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  • Mechanisms of Sex Differences in Fear and PTSD
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-21
    Teniel Sonya Ramikie, Kerry James Ressler

    Following sexual maturity, females disproportionately have higher rates of post-traumatic stress disorder (PTSD) and experience greater symptom severity and chronicity as compared to males. This observation has led many to examine sex differences in PTSD risk factors. Though relatively few, these studies reveal that the root causes of PTSD sex differences are complex, and partly represent interactions between sex-specific non-biological and biological risk factors, which differentially shape PTSD vulnerability. Moreover, these studies suggest that sex-specific PTSD vulnerability is partly regulated by sex differences in fear systems. Fear, which represents a highly conserved adaptive response to threatening environmental stimuli, becomes pathological in trauma- and stress-based psychiatric syndromes, such as PTSD. Over the last 30 years, considerable progress has been made in understanding normal and pathological molecular and behavioral fear processes in humans and animal models. Thus, fear mechanisms represent a tractable PTSD biomarker in the study of sex-differences in normal and pathological fear. In this review, we will discuss studies that examine biological and non-biological sex differences which contribute to normal and pathological fear behaviors in humans and animal models. This, we hope, will shed greater light on the potential mechanisms that contribute to increased PTSD vulnerability in females.

    更新日期:2017-11-21
  • The candidate schizophrenia risk gene DGCR2 regulates early steps of corticogenesis
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-21
    Aude Molinard-Chenu, Alexandre Dayer

    Background Alterations in early steps of cortical circuit assembly are thought to play a critical role in vulnerability to schizophrenia (SZ), but the pathogenic impact of SZ-risk mutations on corticogenesis remains to be determined. DiGeorge Critical Region 2 (DGCR2) is located in the 22q11.2 locus, whose deletion is a major risk factor for SZ. Moreover, exome sequencing of individuals with idiopathic SZ identified a rare missense mutation in DGCR2, further suggesting that DGCR2 is involved in SZ. Methods Here we investigated the function of Dgcr2 and the pathogenic impact of the SZ-risk DGCR2 mutation in mouse corticogenesis using in utero electroporation targeted to projection neurons (PN). Results Dgcr2 knock down (KD) impaired radial locomotion and final translocation of PN, leading to persistent laminar positioning alterations. The DGCR2 missense SZ-risk mutation had a pathogenic impact on PN laminar allocation by reducing protein expression. Mechanistically, we identified DGCR2 as a novel member of the REELIN complex, regulating the phosphorylation of REELIN-dependent substrates and the expression of REELIN-dependent transcriptional targets. Conclusion Overall, this study provides biological evidence that the SZ-risk gene DGCR2 regulates critical steps of early corticogenesis possibly through a REELIN-dependent mechanism. Additionally, we found that the SZ-risk mutation in DGCR2 has a pathogenic impact on cortical formation by reducing protein expression level, suggesting a functional role for DGCR2 haplo-insufficiency in the 22q11.2 deletion syndrome.

    更新日期:2017-11-21
  • Specificity in etiology of subtypes of bipolar disorder: Evidence from a Swedish population-based family study
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-20
    Jie Song, Ralf Kuja-Halkola, Arvid Sjölander, Sarah E. Bergen, Henrik Larsson, Mikael Landén, Paul Lichtenstein

    Background Uncertainty remains whether bipolar I disorder (BDI) and bipolar II disorder (BDII) differ etiologically. We used a population-based family sample to examine the etiological boundaries between BDI and BDII, by assessing their familial aggregation/co-aggregation, and by assessing the co-aggregation between them and schizophrenia, depression, attention-deficit/hyperactivity disorder, eating disorders, autism spectrum disorders, substance use disorders, anxiety disorders and personality disorders. Methods By linking Swedish national registers, we established a population-based cohort (N=15,685,511) and identified relatives with different biological relationships. Odds ratios (ORs) were used to measure the relative risk of BDI and BDII in relatives of individuals diagnosed with BDI (N=4,309) and BDII (N=4,178). The heritability for BDI and BDII and the genetic correlation across psychiatric disorders were estimated by variance decomposition analysis. Results Compared with the general population, the OR of BDI was 17.0 (95% confidence interval (CI) 13.1-22.0) in first-degree relatives of BDI patients; higher than that of BDII patients (OR 9.8, 95% CI 7.7-12.5). The ORs of BDII were 13.6 (95% CI 10.2-18.2) in first-degree relatives of BDII patients and 9.8 (95% CI 7.7-12.4) in relatives of BDI patients. The heritabilities for BDI and BDII were estimated at 57% (95% CI 32%-79%) and 46% (95% CI 21%-67%), respectively, with a genetic correlation estimated as 0.78 (95 %CI 0.36-1.00). The familial co-aggregation of other psychiatric disorders, in particular schizophrenia, showed different patterns for BDI and BDII. Conclusions Our results suggest a distinction between BDI and BDII in etiology, partly due to genetic differences.

    更新日期:2017-11-20
  • The multifaceted role of ventromedial prefrontal cortex in emotion, decision-making, social cognition, and psychopathology
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-20
    Jaryd Hiser, Michael Koenigs

    The ventromedial prefrontal cortex (vmPFC) has been implicated in a variety of social, cognitive, and affective functions that are commonly disrupted in mental illness. In this review, we summarize data from a diverse array of human and animal studies demonstrating that vmPFC is a key node of cortical and subcortical networks that subserve at least three broad domains of psychological function linked to psychopathology. One track of research indicates that vmPFC is critical for the representation of reward and value-based decision-making, through interactions with ventral striatum and amygdala. A second track of research demonstrates that vmPFC is critical for the generation and regulation of negative emotion, through its interactions with amygdala, bed nucleus of stria terminalis, periaqueductal gray, hippocampus, and dorsal anterior cingulate cortex. A third track of research shows the importance of vmPFC in multiple aspects of social cognition, such as facial emotion recognition, theory of mind ability, and processing self-relevant information, through its interactions with posterior cingulate cortex, precuneus, dorsomedial prefrontal cortex, and amygdala. We then present meta-analytic data revealing distinct subregions within vmPFC that correspond to each of these three functions, as well as the associations between these subregions and specific psychiatric disorders (depression, posttraumatic stress disorder, addiction, social anxiety disorder, bipolar disorder, schizophrenia, and attention-deficit/hyperactivity disorder). We conclude by describing several translational possibilities for clinical studies of vmPFC-based circuits, including neuropsychological assessment of transdiagnostic functions, anatomical targets for intervention, predictors of treatment response, markers of treatment efficacy, and subtyping within disorders.

