by
SV Trossbach;
V Bader;
L Hecher;
ME Pum;
ST Masoud;
I Prikulis;
S Schaeble;
MADS Silva;
P Su;
B Boulat;
C Chwiesko;
G Poschmann;
K Stuehler;
KM Lohr;
KA Stout;
A Oskamp;
SF Godsave;
A Mueller-Schiffmann;
T Bilzer;
H Steiner;
PJ Peters;
A Bauer;
M Sauvage;
AJ Ramsey;
Gary Miller;
F Liu;
P Seeman;
NJ Brandon;
JP Huston;
C Korth
Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.
We describe a novel preclinical model of stress-induced relapse to cocaine use in rats using social defeat stress, an ethologically valid psychosocial stressor in rodents that closely resembles stressors that promote craving and relapse in humans. Rats self-administered cocaine for 20 days. On days 11, 14, 17, and 20, animals were subjected to social defeat stress or a nonstressful control condition following the session, with discrete environmental stimuli signaling the impending event. After extinction training, reinstatement was assessed following re-exposure to these discrete cues. Animals re-exposed to psychosocial stress-predictive cues exhibited increased serum corticosterone and significantly greater reinstatement of cocaine seeking than the control group, and active coping behaviors during social defeat episodes were associated with subsequent reinstatement magnitude. These studies are the first to describe an operant model of psychosocial stress-induced relapse in rodents and lay the foundation for future work investigating its neurobiological underpinnings.
by
Oliver J. Bosch;
Joanna Dabrowska;
Meera E. Modi;
Zachary V. Johnson;
Alaine C. Keebaugh;
Catherine E. Barrett;
Todd H. Ahern;
Jidong Guo;
Valery Grinevich;
Donald Rainnie;
Inga D. Neumann;
Larry Young
Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression.
Introduction: Community-based and other epidemiologic studies within the United States have identified substantial disparities in health care among adults with epilepsy. However, few data analyses addressing their health-care access are representative of the entire United States. This study aimed to examine national survey data about adults with epilepsy and to identify barriers to their health care.
Materials and methods: We analyzed data from U.S. adults in the 2010 and the 2013 National Health Interview Surveys, multistage probability samples with supplemental questions on epilepsy. We defined active epilepsy as a history of physician-diagnosed epilepsy either currently under treatment or accompanied by seizures during the preceding year. We employed SAS-callable SUDAAN software to obtain weighted estimates of population proportions and rate ratios (RRs) adjusted for sex, age, and race/ethnicity.
Results: Compared to adults reporting no history of epilepsy, adults reporting active epilepsy were significantly more likely to be insured under Medicaid (RR = 3.58) and less likely to have private health insurance (RR = 0.58). Adults with active epilepsy were also less likely to be employed (RR = 0.53) and much more likely to report being disabled (RR = 6.14). They experience greater barriers to health-care access including an inability to afford medication (RR = 2.40), mental health care (RR = 3.23), eyeglasses (RR = 2.36), or dental care (RR = 1.98) and are more likely to report transportation as a barrier to health care (RR = 5.28).
Conclusions: These reported substantial disparities in, and barriers to, access to health care for adults with active epilepsy are amenable to intervention.
Rationale
There is significant interest in the NMDA-receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis.
Objective
The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine.
Methods
Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic i.v. infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/hr constant infusion) with and without risperidone pretreatment (0.06mg/kg). Statistical parametric maps of ketamine-induced BOLD activation were obtained with appropriate GLM models incorporating motion and hemodynamics of ketamine infusion.
Results
Ketamine infusion induced and sustained robust BOLD activation in a number of cortical and subcortical regions, including the thalamus, cingulate gyrus, and supplementary motor area. Pretreatment with the antipsychotic drug risperidone markedly blunted ketamine-induced activation in many brain areas.
Conclusions
The results are remarkably similar to human imaging studies showing ketamine-induced BOLD activation in many of the same brain areas, and pretreatment with risperidone or another antipsychotic blunting the ketamine response to a similar extent. The strong concordance of the functional imaging data in humans with these results from nonhuman primates highlights the translational value of the model and provides an excellent avenue for future research examining the CNS effects of ketamine. This model may also be a useful tool for evaluating the efficacy of novel antipsychotic drugs.
Both animal research and human research suggest that interictal epileptiform discharges (IEDs) may affect cognition, although the significance of such findings remains controversial. We review a wide range of literature with bearing on this topic and present relevant epilepsy surgery cases, which suggest that the effects of IEDs may be substantial and informative for surgical planning. In the first case, we present a patient with epilepsy with left anterior temporal lobe (TL) seizure onset who experienced frequent IEDs during preoperative neuropsychological assessment. Cognitive results strongly lateralized to the left TL. Because the patient failed performance validity tests and appeared amnestic for verbal materials inconsistent with his work history, selected neuropsychological tests were repeated 6 weeks later. Scores improved one to two standard deviations over the initial evaluation and because of this improvement, were only mildly suggestive of left TL impairment. The second case involves another patient with documented left TL epilepsy who experienced epileptiform activity while undergoing neurocognitive testing and simultaneous ambulatory EEG recording. This patient's verbal memory performance was impaired during the period that IEDs were present but near normal when such activity was absent. Overall, although the presence of IEDs may be helpful in confirming laterality of seizure onset, frequent IEDs might disrupt focal cognitive functions and distort accurate measurement of neuropsychological ability, interfering with accurate characterization of surgical risks and benefits. Such transient effects on daily performance may also contribute to significant functional compromise. We include a discussion of the manner in which IED effects during presurgical assessment can hinder individual patient presurgical planning as well as distort outcome research (e.g., IEDs occurring during presurgical assessment may lead to an underestimation of postoperative neuropsychological decline).
This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with Major Depressive Disorder (MDD). 155 subjects with DSM-IV MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ≥ 15 and baseline biomarker data (IL-1ra, IL-6, hs-CRP, leptin, adiponectin), were randomized between 05/18/06 and 06/30/11, to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg/day, docosahexaenoic acid (DHA)-enriched n-3 900 mg/day, or placebo. Outcomes were determined using mixed model repeated measures (MMRM) analysis for “high” and “low” inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. While overall treatment group differences were negligible (ES=−0.13 to +0.04), subjects with any “high” inflammation improved more on EPA than placebo (ES=−0.39) or DHA (ES=−0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with “high” IL-1ra or hs-CRP or low adiponectin (“high” inflammation) had medium ES decreases in HAM-D-17 scores versus subjects “low” on these biomarkers. Subjects with “high” hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA versus placebo in our cohort. Studies are needed to replicate and extend this proof of concept work.
by
Naomi Sadeh;
Jeffrey M. Spielberg;
Mark W. Logue;
Erika J. Wolf;
Alicia K Smith;
Joanna Lusk;
Jasmeet P. Hayes;
Emily Sperbeck;
William P. Milberg;
Regina E. McGlinchey;
David H. Salat;
Weleetka C. Carter;
Annjanette Stone;
Steven A. Schichman;
Donald E. Humphries;
Mark W. Miller
Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation adj). Specifically, DNA methylation adj was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation adj and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation adj of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.
by
Daniel Umbricht;
Marta del Valle Rubido;
Eric Hollander;
James T McCracken;
Frederick Shic;
Lawrence Scahill;
Jana Noeldeke;
Lauren Boak;
Omar Khwaja;
Lisa Squassante;
Christophe Grundschober;
Heidemarie Kletzl;
Paulo Fontoura
The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ > 70; ABC-Irritability subscale â 1/213). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD.