Heritable variation, with little or no maternal genetics contribution, accounts for recurrence risk to autism spectrum disorder in Sweden Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-21 Benjamin Hon Kei Yip, Dan Bai, Behrang Mahjani, Lambertus Klei, Yudi Pawitan, Christina Hultman, Dorothy Grice, Kathryn Roeder, Joseph D. Buxbaum, Bernie Devlin, Avi Reichenberg, Sven Sandin
BackgroundAutism spectrum disorder (ASD) has both genetic and environmental origins, including potentially ‘maternal effects’. Maternal effects describe association of one or more maternal phenotypes with liability to ASD in progeny that is independent of maternally-transmitted risk alleles. While maternal effects could play an important role, consistent with association to maternal traits such as immune status, no study has estimated maternal, additive genetic and environmental effects in ASD.MethodsUsing a population-based sample consisting of all children born in Sweden from 1998 to 2007 and their relatives, we fitted statistical models to family data to estimate the variance in ASD liability originating from maternal, additive genetic and shared environmental effects. We calculated sibling and cousin family recurrence risk ratio as a direct measure of familial, genetic and environmental risk factors and repeated the calculations on diagnostic subgroups, specifically autistic disorder (AD) and spectrum disorder (SD), which included Asperger’s syndrome and/or pervasive developmental disorder not otherwise specified.ResultsThe sample consisted of 776,212 children of whom 11,231 had a diagnosis of ASD: 4,554 with AD, 6,677 with SD. We found support for large additive genetic contribution to liability, heritability (95% confidence interval) was estimated to 84.8% (73.1%, 87.3%) for ASD, 79.6% (61.2%, 85.1%) for AD and 76.4% (63.0%, 82.5%) for SD.ConclusionsThere was modest, if any, contribution of maternal effects to liability for ASD, including subtypes AD and SD, and there was no support for shared environmental effects. These results show liability to ASD arises largely from additive genetic variation.
Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multi-Site ENIGMA-PGC Study Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-20 Mark W. Logue, Sanne J.H. van Rooij, Emily L. Dennis, Sarah L. Davis, Jasmeet P. Hayes, Jennifer S. Stevens, Maria Densmore, Courtney C. Haswell, Jonathan Ipser, Saskia B. Koch, Mayuresh Korgaonkar, Lauren A.M. Lebois, Matthew Peverill, Justin T. Baker, Premika S.W. Boedhoe, Jessie L. Frijling, Staci A. Gruber, Ilan Harpaz-Rotem, Neda Jahanshad, Sheri Koopowitz, Ifat Levy, Laura Nawijn, Lauren O’Connor, Miranda Olff, David H. Salat, Margaret A. Sheridan, Jeffrey M. Spielberg, Mirjam van Zuiden, Sherry R. Winternitz, Jonathan D. Wolff, Erika J. Wolf, Xin Wang, Kristen Wrocklage, Chadi G. Abdallah, Richard A. Bryant, Elbert Geuze, Tanja Jovanovic, Milissa L. Kaufman, Anthony P. King, John H. Krystal, Jim Lagopoulos, Ruth Lanius, Israel Liberzon, Regina E. McGlinchey, Katie A. McLaughlin, William P. Milberg, Mark W. Miller, Kerry J. Ressler, Dick J. Veltman, Dan J. Stein
Background: Many studies report smaller hippocampal and amygdala volumes in PTSD, but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomic Consortium (PGC)-Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) PTSD Working Group.Methods: We analyzed neuroimaging and clinical data from 1,868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium.Results: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared to trauma-exposed controls (Cohen’s D=-0.17, p=0.00054), and smaller amygdalae (D=-0.11, p=0.025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p<0.0063).Conclusions: Our study is not subject to the biases of meta-analyses of published data, and represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.
The role of the hippocampus in predicting future PTSD symptoms in recently traumatized civilians Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-20 Sanne J.H. van Rooij, Jennifer S. Stevens, Timothy D. Ely, Rebecca C. Hinrichs, Vasiliki Michopoulos, Sterling J. Winters, Yvonne E. Ogbonmwan, Jaemin Shin, Nicole R. Nugent, Lauren A. Hudak, Barbara O. Rothbaum, Kerry J. Ressler, Tanja Jovanovic
Background Understanding the neurobiological mechanisms that predict PTSD in recent trauma survivors is important for early interventions. Impaired inhibition of fear or behavioral responses is thought to be central to PTSD symptomatology, but its role in predicting PTSD is unknown. Here we examine whether brain function during response inhibition early after a civilian trauma can predict future PTSD symptoms. Methods Participants (original sample, N=27; replication sample, N=31) were recruited in the Emergency Department (ED) within 24h of trauma exposure. PTSD symptoms were assessed in the ED and 1, 3 and 6-months post-trauma. A Go/NoGo procedure in a 3T MRI scanner was used to measure neural correlates of response inhibition 1-2 months post-trauma. Elastic net regression was used to define the most optimal model to predict PTSD symptoms at 3-and 6-months among demographic, clinical and imaging measures. Results Less hippocampal activation was a significant predictor in the model predicting PTSD symptoms at 3-months (F(11,22)=4.33, p=0.01) and 6-months (F(9,19)=4.96, p=0.01). Other significant predictors in the model were race and pain level in the ED (3-months), and race and baseline depression symptoms (6-months). Using these predictors in a linear regression in the replication sample again resulted in significant models (F(3,23)=3.03, p=0.05; F(3,20)=5.74, p=0.007) with hippocampal activation predicting PTSD symptoms at 3-and 6-months. Conclusions Decreased inhibition-related hippocampal activation soon after trauma prospectively predicted greater future PTSD symptom severity. This finding may contribute to early identification of at-risk individuals and reveals potential targets for intervention or symptom prevention in the aftermath of trauma.
mGluR5 and Stress Disorders: Knowledge Gained from Receptor Imaging Studies Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-19 Irina Esterlis, Sophie E. Holmes, Priya Sharma, John H. Krystal, Christine DeLorenzo
The metabotropic glutamatergic receptor subtype 5 (mGluR5) may represent a promising therapeutic target for stress-related psychiatric disorders. Here, we describe mGluR5 findings in stress disorders, particularly major depressive disorder (MDD), highlighting insights from positron emission tomography (PET) studies. PET studies report either no differences or lower mGluR5 in MDD; potentially reflecting MDD heterogeneity. Unlike the rapidly acting glutamatergic agent ketamine, mGluR5-specific modulation has not yet shown antidepressant efficacy in MDD and bipolar disorder (BD). Although we recently showed that ketamine may work, in part, through significant mGluR5 modulation, the specific role of mGluR5 downregulation in ketamine’s antidepressant response is unclear. In contrast to MDD, there has been much less investigation of mGluR5 in BD, yet initial studies indicate mGluR5-specific treatments may aid in both depressed and manic mood states. The direction of modulation needed may be state-dependent, however, limiting clinical feasibility. There has been relatively little study of post traumatic stress disorder (PTSD) or obsessive-compulsive disorder (OCD) to date, although there is evidence for the upregulation of mGluR5 in these disorders. However, while antagonism of mGluR5 may reduce fear conditioning, it may also reduce fear extinction. Therefore, studies are needed to determine the role mGluR5 modulation might play in the treatment of these conditions. Further challenges in modulating this prevalent neurotransmitter system include potential induction of significant side effects. As such, more research is needed to identify level and type (positive/negative allosteric modulation or full antagonism) of mGluR5 modulation required to translate existing knowledge into improved therapies.
Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in females Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-14 Natalia Duque-Wilckens, Michael Q. Steinman, Marta Busnelli, Bice Chini, Sae Yokoyama, Mary Pham, Sarah A. Laredo, Rebecca Hao, Allison M. Perkeybile, Vanessa A. Minie, Phillip B. Tan, Karen L. Bales, Brian C. Trainor
Background The neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context-dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT. Methods First, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used EGR1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior. Results A single dose of systemic L-368,899 increased social approach in stressed females and decreased social approach in males naïve to defeat. L-368,899 prevented OT activation of G proteins, and did not activate G-proteins in the absence of OT. Intranasal OT, which reduces social approach in females but not males, increased EGR1 immunoreactivity in the nucleus accumbens (NAc) core and anteromedial BNST in females but not males. Stressed females that received an infusion of L-368,899 in to anteromedial BNST but not the NAc core increased social approach and decreased social vigilance responses. Conclusions Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.
Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-07 Jessica L. Bolton, Jenny Molet, Limor Regev, Yuncai Chen, Neggy Rismanchi, Elizabeth Haddad, Derek Z. Yang, Andre Obenaus, Tallie Z. Baram
Background Anhedonia, the diminished ability to experience pleasure, is an important dimensional entity linked to depression, schizophrenia and other emotional disorders, but its origins and mechanisms are poorly understood. We have previously identified anhedonia, manifest as decreased sucrose preference and social play, in adolescent male rats that experienced chronic early-life adversity/stress (CES). Here we probed the molecular, cellular and circuit processes underlying CES-induced anhedonia and tested them mechanistically. Methods We examined functional brain circuits and neuronal populations activated by social play in adolescent CES and control rats. Structural connectivity between stress- and reward-related networks was probed using high-resolution diffusion tensor imaging (DTI), and cellular/regional activation was probed using cFos. We employed viral-genetic approaches to reduce corticotropin-releasing hormone (Crh) expression in amygdalar central nucleus (ACe) in anhedonic rats, and tested for anhedonia reversal in the same animals. Results Sucrose preference was reduced in adolescent CES rats. Social play, generally considered an independent measure of pleasure, activated brain regions involved in reward circuitry in both control and CES groups. In CES rats, social play activated Crh-expressing neurons in ACe, typically involved in anxiety/fear, indicating aberrant functional connectivity of pleasure/reward and fear circuits. DTI-tractography revealed increased structural connectivity of amygdala to medial prefrontal cortex in CES rats. Crh-shRNA, but not control shRNA, given into ACe reversed CES-induced anhedonia without influencing other emotional measures. Conclusions These findings robustly demonstrate aberrant interactions of stress and reward networks after early-life adversity and suggest mechanistic roles for Crh-expressing amygdala neurons in emotional deficits portending major neuropsychiatric disorders.