    更新日期:2017-11-20
  • Median and dorsal raphe serotonergic neurons control moderate versus compulsive cocaine intake
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-20
    Michel M.M. Verheij, Candice Contet, Peter Karel, Judith Latour, Rick H.A. van der Doelen, Bram Geenen, Josephus A. van Hulten, Francisca Meyer, Tamas Kozicz, Olivier George, George F. Koob, Judith R. Homberg

    Background Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes. Methods We used virally-mediated RNA interference to locally down-regulate SERT expression and compared the results to constitutive SERT knockout. Rats were allowed either short access (ShA, 1 h) or long access (LgA, 6 h) to cocaine self-administration to model moderate versus compulsive-like cocaine taking. Results SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced CRF immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown. Conclusions Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.

    更新日期:2017-11-20
  • Mitochondrial Etiology of Neuropsychiatric Disorders
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-20
    Liming Pei, Douglas C. Wallace

    The brain has the highest mitochondrial energy demand of any organ. Therefore, subtle changes in mitochondrial energy production will preferentially affect the brain. Considerable biochemical evidence has accumulated revealing mitochondrial defects associated with neuropsychiatric diseases. Moreover, the mitochondrial genome encompasses over a thousand nuclear DNA (nDNA) genes plus hundreds to thousands of copies of the maternally-inherited mitochondrial DNA (mtDNA). Therefore, partial defects in either the nDNA or mtDNA genes or combinations of the two can be sufficient to cause neuropsychiatric disorders. Inherited and acquired mtDNA mutations have recently been associated with autism spectrum disorders (ASD), which parallel previous evidence of mtDNA variation in other neurological diseases. Therefore, mitochondrial dysfunction may be central to the etiology of a wide spectrum of neurological diseases. The mitochondria and the nucleus communicate to coordinate energy production and utilization, providing the potential for therapeutics by manipulating nuclear regulation of mitochondrial gene expression.

    更新日期:2017-11-20
  • Current status of animal models of PTSD: behavioral and biological phenotypes, and future challenges in improving translation
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-20
    Jessica Deslauriers, Mate Toth, Andre Der-Avakian, Victoria B. Risbrough

    Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging as it is heterogeneous disorder with 20+ symptoms. Clinical research is increasingly utilizing objective biological measures (e.g. imaging, peripheral biomarkers) or non-verbal behaviors/physiological responses to complement verbally reported symptoms. This shift toward more objectively measurable phenotypes enables refinement of current animal models of PTSD, and supports incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g. sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety- and/or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to chronic SSRIs. Although a few paradigms probed fear conditioning/extinction and/or utilized peripheral immune, sleep, and non-invasive imaging measures, which we argue should be incorporated more to enhance translation. There was little data in females, at different ages across the lifespan, or on temporal trajectories of phenotypes post-stress, which would inform model utility and experimental design for treatment studies. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response and treatment outcome. This shift is exciting, as we and many others hope it will support translation of drug efficacy not only from animal models to clinical trials, but potentially improve predictability of stageII for stageIII clinical trials.

    更新日期:2017-11-20
  • Reproducibility in Imaging Genetics: The Case of Threat-Related Amygdala Reactivity
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-16
    Reut Avinun, Adam Nevo, Annchen R. Knodt, Maxwell L. Elliott, Ahmad R. Hariri

    Background Low reproducibility rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, intermediate brain phenotypes more proximal to putative genetic effects were touted as a strategy leading to increased power and reproducibility. Here we attempt to replicate previously published associations between single nucleotide polymorphisms (SNPs) and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also as a biomarker of future risk. Methods We conducted a literature search for published associations between SNPs and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72±1.25 years) for whom both genetic and functional MRI data were available. Results Of the 37 unique associations identified, only 3 replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: 8 of these were for a different contrast/laterality; 5 for a different sex and/or race/ethnicity; and 15 in the opposite direction as well as for a different contrast, laterality, sex, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for 6 studies. Notably, none of the significant associations survived correction for multiple comparisons. Conclusions We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies as well as the growing importance of advancing the reproducibility of imaging genetics findings.

    更新日期:2017-11-17
  • Psychiatry in a Dish: Stem Cells and Brain Organoids Modeling Autism Spectrum Disorders (Asd)
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-16
    Mirolyba Ilieva, Åsa Fex Svenningsen, Morten Thorsen, Tanja Maria Michel

    Autism Spectrum Disorders (ASD) are a group of pervasive neurodevelopmental conditions with heterogeneous etiology, characterized by deficits in social cognition, communication, and behavioral flexibility. Despite an increasing scientific effort to find the pathophysiological explanations for the disease, the neurobiological links remain unclear. A large amount of evidence suggests that pathological processes, taking place in the early embryonic neurodevelopment, might be responsible for later manifestation of autistic symptoms. This dysfunctional development includes altered maturation/differentiation processes, disturbances in cell-cell communication, and unbalanced ratio between certain neuronal populations. All those processes are highly dependent on the interconnectivity and three-dimensional (3D) organizations of the brain. Moreover, in order to gain a deeper understanding of the complex neurobiology of ASD, valid disease models are pivotal. Induced pluripotent stem cells (iPSC) could potentially help to elucidate the complex mechanisms of the disease and lead to the development of more effective individualized treatment. The iPSC approach allows comparison between the development of various cellular phenotypes generated from cell lines of patients and healthy individuals. A newly advanced organoid technology makes it possible to create three dimensional (3D) in vitro models of the brain development and the structural interconnectivity, based on iPSC derived from the respective individuals. Since the biggest challenge for modeling psychiatric diseases in vitro is finding and establishing the link between cellular and molecular findings with the clinical symptoms, this review aims to give an overview over the feasibility and applicability of this new tissue engineering tool in psychiatry.

