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2.  Amygdala-ventral pallidum pathway decreases dopamine activity following chronic mild stress in rats 
Biological psychiatry  2013;76(3):223-230.
Background
Major depressive disorder (MDD) affects more than 15% of the population across their lifespan. In this study, we used the well-characterized unpredictable chronic mild stress (CMS) model of depression to examine this condition.
Methods
Sprague-Dawley rats were presented randomly with mild stressors for four weeks, with body weight and sucrose intake monitored weekly. Locomotor activity and elevated plus maze test/forced swim test were conducted on week 5; ventral tegmental area (VTA) dopamine (DA) neuron activity was assessed within a week after the behavioral test using three indices: DA neuron population activity (defined as the number of spontaneously firing DA neurons), mean firing rate, and percent burst firing (i.e., the proportion of action potentials occurring in bursts).
Results
Consistent with previous studies, we found that, compared to controls, rats that underwent the CMS procedure were slower in gaining body weight, and developed anxiety- and despair-like behavior. We now report a significant decrease in DA neuron population activity of CMS rats, and this decrease is restored by pharmacologically attenuating the activity of either the basolateral nucleus of the amygdala (BLA), or the ventral pallidum (VP). Moreover, pharmacological activation of the amygdala in non-stressed rats decreases DA neuron population activity similar to that with CMS, which is reversed by blocking the BLA-VP pathway.
Conclusions
The CMS rat depression model is associated with a BLA-VP-VTA inhibition of DA neuron activity. This information can provide insight into the circuitry underlying MDD and serve as a template for refining therapeutic approaches to this disorder.
doi:10.1016/j.biopsych.2013.09.020
PMCID: PMC3969414  PMID: 24209776
unpredictable chronic mild stress; rat; ventral tegmental area; amygdala; ventral pallidum; dopamine
3.  Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula 
Biological psychiatry  2013;76(3):258-266.
Background
Somatic complaints and altered interoceptive awareness are common features in the clinical presentation of major depressive disorder (MDD). Recently, neurobiological evidence has accumulated demonstrating that the insula is one of the primary cortical structures underlying interoceptive awareness. Abnormal interoceptive representation within the insula may thus contribute to the pathophysiology and symptomatology of MDD.
Methods
We compared fMRI blood oxygenation level-dependent (BOLD) responses between twenty unmedicated adults with MDD and twenty healthy control participants during a task requiring attention to visceral interoceptive sensations and also assessed the relationship of this BOLD response to depression severity, as rated using the Hamilton Depression Rating Scale (HDRS). Additionally, we examined between-group differences in insula resting-state functional connectivity, and its relationship to HDRS ratings of depression severity.
Results
Relative to the healthy controls, unmedicated MDD subjects exhibited decreased activity bilaterally in the dorsal mid-insula cortex (dmIC) during interoception, as well as within a network of brain regions implicated previously in emotion and visceral control. Activity within the insula during the interoceptive attention task was negatively correlated with both depression severity and somatic symptom severity in depressed subjects. MDD also was associated with greater resting-state functional connectivity between the dmIC and limbic brain regions implicated previously in MDD, including the amygdala, subgenual prefrontal cortex, and orbitofrontal cortex. Moreover, functional connectivity between these regions and the dmIC was positively correlated with depression severity.
Conclusions
MDD and the somatic symptoms of depression are associated with abnormal interoceptive representation within the insula.
doi:10.1016/j.biopsych.2013.11.027
PMCID: PMC4048794  PMID: 24387823
Interoception; major depressive disorder; insula; fMRI; functional connectivity; depression severity
4.  Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats 
Biological psychiatry  2013;76(3):213-222.
Background
Dynorphin, an endogenous ligand at kappa opioid receptors (KOR), produces depressive-like effects and contributes to addictive behavior in male non-human primates and rodents. Although comorbidity of depression and addiction is greater in women than men, the role of KORs in female motivated behavior is unknown.
Methods
In adult Sprague Dawley rats, we used intracranial self-stimulation (ICSS) to measure effects of the KOR agonist (±)-trans-U-50488 methanesulfonate salt (U-50488) (0.0 – 10.0 mg/kg) on brain stimulation reward in gonadally intact and castrated males and in females at estrous cycle stages associated with low and high estrogen levels. Pharmacokinetic studies of U-50488 in plasma and brain were conducted. Immunohistochemistry was used to identify sex-dependent expression of U-50488-induced c-Fos in brain.
Results
U-50488 dose-dependently increased the frequency of stimulation (threshold) required to maintain ICSS responding in male and female rats, a depressive-like effect. However, females were significantly less sensitive than males to the threshold-increasing effects of U-50488, independent of estrous cycle stage in females or gonadectomy in males. Although initial plasma concentrations of U-50488 were higher in females, there were no sex differences in brain concentrations. Sex differences in U-50488-induced c-Fos activation were observed in CRF-containing neurons of the paraventricular nucleus (PVN) of the hypothalamus and primarily in non-CRF-containing neurons of the bed nucleus of the stria terminalis (BNST).