Locus Coeruleus Activity Mediates Hyper-Responsiveness in Posttraumatic Stress Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-07 Christoph Naegeli, Thomas Zeffiro, Marco Piccirelli, Assia Jaillard, Anina Weilenmann, Katayun Hassanpour, Matthis Schick, Michael Rufer, Scott P. Orr, Christoph Mueller-Pfeiffer
Background Patients with posttraumatic stress disorder (PTSD) are hyper-responsive to unexpected or potentially threatening environmental stimuli. Research in lower animals and humans suggests that sensitization of the locus coeruleus-norepinephrine system may underlie behavioral and autonomic hyper-responsiveness in PTSD. However, direct evidence linking locus coeruleus system hyperactivity to PTSD hyper-responsiveness is sparse. Methods Psychophysiological recording and fMRI was used during passive listening to brief, 95 dB sound pressure level, white noise bursts presented intermittently to determine whether behavioral and autonomic hyper-responsiveness to sudden sounds in PTSD is associated with locus coeruleus hyper-responsiveness. Results Participants with PTSD (n = 28) showed more eyeblink reflexes and larger heart rate, skin conductance and pupil area responses to loud sounds (multivariate p = 0.007) compared to trauma-exposed participants without PTSD (n = 26). PTSD participants exhibited larger responses in locus coeruleus (t = 2.60, ROI FWE-corrected), intraparietal sulcus, caudal dorsal premotor cortex, and cerebellar lobule VI (t's ≥ 4.18, whole-brain FWE-corrected). Caudal dorsal premotor cortex activity was associated with both psychophysiological response magnitude and levels of exaggerated startle responses in daily life in PTSD participants (t's ≥ 4.39, whole-brain FWE-corrected). Conclusions Behavioral and autonomic hyper-responsiveness in PTSD may arise from a hyperactive alerting/orienting system in which processes related to attention and motor preparation localized to lateral premotor cortex, intraparietal sulcus and posterior superior cerebellar cortex are modulated by atypically high phasic noradrenergic influences originating in the locus coeruleus.
In Vivo Brain Glycine and Glutamate Concentrations in Patients with First-Episode Psychosis Measured by Echo-Time-Averaged Proton MR Spectroscopy at 4 Tesla Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-07 Sang-Young Kim, Marc J. Kaufman, Bruce M. Cohen, J. Eric Jensen, Joseph T. Coyle, Fei Du, Dost Öngür
Background Accumulating evidence suggests the involvement of abnormal glutamateric neurotransmission and N-methyl-D-aspartate receptor (NMDAR) hypofunction in the pathophysiology of psychotic disorders. The purpose of this study was to quantify in vivo glutamate (Glu) and glycine (Gly) levels in patients with first-episode psychosis as well as age-matched healthy controls with MR spectroscopy. Methods The subjects were 46 patients with first-episode psychosis (20 schizophrenia-spectrum disorders (SZ), 26 bipolar disorder (BD)) and 50 age-matched healthy controls (HC). Glu and Gly levels were measured in vivo in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) of the subjects by using the echo-time (TE)-averaged proton MR spectroscopy technique (1H-MRS) at 4 T (i.e., modified PRESS sequence: 24 TE steps with 20 ms increments). Metabolite levels were quantified using LCModel with simulated basis sets. Results Significantly higher Glu and Gly levels were found in both the ACC and PCC of patients with first-episode psychosis as compared to healthy controls. Glu and Gly levels were positively correlated in patients. SZ and BD patients showed similar abnormalities. Conclusions Our findings demonstrate abnormally elevated brain Glu and Gly levels in patients with first-episode psychosis by means of TE-averaged 1H-MRS at 4 T. The findings implicate dysfunction of NMDAR and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses.
Amygdala reward reactivity mediates the association between preschool stress response and depression severity Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-07 Michael S. Gaffrey, Deanna M. Barch, Ryan Bogdan, Katrina Farris, Steven E. Petersen, Joan L. Luby
Background Research in adolescents and adults has suggested that altered neural processing of reward following early life adversity is a highly promising depressive intermediate phenotype. However, very little is known about how stress reactivity, neural processing of reward, and depression are related in very young children. Motivated by this knowledge gap, the present study examined the concurrent associations between cortisol response following a stressor, functional brain activity to reward, and depression severity in 4-6 year old children. Methods Fifty-two medication naïve 4-6 year olds participated in a study using functional magnetic resonance imaging (fMRI) to assess neural reactivity to reward, including gain, loss, and neutral outcomes. Parent-reported child depression severity and child cortisol response following stress were also measured. Results Greater caudate and medial prefrontal cortex reactivity to gain outcomes and increased amygdala reactivity to salient (i.e., both gain and loss) outcomes were observed. Higher total cortisol output following a stressor was associated with increased depression severity and reduced amygdala reactivity to salient outcomes. Amygdala reactivity was also inversely associated with depression severity and found to mediate the relationship between cortisol output and depression severity. Conclusions Results suggest that altered neural processing of reward is already related to increased cortisol output and depression severity in preschoolers. They also demonstrate an important role for amygdala function as a mediator of this relationship at a very early age. Our results further underscore early childhood as an important developmental period for understanding the neurobiological correlates of early stress and increased risk for depression.
Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse: a review of preclinical studies and their clinical implications Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-05 Daniele Caprioli, Zuzana Justinova, Marco Venniro, Yavin Shaham
Results from preclinical rodent studies during the last 20 years have implicated glutamate neurotransmission in different brain regions in drug self-administration and rodent models of relapse. These results, along with evidence for drug-induced neuroadaptations in glutamatergic neurons and receptors, suggest that addiction might be treatable by medications that inhibit glutamatergic responses to drugs of abuse, drug-associated cues, and stressors. This idea is supported by findings that drug self-administration and relapse, in rodent and primate models, are reduced by systemic injections of antagonists of ionotropic glutamate receptors or metabotropic glutamate receptors (mGluRs) or orthosteric agonists of mGluR2/3 receptors. However, these compounds have not advanced to clinical use because of potential side effects and other factors. This state-of-affairs has led to the development of positive and negative allosteric modulators (PAMs and NAMs) of mGluRs. PAMs and NAMs of mGluRs, either of which can inhibit evoked glutamate release, may be suitable for testing in humans. Here, we review results from recent studies of systemically injected PAMs and NAMs of mGluRs in rodents and monkeys, focusing on whether they reduce drug self-administration, reinstatement of drug seeking, and incubation of drug craving. We also review results from rat studies in which PAMs or NAMs of mGluRs were injected intracranially to reduce drug self-administration and reinstatement. We conclude that PAMs and NAMs of mGluRs should be considered for clinical trials.
Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish Twin Register Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-01 Rikke Hilker, Dorte Helenius, Birgitte Fagerlund, Axel Skytthe, Kaare Christensen, Thomas M. Werge, Merete Nordentoft, Birte Glenthøj
Background Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia risk. Heritability estimates of schizophrenia in twin samples have varied methodologically. This study provides updated heritability estimates based on nationwide twin data and an improved statistical methodology. Method Combining two nationwide registers, the Danish Twin Register and the Danish Psychiatric Research Register, we identified a sample of twins born 1951-2000 (N=31,524 twin pairs). Twins were followed up until June 1st 2011. Liability threshold models adjusting for censoring with inverse probability weighting were used to estimate probandwise concordance rates and heritability of the diagnoses of schizophrenia and schizophrenia spectrum disorders. Results The probandwise concordance rate of schizophrenia is 33% in monozygotic (MZ) twins and 7% in dizygotic (DZ) twins. We estimated the heritability of schizophrenia to be 79%. When expanding illness outcome to include schizophrenia spectrum disorders, the heritability estimate was almost similar, 73%. Conclusion The key strength of this study is the application of a novel statistical method accounting for censoring in the follow-up period to a nationwide twin sample. The estimated 79% heritability of schizophrenia is congruent with previous reports and indicates a substantial genetic risk. The high genetic risk also applies to a broader phenotype of schizophrenia spectrum disorders. The low concordance rate of 33% in MZ twins demonstrates that illness vulnerability is not solely indicated by genetic factors.
Harnessing Gut Microbes for Mental Health: Getting from Here to There Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-30 Annadora Bruce-Keller, J. Michael Salbaum, Hans-Rudolf Berthoud
There has been an explosion of interest in the study of microorganisms inhabiting the gastrointestinal tract (gut microbiota) and their impact on host health and physiology. Accumulating data suggest that altered communication between gut microbiota and host systems could participate in disorders such as obesity, diabetes mellitus, and autoimmune disorders; as well as neuropsychiatric disorders including autism, anxiety, and major depressive disorders. The conceptual development of the microbiome-gut-brain axis has facilitated understanding of the complex and bidirectional networks between gastrointestinal microbiota and their host, highlighting potential mechanisms through which this environment influences central nervous system (CNS) physiology. Communication pathways between gut microbiota and the CNS could include autonomic, neuroendocrine, enteric, and immune systems; with pathology resulting in disruption to neurotransmitter balance, increases in chronic inflammation, and/or exacerbated hypothalamic-pituitary-adrenal (HPA)-axis activity. However, uncertainty remains as to the generalizability of controlled animal studies to the more multifaceted pattern of human pathophysiology, especially with regard to the therapeutic potential for neuropsychiatric health. This narrative review summarizes current understanding of gut microbial influence over physiologic function, with an emphasis on neurobehavioral and neurologic impairment based on growing understanding of the gut-brain axis. Experimental and clinical data regarding means of therapeutic manipulation of gut microbiota as a novel treatment option for mental health are described, and important knowledge gaps are identified and discussed.