    更新日期:2017-11-17
  • The Mediodorsal Thalamus: An Essential Partner of Prefrontal Cortex for Cognition
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-15
    Sebastien Parnaudeau, Scott S. Bolkan, Christoph Kellendonk

    Deficits in cognition are a core feature of many psychiatric conditions, including schizophrenia, where the severity of such deficits is a strong predictor of long-term outcome. Impairment in cognitive domains, such as working memory and behavioral flexibility, have classically been associated with prefrontal cortex (PFC) dysfunction. However, there is increasing evidence that the PFC cannot be dissociated from its main thalamic counterpart, the mediodorsal thalamus (MD). Since the causal relationships between MD-PFC abnormalities and cognitive impairment, as well as the neuronal mechanisms underlying them, are difficult to address in humans, animal models have been employed for mechanistic insight. In this review, we discuss anatomical, behavioral, and electrophysiological findings from animal studies that provide a new understanding on how MD-PFC circuits support higher-order cognitive function. We argue that the MD may be required for amplifying and sustaining cortical representations under different behavioral conditions. These findings advance a new framework for the broader involvement of distributed thalamo-frontal circuits in cognition and point to the MD as a potential therapeutic target for improving cognitive deficits in schizophrenia and other disorders.

    更新日期:2017-11-17
  • Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-14
    Irene Corradini, Elisa Focchi, Marco Rasile, Raffaella Morini, Genni Desiato, Romana Tomasoni, Michela Lizier, Elsa Ghirardini, Riccardo Fesce, Diego Morone, Isabella Barajon, Flavia Antonucci, Davide Pozzi, Michela Matteoli

    BackgroundThe association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined.MethodsPregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses.ResultsPrenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na+-K+-2Cl− cotransporter 1 and the K+-Cl− cotransporter 2 (KCC2). This results in delayed gamma-aminobutyric acid switch and higher susceptibility to seizures, which endures up to adulthood. Chromatin immunoprecipitation experiments reveal increased binding of the repressor factor RE1-silencing transcription (also known as neuron-restrictive silencer factor) to position 509 of the KCC2 promoter that leads to downregulation of KCC2 transcription in prenatally exposed offspring. Interleukin-1 receptor type I knockout mice, which display braked immune response and no brain cytokine elevation upon maternal immune activation, do not display KCC2/Na+-K+-2Cl− cotransporter 1 imbalance when implanted in a wild-type dam and prenatally exposed. Notably, pretreatment of pregnant dams with magnesium sulfate is sufficient to prevent the early inflammatory state and the delay in excitatory-to-inhibitory switch associated to maternal immune activation.ConclusionsWe provide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to-inhibitory gamma-aminobutyric acid switch; defects in this switch have been unequivocally linked to diseases such as autism spectrum disorder or epilepsy. These data open the avenue for a safe pharmacological treatment that may prevent the neurodevelopmental defects caused by prenatal immune activation in a specific pregnancy time window.

    更新日期:2017-11-15
  • Understanding neurodevelopmental disorders: the promise of regulatory variation in the 3’UTRome
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-14
    Kai Wanke, Paolo Devanna, Sonja C. Vernes

    Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome-sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1-2% of the human genome. With the advent of whole-genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and non-coding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of non-coding variants identified per individual can be overwhelming, making it prudent to focus on non-coding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3’UTRome is a region of the non-coding genome that perfectly fulfils these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3’UTRome as binding sites for microRNAs, RNA binding proteins or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3’UTRome will lead to the identification of new risk factors, new candidate disease genes and a better understanding of the molecular mechanisms contributing to NDDs.

    更新日期:2017-11-15
  • Exploring the Role of Astroglial Glutamate Release and Association with Synapses in Neuronal Function and Behavior
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-11
    Michael D. Scofield

    Astrocytes are stellate cells whose appearance can resemble a pointed star, especially when visualizing glial fibrillary acidic protein (GFAP), a canonical marker for astrocytes. Accordingly, there is a commonly made connection between the points of light that shine in the night sky and the diffuse and abundant cells that buffer ions and provide support for neurons. An exceptional amount of function has been attributed to, negated and potentially reaffirmed for these cells, especially regarding their ability to release neuroactive molecules and influence synaptic plasticity. This makes the precise role of astrocytes in tuning neural communication seem difficult to grasp. However, data from animal models of addiction demonstrate that a variety of drug-induced molecular adaptations responsible for relapse vulnerability take place in astrocyte systems that regulate glutamate uptake and release. These findings highlight astrocytes as a critical component of the neural systems responsible for addiction, serving as a key component of the plasticity responsible for relapse and drug-seeking. Here I assemble recent findings that utilize genetic tools to selectively manipulate or measure flux of internal calcium in astrocytes, focusing on GPCR-mediated mobilization of calcium and the induction of glutamate release. Further, I compile evidence regarding astrocyte glutamate release as well as astrocyte association with synapses with respect to the impact of these cellular phenomena in shaping synaptic transmission. I also place these findings in the context of the previous studies of Scofield et al which explore the role of astrocytes in the nucleus accumbens in the neural mechanisms underlying cocaine seeking.

    更新日期:2017-11-11
  • Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-10
    Anne Weigand, Andreas Horn, Ruth Caballero, Danielle Cooke, Adam P. Stern, Stephan F. Taylor, Daniel Press, Alvaro Pascual-Leone, Michael D. Fox

    BackgroundThe optimal target in the dorsolateral prefrontal cortex (DLPFC) for treating depression with repetitive transcranial magnetic stimulation (rTMS) remains unknown. Better efficacy has been associated with stimulation sites that are 1) more anterior and lateral and 2) more functionally connected to the subgenual cingulate. Here we prospectively test whether these factors predict response in individual patients.MethodsA primary cohort (Boston, N = 25) with medication-refractory depression underwent conventional open-label rTMS to the left DLPFC. A secondary cohort (Michigan, N = 16) underwent 4 weeks of sham followed by open label rTMS for non-responders (N = 12). In each patient, the location of the stimulation site was recorded with frameless stereotaxy. Connectivity between each patient’s stimulation site and the subgenual cingulate was assessed using resting state fcMRI from a cohort of healthy subjects (N = 1000), and confirmed using connectivity from depression patients (N = 38).ResultsIn our primary cohort, antidepressant efficacy was predicted by stimulation sites that were both more antero-lateral (r = .51, p < .01) and more negatively correlated with the subgenual cingulate (r = -.55, p < .005). However, subgenual connectivity was the only independent predictor of response and the only factor to predict response to active (r = -.52, p < .05) but not sham rTMS in our secondary cohort.ConclusionsThis study provides prospective validation that functional connectivity between an individual’s rTMS cortical target and the subgenual cingulate predicts antidepressant response. Implications for improving the cortical rTMS target for depression are discussed.