Conclusions
These data suggest that the role of KORs in motivated behavior of rats is sexdependent, which has important ramifications for the study and treatment of mood-related disorders including depression and drug addiction in people.
doi:10.1016/j.biopsych.2013.07.042
PMCID: PMC4476271  PMID: 24090794
dynorphin; female; stress; intracranial self-stimulation; pharmacokinetics; c-Fos
5.  Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems 
Biological psychiatry  2013;76(3):203-212.
Background
Cortical deep brain stimulation (DBS) is a promising therapeutic option for treatment-refractory depression but its mode of action remains enigmatic. Serotonin (5-HT) systems are engaged indirectly by ventromedial prefrontal cortex (vmPFC) DBS. Resulting neuroplastic changes in 5-HT systems could thus coincide with the long-term therapeutic activity of vmPFC DBS.
Methods
We tested this hypothesis by evaluating the antidepressant-like activity of vmPFC DBS in the chronic social defeat stress (CSDS) model of depression (n = 8-13 mice per group). Circuit-wide activation induced by vmPFC DBS was mapped using c-Fos immunolabeling. The effects of chronic vmPFC DBS on the physiology and morphology of genetically-identified 5-HT cells from the Dorsal Raphe Nucleus (DRN) were examined using whole-cell recording, somatodendritic 3-D reconstructions and morphometric analyses of presynaptic boutons along 5-HT axons.
Results
Acute DBS drove c-Fos expression locally in the vmPFC and in several distal monosynaptically-connected regions, including the DRN. Chronic DBS reversed CSDS-induced social avoidance, restored the disrupted balance of excitatory/inhibitory inputs onto 5-HT neurons, and reversed 5-HT hypoexcitability observed after CSDS. Furthermore, vmPFC DBS reversed CSDS-induced arborization of 5-HT dendrites in the DRN and increased the size and density of 5-HT presynaptic terminals in the dentate gyrus and vmPFC.
Conclusions
We validate a new preclinical paradigm to examine cellular mechanisms underlying the antidepressant-like activity of vmPFC DBS and identify dramatic circuit-mediated cellular adaptations which coincide with this treatment. These neuroplastic changes of 5-HT neurons may contribute to the progressive mood improvements reported in patients treated with chronic courses of cortical DBS.
doi:10.1016/j.biopsych.2013.12.009
PMCID: PMC4072754  PMID: 24503468
Deep Brain Stimulation; Depression; Dorsal Raphe; Prefrontal Cortex; Neuroplasticity; Social Defeat
6.  Shared and Distinct Intrinsic Functional Network Centrality in Autism and Attention-Deficit/Hyperactivity Disorder 
Biological psychiatry  2013;74(8):623-632.
Background
Individuals with autism spectrum disorders (ASD) often exhibit symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). Across both disorders, observations of distributed functional abnormalities suggest aberrant large-scale brain network connectivity. Yet, common and distinct network correlates of ASD and ADHD remain unidentified. Here, we aimed to examine patterns of dysconnection in school-age children with ASD, ADHD and typically developing children (TDC) who completed a resting state fMRI (R-fMRI) scan.
Methods
We measured voxel-wise network centrality, functional connectivity metrics indexing local (degree centrality; DC) and global (eigenvector centrality; EC) functional relationships across the entire brain connectome, in R-fMRI data from 56 children with ASD, 45 children with ADHD and 50 TDC. A one-way ANCOVA, with group as fixed factor (whole-brain corrected), was followed by post-hoc pair-wise comparisons.
Results
Cortical and subcortical areas exhibited centrality abnormalities; some common to both ADHD and ASD, such as in precuneus. Others were disorder-specific and included ADHD-related increases in DC in right striatum/pallidum, in contrast with ASD-related increases in bilateral temporolimbic areas. Secondary analyses differentiating children with ASD into those with or without ADHD-like comorbidity (ASD+ and ASD−, respectively) revealed that the ASD+ group shared ADHD-specific abnormalities in basal ganglia. By contrast, centrality increases in temporolimbic areas characterized children with ASD regardless of ADHD-like comorbidity. At the cluster level eignevector centrality group patterns were similar to DC.
Conclusions
ADHD and ASD are neurodevelopmental disorders with distinct and overlapping clinical presentations. This work provides evidence for both shared and distinct underlying mechanisms at the large-scale network level.
doi:10.1016/j.biopsych.2013.02.011
PMCID: PMC4508007  PMID: 23541632
Autism; ADHD; Network Centrality; Functional Connectivity; resting state fMRI; Caudate; amygdala; precuneus
7.  Elevated Viral Restriction Factor Levels in Cortical Blood Vessels in Schizophrenia 
Biological psychiatry  2013;76(2):160-167.