Expression of the PPM1F gene is regulated by stress and associated with anxiety and depression Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-30 Aliza P. Wingo, Eric Velasco, Antonio Florido, Adriana Lori, Dennis C. Choi, Tanja Jovanovic, Kerry J. Ressler, Raül Andero
Background Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as Post-Traumatic Stress Disorder (PTSD) and depression, are not well understood. Methods Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. Results From a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F mRNA levels in human blood were down-regulated in cases with symptoms of comorbid PTSD and depression (PTSD&Dep), and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we show that a genetic variant of PPM1F, rs17759843, was associated with PTSD&Dep and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2, we examined blood mRNA of CAMK2G in human and found it to be lower in PTSD&Dep. We also found that Ppm1f protein levels and its colocalization with Camk2G were altered in the amygdala and mPFC of male mice. Additionally, we found a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and mRNA levels of Ppm1f in the amygdala and mPFC in male mice and in the mPFC of female mice. Discussion Taken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress and trauma-related manifestation of anxiety and depression across species.
Altered medial frontal feedback learning signals in anorexia nervosa Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-30 Fabio Bernardoni, Daniel Geisler, Joseph A. King, Amir-Homayoun Javadi, Franziska Ritschel, Julia Murr, Andrea M.F. Reiter, Veit Rössner, Michael N. Smolka, Stefan Kiebel, Stefan Ehrlich
Background In their relentless pursuit of thinness, individuals with anorexia nervosa (AN) engage in maladaptive behaviors (restrictive food choices, over-exercising) which may originate in altered decision-making and learning. Methods In this fMRI study we employed computational modelling to elucidate the neural correlates of feedback learning and value-based decision making in 36 female AN patients and 36 age-matched healthy volunteers (12-24 years). Participants performed a decision task which required adaptation to changing reward contingencies. Data were analyzed within a hierarchical Gaussian filter model, which captures inter-individual variability in learning under uncertainty. Results Behaviorally, patients displayed an increased learning rate specifically after punishments. At the neural level, hemodynamic correlates for learning rate, expected value and prediction error did not differ between the groups. However, activity in the posterior medial frontal cortex was elevated in AN following punishment. Conclusion Our findings suggest that the neural underpinning of feedback learning is selectively altered for punishment in AN.
Serine Racemase and D-serine in the Amygdala are Dynamically Involved in Fear Learning Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-26 Darrick T. Balu, Kendall Taylor Presti, Cathy C.Y. Huang, Kevin Muszynski, Inna Radzishevsky, Herman Wolosker, Guia Guffanti, Kerry J. Ressler, Joseph T. Coyle
Background The amygdala is a central component of the neural circuitry that underlies fear learning. N-methyl-D-aspartate receptor (NMDAR)-dependent plasticity in the amygdala is required for Pavlovian fear conditioning and extinction. NMDAR activation requires the binding of a co-agonist, D-serine, which is synthesized from L-serine by the neuronal enzyme serine racemase (SR). However, little is known about SR and D-serine function in the amygdala. Methods We used immunohistochemical methods to characterize the cellular localization of SR and D-serine in the mouse and human amygdala. Using biochemical and molecular techniques, we determined whether trace fear conditioning and extinction engages the SR and D-serine in the brain. D-serine was administered systemically to mice evaluate its effect on fear extinction. Finally, we investigated whether a functional SNP (rs4523957), which is an expression-linked quantitative trait locus (eQTL) of the human serine racemase (SRR) gene, was associated with fear-related phenotypes in a highly traumatized human cohort. Results We demonstrate that approximately half of the neurons in the amygdala express SR, including both excitatory and inhibitory neurons. We find that the acquisition and extinction of fear memory engages the SR/D-serine system in the mouse amygdala and that D-serine administration facilitates fear extinction. We also demonstrate that the SRR SNP, rs4523957, is associated with post-traumatic stress disorder (PTSD) in humans, consistent with the facilitatory effect of D-serine on fear extinction. Conclusions These new findings have important implications for understanding D-serine mediated NMDAR plasticity in the amygdala and how this system could contribute to disorders with maladaptive fear circuitry.
Structural Neuroimaging of Anorexia Nervosa: Future Directions in the Quest for Mechanisms Underlying Dynamic Alterations Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-24 Joseph A. King, Guido K.W. Frank, Paul M. Thompson, Stefan Ehrlich
Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and extreme weight loss. Pseudoatrophic brain changes are often readily visible in individual brain scans and AN may be a valuable model disorder to study structural neuroplasticity. Structural MRI studies have found reduced gray matter (GM) volume and cortical thinning in acutely underweight patients to normalize following successful treatment. However, some well-controlled studies have found regionally greater GM and persistence of structural alterations following long-term recovery. Findings from diffusion tensor imaging studies of white matter (WM) integrity and connectivity are also inconsistent. Furthermore, despite the severity of AN, the number of existing structural neuroimaging studies is still relatively low and our knowledge of the underlying cellular and molecular mechanisms for macrostructural brain changes is rudimentary. Here we critically review the current state of structural neuroimaging in AN and discuss the potential neurobiological basis of structural brain alterations in the disorder – highlighting impediments to progress, recent developments and promising future directions. In particular, we argue for the utility of more standardized data collection, adopting a connectomics approach to understanding brain network architecture, employing advanced MRI methods that quantify biomarkers of brain tissue microstructure, integrating data from multiple imaging modalities, strategic longitudinal observation during weight restoration and large-scale data pooling. Our overarching objective is to motivate carefully controlled research of brain structure in eating disorders, which will ultimately help predict therapeutic response and improve treatment.
Anti-Amyloid-β Monoclonal Antibodies for Alzheimer’s Disease: Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-24 Christopher H. van Dyck
The majority of putative “disease-modifying” treatments in development for Alzheimer’s disease (AD) are directed against the amyloid-β (Aβ) peptide. Among the anti-Aβ therapeutic approaches, the most extensively developed is immunotherapy—and specifically, passive immunization through the administration of exogenous monoclonal antibodies (mAbs). Although the testing of mAbs has been fraught with failure and confusing results, the experience gained from these trials has provided important clues for better treatments. This review summarizes the experience to date with the anti-Aβ mAbs to enter clinical trials for AD and examines the evidence for clinical efficacy, and the major problems with safety—i.e., amyloid related imaging abnormalities (ARIA). Since mAbs differ considerably with regard to their epitopes and the conformations of Aβ that they recognize (monomers, oligomers, protofibrils, fibrils), the consequences of targeting different species are also considered. An often-cited explanation for the failure of anti-Aβ mAb trials is that they are set too late in the disease process. New trials are indeed evaluating treatments at prodromal and preclinical stages. We should expect to see additional studies of pre-symptomatic AD to join the ongoing prevention trials—for which mAbs continue to serve as the mainstay.
Sustained molecular pathology across episodes and remission in major depression Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-18 Enzo Scifo, Mohan Pabba, Fenika Kapadia, Tianzhou Ma, David A. Lewis, George C. Tseng, Etienne Sibille
Background Major depressive disorder (MDD) is a debilitating mental illness and a major cause of lost productivity worldwide. MDD patients often suffer from life-long recurring episodes of increasing severity, reduced therapeutic response and shorter remission periods, suggesting the presence of a persistent and potentially progressive pathology. Methods Subgenual anterior cingulate cortex postmortem samples from four MDD cohorts (single episode, n=20; single episode in remission, n=15; recurrent episode, n=20 and recurrent episode in remission, n=15), and one control cohort (n=20) were analyzed by mass spectrometry (MS)-based proteomics (n=3630 proteins) combined with statistical analyses. The data was investigated for trait and state progressive neuropathologies in MDD using both unbiased approaches and tests of a priori hypotheses. Results The data provided weak evidence for proteomic differences as a function of state (depressed/remitted) or number of prior episodes. Instead it suggested the presence of persistent MDD effects, regardless of episodes or remitted state, namely on proteomic measures related to presynaptic neurotransmission, synaptic function, cytoskeletal re-arrangements, energy metabolism, phospholipid biosynthesis/metabolism and calcium ion homeostasis. Selected proteins (DRP-1, SNAP-29, GAD-67, mGluR1 and EAAT3) were validated by Western blot analysis. The findings were independent of technical, demographic (sex, age) or other clinical parameters (death by suicide and drug treatment). Conclusion Collectively, the results provide evidence for persistent MDD effects across current episodes or remission, in the absence of detectable progressive neuropathology.
Mitochondrial targeted therapies: where do we stand in mental disorders? Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-15 Dorit Ben-Shachar, Hila M. Ene
The neurobiology of psychiatric disorders is still unclear, although changes in multiple neuronal systems, specifically the dopaminergic, glutamatergic and GABAergic systems as well as abnormalities in synaptic plasticity and neural connectivity, are currently suggested to underlie their pathophysiology. A growing body of evidence suggests multifaceted mitochondrial dysfunction in mental disorders, which is in line with their role in neuronal activity, growth, development and plasticity. In this review, we will describe the main endeavors towards development of treatments that will enhance mitochondrial function and their transition into clinical use, in congenital mitochondrial diseases and chronic disorders such as diabetes type I&II, cardiovascular disorders and cancer. In addition, we will discuss the relevance of mitochondrial targeted treatments to mental disorders and their potential to become a novel therapeutic strategy that will improve the efficiency of the current treatments.