    更新日期:2017-11-10
  • A schizophrenia-linked KALRN coding variant alters neuron morphology, protein function, and transcript stability
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-07
    Theron A. Russell, Melanie J. Grubisha, Christine L. Remmers, Seok Kyu Kang, Marc P. Forrest, Katharine R. Smith, Katherine J. Kopeikina, Ruoqi Gao, Robert A. Sweet, Peter Penzes

    BackgroundLarge-scale genetic studies have revealed that rare sequence variants, including single nucleotide variants (SNVs), in glutamatergic synaptic genes are enriched in schizophrenia (SZ) patients. However, the majority are too rare to show any association with disease, and have not been examined functionally. One such SNV, KALRN-P2255T displays a penetrance which greatly exceeds that of previously identified SZ-associated SNVs. Therefore, we sought to characterize its effects on the function of Kalirin-9 (Kal9), a dual Rac1 and RhoA guanine nucleotide exchange factor (GEF), upregulated in human SZ brain tissue.MethodsKal9 was overexpressed in primary rat cortical neurons or hEK293 cells. The effects of the P2255T variant on dendritic branching, dendritic spine morphology, protein and mRNA stability, and catalytic activity were examined.ResultsKal9-P2255T leads to diminished basal dendritic branching and dendritic spine size, compared to wildtype Kal9 (Kal9-WT). The P2255T SNV directly affected Kal9 protein function, causing increased RhoA activation in hEK203 cells, but had no effect on Rac1 activation. Consistent with human postmortem findings, we found that Kal9-P2255T protein levels were higher than those of Kal9-WT in neurons. Increased mRNA stability was detected in hEK293 cells, indicating that this was the cause of the higher protein levels. When analyzed together, increased intrinsic RhoA-GEF catalytic activity combined with increased mRNA expression led to net enhancement of RhoA activation, known to negatively impact neuronal morphology.ConclusionsTaken together, our data reveal a novel mechanism for disease-associated SNVs and provide a platform for modeling morphological changes in mental disorders.

    更新日期:2017-11-10
  • (-)-P7C3-S243 protects a rat model of Alzheimer’s disease from neuropsychiatric deficits and neurodegeneration without altering amyloid deposition or reactive glia
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-06
    Jaymie R. Voorhees, Matthew T. Remy, Coral J. Cintrón-Pérez, Eli El Rassi, Michael Z. Kahn, Laura M. Dutca, Terry C. Yin, Latisha M. McDaniel, Noelle S. Williams, Daniel J. Brat, Andrew A. Pieper

    BackgroundIn addition to cognitive deficits, Alzheimer’s disease (AD) is also associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might thus be uniquely applicable to patients with AD, given the co-morbid presentation of depression and cognitive deficits.MethodsAging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered daily (-)-P7C3-S243 for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months.Results(-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation.ConclusionsNeuronal cell death-specific treatment approaches, such as offered by P7C3 compounds, may represent a new treatment approach for patients suffering from the combination of cognitive deficits and depression associated with AD.

    更新日期:2017-11-10
  • Prefrontal cortex stimulation enhances fear extinction memory in humans
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-06
    Tommi Raij, Aapo Nummenmaa, Marie-France Marin, Daria Porter, Sharon Furtak, Kawin Setsompop, Mohammed Milad

    BackgroundAnimal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic (IL) cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translate this finding to humans with MRI-navigated transcranial magnetic stimulation (TMS).MethodsSubjects (N=28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat IL: brief pulse trains (300 ms at 20 Hz) starting 100ms after cue onset, total of 4 trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (Target 1) and the other unconnected (Target 2, control) with a human homologue of IL in the ventromedial prefrontal cortex (vmPFC). Skin conductance responses (SCRs) were used as an index of conditioned fear.ResultsDuring extinction recall (day 3), the cue paired with TMS to Target 1 showed significantly reduced SCRs, whereas TMS to Target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion MRI connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced vs. increased fear.ConclusionsThe results show that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory, and suggest novel cortical areas and large-scale networks for targeting in future studies.

    更新日期:2017-11-10
  • Brain regions showing white matter loss in Huntington’s disease are enriched for synaptic and metabolic genes
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-26
    Peter McColgan, Sarah Gregory, Kiran K. Seunarine, Adeel Razi, Marina Papoutsi, Eileanoir Johnson, Alexandra Durr, Raymund AC. Roos, Blair R. Leavitt, Peter Holmans, Rachael I. Scahill, Chris A. Clark, Geraint Rees, Sarah J. Tabrizi

    Background The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum and in posterior white matter tracts. While experimental evidence suggests these changes may be related to abnormal gene transcription we lack an understanding of the biological processes driving this regional vulnerability. Methods Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute of Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in premanifest Huntington’s disease relative to controls. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy controls. Results We show that loss of cortico-striatal, inter-hemispheric and intra-hemispheric white matter connections at baseline and over 24 months, in premanifest Huntington’s disease, is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Cortico-striatal gene expression profiles are predominately associated with motor, parietal and occipital regions, while inter-hemispheric expression profiles are associated with fronto-temporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are over-represented in synaptic gene expression profiles but not metabolic gene expression profiles. Conclusions These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, where abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss.

    更新日期:2017-10-27
  • Defects in bioenergetic coupling in schizophrenia
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-24
    Courtney R. Sullivan, Sinead O’Donovan, Robert E. McCullumsmith, Amy Ramsey

    Synaptic neurotransmission relies on maintenance of the synapse and meeting the energy demands of neurons. Defects in excitatory and inhibitory synapses have been implicated in schizophrenia, likely contributing to positive and negative symptoms as well as impaired cognition. Recently, accumulating evidence suggests bioenergetic systems, important in both synaptic function and cognition, are abnormal in psychiatric illnesses such as schizophrenia. Animal models of synaptic dysfunction demonstrate endophenotypes of schizophrenia, as well as bioenergetic abnormalities. Here we report findings on the bioenergetic interplay of astrocytes and neurons and discuss how dysregulation of these pathways may contribute to the pathogenesis of schizophrenia, highlighting metabolic systems as important therapeutic targets.