Background
Higher tissue transcript levels of immune-related markers, including the recently discovered viral restriction factor interferon-induced transmembrane protein (IFITM) which inhibits viral entry and replication, have been reported in the prefrontal cortex in schizophrenia. Interestingly, mouse models of neuroinflammation have higher IFITM levels and deficits in GABA-related markers that are similar to findings in schizophrenia, suggesting that a shared pathogenetic process may underlie diverse cortical pathology in the disorder. However, the cell types that overexpress IFITM mRNA in schizophrenia are unknown, and it is unclear whether higher IFITM mRNA levels are associated with lower GABA-related marker levels in the same schizophrenia subjects.
Methods
We used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify IFITM mRNA levels in prefrontal cortex area 9 of 57 schizophrenia and 57 healthy comparison subjects and in antipsychotic-exposed monkeys.
Results
Quantitative PCR and in situ hybridization film analysis revealed markedly elevated IFITM mRNA levels (+114% and +117%, respectively) in prefrontal gray matter in schizophrenia. Interestingly, emulsion-dipped, Nissl-stained sections from schizophrenia and comparison subjects revealed IFITM mRNA expression in pia mater and blood vessels. IFITM grain density over blood vessels was 71% higher in schizophrenia. IFITM mRNA levels were negatively correlated with GABA-related mRNAs in the same schizophrenia subjects.
Conclusions
The finding that schizophrenia subjects with higher IFITM mRNA levels in cortical blood vessels have greater disturbances in cortical GABA neurons suggests that these cell-type distinct pathological disturbances may be influenced by a shared upstream insult that involves immune activation.
doi:10.1016/j.biopsych.2013.09.019
PMCID: PMC3969896  PMID: 24209773
IFITM; immune; inflammation; GABA; GAD67; parvalbumin
8.  Reversible overexpression of BACE1-cleaved neuregulin-1 N-terminal fragment induces schizophrenia-like phenotypes in mice 
Biological psychiatry  2013;76(2):120-127.
Background
Neuregulin-1 (Nrg1) is a pleiotropic signaling molecule that regulates neural development and mutation of Nrg1 is a risk factor for schizophrenia. Cleavage of type I β1 Nrg1 isoform by BACE1 releases a secreted N-terminal fragment (Nrg1-ntfβ), which can bind to a cognate ErbB receptor to activate the specific signaling cascade. This study aimed to determine whether increased expression of Nrg1 is beneficial for brain development and functions.
Methods
We generated transgenic mice overexpressing this fragment under the control of a tetracycline-inducible promoter and examined functional and behavioral changes in mice upon reversible expression of the transgene.
Results
Increased expression of full length Nrg1 in mouse neurons has been previously shown to enhance myelination in the central nervous system. Overexpressing Nrg1-ntfβ enhanced the expression of myelin proteins, consistent with the expected activation of the Nrg1 signaling pathway by Nrg1-ntfβ. Contrary to expectations, overexpressing Nrg1-ntfβ transgene caused schizophrenia-like behaviors in transgenic mice and these abnormal behaviors were reversible if the expression of the Nrg1-ntfβ transgene was turned off. Our molecular assay suggests that protein levels of NMDA receptors (NMDARs) are reduced in this transgenic mouse model, which may underlie the observed social and cognitive behavioral impairments.
Conclusion
Our results indicate that overexpressing the secreted form of Nrg1 is sufficient to cause schizophrenia-like behaviors in a mouse model, meaning the effect is independent of the transmembrane and C-terminal domains of Nrg1. Hence, genetic gain-of-function mutations of Nrg1 are also risk factors for schizophrenia.
doi:10.1016/j.biopsych.2013.09.026
PMCID: PMC3976896  PMID: 24210810
BACE1; neuregulin; schizophrenia; NMDA receptor; transgenic mice; tetracycline control expression
9.  Neuroimaging Biomarkers for Early Drug Development in Schizophrenia 
Biological psychiatry  2013;76(2):111-119.