Familial liability to Epilepsy and ADHD: A Nationwide Cohort Study Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-12 Isabell Brikell, Laura Ghirardi, Brian M. D'Onofrio, David W. Dunn, Catarina Almqvist, Søren Dalsgaard, Ralf Kuja-Halkola, Henrik Larsson
Background Epilepsy and ADHD are strongly associated, however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Our goal was therefore to investigate the familial co-aggregation of epilepsy and ADHD, and to estimate the contribution of genetic and environmental risk factors to their co-occurrence. Methods We identified 1 899 654 individuals born 1987-2006 via national Swedish registers and linked each individual to their biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD, within-individual and across relatives. Quantitative genetic modelling was used to decompose the cross-disorder covariance into genetic and environmental factors. Results Individuals with epilepsy had a statistically significant increased risk of ADHD (OR=3·47, 95%CI=3·33-3·62). This risk increase extended to children whose mothers had epilepsy (OR=1·85, 95%CI=1·75-1·96), children whose fathers had epilepsy (OR=1·64, 95%CI=1·54-1·74), full-siblings (OR=1·56, 95%CI=1·46-1·67), maternal half-siblings (OR=1·28, 95%CI=1·14-1·43), paternal half-siblings (OR=1·10, 95%CI=0·96-1·25), and cousins (OR=1·15, 95%CI=1·10-1·20). The genetic correlation was 0·21 (95%CI=0·02-0·40) and explained 40% the phenotypic correlation between epilepsy and ADHD, with remaining variance largely explained by non-shared environmental factors (49%, rE 0·36, 95%CI=0·23-0·49). The contribution of shared environmental factors to the cross-disorder overlap was not statically significant (11%, rC 0·32, 95%CI=-0·16-0·79). Conclusions This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique the individual contributing to co-occurrence between the disorders. Our findings suggest that epilepsy may share less genetic risk with ADHD, as compared to other neurodevelopmental disorders.
Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a PET study Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-12 Sophie E. Holmes, Rainer Hinz, Silke Conen, Catherine J. Gregory, Julian C. Matthews, Jose M. Anton-Rodriguez, Alexander Gerhard, Peter S. Talbot
Background Major Depressive Disorder (MDD) is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of depressed individuals, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia, predominantly microglia, can be measured as an indication of neuroinflammation in-vivo using Positron Emission Tomography (PET) and TSPO-specific radioligands. Methods We used [11C](R)-PK11195 PET to compare TSPO availability in anterior cingulate cortex (ACC), prefrontal cortex (PFC) and insula between fourteen medication-free patients in a major depressive episode (MDE) of at least moderate severity and thirteen matched healthy controls. In a post-hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts. Results Multivariate analysis of variance indicated significantly higher TSPO in patients compared to controls (p=0.005). The elevation was of large effect size and significant in ACC (p=0.022; Cohen’s d=0.95), with smaller, non-significant elevations in PFC (p=0.342; Cohen’s d=0.38) and insula (p=0.466; Cohen’s d=0.29). TSPO was not elevated in patients without suicidal thinking, but was significantly increased in those with suicidal thoughts compared to those without, most robustly in ACC (p=0.008) and insula (p=0.023). Conclusions We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe MDE. Our findings provide further incentive for evaluating anti-inflammatory therapies in MDD.
Modulation of γ- and β-Secretases as early prevention against Alzheimer’s Disease Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-10 Iryna Voytyuk, Bart De Strooper, Lucia Chavez-Gutierrez
The genetic evidence implying Aβ in the initial stage of Alzheimer's disease (AD) is unequivocal. However, the long biochemical and cellular prodromal phases of the disease suggest that dementia is the result of a series of molecular and cellular cascades which nature and connections remain unknown.Therefore, it is unlikely that treatments directed at Aβ will have major clinical effects in the later stages of the disease. We discuss here the two major candidate therapeutic targets to lower Aβ in a preventive mode, i.e. γ- and β-secretase; the rationale behind these two targets; and the current state of the field.
A novel miR-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer’s disease Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-10 Xiong Wang, Dan Liu, He-Zhou Huang, Zhi-Hao Wang, Tong-Yao Hou, Xin Yang, Pei Pang, Na Wei, Ya-Fan Zhou, Marie-Josée Dupras, Frédéric Calon, Yu-Tian Wang, Heng-Ye Man, Jian-Guo Chen, Jian-Zhi Wang, Sébastien S. Hébert, Youming Lu, Ling-Qiang Zhu
Background Synaptic loss is an early pathological event in Alzheimer’s disease (AD), but its underlying molecular mechanisms remain largely unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of synaptic function and memory. Methods We used miRNA array and Q-PCR verify to examine the alteration of miRNAs in the AD mice and patients, the morris water maze to evaluate the mice learning and memor. We also used AAV or lentivirus to introduce PTPN1 expression of silencing RNAs. LTP and Golgi staining were used to evaluate the syanptic function and structure. We designed a peptide to interrupt miR-124/PTPN1 interation. Results Here we report that neuronal miR-124 is dramatically increased in the hippocampus of Tg2576 mice, a recognized AD mouse model. Similar changes were observed in specific brain regions of affected AD individuals. We further identified tyrosine-protein phosphatase non-receptor type 1 (PTPN1/PTP1B) as a direct target of miR-124. Overexpression of miR-124 or knockdown of PTPN1 recapitulated AD-like phenotypes in mice, including deficits in synaptic transmission and plasticity as well as memory by impairing the GluR2 membrane insertion. Most importantly, rebuilding the miR-124/PTPN1 pathway by suppression of miR-124, overexpression of PTPN1, or application of a peptide that disrupts the miR-124/PTPN1 interaction could restore synaptic failure and memory deficits. Conclusions Taken together, these results identified the miR-124/PTPN1 pathway as a critical mediator of synaptic dysfunction and memory loss in AD, and the miR-124/PTPN1 pathway could consider as a promising novel therapeutic target for AD patients.
Network Mechanisms of Clinical Response to Transcranial Magnetic Stimulation in Posttraumatic Stress Disorder and Major Depressive Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-08 Noah S. Philip, Jennifer Barredo, Mascha van ’t Wout-Frank, Audrey R. Tyrka, Lawrence H. Price, Linda L. Carpenter
Background Repetitive transcranial magnetic stimulation (TMS) therapy can modulate pathological neural network functional connectivity in major depressive disorder (MDD). Posttraumatic stress disorder is often comorbid with MDD, and symptoms of both disorders can be alleviated with TMS therapy. This is the first study to evaluate TMS-associated changes in connectivity in patients with comorbid posttraumatic stress disorder and MDD. Methods Resting-state functional connectivity magnetic resonance imaging was acquired before and after TMS therapy in 33 adult outpatients in a prospective open trial. TMS at 5 Hz was delivered, in up to 40 daily sessions, to the left dorsolateral prefrontal cortex. Analyses used a priori seeds relevant to TMS, posttraumatic stress disorder, or MDD (subgenual anterior cingulate cortex [sgACC], left dorsolateral prefrontal cortex, hippocampus, and basolateral amygdala) to identify imaging predictors of response and to evaluate clinically relevant changes in connectivity after TMS, followed by leave-one-out cross-validation. Imaging results were explored using data-driven multivoxel pattern activation. Results More negative pretreatment connectivity between the sgACC and the default mode network predicted clinical improvement, as did more positive amygdala-to-ventromedial prefrontal cortex connectivity. After TMS, symptom reduction was associated with reduced connectivity between the sgACC and the default mode network, left dorsolateral prefrontal cortex, and insula, and reduced connectivity between the hippocampus and the salience network. Multivoxel pattern activation confirmed seed-based predictors and correlates of treatment outcomes. Conclusions These results highlight the central role of the sgACC, default mode network, and salience network as predictors of TMS response and suggest their involvement in mechanisms of action. Furthermore, this work indicates that there may be network-based biomarkers of clinical response relevant to these commonly comorbid disorders.
The cortico-striatal adenosine A2A receptor controls maintenance and retrieval of spatial working memory Biol. Psychiatry (IF 11.412) Pub Date : 2017-08-01 Zhihui Li, Xingjun Chen, Tao Wang, Ying Gao, Fei Li, Long Chen, Jin Xue, Yan He, Yan Li, Wei Guo, Wu Zheng, Liping Zhang, Fenfen Ye, Xiangpeng Ren, Yue Feng, Piu Chan, Jiang-Fan Chen
Background Working memory (WM) taps into multiple executive processes including encoding, maintenance and retrieval of information, but the molecular and circuit modulation of these WM processes remain undefined due to lack of the methods to control G-protein coupled receptor signaling with temporal resolution of seconds. Methods By coupling optogenetic control of the adenosine A2A receptor (A2AR) signaling (“optoA2AR”), the Cre-loxP-mediated focal A2AR knockdown with a delayed non-match-to-place (DNMTP) task, we investigated the effect of optogenetic activation and focal knockdown of A2ARs in the dorsomedial striatum (DMS) (n=8-14/group) and medial prefrontal cortex (mPFC) (n=16-22/group) on distinct executive processes of spatial WM (SWM). We also evaluated the therapeutic effect of the A2AR antagonist KW6002 on delayed match-to-sample/place (DMTS/DMTP) task in six normal and six MPTP-treated Cynomolgus monkeys. Results Optogenetic activation of striatopallidal A2ARs in DMS selectively at the delay and choice (not sample) phases impaired DNMTP performance. Optogenetic activation of A2ARs in mPFC selectively at the delay (not sample or choice) phase improved DNMTP performance. The cortico-striatal A2AR control of SWM was specific for novel but not well-trained DNMTP task. Focal DMS A2AR knockdown or KW6002 improved DNMTP performance in mice. Lastly, KW6002 improved SWM in DMTS and DMTP tasks of normal and dopamine-depleted Cynomolgus monkeys. Conclusions The A2ARs in striatopallidal and mPFC neurons exert distinctive control of WM maintenance and retrieval to achieve cognitive stability and flexibility. The pro-cognitive effect of KW6002 in non-human primate provides the preclinical data to translate A2AR antagonists for improving cognitive impairments in Parkinson's disease.