    更新日期:2017-10-25
  • Antidepressants rescue stress-induced disruption of synaptic plasticity via serotonin transporter-independent inhibition of L-type Ca2+-channels
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-19
    Claus Normann, Sibylle Frase, Verena Haug, Gregor von Wolff, Kristin Clark, Patrick Münzer, Alexandra Dorner, Jonas Scholliers, Max Horn, Tanja Vo Van, Gabriel Seifert, Tsvetan Serchov, Knut Biber, Christoph Nissen, Norbert Klugbauer, Josef Bischofberger

    BackgroundLong-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and to regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress, in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both, animal models and in humans; however, the underlying mechanism is unclear.MethodsWe examined the modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knock-out mice. Recombinant voltage-gated Ca2+ channels in heterologous expression systems were used to determine the modulation of Ca2+ channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and the absence of the serotonin transporter.ResultsSSRIs selectively inhibit hippocampal long-term synaptic depression (LTD). The inhibition of LTD by SSRIs is mediated by a direct block of voltage-activated L-type Ca2+-channels and is independent of the SERT. Furthermore, SSRIs protect both wild-type and SERT-knockout mice from behavioral despair induced by chronic stress. Finally, LTD was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment.ConclusionsThese results show that antidepressants protect synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca2+-channels and synaptic plasticity independent of SERT. Thus, L-type Ca2+-channels might constitute an important signaling hub for stress response and for the pathophysiology and the treatment of depression.

    更新日期:2017-10-20
  • Microglia-mediated neuroprotection, TREM2 and Alzheimer’s disease: Evidence from Optical Imaging
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-14
    Carlo Condello, Peng Yuan, Jaime Grutzendler

    Recent genetic studies have provided overwhelming evidence of the involvement of microglia-related molecular networks in the pathophysiology of Alzheimer disease (AD). However, the precise mechanisms by which microglia alter the course of AD neuropathology remain poorly understood. Here we discuss current evidence of the neuroprotective functions of microglia with a focus on optical imaging studies that have revealed a role of these cells in the encapsulation of amyloid deposits (“microglia barrier”). This barrier modulates the degree of plaque compaction, amyloid fibril surface area and insulation from adjacent axons thereby reducing neurotoxicity. We discuss findings implicating genetic variants of the microglia receptor, Triggering Receptor Expressed On Myeloid Cells 2 (TREM2), in the increased risk of late onset AD. We provide evidence that increased AD risk is at least partly mediated by deficient microglia polarization towards amyloid deposits, resulting in ineffective plaque encapsulation and reduced plaque compaction, which is associated with worsened axonal pathology. Finally, we propose possible avenues for therapeutic targeting of plaque-associated microglia with the goal of enhancing the microglia barrier and potentially reducing disease progression.

    更新日期:2017-10-14
  • Amygdala inhibitory circuits regulate associative fear conditioning
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-14
    Sabine Krabbe, Jan Gründemann, Andreas Lüthi

    Associative memory formation is essential for an animal’s survival by ensuring adaptive behavioral responses in an ever-changing environment. This is particularly important under conditions of immediate threads such as in fear learning. One of the key brain regions involved in associative fear learning is the amygdala. The basolateral amygdala (BLA) is the main entry site for sensory information to the amygdala complex, and local plasticity in excitatory BLA principal neurons is considered to be crucial for learning of conditioned fear responses. However, activity and plasticity of excitatory circuits are tightly controlled by local inhibitory interneurons in a spatially and temporally defined manner. In this review, we provide an update view on how distinct interneuron subtypes in the BLA contribute to the acquisition and extinction of conditioned fear memories.

    更新日期:2017-10-14
  • Face Perception in Social Anxiety: Visuocortical Dynamics Reveal Propensities for Hypervigilance or Avoidance
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-13
    Lisa M. McTeague, Marie-Claude Laplante, Hailey W. Bulls, Joshua R. Shumen, Peter J. Lang, Andreas Keil.

    Background Theories of aberrant attentional processing in social anxiety, and anxiety disorders more broadly, have postulated an initial hypervigilance or facilitation to clinically relevant threats and consequent defensive avoidance. However, existing objective measurements utilized to explore this phenomenon lack the resolution to elucidate attentional dynamics, particularly covert influences. Methods We utilized a continuous measure of visuocortical engagement, the steady-state visual evoked potential in response to naturalistic angry, fearful, happy and neutral facial expressions. Participants were treatment-seeking patients with principal diagnoses of social anxiety circumscribed to performance situations (n=21) or generalized across interaction contexts (n=42), panic disorder with agoraphobia (n=25), and 17 healthy participants. Results At the principal disorder level, only circumscribed social anxiety patients showed sustained visuocortical facilitation to aversive facial expressions. Control participants as well as patients with panic disorder with agoraphobia and generalized social anxiety showed no bias. More finely stratifying the sample according to clinical judgment of social anxiety severity and interference revealed a linear increase in visuocortical bias to aversive expressions for all but the most severely impaired patients. This group showed an opposing sustained attentional disengagement. Conclusions Rather than shifts between covert vigilance and avoidance of aversive facial expressions, social anxiety appears to confer a sustained bias for one or the other. While vigilant attention reliably increases with social anxiety severity for the majority of patients, the most impaired show an opposing avoidance. These distinct patterns of attentional allocation could provide a powerful means of personalizing neuroscience-based interventions to modify attention bias and related impairment.

    更新日期:2017-10-14
  • “Parental advisory: maternal and paternal stress can impact offspring neurodevelopment”
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-13
    Jennifer C. Chan, Bridget M. Nugent, Tracy L. Bale

    Parental stress exposures are implicated in the risk for offspring neurodevelopmental and neuropsychiatric disorders, prompting critical examination of preconception and prenatal periods as vulnerable to environmental insults such as stress. Evidence from human studies and animal models demonstrates the influence that both maternal and paternal stress exposures have in changing the course of offspring brain development. Mechanistic examination of modes of intergenerational transmission of exposure during pregnancy has pointed to alterations in placental signaling, including changes in inflammatory, nutrient-sensing, and epigenetic pathways. Transmission of preconception paternal stress exposure is associated with changes in epigenetic marks in sperm, with a primary focus on the reprogramming of DNA methylation, histone post-translational modifications, and small non-coding RNAs. In this review, we discuss evidence supporting the important contribution of intergenerational parental stress in offspring neurodevelopment and disease risk, and the currently known epigenetic mechanisms underlying this transmission.