Given the relative inability of currently available antipsychotic treatments to adequately provide sustained recovery and improve quality of life for patients with schizophrenia, new treatment strategies are urgently needed. One way to improve the therapeutic development process may be an increased use of biomarkers in early clinical trials. Reliable biomarkers that reflect aspects of disease pathophysiology can be used to determine if potential treatment strategies are engaging their desired biological targets. This review evaluates three potential neuroimaging biomarkers: hippocampal hyperactivity, gamma-band deficits and default network abnormalities. These deficits have been widely replicated in the illness, correlate with measures of positive symptoms, are consistent with models of disease pathology, and have shown initial promise as biomarkers of biological response in early studies of potential treatment strategies. Two key features of these deficits, and a guiding rational for the focus of this review, is that the deficits are not dependent upon patients' performance of specific cognitive tasks, and have analogues in animal models of schizophrenia, greatly increasing their appeal for use as biomarkers. Using neuroimaging biomarkers such as those proposed here to establish early in the therapeutic development process if treatment strategies are having their intended biological effect in humans may facilitate development of new treatments for schizophrenia.
doi:10.1016/j.biopsych.2013.08.025
PMCID: PMC4026337  PMID: 24094513
schizophrenia; neuroimaging; biomarkers; hippocampus; gamma-band; default network
10.  Neurod1 Modulates Opioid Antinociceptive Tolerance via Two Distinct Mechanisms 
Biological psychiatry  2014;76(10):775-784.
Background
The activity of neurogenic differentiation 1 (Neurod1) decreases after morphine administration, which leads to impairments of the stability of dendritic spines in primary hippocampal neurons, adult neurogenesis in mouse hippocampi, and drug-associated contextual memory. The current study examined whether Neurod1 could affect the development of opioid tolerance.
Methods
Lentivirus encoding Neurod1, microRNA-190 (miR-190), or short hairpin RNA against Neurod1 was injected into mouse hippocampi separately or combined (more than eight mice for each treatment) to modulate Neurod1 activity. The antinociceptive median effective dose values of morphine and fentanyl were determined with tail-flick assay and used to calculate development of tolerance. Contextual learning and memory were assayed using the Morris water maze.
Results
Decrease in NeuroD1 activity increased the initial antinociceptive median effective dose values of both morphine and fentanyl, which was reversed by restoring NeuroD1 activity. In contrast, decrease in NeuroD1 activity inhibited development of tolerance in a time-dependent manner, paralleling its effects on the acquisition and extinction of contextual memory. In addition, only development of tolerance, but not antinociceptive median effective dose values, was modulated by the expression of miR-190 and Neurod1 driven by Nestin promoter.
Conclusions
Neurod1 regulates the developments of opioid tolerance via a time-dependent pathway through contextual learning and a short-response pathway through antinociception.
doi:10.1016/j.biopsych.2014.05.013
PMCID: PMC4503258  PMID: 24993058
Analgesia; learning; Neurod1; opioid; tolerance; water maze
11.  Reduced Face Preference in Infancy: A Developmental Precursor to Callous-Unemotional Traits? 
Biological Psychiatry  2015;78(2):144-150.
Background
Children with callous-unemotional (CU) traits, a proposed precursor to adult psychopathy, are characterized by impaired emotion recognition, reduced responsiveness to others’ distress, and a lack of guilt or empathy. Reduced attention to faces, and more specifically to the eye region, has been proposed to underlie these difficulties, although this has never been tested longitudinally from infancy. Attention to faces occurs within the context of dyadic caregiver interactions, and early environment including parenting characteristics has been associated with CU traits. The present study tested whether infants’ preferential tracking of a face with direct gaze and levels of maternal sensitivity predict later CU traits.
Methods
Data were analyzed from a stratified random sample of 213 participants drawn from a population-based sample of 1233 first-time mothers. Infants’ preferential face tracking at 5 weeks and maternal sensitivity at 29 weeks were entered into a weighted linear regression as predictors of CU traits at 2.5 years.
Results
Controlling for a range of confounders (e.g., deprivation), lower preferential face tracking predicted higher CU traits (p = .001). Higher maternal sensitivity predicted lower CU traits in girls (p = .009), but not boys. No significant interaction between face tracking and maternal sensitivity was found.
Conclusions
This is the first study to show that attention to social features during infancy as well as early sensitive parenting predict the subsequent development of CU traits. Identifying such early atypicalities offers the potential for developing parent-mediated interventions in children at risk for developing CU traits.
doi:10.1016/j.biopsych.2014.09.022
PMCID: PMC4510143  PMID: 25526972
Callous-unemotional traits; Face preference; Maternal sensitivity; Infant development; Precursor; Psychopathy
12.  Nicotinic acetylcholine receptors containing the α4 subunit modulate alcohol reward 
Biological psychiatry  2012;73(8):738-746.
Background
Nicotine and alcohol are the two most co-abused drugs in the world suggesting a common mechanism of action may underlie their rewarding properties. While nicotine elicits reward by activating ventral tegmental area (VTA) dopaminergic (DAergic) neurons via high affinity neuronal nicotinic acetylcholine receptors (nAChRs), the mechanism by which alcohol activates these neurons is unclear.
Methods
Because the majority of high affinity nAChRs expressed in VTA DAergic neurons contain the α4 subunit, we measured ethanol-induced activation of DAergic neurons in midbrain slices from two complementary mouse models, an α4 knock-out (KO) mouse line and a knock-in line (Leu9’Ala) expressing α4 subunit-containing nAChRs hypersensitive to agonist compared to wild-type (WT). Activation of DAergic neurons by ethanol was analyzed using both biophysical and immunohistochemical approaches in midbrain slices. The ability of alcohol to condition a place preference in each mouse model was also measured.