Vicarious Social Defeat Stress Induces Depression-related Outcomes in Female Mice Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-29 Sergio D. Iñiguez, Francisco J. Flores-Ramirez, Lace M. Riggs, Jason B. Alipio, Israel Garcia, Mirella A. Hernandez, David O. Sanchez, Mary Kay Lobo, Peter A. Serrano, Stephen H. Braren, Samuel A. Castillo
Background Stress is a prevailing risk factor for mood-related illnesses, wherein women represent the majority of those afflicted with major depression. Despite the growing literature suggesting that affective disorders can arise after a traumatic event is vicariously experienced, this relationship remains understudied in females at the preclinical level. Thus, the objective of the current investigation was to examine whether exposure to emotional/psychological stress (ES) mediates depression-related outcomes in female mice. Methods Female c57BL/6 mice (8-week old, nullparity) vicariously experienced the defeat bout of a male conspecific, by a male CD1 aggressor, for 10 consecutive days. Twenty-four h after the last stress exposure, female mice were tested in the social interaction, sucrose preference, tail suspension, or elevated plus-maze tests. Furthermore, we examined whether ketamine and chlordiazepoxide, pharmacological agents used to treat mood-related disorders in the clinical population, would reverse the ES-induced social dysfunction. Results When compared to controls, female mice exposed to ES displayed decreased social behavior and preference for sucrose, along with increased immobility in the tail suspension test. Also, they displayed higher levels of blood serum corticosterone, as well as decreased body weight. Lastly, the ES-induced avoidance-like phenotype was ameliorated by both ketamine and chlordiazepoxide. Conclusions Our data indicate that female mice exposed to ES display a behavioral- and physiologic-profile that mimics symptoms of depression in the clinical population. As such, this experimental model may be adopted to examine vicarious stress-induced mood-related disorders, as well as pharmacological antidepressant response, in a sex specific manner.
The Association Between Prenatal Stress And Externalizing Symptoms In Childhood: Evidence From The Avon Longitudinal Study Of Parents And Children Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-27 Nathalie MacKinnon, Mila Kingsbury, Liam Mahedy, Jonathan Evans, Ian Colman
Background It has been suggested that prenatal maternal stress may increase risk of childhood externalizing disorders, yet no large cohort study has investigated this association across a large range of acute stressors. Our objective was to estimate the association between prenatal stressful events and risk of offspring conduct disorder and hyperactivity. Methods We used data from 10,184 mother-offspring pairs from the UK-based Avon Longitudinal Study of Parents and Children. Mothers self-reported 42 prenatal stressful life events at 18 weeks gestation. Symptoms of conduct disorder and hyperactivity were measured at age 6, 9, 11, 13, and 16 by the Strengths and Difficulties Questionnaire. The primary outcome was membership in high-symptom trajectories of (1) conduct disorder and (2) hyperactivity throughout childhood, identified using latent class growth modeling. Multinomial logistic regression models estimated the association between prenatal stress and both conduct disorder and hyperactivity, after adjusting for sex, parental education, low birth weight, pre-term birth, parental social class, maternal smoking and drinking, maternal mental health, offspring stressful life events, and offspring depressive and anxious symptoms. Results Those exposed to the highest quartile of prenatal stress were more likely to belong to the high symptom trajectory for hyperactivity (B = 0.46, p<.05) and conduct disorder (B = 0.88, p<.01), respectively. Prenatal stress further demonstrated a positive, dose response relationship with symptoms of externalizing disorders at independent time points. Conclusions The findings suggest that prenatal stressful events may be an independent risk factor for offspring externalizing symptoms, regardless of maternal mental health and offspring internalizing.
Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-27 Pierre-Eric Lutz, Jeffrey A. Gross, Sabine K. Dhir, Gilles Maussion, Jennie Yang, Alexandre Bramoulle, Michael J. Meaney, Gustavo Turecki
Background Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects. Methods Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA. Results A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor. Conclusions Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life.
Intergenerational Effect of Maternal Exposure to Childhood Maltreatment on Newborn Brain Anatomy Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-21 Nora K. Moog, Sonja Entringer, Jerod M. Rasmussen, Martin Styner, John H. Gilmore, Norbert Kathmann, Christine M. Heim, Pathik D. Wadhwa, Claudia Buss
Background Childhood maltreatment (CM) confers deleterious long-term consequences, and growing evidence suggests some of these effects may be transmitted across generations. We examined the intergenerational effect of maternal CM exposure on child brain structure and also addressed the hypothesis that this effect may start during the child’s intrauterine period of life. Methods A prospective longitudinal study was conducted in a clinical convenience sample of 80 mother-child dyads. Maternal CM exposure was assessed using the Childhood Trauma Questionnaire. Structural magnetic resonance imaging was employed to characterize newborn global and regional brain (tissue) volumes near the time of birth. Results CM exposure was reported by 35% of the women. Maternal CM exposure was associated with lower child intracranial volume (F1,70 = 6.84, p = .011), which was primarily due to a global difference in cortical gray matter (F1,70 = 9.10, p = .004). The effect was independent of potential confounding variables, including maternal socioeconomic status, obstetric complications, obesity, recent interpersonal violence, pre- and early postpartum stress, gestational age at birth, infant sex, and postnatal age at magnetic resonance imaging scan. The observed group difference between offspring of CM-exposed mothers versus nonexposed mothers was 6%. Conclusions These findings represent the first report to date associating maternal CM exposure with variation in newborn brain structure. These observations support our hypothesis of intergenerational transmission of the effects of maternal CM exposure on child brain development and suggest this effect may originate during the child’s intrauterine period of life, which may have downstream neurodevelopmental consequences.
Persistent Increase in Microglial RAGE Contributes to Chronic Stress–Induced Priming of Depressive-like Behavior Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-21 Tina C. Franklin, Eric S. Wohleb, Yi Zhang, Manoela Fogaça, Brendan Hare, Ronald S. Duman
Background Chronic stress–induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. Methods Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)–induced behavioral deficits, including long-term, persistent changes after CUS. Results The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. Conclusions Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure.
Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder with Oppositional Defiant Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-21 Siri D.S. Noordermeer, Marjolein Luman, Corina U. Greven, Kim Veroude, Stephen V. Faraone, Catharina A. Hartman, Pieter J. Hoekstra, Barbara Franke, Jan K. Buitelaar, Dirk J. Heslenfeld, Jaap Oosterlaan
Background Attention-Deficit/Hyperactivity-Disorder (ADHD) is associated with structural abnormalities in total gray matter, basal ganglia and cerebellum. Findings of structural abnormalities in frontal and temporal lobes, amygdala, and insula are less consistent. Remarkably, the impact of comorbid Oppositional Defiant Disorder (ODD) (comorbidity rates up to 60%) on these neuroanatomical differences is scarcely studied, while ODD (in combination with Conduct Disorder (CD)) has been associated with structural abnormalities of the frontal lobe, amygdala, and insula. The aim of this study was to investigate the effect of comorbid ODD on cerebral volume and cortical thickness in ADHD. Methods Three groups (mean age 16 year, SD=3.5, range 7-29) were studied on volumetric and cortical thickness characteristics using structural magnetic resonance imaging (Surface-Based Morphometry): ADHD+ODD (n=67), ADHD-only (n=243), and controls (n=233). Analyses included moderators age, gender, IQ, scan-site. Results ADHD+ODD and ADHD-only showed volumetric reductions in total gray matter and (mainly) frontal brain areas. Stepwise volumetric reductions (ADHD+ODD
No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-13 Emma C. Johnson, Richard Border, Whitney E. Melroy-Greif, Christiaan A. de Leeuw, Marissa A. Ehringer, Matthew C. Keller
Background A recent analysis of 25 historical candidate gene polymorphisms for schizophrenia in the largest genome-wide association study conducted to date suggested that these commonly studied variants were no more associated with the disorder than would be expected by chance. However, the same study identified other variants within those candidate genes that demonstrated genome-wide significant associations with schizophrenia. As such, it is possible that variants within historic schizophrenia candidate genes are associated with schizophrenia at levels above those expected by chance, even if the most-studied specific polymorphisms are not. Methods The present study used association statistics from the largest schizophrenia genome-wide association study conducted to date as input to a gene set analysis to investigate whether variants within schizophrenia candidate genes are enriched for association with schizophrenia. Results As a group, variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes. While a small subset of candidate genes did appear to be significantly associated with schizophrenia, these genes were not particularly noteworthy given the large number of more strongly associated noncandidate genes. Conclusions The history of schizophrenia research should serve as a cautionary tale to candidate gene investigators examining other phenotypes: our findings indicate that the most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.
Increased Occipital Gyrification and Development of Psychotic Disorders in Individuals With an At-Risk Mental State: A Multicenter Study Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-11 Daiki Sasabayashi, Yoichiro Takayanagi, Tsutomu Takahashi, Shinsuke Koike, Hidenori Yamasue, Naoyuki Katagiri, Atsushi Sakuma, Chika Obara, Mihoko Nakamura, Atsushi Furuichi, Mikio Kido, Yumiko Nishikawa, Kyo Noguchi, Kazunori Matsumoto, Masafumi Mizuno, Kiyoto Kasai, Michio Suzuki
Background Anomalies of brain gyrification have been reported in schizophrenia, possibly reflecting its neurodevelopmental pathology. However, it remains elusive whether individuals at risk for psychotic disorders exhibit deviated gyrification patterns, and whether such findings, if present, are predictive of transition to psychotic disorders. Methods This multicenter magnetic resonance imaging study investigated brain gyrification and its relationship to later transition to psychotic disorders in a large sample of at-risk mental state (ARMS) individuals. T1-weighted magnetic resonance imaging scans were obtained from 104 ARMS individuals, of whom 21 (20.2%) exhibited the transition to psychotic disorders during clinical follow-up (mean = 4.9 years, SD = 2.6 years), and 104 healthy control subjects at 4 different sites. The local gyrification index (LGI) of the entire cortex was compared across the groups using FreeSurfer software. Results Compared with the control subjects, ARMS individuals showed a significantly higher LGI in widespread cortical areas, including the bilateral frontal, temporal, parietal, and occipital regions, which was partly associated with prodromal symptomatology. ARMS individuals who exhibited the transition to psychotic disorders showed a significantly higher LGI in the left occipital region compared with individuals without transition. Conclusions These findings suggested that increased LGI in diverse cortical regions might represent vulnerability to psychopathology, while increased LGI in the left occipital cortex might be related to subsequent manifestation of florid psychotic disorders as a possible surrogate marker.
Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-08 Richard A. Slivicki, Zhili Xu, Pushkar M. Kulkarni, Roger G. Pertwee, Ken Mackie, Ganesh A. Thakur, Andrea G. Hohmann
Background Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist. Methods GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group. Results GAT211 suppressed allodynia induced by complete Freund’s adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion. Conclusions Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.
Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-08 Stephanie E. Sillivan, Nadine F. Joseph, Sarah Jamieson, Michelle L. King, Itzamarie Chévere-Torres, Illeana Fuentes, Gleb P. Shumyatsky, Alicia F. Brantley, Gavin Rumbaugh, Courtney A. Miller
Background The limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible and stress-resilient subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. Methods We employed a SEFL paradigm in inbred male and female C57BL/6 mice that combines acute stress with fear conditioning to precipitate traumatic-like memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence, and RNA sequencing of the basolateral amygdala. Results Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced male subgroups with differential susceptibility that were identified without posttraining phenotyping. Additional phenotyping of male mice revealed PTSD-associated behaviors, including extinction-resistant fear memory, hyperarousal, generalization, and dysregulated corticosterone in stress-susceptible male mice. Altered Fos activation was also seen in the infralimbic cortex and basolateral amygdala of stress-susceptible male mice after remote memory retrieval. Key behavioral outcomes, including susceptibility, were replicated by two independent laboratories. RNA sequencing of the basolateral amygdala revealed transcriptional divergence between the male subgroups, including genes with reported polymorphic association to patients with PTSD. Conclusions This SEFL model provides a tool for development of PTSD therapeutics that is compatible with the growing number of mouse-specific resources. Furthermore, use of an inbred strain allows for investigation into epigenetic mechanisms that are expected to critically regulate susceptibility and resilience.
Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-06 Gwenaël G.R. Leday, Petra E. Vértes, Sylvia Richardson, Jonathan R. Greene, Tim Regan, Shahid Khan, Robbie Henderson, Tom C. Freeman, Carmine M. Pariante, Neil A. Harrison, V. Hugh Perry, Wayne C. Drevets, Gayle M. Wittenberg, Edward T. Bullmore
Background Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Methods We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. Results A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies). Conclusions MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.
Cell- and Single Molecule-Based Methods to Detect Anti-N-Methyl-D-Aspartate Receptor Autoantibodies in Patients With First-Episode Psychosis From the OPTiMiSE Project Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-06 Julie Jézéquel, Véronique Rogemond, Thomas Pollak, Marilyn Lepleux, Leslie Jacobson, Hélène Gréa, Conrad Iyegbe, Rene Kahn, Philip McGuire, Angela Vincent, Jérôme Honnorat, Marion Leboyer, Laurent Groc
Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating autoantibodies against glutamatergic NMDAR in psychotic disorders remains controversial, with detection prevalence rates and immunoglobulin classes varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of patients with first-episode psychosis using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating autoantibodies against glutamatergic NMDAR in approximately 5% of patients with first-episode psychosis. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need for new sensitive methods to detect the presence of low-titer autoantibodies against glutamatergic NMDAR in seropositive patients who cannot be clinically identified from seronegative ones.
Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-07-04 Boadie W. Dunlop, Elisabeth B. Binder, Dan Iosifescu, Sanjay J. Mathew, Thomas C. Neylan, Julius C. Pape, Tania Carrillo-Roa, Charles Green, Becky Kinkead, Dimitri Grigoriadis, Barbara O. Rothbaum, Charles B. Nemeroff, Helen S. Mayberg
Background Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD. Methods We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period. Results In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n = 6) but not with placebo (n = 7) on the PTSD Symptom Scale–Self-Report. Conclusions The results of this trial, the first evaluating a CRF1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF1 receptor antagonists lack efficacy as monotherapy agents for these conditions.
Cross-Sectional and Longitudinal Associations of Chronic Posttraumatic Stress Disorder With Inflammatory and Endothelial Function Markers in Women Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-27 Jennifer A. Sumner, Qixuan Chen, Andrea L. Roberts, Ashley Winning, Eric B. Rimm, Paola Gilsanz, M. Maria Glymour, Shelley S. Tworoger, Karestan C. Koenen, Laura D. Kubzansky
Background Posttraumatic stress disorder (PTSD) may contribute to heightened cardiovascular disease risk by promoting a proinflammatory state and impaired endothelial function. Previous research has demonstrated associations of PTSD with inflammatory and endothelial function biomarkers, but most work has been cross-sectional and does not separate the effects of trauma exposure from those of PTSD. Methods We investigated associations of trauma exposure and chronic PTSD with biomarkers of inflammation (C-reactive protein and tumor necrosis factor alpha receptor II) and endothelial function (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in 524 middle-aged women in the Nurses’ Health Study II. Using linear mixed models, we examined associations of trauma/PTSD status with biomarkers measured twice, 10 to 16 years apart, in cardiovascular disease–free women, considering either average levels over time (cross-sectional) or change in levels over time (longitudinal). Biomarker levels were log-transformed. Trauma/PTSD status (based on structured diagnostic interviews) was defined as no trauma at either blood draw (n = 175), trauma at blood draw 1 but no PTSD at either draw (n = 175), and PTSD that persisted beyond blood draw 1 (chronic PTSD; n = 174). The reference group was women without trauma. Results In models adjusted for known potential confounders, women with chronic PTSD had higher average C-reactive protein (B = 0.27, p < .05), tumor necrosis factor alpha receptor II (B = 0.07, p < .01), and intercellular adhesion molecule-1 (B = 0.04, p < .05) levels. Women with trauma but without PTSD had higher average tumor necrosis factor alpha receptor II levels (B = 0.05, p < .05). In addition, women with chronic PTSD had a greater increase in vascular cell adhesion molecule-1 over time (B = 0.003, p < .05). Conclusions Increased inflammation and impaired endothelial function may be pathways by which chronic PTSD increases cardiovascular disease risk.
Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-27 Puja K. Parekh, Darius Becker-Krail, Poornima Sundaravelu, Shinsuke Ishigaki, Haruo Okado, Gen Sobue, Yanhua Huang, Colleen A. McClung
Background Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood. Methods Using ex vivo whole-cell patch-clamp electrophysiology in ClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression of Gria1 in the NAc and behavioral assays were also used. Results Compared with wild-type mice, ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor–mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functional Gria1 in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state. Conclusions Together, our findings demonstrate that NAc excitatory signaling via Gria1 expression is integral to the effects of Clock gene disruption on manic-like behaviors.
Infant Gut Microbiome Associated With Cognitive Development Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-27 Alexander L. Carlson, Kai Xia, M. Andrea Azcarate-Peril, Barbara D. Goldman, Mihye Ahn, Martin A. Styner, Amanda L. Thompson, Xiujuan Geng, John H. Gilmore, Rebecca C. Knickmeyer
Background Studies in rodents provide compelling evidence that microorganisms inhabiting the gut influence neurodevelopment. In particular, experimental manipulations that alter intestinal microbiota impact exploratory and communicative behaviors and cognitive performance. In humans, the first years of life are a dynamic time in gut colonization and brain development, but little is known about the relationship between these two processes. Methods We tested whether microbial composition at 1 year of age is associated with cognitive outcomes using the Mullen Scales of Early Learning and with global and regional brain volumes using structural magnetic resonance imaging at 1 and 2 years of age. Fecal samples were collected from 89 typically developing 1-year-olds. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa. Results Cluster analysis identified 3 groups of infants defined by their bacterial composition. Mullen scores at 2 years of age differed significantly between clusters. In addition, higher alpha diversity was associated with lower scores on the overall composite score, visual reception scale, and expressive language scale at 2 years of age. Exploratory analyses of neuroimaging data suggest the gut microbiome has minimal effects on regional brain volumes at 1 and 2 years of age. Conclusions This is the first study to demonstrate associations between the gut microbiota and cognition in human infants. As such, it represents an essential first step in translating animal data into the clinic.
Converging Prefronto-Insula-Amygdala Pathways in Negative Emotion Regulation in Marmoset Monkeys Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-23 Yoshiro Shiba, Lydia Oikonomidis, Stephen Sawiak, Tim D. Fryer, Young T. Hong, Gemma Cockcroft, Andrea M. Santangelo, Angela C. Roberts
Background Impaired regulation of emotional responses to potential threat is a core feature of affective disorders. However, while the subcortical circuitry responsible for processing and expression of fear has been well characterized, the top-down control of this circuitry is less well understood. Our recent studies demonstrated that heightened emotionality, as measured both physiologically and behaviorally, during conditioned fear and innate/social threat was induced, independently, by excitotoxic lesions of either the anterior orbitofrontal cortex (antOFC) or ventrolateral prefrontal cortex (vlPFC). An important outstanding question is whether the antOFC and vlPFC act on common or distinct downstream targets to regulate negative emotion. Methods The question was addressed by combining localized excitotoxic lesions in the PFC of a nonhuman primate and functional neuroimaging ([18F]fluorodeoxyglucose positron emission tomography) with a fear-regulating extinction paradigm. Marmoset monkeys with unilateral lesions of either the antOFC or vlPFC were scanned immediately following exposure to a fearful or safe context, and differences in [18F]fluorodeoxyglucose uptake were evaluated. Results [18F]fluorodeoxyglucose uptake in the insula and amygdala of the intact hemisphere was significantly increased in response to the fearful context compared with the safe context. Such discrimination between the two contexts was not reflected in the activity of the insula-amygdala of the antOFC or vlPFC-lesioned hemisphere. Instead, uptake was at an intermediate level in both contexts. Conclusions These findings demonstrate that the distinct control functions of the antOFC and vlPFC converge on the same downstream targets to promote emotion regulation, taking us closer to a mechanistic understanding of different forms of anxiety.
Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-23 Sriparna Ghosal, Eunyoung Bang, Wenzhu Yue, Brendan D. Hare, Ashley E. Lepack, Matthew J. Girgenti, Ronald S. Duman
Background Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology and treatment of depression. Recent clinical studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in patients with depression. Rodent studies demonstrate that scopolamine increases glutamate transmission and synaptogenesis in the medial prefrontal cortex (mPFC). Here we tested the hypothesis that activity-dependent BDNF release within the mPFC is necessary for the antidepressant actions of scopolamine. Methods Behavioral effects of scopolamine were assessed in BDNF Val/Met knock-in mice, in which BDNF processing and release are impaired. In addition, intra-mPFC infusion of a BDNF-neutralizing antibody was performed to test the necessity of BDNF release in driving scopolamine-induced behavioral responses. Further in vivo and in vitro experiments were performed to delineate BDNF-dependent mechanisms underlying the effects of scopolamine. Results We found that BDNF Met/Met mice have attenuated responses to scopolamine and that anti-BDNF antibody infusions into the mPFC prevented the antidepressant-like behavioral effects of scopolamine. In vitro experiments show that scopolamine rapidly stimulates BDNF release and tropomyosin receptor kinase B–extracellular signal-regulated kinase signaling. Moreover, these effects require alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor activation and are blocked by neuronal silencing. Importantly, pretreatment with verapamil prevented scopolamine-induced behavioral responses and BDNF–tropomyosin receptor kinase B signaling, suggesting that these effects are dependent on activation of voltage-dependent calcium channels. Conclusions The results identify an essential role for activity-dependent BDNF release in the rapid antidepressant effects of scopolamine. Attenuation of responses in BDNF Met mice indicates that patients with the Met allele may be less responsive to scopolamine.
Affected Anatomical Rich Club and Structural–Functional Coupling in Young Offspring of Schizophrenia and Bipolar Disorder Patients Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-21 Guusje Collin, Lianne H. Scholtens, René S. Kahn, Manon H.J. Hillegers, Martijn P. van den Heuvel
Background Emerging evidence suggests disruptions in the wiring organization of the brain’s network in schizophrenia (SZ) and bipolar disorder (BD). As the importance of genetic predisposition has been firmly established in these illnesses, children (offspring) of patients constitute an at-risk population. This study examines connectome organization in children at familial high risk for psychosis. Methods Diffusion-weighted magnetic resonance imaging scans were collected from 127 nonpsychotic offspring 8 to 18 years of age (average age = 13.5 years) of a parent diagnosed with SZ (SZ offspring; n = 28) or BD (BD offspring; N = 60) and community control subjects (n = 39). Resting-state functional magnetic resonance imaging scans were available for 82 subjects. Anatomical and functional brain networks were reconstructed and examined using graph theoretical analysis. Results SZ offspring were found to show connectivity deficits of the brain’s central rich club (RC) system relative to both control subjects and BD offspring. The disruption in anatomical RC connectivity in SZ offspring was associated with increased modularity of the functional connectome. In addition, increased coupling between structural and functional connectivity of long-distance connections was observed in both SZ offspring and BD offspring. Conclusions This study shows lower levels of anatomical RC connectivity in nonpsychotic young offspring of SZ patients. This finding suggests that the brain’s anatomical RC system is affected in at-risk youths, reflecting a connectome signature of familial risk for psychotic illness. Moreover, finding no RC deficits in offspring of BD patients suggest a differential effect of genetic predisposition for SZ versus BD on the developmental formation of the connectome.
Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-19 Alice M. Graham, Jerod M. Rasmussen, Marc D. Rudolph, Christine M. Heim, John H. Gilmore, Martin Styner, Steven G. Potkin, Sonja Entringer, Pathik D. Wadhwa, Damien A. Fair, Claudia Buss
Background Maternal inflammation during pregnancy increases the risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the developing fetal brain is hypothesized as one potential mechanism but has not been examined in humans. Methods Participants were adult women (N = 86) who were recruited during early pregnancy and whose offspring were born after 34 weeks’ gestation. A biological indicator of maternal inflammation (interleukin-6) that has been shown to influence fetal brain development in animal models was quantified serially in early, mid-, and late pregnancy. Structural and functional brain magnetic resonance imaging scans were acquired in neonates shortly after birth. Infants’ amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24 months of age, children completed a snack delay task to assess impulse control. Results Higher average maternal interleukin-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, and thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age, and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control. Conclusions These findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts.
DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-16 Lauren M. Reynolds, Matthew Pokinko, Angélica Torres-Berrío, Santiago Cuesta, Laura C. Lambert, Esther Del Cid Pellitero, Michael Wodzinski, Colleen Manitt, Paul Krimpenfort, Bryan Kolb, Cecilia Flores
Background Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. Methods We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. Results We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. Conclusions The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex.
Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-16 David Soto, Mireia Olivella, Cristina Grau, Judith Armstrong, Clara Alcon, Xavier Gasull, Macarena Gómez de Salazar, Esther Gratacòs-Batlle, David Ramos-Vicente, Víctor Fernández-Dueñas, Francisco Ciruela, Àlex Bayés, Carlos Sindreu, Anna López-Sala, Àngels García-Cazorla, Xavier Altafaj
Background N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p.P553T) coding for the GluN2B subunit of NMDAR. Methods We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. Results Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. Conclusions Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.
Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-16 Ruth J. van Holst, Guillaume Sescousse, Lieneke K. Janssen, Marcel Janssen, Anne S. Berry, William J. Jagust, Roshan Cools
Background The hypothesis that dopamine plays an important role in the pathophysiology of pathological gambling is pervasive. However, there is little to no direct evidence for a categorical difference between pathological gamblers and healthy control subjects in terms of dopamine transmission in a drug-free state. Here we provide evidence for this hypothesis by comparing dopamine synthesis capacity in the dorsal and ventral parts of the striatum in 13 pathological gamblers and 15 healthy control subjects. Methods This was achieved using [18F]fluoro-levo-dihydroxyphenylalanine dynamic positron emission tomography scans and striatal regions of interest that were hand-drawn based on visual inspection of individual structural magnetic resonance imaging scans. Results Our results show that dopamine synthesis capacity was increased in pathological gamblers compared with healthy control subjects. Dopamine synthesis was 16% higher in the caudate body, 17% higher in the dorsal putamen, and 17% higher in the ventral striatum in pathological gamblers compared with control subjects. Moreover, dopamine synthesis capacity in the dorsal putamen and caudate head was positively correlated with gambling distortions in pathological gamblers. Conclusions Taken together, these results provide empirical evidence for increased striatal dopamine synthesis in pathological gambling.
Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-15 David Carlson, Lisa K. David, Neil M. Gallagher, Mai-Anh T. Vu, Matthew Shirley, Rainbo Hultman, Joyce Wang, Caley Burrus, Colleen A. McClung, Sunil Kumar, Lawrence Carin, Stephen D. Mague, Kafui Dzirasa
Background The prefrontal cortex plays a critical role in regulating emotional behaviors, and dysfunction of prefrontal cortex–dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder. Methods Here we acquired multicircuit in vivo activity from eight cortical and limbic brain regions as mice were subjected to the tail suspension test (TST) and an open field test. We used a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and open field test. We then performed repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure. Results The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex and medial dorsal thalamus, and to an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using closed-loop optogenetic stimulation is sufficient to increase movement in the TST in stress-naive mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in infralimbic cortex–medial dorsal thalamus circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. Conclusions Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies.
Dopa Decarboxylase Modulates Tau Toxicity Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-15 Rebecca L. Kow, Carl Sikkema, Jeanna M. Wheeler, Charles W. Wilkinson, Brian C. Kraemer
Background The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. Methods To better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene–induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors. Results We identified one dopamine synthesis gene, dopa decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. Conclusions Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.
Targeting Fyn Kinase in Alzheimer’s Disease Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-13 Haakon B. Nygaard
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer’s disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.
Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-12 Eric S. Wohleb, Rosemarie Terwilliger, Catharine H. Duman, Ronald S. Duman
Background Chronic stress exposure causes neuronal atrophy and synaptic deficits in the medial prefrontal cortex (PFC), contributing to development of anxiety- and depressive-like behaviors. Concomitantly, microglia in the PFC undergo morphological and functional changes following stress exposure, suggesting that microglia contribute to synaptic deficits underlying behavioral consequences. Methods Male and female mice were exposed to chronic unpredictable stress (CUS) to examine the role of neuron–microglia interactions in the medial PFC during development of anxiety- and depressive-like behaviors. Thy1-GFP-M mice were used to assess microglia-mediated neuronal remodeling and dendritic spine density in the medial PFC. Viral-mediated knockdown of neuronal colony stimulating factor 1 (CSF1) was used to modulate microglia function and behavioral consequences after CUS. Results CUS promoted anxiety- and depressive-like behaviors that were associated with increased messenger RNA levels of CSF1 in the PFC. Increased CSF1 messenger RNA levels were also detected in the postmortem dorsolateral PFC of individuals with depression. Moreover, microglia isolated from the frontal cortex of mice exposed to CUS show elevated CSF1 receptor expression and increased phagocytosis of neuronal elements. Notably, functional alterations in microglia were more pronounced in male mice compared with female mice. These functional changes in microglia corresponded with reduced dendritic spine density on pyramidal neurons in layer 1 of the medial PFC. Viral-mediated knockdown of neuronal CSF1 in the medial PFC attenuated microglia-mediated neuronal remodeling and prevented behavioral deficits caused by CUS. Conclusions These findings revealed that stress-induced elevations in neuronal CSF1 provokes microglia-mediated neuronal remodeling in the medial PFC, contributing to synaptic deficits and development of anxiety- and depressive-like behavior.
Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-08 Corey Fee, Mounira Banasr, Etienne Sibille
The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory gamma-aminobutyric acidergic (GABAergic) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder, anxiety disorders, and schizophrenia. Specifically, nearly 3 decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that coexpress the neuropeptide somatostatin (SST). Advances in cell type–specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders and specifically in MDD. We then focus on properties of the cortical microcircuit, where SST-positive GABAergic interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions.
Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia Biol. Psychiatry (IF 11.412) Pub Date : 2017-06-06 Sarah M. Hartz, Amy C. Horton, Mary Oehlert, Caitlin E. Carey, Arpana Agrawal, Ryan Bogdan, Li-Shiun Chen, Dana B. Hancock, Eric O. Johnson, Carlos N. Pato, Michele T. Pato, John P. Rice, Laura J. Bierut
Background There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. Methods We tested the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: the Collaborative Genetic Study of Nicotine Dependence (ascertained for tobacco use disorder; n = 918 cases; 988 control subjects), the Collaborative Study on the Genetics of Alcoholism (ascertained for alcohol use disorder; n = 643 cases; 384 control subjects), and the Family Study of Cocaine Dependence (ascertained for cocaine use disorder; n = 210 cases; 317 control subjects). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to the 1000 Genomes reference panel. Results In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo-R2 range 0.8–3.7%; minimum p = 4 × 10–23). Conclusions These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.
Mechanistic Target of Rapamycin–Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model Biol. Psychiatry (IF 11.412) Pub Date : 2017-05-31 Chun Yang, Qian Ren, Youge Qu, Ji-Chun Zhang, Min Ma, Chao Dong, Kenji Hashimoto
Background The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. Methods The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. Results The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S)-ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. Conclusions This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine’s antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine.
Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A Biol. Psychiatry (IF 11.412) Pub Date : 2017-05-31 Rajesh Narendran, Roberto Ciccocioppo, Brian Lopresti, Jennifer Paris, Michael L. Himes, N. Scott Mason
Background The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. Methods Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. Results Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. Conclusions The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.
Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume Biol. Psychiatry (IF 11.412) Pub Date : 2017-05-22 Timothy J. Schoenfeld, Hayley C. McCausland, H. Douglas Morris, Varun Padmanaban, Heather A. Cameron
Background Hippocampal volume loss is a hallmark of clinical depression. Chronic stress produces volume loss in the hippocampus in humans and atrophy of CA3 pyramidal cells and suppression of adult neurogenesis in rodents. Methods To investigate the relationship between decreased adult neurogenesis and stress-induced changes in hippocampal structure and volume, we compared the effects of chronic unpredictable restraint stress and inhibition of neurogenesis in a rat pharmacogenetic model. Results Chronic unpredictable restraint stress over 4 weeks decreased total hippocampal volume, reflecting loss of volume in all hippocampal subfields and in both dorsal and ventral hippocampus. In contrast, complete inhibition of adult neurogenesis for 4 weeks led to volume reduction only in the dentate gyrus. With prolonged inhibition of neurogenesis for 8 or 16 weeks, volume loss spread to the CA3 region, but not CA1. Combining stress and inhibition of adult neurogenesis did not have additive effects on the magnitude of volume loss but did produce a volume reduction throughout the hippocampus. One month of chronic unpredictable restraint stress and inhibition of adult neurogenesis led to atrophy of pyramidal cell apical dendrites in dorsal CA3 and to neuronal reorganization in ventral CA3. Stress also significantly affected granule cell dendrites. Conclusions The findings suggest that adult neurogenesis is required to maintain hippocampal volume but is not responsible for stress-induced volume loss.
Untangling Genetic Risk for Alzheimer’s Disease Biol. Psychiatry (IF 11.412) Pub Date : 2017-05-22 Anna A. Pimenova, Towfique Raj, Alison M. Goate
Alzheimer’s disease (AD) is a genetically heterogeneous neurodegenerative disorder caused by fully penetrant single gene mutations in a minority of cases, while the majority of cases are sporadic or show modest familial clustering. These cases are of late onset and likely result from the interaction of many genes and the environment. More than 30 loci have been implicated in AD by a combination of linkage, genome-wide association, and whole genome/exome sequencing. We have learned from these studies that perturbations in endolysosomal, lipid metabolism, and immune response pathways substantially contribute to sporadic AD pathogenesis. We review here current knowledge about functions of AD susceptibility genes, highlighting cells of the myeloid lineage as drivers of at least part of the genetic component in late-onset AD. Although targeted resequencing utilized for the identification of causal variants has discovered coding mutations in some AD-associated genes, a lot of risk variants lie in noncoding regions. Here we discuss the use of functional genomics approaches that integrate transcriptomic, epigenetic, and endophenotype traits with systems biology to annotate genetic variants, and to facilitate discovery of AD risk genes. Further validation in cell culture and mouse models will be necessary to establish causality for these genes. This knowledge will allow mechanism-based design of novel therapeutic interventions in AD and promises coherent implementation of treatment in a personalized manner.
When Habits Are Dangerous: Alcohol Expectancies and Habitual Decision Making Predict Relapse in Alcohol Dependence Biol. Psychiatry (IF 11.412) Pub Date : 2017-05-22 Miriam Sebold, Stephan Nebe, Maria Garbusow, Matthias Guggenmos, Daniel J. Schad, Anne Beck, Soeren Kuitunen-Paul, Christian Sommer, Robin Frank, Peter Neu, Ulrich S. Zimmermann, Michael A. Rapp, Michael N. Smolka, Quentin J.M. Huys, Florian Schlagenhauf, Andreas Heinz
Background Addiction is supposedly characterized by a shift from goal-directed to habitual decision making, thus facilitating automatic drug intake. The two-step task allows distinguishing between these mechanisms by computationally modeling goal-directed and habitual behavior as model-based and model-free control. In addicted patients, decision making may also strongly depend upon drug-associated expectations. Therefore, we investigated model-based versus model-free decision making and its neural correlates as well as alcohol expectancies in alcohol-dependent patients and healthy controls and assessed treatment outcome in patients. Methods Ninety detoxified, medication-free, alcohol-dependent patients and 96 age- and gender-matched control subjects underwent functional magnetic resonance imaging during the two-step task. Alcohol expectancies were measured with the Alcohol Expectancy Questionnaire. Over a follow-up period of 48 weeks, 37 patients remained abstinent and 53 patients relapsed as indicated by the Alcohol Timeline Followback method. Results Patients who relapsed displayed reduced medial prefrontal cortex activation during model-based decision making. Furthermore, high alcohol expectancies were associated with low model-based control in relapsers, while the opposite was observed in abstainers and healthy control subjects. However, reduced model-based control per se was not associated with subsequent relapse. Conclusions These findings suggest that poor treatment outcome in alcohol dependence does not simply result from a shift from model-based to model-free control but is instead dependent on the interaction between high drug expectancies and low model-based decision making. Reduced model-based medial prefrontal cortex signatures in those who relapse point to a neural correlate of relapse risk. These observations suggest that therapeutic interventions should target subjective alcohol expectancies.
Circadian Disruptions in the Myshkin Mouse Model of Mania Are Independent of Deficits in Suprachiasmatic Molecular Clock Function Biol. Psychiatry (IF 11.412) Pub Date : 2017-05-20 Joseph W.S. Timothy, Natasza Klas, Harshmeena R. Sanghani, Taghreed Al-Mansouri, Alun T.L. Hughes, Greer S. Kirshenbaum, Vincent Brienza, Mino D.C. Belle, Martin R. Ralph, Steven J. Clapcote, Hugh D. Piggins
Background Alterations in environmental light and intrinsic circadian function have strong associations with mood disorders. The neural origins underpinning these changes remain unclear, although genetic deficits in the molecular clock regularly render mice with altered mood-associated phenotypes. Methods A detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase α3 Myshkin (Myk/+) mouse model of mania was performed. Na+/K+-ATPase α3 does not reside within the core circadian molecular clockwork, but Myk/+ mice exhibit concomitant disruption in circadian rhythms and mood. The neural basis of this phenotype was investigated through molecular and electrophysiological dissection of the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Light input and glutamatergic signaling to the SCN were concomitantly assessed through behavioral assays and calcium imaging. Results In vivo assays revealed several circadian abnormalities including lengthened period and instability of behavioral rhythms, and elevated metabolic rate. Grossly aberrant responses to light included accentuated resetting, accelerated re-entrainment, and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PERIOD2) output from ex vivo SCN revealed no deficits in Myk/+ molecular clock function. Optic nerve crush rescued the circadian period of Myk/+ behavior, highlighting that afferent inputs are critical upstream mediators. Electrophysiological and calcium imaging SCN recordings demonstrated changes in the response to glutamatergic stimulation as well as the electrical output indicative of altered retinal input processing. Conclusions The Myshkin model demonstrates profound circadian and light-responsive behavioral alterations independent of molecular clock disruption. Afferent light signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.
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