    更新日期:2017-10-14
  • Aberrant Cross-Brain Network Interaction in Children With Attention-Deficit/Hyperactivity Disorder and Its Relation to Attention Deficits: A Multisite and Cross-Site Replication Study
    Biol. Psychiatry (IF 11.412) Pub Date : 2015-11-02
    Weidong Cai, Tianwen Chen, Luca Szegletes, Kaustubh Supekar, Vinod Menon

    Background Attention-deficit/hyperactivity disorder (ADHD) is increasingly viewed as a disorder stemming from disturbances in large-scale brain networks, yet the exact nature of these impairments in affected children is poorly understood. We investigated a saliency-based triple-network model and tested the hypothesis that cross-network interactions between the salience network (SN), central executive network, and default mode network are dysregulated in children with ADHD. We also determined whether network dysregulation measures can differentiate children with ADHD from control subjects across multisite datasets and predict clinical symptoms. Methods Functional magnetic resonance imaging data from 180 children with ADHD and control subjects from three sites in the ADHD-200 database were selected using case-control design. We investigated between-group differences in resource allocation index (RAI) (a measure of SN-centered triple network interactions), relation between RAI and ADHD symptoms, and performance of multivariate classifiers built to differentiate children with ADHD from control subjects. Results RAI was significantly lower in children with ADHD than in control subjects. Severity of inattention symptoms was correlated with RAI. Remarkably, these findings were replicated in three independent datasets. Multivariate classifiers based on cross-network coupling measures differentiated children with ADHD from control subjects with high classification rates (72% to 83%) for each dataset. A novel cross-site classifier based on training data from one site accurately (62% to 82%) differentiated children with ADHD on test data from the two other sites. Conclusions Aberrant cross-network interactions between SN, central executive network, and default mode network are a reproducible feature of childhood ADHD. The triple-network model provides a novel, replicable, and parsimonious systems neuroscience framework for characterizing childhood ADHD and predicting clinical symptoms in affected children.

    更新日期:2017-10-13
  • Cerebellar volume in autism: Literature meta-analysis and analysis of the ABIDE cohort
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-10
    Nicolas Traut, Anita Beggiato, Thomas Bourgeron, Richard Delorme, Laure Rondi-Reig, Anne-Lise Paradis, Roberto Toro

    Background The neuroanatomical bases of Autism Spectrum Disorders remain largely unknown. Among the most widely discussed candidate endophenotypes, differences in cerebellar volume have been often reported as statistically significant. Methods We aimed at objectifying this possible alteration by performing a systematic meta-analysis of the literature, and an analysis of the Autism Brain Imaging Data Exchange (ABIDE 1) cohort. Our meta-analysis sought to determine a combined effect size of autism spectrum disorder diagnosis on different measures of the cerebellar anatomy, as well as the effect of possible factors of variability across studies. We then analyzed the cerebellar volume of 328 patients and 353 controls from the Autism Brain Imaging Data Exchange project. Results The meta-analysis of the literature suggested a weak but significant association between autism spectrum disorder diagnosis and increased cerebellar volume (p=0.049, uncorrected), but the analysis of ABIDE did not show any relationship. The studies meta-analyzed were generally underpowered, however, the number of statistically significant findings was larger than expected. Conclusions Although we could not provide a conclusive explanation for this excess of significant findings, our analyses would suggest publication bias as a possible reason. Finally, age, sex and intelligence quotient were important sources of cerebellar volume variability, however, independent of autism diagnosis.

    更新日期:2017-10-10
  • Prefrontal and Striatal γ-aminobutyric acid levels and the effect of antipsychotic treatment in first-episode psychosis patients
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-10
    Camilo de la Fuente-Sandoval, Francisco Reyes-Madrigal, Xiangling Mao, Pablo León-Ortiz, Oscar Rodríguez-Mayoral, Helgi Jung-Cook, Rodolfo Solís-Vivanco, Ariel Graff-Guerrero, Dikoma C. Shungu

    Background Abnormally elevated levels of γ-aminobutyric acid (GABA) in the medial prefrontal cortex (MPFC) have been reported in antipsychotic-free patients with schizophrenia. Whether such GABA elevations are also present in other brain regions and persist after antipsychotic treatment has not been previously investigated. Methods Twenty-eight antipsychotic-naive first-episode psychosis (FEP) patients and 18 control subjects completed the study. Following baseline proton magnetic resonance spectroscopy scans targeting the MPFC and a second region, the dorsal caudate, FEP patients were treated with oral risperidone for 4 weeks, at an initial dose of 1mg/day that was titrated as necessary based on clinical judgment. After the 4-week treatment period, both groups were brought back to undergo outcome MRS scans, which were identical to the scans conducted at baseline. Results At baseline, higher GABA levels were found both in the MPFC and in the dorsal caudate of FEP patients than in healthy control subjects. Following 4 weeks of antipsychotic treatment, GABA levels in FEP patients decreased relative to baseline in the MPFC, while decreasing only at the trend-level relative to baseline in the dorsal caudate. For either brain region, GABA levels at 4 weeks or post-treatment did not differ between FEP patients and healthy control subjects. Conclusions The results of the present study have documented elevations of GABA levels in both the MPFC and, for the first time, in the dorsal caudate of antipsychotic-naive FEP patients, which normalized in both regions following 4 weeks of antipsychotic treatment.

    更新日期:2017-10-10
  • Stress promotes drug seeking through glucocorticoid-dependent endocannabinoid mobilization in prelimbic cortex
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-06
    Jayme R. McReynolds, Elizabeth M. Doncheck, Yan Li, Oliver Vranjkovic, Evan N. Graf, Daisuke Ogasawara, Benjamin F. Cravatt, David A. Baker, Qing-song Liu, Cecilia J. Hillard, John R. Mantsch

    Background Clinical reports suggest that, rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone “set the stage” for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL). Methods We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, ip). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL micro-infusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons. Results Corticosterone application attenuated inhibitory synaptic transmission in the PL via CB1R- and 2-arachidonoylglycerol (2-AG)-dependent inhibition of GABA release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB1R agonist WIN 55-212,2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB1R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34. Conclusions These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-AG in the PL, resulting in CB1R-mediated attenuation of inhibitory transmission in this brain region.