Results
At intoxicating concentrations, ethanol activation of DAergic neurons was significantly reduced in α4 KO mice compared to WT. Conversely, in Leu9’Ala mice, DAergic neurons were activated by low ethanol concentrations that did not increase activity of WT neurons. In addition, alcohol potentiated the response to ACh in DAergic neurons, an effect reduced in α4 KO mice. Paralleling alcohol effects on DAergic neuron activity, rewarding alcohol doses failed to condition a place preference in α4 KO mice, whereas a sub-rewarding alcohol dose was sufficient to condition a place preference in Leu9’Ala mice.
Conclusions
Together, these data indicate that nAChRs containing the α4 subunit modulate alcohol reward.
doi:10.1016/j.biopsych.2012.09.019
PMCID: PMC4501776  PMID: 23141806
dopamine; alcoholism; reward; acetylcholine; mice; nicotinic receptor
13.  Inhibitory Control in High-Functioning Autism: Decreased Activation and Underconnectivity in Inhibition Networks 
Biological psychiatry  2006;62(3):198-206.
Background
Inhibiting prepotent responses is critical to optimal cognitive and behavioral function across many domains. Several behavioral studies have investigated response inhibition in autism, and the findings varied according to the components involved in inhibition. There has been only one published functional magnetic resonance imaging (fMRI) study so far on inhibition in autism, which found greater activation in participants with autism than control participants.
Methods
This study investigated the neural basis of response inhibition in 12 high-functioning adults with autism and 12 age- and intelligence quotient (IQ)-matched control participants during a simple response inhibition task and an inhibition task involving working memory.
Results
In both inhibition tasks, the participants with autism showed less brain activation than control participants in areas often found to be active in response inhibition tasks, namely the anterior cingulate cortex. In the more demanding inhibition condition, involving working memory, the participants with autism showed more activation than control participants in the premotor areas. In addition to the activation differences, the participants with autism showed lower levels of synchronization between the inhibition network (anterior cingulate gyrus, middle cingulate gyrus, and insula) and the right middle and inferior frontal and right inferior parietal regions.
Conclusions
The results indicate that the inhibition circuitry in the autism group is activated atypically and is less synchronized, leaving inhibition to be accomplished by strategic control rather than automatically. At the behavioral level, there was no difference between the groups.
doi:10.1016/j.biopsych.2006.08.004
PMCID: PMC4492460  PMID: 17137558
Autism; factor analysis; fMRI; functional connectivity; inhibitory control; response inhibition; underconnectivity
14.  Diminished Role of Dopamine D1-Receptor Signaling with the Development of An Addicted Phenotype in Rats 
Biological psychiatry  2013;76(1):8-14.
Background
While considerable evidence implicates DA D1-receptor signaling in the nucleus accumbens in motivation for cocaine during early stages of addiction, less is known regarding its role following the development of addiction. Here, we examined its role in the development of an addicted phenotype in intact male and female rats, and in female rats that were either resistant or vulnerable to developing this phenotype.
Methods
Intact males, females, and ovariectomized (OVX) females with and without estradiol (vulnerable, OVX+E; resistant, OVX+Veh) were given either short access (ShA; 3 fixed-ratio 1 sessions, maximum of 20 infusions) or 24-hr extended access (ExA) to cocaine for 10 days (4 trials/hr). Motivation for cocaine was assessed following a 14-day abstinence period using a progressive-ratio schedule. Once responding stabilized, the effects of intra-accumbens infusion of the D1-receptor antagonist, SCH-23390 (0, 0.3, 1.0, 3.0 μg), were examined.
Results
Motivation for cocaine was markedly higher following abstinence from ExA versus ShA self-administration in intact males and females, indicating the development of an addicted phenotype in these groups. Motivation for cocaine was also higher than ShA controls in OVX+E, but not OVX+Veh females following ExA self-administration, confirming the categorization of these groups as vulnerable versus resistant. Following ExA self-administration, intact males and females and OVX+E, but not OVX+Veh females, were less sensitive to the effects of D1-receptor antagonism as compared to their ShA counterparts.
Conclusions
These results suggest that the role of D1-receptor signaling, though critical in “non-addicted” stages, becomes diminished once addiction has developed.
doi:10.1016/j.biopsych.2013.09.028
PMCID: PMC3976474  PMID: 24199666
cocaine; estradiol; extended access; nucleus accumbens; SCH-23390; self-administration
15.  Methamphetamine-Associated Memory is Regulated by a Writer and an Eraser of Permissive Histone Methylation 
Biological psychiatry  2013;76(1):57-65.
