrites; prolonged abstinence; spine density; addiction
17.  Analysis of miR-137 Expression and rs1625579 in Dorsolateral Prefrontal Cortex 
Journal of psychiatric research  2013;47(9):1215-1221.
MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia (Ripke et al., 2011). Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) (Potkin et al., 2010).
We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: 1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and 2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value=0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value=1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders.
doi:10.1016/j.jpsychires.2013.05.021
PMCID: PMC3753093  PMID: 23786914
schizophrenia; bipolar disorder; rs1625579; miR-137; TCF4; gene expression
18.  High Novelty-Seeking Rats Are Resilient to Negative Physiological Effects of the Early Life Stress 
Stress (Amsterdam, Netherlands)  2013;17(1):97-107.
Exposure to early life stress dramatically impacts adult behavior, physiology, and neuroendocrine function. Using rats bred for novelty-seeking differences and known to display divergent anxiety, depression, and stress vulnerability, we examined the interaction between early life adversity and genetic predisposition for high- versus low-emotional reactivity. Thus, bred Low Novelty Responder (bLR) rats, which naturally exhibit high anxiety- and depression-like behavior, and bred High Novelty Responder (bHR) rats, which show low anxiety/depression together with elevated aggression, impulsivity, and addictive behavior, were subjected to daily 3 h maternal separation (MS) stress postnatal days 1–14. We hypothesized that MS stress would differentially impact adult bHR/bLR behavior, physiology (stress-induced defecation), and neuroendocrine reactivity. While MS stress did not impact bHR and bLR anxiety-like behavior in the open field test and elevated plus maze, it exacerbated bLRs’ already high physiological response to stress – stress-induced defecation. In both tests, MS bLR adult offspring showed exaggerated stress-induced defecation compared to bLR controls while bHR offspring were unaffected. MS also selectively impacted bLRs’ (but not bHRs’) neuroendocrine stress reactivity, producing an exaggerated corticosterone acute stress response in MS bLR versus control bLR rats. These findings highlight how genetic predisposition shapes individuals’ response to early life stress. Future work will explore neural mechanisms underlying the distinct behavioral and neuroendocrine consequences of MS in bHR/bLR animals.
doi:10.3109/10253890.2013.850670
PMCID: PMC4141530  PMID: 24090131
bred High Responder (bHR); bred Low Responder (bLR); stress-induced defecation; maternal separation stress; corticosterone
19.  Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse 
Hippocampal plasticity (e.g., neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and BrdU for older cells born prior to sensitization. Results show that: (1) bHRs exhibited greater psychomotor response to cocaine than bLRs. (2) Acute cocaine did not alter cell proliferation in bLR/bHR rats. (3) Chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence. (4) Neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype. (5) Cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine. (6) Cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR versus bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization.
PMCID: PMC4037740  PMID: 20104651
psychomotor sensitization; cell genesis; dentate gyrus; hippocampus; bLR/bHR rats
20.  Male rats that differ in novelty exploration demonstrate distinct patterns of sexual behavior 
Behavioral neuroscience  2013;127(1):47-58.
High versus low novelty exploration predicts a variety of behavioral differences. For example, rats selectively-bred for high novelty exploration (bred High Responders, bHR) exhibit exaggerated aggression, impulsivity, and proclivity to addictive behaviors compared to low novelty-reactive rats (bred Low Responders, bLRs), which are characterized by a high anxiety/depressive-like phenotype. Since bHR/bLR rats exhibit differences in dopaminergic circuitry and differential response to rewarding stimuli (i.e., psychostimulants, food), the present study examined whether they also differ in another key hedonic behavior – sex. Thus, adult bHR/bLR males were given five 30-min opportunities to engage in sexual activity with a receptive female. Sexual behavior and motivation were examined and compared between the groups. The bHR/bLR phenotype affected both sexual motivation and behavior, with bLR males demonstrating reduced motivation for sex compared with bHR males (i.e., fewer animals copulated, longer latency to engage in sex). The bHR males required more intromissions at a faster pace per ejaculation than did bLR males. Thus, neurobiological differences that affect motivation for drugs of abuse, aggression, and impulsivity in rats also affect sexual motivation and performance.
doi:10.1037/a0031528
PMCID: PMC3982402  PMID: 23398441
bred High Responder (bHR); bred Low Responder (bLR); sexual performance; reward; dopamine
21.  Novelty-Seeking Behavior Predicts Vulnerability in a Rodent Model of Depression 
Physiology & behavior  2011;103(2):210-216.
Background
The onset of major depressive disorder is likely precipitated by a combination of heredity and life stress. The present study tested the hypothesis that rats selectivity bred on a trait related to emotional reactivity would show differential susceptibility or resilience to the development of depression-like signs in response to chronic mild variable intermittent stress (CMS).
Methods
Male Sprague-Dawley rats that were bred based on the trait of either high or low locomotor activity in response to a novel environment were exposed to four weeks of CMS or control conditions. Changes in hedonic behavior were assessed using weekly sucrose preference tests and anxiety-like behavior was evaluated using the novelty-suppressed feeding test.
Results
During four weeks of CMS, bred low responder (bLR) rats became anhedonic at a faster rate and to a larger degree than bred high responder (bHR) rats, based on weekly sucrose preference tests. Measures of anxiety-like behavior in the novelty-suppressed feeding test were also significantly increased in the CMS-exposed bLR rats, though no differences were observed between CMS-exposed bHR rats and their unstressed controls.
Conclusions
These findings present further evidence that increased emotional reactivity is an important factor in stress susceptibility and the etiology of mood disorders, and that bHR and bLR rats provide a model of resistance or vulnerability to stress-induced depression. Furthermore, exposing bHR and bLR rats to CMS provides an excellent way to study the interaction of genetic and environmental factors in the development of depression-like behavior.
doi:10.1016/j.physbeh.2011.02.001
PMCID: PMC3925672  PMID: 21303678
depression; chronic mild stress; high responder; low responder; selectively bred rat; vulnerability
22.  3xTg-AD Mice Exhibit an Activated Central Stress Axis during Early-Stage Pathology 
Activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to the organism’s innate need for homeostasis. The glucocorticoids (GCs) that are released into the circulation upon acute activation of the HPA axis perform stress-adaptive functions and provide negative feedback to turn off the HPA axis, but can be detrimental when in excess. Long-term activation of the HPA axis (such as with chronic stress) enhances susceptibility to neuronal dysfunction and death, and increases vulnerability to Alzheimer’s disease (AD). However, little is known how components of the HPA axis, upstream of GCs, impact vulnerability to AD. This study examined basal gene expression of stress-related molecules in brains of 3xTg-AD mice during early-stage pathology. Basal glucocorticoid levels and mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and corticotropic releasing hormone (CRH) in several stress- and emotionality-related brain regions were measured in 3–4-month-old 3xTg-AD mice. Despite normal glucocorticoid levels, young 3xTg-AD mice exhibit an activated central HPA axis, with altered mRNA levels of MR and GR in the hippocampus, GR and CRH in the paraventricular nucleus of the hypothalamus, GR and CRH in the central nucleus of the amygdala, and CRH in the bed nucleus of the stria terminalis. This HPA axis activation is present during early-stage neuropathology when 3xTg-AD mice show mild behavioral changes, suggesting an ongoing neuroendocrine regulation that precedes the onset of severe AD-like pathology and behavioral deficits.
doi:10.3233/JAD-2012-121438
PMCID: PMC3525735  PMID: 22976078
HPA axis; stress; corticotropic releasing hormone; glucocorticoid receptor; mineralocorticoid receptor; Alzheimer’s disease
23.  Altered choroid plexus gene expression in major depressive disorder 
Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFβ) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.
doi:10.3389/fnhum.2014.00238
PMCID: PMC4001046  PMID: 24795602
cytoskeleton; mRNA; hippocampus; depression; brain
24.  G protein-linked signaling pathways in bipolar and major depressive disorders 
Frontiers in Genetics  2013;4:297.
The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, “activated” cAMP signaling activity in BPD and “blunted” cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.
doi:10.3389/fgene.2013.00297
PMCID: PMC3870297  PMID: 24391664
G-protein coupled receptor (GPCR); transcriptome; bipolar disorder; major depressive disorder; GPR37; GPRC5B; cyclic AMP; phosphatidylinositol
25.  Methodological Considerations For Gene Expression Profiling Of Human Brain 
Journal of neuroscience methods  2007;163(2):10.1016/j.jneumeth.2007.03.022.
Gene expression profiles of postmortem brain tissue represent important resources for understanding neuropsychiatric illnesses. The impact(s) of quality covariables on the analysis and results of gene expression studies are important questions. This paper addressed critical variables which might affect gene expression in two brain regions. Four broad groups of quality indicators in gene expression profiling studies (clinical, tissue, RNA, and microarray quality) were identified. These quality control indicators were significantly correlated, however one quality variable did not account for the total variance in microarray gene expression. The data showed that agonal factors and low pH correlated with decreased integrity of extracted RNA in two brain regions. These three parameters also modulated the significance of alterations in mitochondrial-related genes. The average F-ratio summaries across all transcripts showed that RNA degradation from the AffyRNAdeg program accounted for higher variation than all other quality factors. Taken together, these findings confirmed prior studies, which indicated that quality parameters including RNA integrity, agonal factors, and pH are related to differences in gene expression profiles in postmortem brain. Individual candidate genes can be evaluated with these quality parameters in posthoc analysis to help strengthen the relevance to psychiatric disorders. We find that clinical, tissue, RNA, and microarray quality are all useful variables for collection and consideration in study design, analysis, and interpretation of gene expression results in human post-mortem studies.
doi:10.1016/j.jneumeth.2007.03.022
PMCID: PMC3835340  PMID: 17512057

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