    更新日期:2017-10-06
  • Transcriptome Alterations in Post-traumatic Stress Disorder
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-04
    Matthew J. Girgenti, Ronald S. Duman

    Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with a life-time prevalence of nearly 8% in the general population. While the underlying molecular and cellular mechanisms of PTSD remain unknown, recent studies indicate that PTSD is associated with aberrant gene expression in brain as well as peripheral blood cells. The advent of next generation sequencing technologies will allow us to elucidate the gene expression changes occurring in both brain and blood of patients with PTSD. RNA sequencing allows for analysis of the amount of transcript being made as well as alternative splicing, novel transcript identification, micro-RNA, and noncoding RNA quantification. Here we provide an overview of the different types of transcriptomic technologies, the gene expression studies performed in human peripheral blood and animal models of PTSD, and review the human PTSD post-mortem brain gene profiling studies performed to date.

    更新日期:2017-10-04
  • Modeling the interplay between neurons and astrocytes in autism using human induced pluripotent stem cells
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-10-03
    Fabiele Baldino Russo, Beatriz Camille Freitas, Graciela Conceição Pignatari, Isabella Rodrigues Fernandes, Jonathan Sebat, Alysson Renato Muotri, Patricia Cristina Baleeiro Beltrão-Braga

    Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with unclear etiology and imprecise genetic causes. The main goal of this work was to investigate neuronal connectivity and the interplay between neurons and astrocytes from non-syndromic ASD individuals using induced Pluripotent Stem Cells (iPSCs). Methods Our iPSCs were derived from a clinically well-characterized cohort of three non-syndromic ASD individuals, sharing common behaviors, and three controls, two clones each. We generated mixed neural cultures analyzing synaptogenesis and neuronal activity using a multi-electrode array (MEA) platform. Furthermore, using an enriched astrocytes population we investigated their role in neuronal maintenance. Results Our results revealed that ASD-derived neurons had a significant decrease in synaptic gene expression and protein levels, glutamate neurotransmitter release and, consequently, reduced spontaneous firing rate. Based on co-culture experiments, we observed that ASD-derived astrocytes interfered with proper neuronal development. In contrast, control-derived astrocytes rescued the morphological neuronal phenotype and synaptogenesis defects from ASD neuronal co-cultures. Furthermore, after identifying IL-6 secretion from astrocytes in our ASD individuals as a possible culprit for neural defects, we were able to increase synaptogenesis by blocking IL-6 levels. Conclusions Our findings reveal astrocytes contribution to neuronal phenotype and confirm previous studies linking IL-6 and autism, suggesting potential novel therapeutic pathways for a subtype of ASD individuals. This is the first report demonstrating that glial dysfunctions could contribute to non-syndromic autism pathophysiology using iPSCs modeling disease technology.

    更新日期:2017-10-04
  • Developmental changes within the genetic architecture of social communication behaviour: A multivariate study of genetic variance in unrelated individuals
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-28
    Beate St Pourcain, Lindon J. Eaves, Susan M. Ring, Simon E. Fisher, Sarah Medland, David M. Evans, George Davey Smith

    Background Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert their maximum influence during different periods of development. This includes analyses of social-communciation difficulties that share, depending on their developmental stage, stronger genetic links with either Autism Spectrum Disorder or schizophrenia. Here we developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social-communication difficulties, during a ∼10-year period spanning childhood and adolescence. Methods Longitudinally assessed quantitative social-communication problems (N≤ 5,551) were studied in participants from a UK birth cohort (ALSPAC, 8 to 17 years). Using standardised measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models (GSEM) incorporating whole-genome genotyping information. Analogous to twin research, GSEM included Cholesky decomposition, common pathway and independent pathway models. Results A 2-factor Cholesky decomposition model described the data best. One genetic factor was common to SCDC measures across development, the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only ∼50% of the genetic variation at 17 years. Conclusion Using latent factor models, we identified developmental changes in the genetic architecture of social-communication difficulties that enhance the understanding of ASD and schizophrenia-related dimensions. More generally, GSEM present a framework for modelling shared genetic aetiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap.

    更新日期:2017-09-29
  • Prefrontal-Thalamic anatomical connectivity and executive cognitive function in schizophrenia
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-28
    Monica Giraldo-Chica, Baxter P. Rogers, Stephen M. Damon, Bennett A. Landman, Neil D. Woodward

    Background Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal (MD) nucleus. This raises the possibility that anatomical connectivity between the PFC and MD thalamus may be: 1) reduced in schizophrenia; and 2) related to deficits in executive function. The current investigation tested these hypotheses. Methods 45 healthy subjects and 62 individuals with a schizophrenia spectrum disorder completed a battery of tests of executive function and underwent diffusion-weighted imaging (DWI). Probabilistic tractography was used to quantify anatomical connectivity between six cortical regions, including the PFC, and the thalamus. Thalamocortical anatomical connectivity was compared between healthy subjects and schizophrenia using region-of-interest and voxel-wise approaches, and the association between PFC-thalamic anatomical connectivity and severity of executive function impairment was examined in patients. Results Anatomical connectivity between the thalamus and PFC was reduced in schizophrenia. Voxel-wise analysis localized the reduction to areas of the MD thalamus connected to lateral PFC. Reduced PFC-thalamic connectivity in schizophrenia correlated with impaired working memory, but not cognitive flexibility and inhibition. In contrast to reduced PFC-thalamic connectivity, thalamic connectivity with somatosensory and occipital cortices was increased in schizophrenia. Conclusions The results are consistent with models implicating dysrupted PFC-thalamic connectivity in the pathophysiology of schizophrenia and mechanisms of cognitive impairment. PFC-thalamic anatomical connectivity may be an important target for pro-cognitive interventions. Further work is needed to determine the implications of increased thalamic connectivity with sensory cortex.

    更新日期:2017-09-29
  • Drug cues, conditioned reinforcement and drug seeking: the sequelae of a collaborative venture with Athina Markou Short title: Drug cues and drug seeking
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-25
    Barry J. Everitt

    Athina Markou spent a research period in my laboratory, then in the Department of Anatomy in Cambridge University, in 1991 to help us establish a cocaine-seeking procedure. Thus we embarked on developing a second-order schedule of intravenous cocaine reinforcement in order to investigate the neural basis of the pronounced effects of cocaine-associated conditioned stimuli on cocaine seeking. This brief review summarizes the fundamental aspects of cocaine seeking measured using this approach and the importance of the methodology in enabling us to define the neural mechanisms and circuitry underlying conditioned reinforcement and cocaine, heroin and alcohol seeking. The shift over time and experience of control over drug seeking from a limbic cortical-ventral striatal circuit underlying goal directed drug seeking to a dorsal striatal system mediating habitual drug seeking are also summarised. The theoretical implications of these data are discussed, thereby revealing the ways in which the outcomes of a collaboration can endure.