Background
Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder by triggering craving. The nucleus accumbens (NAc) is essential to these drug-associated memories, but underlying mechanisms are poorly understood. Posttranslational chromatin modifications, such as histone methylation, modulate gene transcription, thus we investigated the role of the associated epigenetic modifiers in METH-associated memory.
Methods
Conditioned place preference was used to assess the epigenetic landscape in the NAc supporting METH-associated memory (n=79). The impact of histone methylation (H3K4me2/3) on the formation and expression of METH-associated memory was determined by focal, intra NAc knockdown (KD) of a writer, the methyltransferase MLL1 (n=26), and an eraser, the histone demethylase KDM5C (n=38), of H3K4me2/3.
Results
A survey of chromatin modifications in the NAc of animals forming a METH-associated memory revealed the global induction of several modifications associated with active transcription. This correlated with a pattern of gene activation, as revealed by microarray analysis, including upregulation of Oxtr and Fos, whose promoters also had increased H3K4me3. KD of Mll1 reduced H3K4me3, Fos and Oxtr levels and disrupted METH-associated memory. KD of Kdm5c resulted in hypermethylation of H3K4 and prevented the expression of METH-associated memory.
Conclusions
The development and expression of METH-associated memory are supported by regulation of H3K4me2/3 levels by MLL1 and KDM5C, respectively, in the NAc. These data indicate that permissive histone methylation, and the associated epigenetic writers and erasers, represent potential targets for the treatment of substance abuse relapse, a psychiatric condition perpetuated by unwanted associative memories.
doi:10.1016/j.biopsych.2013.09.014
PMCID: PMC4024089  PMID: 24183790
epigenetics; nucleus accumbens; methyltransferase; demethylase; MLL; KDM5C
16.  Methamphetamine down-regulates striatal glutamate receptors via diverse epigenetic mechanisms 
Biological psychiatry  2013;76(1):47-56.
Background
Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses.
Methods
To identify the METH-induced epigenetic underpinnings of these adaptations in the brain, we injected increasing METH doses to rats for two weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation using chromatin immunoprecipitation (ChIP) and qPCR. We also measured METH-induced changes in DNA methylation and hydroxylation by using methylated (Me) and hydroxymethylated (hMe) DNA precipitation (DIP) and qPCR.
Results
Chronic METH decreased transcript and protein expression of GluA1 and GluA2 AMPAR and GluN1 NMDAR subunits. These changes were associated with decreased electrophysiological glutamatergic responses in striatal neurons. ChIP-PCR revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. METH also increased protein levels of histone deacetylases (HDAC1, HDAC2 and SIRT2), protein repressors (REST and CoREST), and of the methylated DNA binding protein, MeCP2. Moreover, METH exposure increased CoREST, MeCP2, and HDAC2, but not SIRT1 or SIRT2, enrichment onto GluA1 and GluA2 gene sequences. Furthermore, METH caused interactions of CoREST and MeCP2 with HDAC2 and of REST with HDAC1. Surprisingly, MeDIP and hMeDIP-PCR revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Furthermore, the HDAC inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and NMDAR subunits. Finally, valproic acid also attenuated METH-induced decreased H4K16Ac recruitment on AMPAR gene sequences.
Conclusions
These observations suggest that histone H4 hypoacetylation might be the main determinant of METH-induced decreased striatal glutamate receptor expression.
doi:10.1016/j.biopsych.2013.09.034
PMCID: PMC3989474  PMID: 24239129
Addiction; AMPAR; CoREST; HDAC2; MeCP2; NMDAR; REST; valproic acid
17.  Brain Potentials Measured During a Go/NoGo Task Predict Completion of Substance Abuse Treatment 
Biological psychiatry  2013;76(1):75-83.
Background
US nationwide estimates indicate 50–80% of prisoners have a history of substance abuse or dependence. Tailoring substance abuse treatment to specific needs of incarcerated individuals could improve effectiveness of treating substance dependence and preventing drug abuse relapse. The purpose of the present study was to test the hypothesis that pre-treatment neural measures of a Go/NoGo task would predict which individuals would or would not complete a 12-week cognitive behavioral substance abuse treatment program.
Methods
Adult incarcerated participants (N=89; Females=55) who volunteered for substance abuse treatment performed a response inhibition (Go/NoGo) task while event-related potentials (ERP) were recorded. Stimulus- and response-locked ERPs were compared between individuals who completed (N=68; Females=45) and discontinued (N=21; Females=10) treatment.
Results
As predicted, stimulus-locked P2, response-locked error-related negativity (ERN/Ne), and response-locked error positivity (Pe), measured with windowed time-domain and principal component analysis, differed between groups. Using logistic regression and support-vector machine (i.e., pattern classifiers) models, P2 and Pe predicted treatment completion above and beyond other measures (i.e., N2, P300, ERN/Ne, age, sex, IQ, impulsivity, and self-reported depression, anxiety, motivation for change, and years of drug abuse).