    更新日期:2017-09-29
  • Mature hippocampal neurons require LIS1 for synaptic integrity: implications for cognition
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-23
    Anamaria Sudarov, Xin-Jun Zhang, Leighton Braunstein, Eve Lo Castro, Shawn Singh, Yu Taniguchi, Ashish Raj, Song-Hai Shi, Holly Moore, M. Elizabeth Ross

    Background LIS1 (aka PAFAH1B1), a critical mediator of neuronal migration in developing brain, is expressed throughout life. However, relatively little is known about LIS1 function in the mature brain. We previously demonstrated LIS1 involvement in the formation and turnover of synaptic protrusions and synapses of young brain, after neuronal migration is complete. Here we examine the requirement for LIS1 to maintain hippocampal circuit function in adulthood. Methods Effects of conditional Lis1 inactivation in excitatory pyramidal neurons, starting in juvenile mouse brain, were probed using high-resolution approaches combining mouse genetics, designer receptor (DREADD) technology to specifically manipulate CA1 pyramidal neuron excitatory activity, electrophysiology, hippocampus selective behavioral testing and MRI tractography to examine connectivity of LIS1 deficient neurons. Results We found progressive excitatory and inhibitory postsynaptic dysfunction as soon as 10 days following conditional inactivation of Lis1 targeting CA1 pyramidal neurons. Surprisingly, by P60, it also caused CA1 histological disorganization with a selective decline in parvalbumin expressing interneurons and further reduction in inhibitory neurotransmission. Accompanying these changes were behavioral and cognitive deficits that could be rescued by either DREADD-directed specific increases in CA1 excitatory transmission or pharmacological enhancement of GABA transmission. Lagging behind electrophysiological changes was a progressive, selective decline in neural connectivity, affecting hippocampal efferent pathways documented by MRI tractography. Conclusions LIS1 supports synaptic function and plasticity of mature CA1 neurons. Post-juvenile loss of LIS1 there disrupts the structure and cellular make-up of the hippocampus, its connectivity with other brain regions, and cognition dependent on hippocampal circuits.

    更新日期:2017-09-29
  • What can mitochondrial DNA analysis tell us about mood disorders?
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-21
    Takaoki Kasahara, Tadafumi Kato

    Variants in mitochondrial DNA (mtDNA) and nuclear genes encoding mitochondrial proteins in bipolar disorder, depression, or other psychiatric disorders have been studied for decades, since mitochondrial dysfunction was first suggested in the brains of patients with these diseases. Candidate gene association studies initially resulted in findings compatible with the mitochondrial dysfunction hypothesis. Many of those studies, however, were conducted with a modest sample size (such as n < 1000), which could cause false positive findings. Furthermore, the DNA samples examined in these studies including GWAS were generally derived from peripheral tissues. One key unanswered question is whether there is an association between mood disorders and somatic mtDNA mutations (deletions and point mutations) in brain regions which accumulate a high amount of mtDNA mutations and/or are involved in the regulation of mood. Two lines of robust evidence supporting the importance of mtDNA mutations in the brain tissues for mood disorders have come from clinical observation of mitochondrial disease patients and an animal model study. More than half of them have comorbid mood disorders, and carry primary mtDNA mutations or accumulate secondary mtDNA mutations due to nuclear mutations. Mice carrying a neuron-specific expression of mutant mtDNA polymerase show spontaneous depression-like episodes. In this review, we first summarize current knowledge of mtDNA and its genetics and discuss what mtDNA analysis tells us about neuropsychiatric disorders based on an example of Parkinson's disease. We also discuss challenges and future directions beyond mtDNA analysis towards an understanding of the pathophysiology of "idiopathic" mood disorders.

    更新日期:2017-09-29
  • Does childhood trauma moderate polygenic risk for depression? A meta-analysis of 5,765 subjects from the Psychiatric Genomics Consortium
    Biol. Psychiatry (IF 11.412) Pub Date : 2017-09-21
    Wouter J. Peyrot, Sandra Van der Auwera, Yuri Milaneschi, Conor V. Dolan, Pamela AF. Madden, Patrick F. Sullivan, Jana Strohmaier, Stephan Ripke, Marcella Rietschel, Michel G. Nivard, Niamh Mullins, Grant W. Montgomery, Anjali K. Henders, Andrew C. Heat, Helen L. Fisher, Erin C. Dunn, Enda M. Byrne, Tracy A. Air, Bernhard T. Baune, Gerome Breen, Douglas F. Levinson, Cathryn M. Lewis, Nick G. Martin, Elliot N. Nelson, Dorret I. Boomsma, Hans J. Grabe, Naomi R. Wray, Brenda WJH. Penninx

    Background The heterogeneity of genetic effects on Major Depressive Disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRS) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRSxCT interaction results across these two and other cohorts, while applying more accurate PRS based on a larger discovery sample. Methods and Materials Data were combined from 3,024 MDD cases and 2,741 controls from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of approximately 110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 controls, a more detailed 5-domain measure additionally included emotional abuse, physical neglect and emotional neglect. Results MDD was associated with the MDD-PRS (OR=1.24, p=3.6e-5, R2=1.18%) and with CT (OR=2.63, p=3.5e-18 and OR=2.62, p=1.4e-5 for the 2- and 5-domain measures respectively). No interaction was found between MDD-PRS and the 2-domain and 5-domain CT measure (OR=1.00, p=0.89 and OR=1.05, p=0.66). Conclusions No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.

    更新日期:2017-09-29
  • 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

    Background Autism 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. Methods Using 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. Results The 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. Conclusions There 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.

    更新日期:2017-09-21
  • 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.

    更新日期:2017-09-20
  • 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.

    更新日期:2017-09-20
  • 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.

    更新日期:2017-09-19
  • 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.

    更新日期:2017-09-14
  • 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.

    更新日期:2017-09-08
  • 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.

    更新日期:2017-09-08
  • 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.

    更新日期:2017-09-08
  • 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.

    更新日期:2017-09-08
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
  • 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.

    更新日期:2017-09-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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