Conclusions
We conclude individuals who discontinue treatment exhibited deficiencies in sensory gating, as indexed by smaller P2, error-monitoring, as indexed by smaller ERN/Ne, and adjusting response strategy post-error, as indexed by larger Pe. However, the combination of P2 and Pe reliably predicted 83.33% of individuals who discontinued treatment. These results may help in the development of individualized therapies, which could lead to more favorable, long-term outcomes.
doi:10.1016/j.biopsych.2013.09.030
PMCID: PMC3984370  PMID: 24238783
Drug Treatment; Event-Related Potentials; Principal Component Analysis; Response Inhibition; Response Errors; Support Vector Machine; Pattern Classifier
18.  Genomewide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways 
Biological psychiatry  2013;76(1):66-74.
Background
We report a GWAS of two populations, African- and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify pathways, genes, and alleles important in OD risk.
Methods
Design employed three phases (based on separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5,697 subjects (58% AA) diagnosed with opioid and/or other substance dependence (SD), and controls. Subjects were genotyped using the Illumina OmniQuad microarray, yielding 890,000 SNPs suitable for analysis. Additional genotypes were imputed using the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available SAGE dataset, with GWAS data from 4,063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2,549 independent subjects (32% AA). Analyses were performed using case-control and ordinal trait designs.
Results
Most significant results emerged from the AA subgroup. Genomewide-significant associations (p<5.0×10−8) were observed with SNPs from multiple loci - KCNC1*rs60349741 most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1, KCNG2, and KCNA4). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation.
Conclusions
This is the first study to identify risk variants for OD using GWAS. Our results strongly implicate risk pathways, provide insights into novel therapeutic and prevention strategies, and may provide biologically bridge OD and other non-SD psychiatric traits where similar pathways have been implicated.
doi:10.1016/j.biopsych.2013.08.034
PMCID: PMC3992201  PMID: 24143882
opioid dependence; genomewide association; complex traits; calcium signaling; potassium; convergence
19.  Diminished Role for Dopamine D1 Receptors in Cocaine Addiction? 
Biological psychiatry  2014;76(1):2-3.
doi:10.1016/j.biopsych.2014.04.006
PMCID: PMC4237589  PMID: 24925888
20.  Quantitative Magnetization Transfer Imaging as a Biomarker for Effects of Systemic Inflammation on the Brain 
Biological Psychiatry  2015;78(1):49-57.
Background
Systemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer’s disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging.
Methods
We used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge.
Results
The qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge.
Conclusions
Together these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses.
doi:10.1016/j.biopsych.2014.09.023
PMCID: PMC4503794  PMID: 25526971
Biomarker; Cytokine; Depression; Fatigue; Inflammation; Insula; MRI
22.  Differential relationships of mismatch negativity and visual P1 deficits to premorbid characteristics and functional outcome in schizophrenia 
Biological psychiatry  2011;71(6):521-529.
Background
Mismatch negativity (MMN) and visual P1 event-related potentials (ERPs) are established markers of impaired auditory and visual sensory dysfunction in schizophrenia, respectively. Differential relationships of these measures with premorbid and present function and with clinical course have been noted in independent cohorts, but measures have not been compared previously within the same patient group.
Methods
26 patients with schizophrenia and 19 controls participated in a simultaneous visual and auditory ERPs experiment. Attended visual ERPs were obtained to low- and high-spatial frequency stimuli. Simultaneously, MMN was obtained to unattended pitch, duration and intensity deviant stimuli. Permorbid function, symptom and global outcome measures were obtained as correlational measures.
Results
Patients showed substantial P1 reductions to low-, but not high- SF stimuli, unrelated to visual acuity. Patients also exhibited reduced MMN to all deviant types. No significant correlations were observed between visual ERPs and either premorbid or global outcome measures or with illness duration. In contrast, MMN amplitude correlated significantly and independently with premorbid educational achievement, cognitive symptoms and global function, as well as duration of illness. MMN to duration vs. other deviants was differentially reduced in individuals with poor premorbid function.
Conclusion
Visual and auditory ERP measures were differentially related to the pathophysiology of schizophrenia. Visual deficits correlated poorly with both functional measures and illness duration, and so may be viewed best as trait vulnerability markers. Deficits in MMN are independently related to premorbid function and illness duration, suggesting independent neurodevelopmental and neurodegenerative contributions. Findings suggest that different underlying pathophysiological mechanisms may account for impaired visual and auditory neurophysiological dysfunction in schizophrenia.
doi:10.1016/j.biopsych.2011.10.037
PMCID: PMC4469217  PMID: 22192361
23.  Translation: Screening for Novel Therapeutics Using Disease-Relevant Cell Types Derived from Human Stem Cell Models 
Biological psychiatry  2013;75(12):952-960.
The advent of somatic cell reprogramming technologies, which enables the generation of patient-specific, induced pluripotent stem cell (iPSC) and other trans-differentiated human neuronal cell models, provides new means of gaining insight into the molecular mechanisms and neural substrates of psychiatric disorders. By allowing a more precise understanding of genotype-phenotype relationship in disease-relevant human cell types, the use of reprogramming technologies in tandem with emerging genome engineering approaches provides a previously ‘missing link’ between basic research and translational efforts. In this review, we summarize advances in applying human pluripotent stem cell and reprogramming technologies to generate specific neural subtypes with a focus on the use of these in vitro systems for the discovery of small molecule-probes and novel therapeutics. Examples are given where human cell models of psychiatric disorders have begun to reveal new mechanistic insight into pathophysiology and simultaneously have provided the foundation for developing disease-relevant, phenotypic assays suitable for both functional genomic and chemical screens. A number of areas for future research are discussed, including the need to develop robust methodology for the reproducible, large-scale production of disease-relevant, neural cell types in formats compatible with high-throughput screening modalities, including high-content imaging, multidimensional, signature-based screening, and in vitro network using multielectrode arrays. Limitations, including the challenges in recapitulating neurocircuits and non-cell autonomous phenotypes are discussed. While these technologies are still in active development, we conclude that as our understanding of how to efficiently generate and probe the plasticity of patient-specific stem models improves, their utility is likely to advance rapidly.
doi:10.1016/j.biopsych.2013.05.028
PMCID: PMC3815991  PMID: 23876186
reprogramming; induced pluripotent stem cells; neural progenitors; disease-relevant cell type; phenotypic assays; neuroplasticity; neuropharmacology; high-throughput screening
24.  THE GENOME IN 3D: A NEW FRONTIER IN HUMAN BRAIN RESEARCH 
Biological psychiatry  2013;75(12):961-969.
Less than 1.5% of the human genome encodes protein. However, vast portions of the human genome are subject to transcriptional and epigenetic regulation and many non-coding regulatory DNA elements are thought to regulate the spatial organization of interphase chromosomes. For example, chromosomal ‘loopings’ are pivotal for the orderly process of gene expression, by enabling distal regulatory enhancer or silencer elements to directly interact with proximal promoter and transcription start sites, potentially bypassing hundreds of kilobases of interspersed sequence on the linear genome. To date, however, epigenetic studies in the human brain are mostly limited to the exploration of DNA methylation and posttranslational modifications of the nucleosome core histones. In contrast, very little is known about the regulation of supranucleosomal structures in brain nuclei. Here, we show that chromosome conformation capture (3C), a widely used approach to study higher order chromatin, is applicable to tissue collected postmortem, thereby informing about genome organization in the human brain. We introduce 3C protocols for brain, and compare higher order chromatin structures at the chromosome 6p22.2–22.1 schizophrenia and bipolar susceptibility locus and neurodevelopmental risk genes (DPP10, MCPH1) in adult prefrontal cortex and various cell culture systems, including neurons derived from reprogrammed skin cells. We predict that the exploration of three-dimensional genome architectures and function will open up new frontiers in human brain research and psychiatric genetics, and provide novel insights into the epigenetic risk architectures of regulatory non-coding DNA.
doi:10.1016/j.biopsych.2013.07.015
PMCID: PMC3925763  PMID: 23958183
higher order chromatin; chromosome conformation capture; chromatin fiber; chromosomal looping; human brain; genome in 3D
25.  Modeling heterogeneous patients with a clinical diagnosis of schizophrenia using induced pluripotent stem cells 
Biological psychiatry  2013;75(12):936-944.
Schizophrenia (SZ) is a devastating complex genetic mental condition that is heterogeneous in terms of clinical etiologies, symptoms and outcomes. Despite decades of postmortem, neuroimaging, pharmacological and genetic studies of patients, in addition to animal models, much of the biological mechanisms that underlie the pathology of SZ remain unknown. The ability to reprogram adult somatic cells into human induced pluripotent stem cells (hiPSCs) provides a new tool that supplies live human neurons for modeling complex genetic conditions such as SZ. The purpose of this review is to discuss the technical and clinical constraints currently limiting hiPSC based studies. We posit that reducing the clinical heterogeneity of hiPSC-based studies, by selecting subjects with common clinical manifestations or rare genetic variants, will help our ability to draw meaningful insights from the necessarily small patient cohorts that can be studied at this time.
doi:10.1016/j.biopsych.2013.10.025
PMCID: PMC4022707  PMID: 24331955
schizophrenia; human induced pluripotent stem cells; neuronal differentiation; clinical heterogeneity; mouse model; genetics

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