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Molecular Psychiatry

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https://www.readbyqxmd.com/read/29203852/the-dynamics-of-stress-a-longitudinal-mri-study-of-rat-brain-structure-and-connectome
#1
R Magalhães, D A Barrière, A Novais, F Marques, P Marques, J Cerqueira, J C Sousa, A Cachia, F Boumezbeur, M Bottlaender, T M Jay, S Mériaux, N Sousa
Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29203851/dynamic-landscape-of-the-local-translation-at-activated-synapses
#2
T M Khlebodarova, V V Kogai, E A Trifonova, V A Likhoshvai
The mammalian target of rapamycin (mTOR) signaling pathway is the central regulator of cap-dependent translation at the synapse. Disturbances in mTOR pathway have been associated with several neurological diseases, such as autism and epilepsy. RNA-binding protein FMRP, a negative regulator of translation initiation, is one of the key components of the local translation system. Activation and inactivation of FMRP occurs via phosphorylation by S6 kinase and dephosphorylation by PP2A phosphatase, respectively...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29203850/polygenic-prediction-of-obsessive-compulsive-symptoms
#3
N R Zilhão, A Abdellaoui, D J A Smit, D C Cath, J J Hottenga, D I Boomsma
No abstract text is available yet for this article.
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29203849/an-integrated-brain-behavior-model-for-working-memory
#4
D A Moser, G E Doucet, A Ing, D Dima, G Schumann, R M Bilder, S Frangou
Working memory (WM) is a central construct in cognitive neuroscience because it comprises mechanisms of active information maintenance and cognitive control that underpin most complex cognitive behavior. Individual variation in WM has been associated with multiple behavioral and health features including demographic characteristics, cognitive and physical traits and lifestyle choices. In this context, we used sparse canonical correlation analyses (sCCAs) to determine the covariation between brain imaging metrics of WM-network activation and connectivity and nonimaging measures relating to sensorimotor processing, affective and nonaffective cognition, mental health and personality, physical health and lifestyle choices derived from 823 healthy participants derived from the Human Connectome Project...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29203848/bdnf-release-and-signaling-are-required-for-the-antidepressant-actions-of-glyx-13
#5
T Kato, M V Fogaça, S Deyama, X-Y Li, K Fukumoto, R S Duman
Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-d-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29203847/reconceptualization-of-translocator-protein-as-a-biomarker-of-neuroinflammation-in-psychiatry
#6
T Notter, J M Coughlin, A Sawa, U Meyer
A great deal of interest in psychiatric research is currently centered upon the pathogenic role of inflammatory processes. Positron emission tomography (PET) using radiolabeled ligands selective for the 18 kDa translocator protein (TSPO) has become the most widely used technique to assess putative neuroimmune abnormalities in vivo. Originally used to detect discrete neurotoxic damages, TSPO has generally turned into a biomarker of 'neuroinflammation' or 'microglial activation'. Psychiatric research has mostly accepted these denotations of TSPO, even if they may be inadequate and misleading under many pathological conditions...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29180675/protein-kinase-m%C3%AE-in-medial-prefrontal-cortex-mediates-depressive-like-behavior-and-antidepressant-response
#7
W Yan, J-F Liu, Y Han, W Zhang, Y-X Luo, Y-X Xue, W-L Zhu, C Yang, W-H Chen, H-L Guo, Y-N Ma, K Yuan, J-S Wang, J Shi, L Lu
Neuronal atrophy and alterations of synaptic structure and function in the medial prefrontal cortex (mPFC) have been implicated in the pathogenesis of depression, but the underlying molecular mechanisms are largely unknown. The protein kinase Mζ (PKMζ), a brain-specific atypical protein kinase C isoform, is important for maintaining long-term potentiation and storing memory. In the present study, we explored the role of PKMζ in mPFC in two rat models of depression, chronic unpredictable stress (CUS) and learned helplessness...
November 28, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29180674/why-is-there-selective-subcortical-vulnerability-in-adhd-clues-from-postmortem-brain-gene-expression-data
#8
J L Hess, G C Akutagava-Martins, J D Patak, S J Glatt, S V Faraone
Sub-cortical volumetric differences were associated with attention-deficit/hyperactivity disorder (ADHD) in a recent multi-site, mega-analysis of 1713 ADHD persons and 1529 controls. As there was a wide range of effect sizes among the sub-cortical volumes, it is possible that selective neuronal vulnerability has a role in these volumetric losses. To address this possibility, we used data from Allen Brain Atlas to investigate variability in gene expression profiles between subcortical regions of typically developing brains...
November 28, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29180673/calhm2-governs-astrocytic-atp-releasing-in-the-development-of-depression-like-behaviors
#9
M Jun, Q Xiaolong, Y Chaojuan, P Ruiyuan, W Shukun, W Junbing, H Li, C Hong, C Jinbo, W Rong, L Yajin, M Lanqun, W Fengchao, W Zhiying, A Jianxiong, W Yun, Z Xia, Z Chen, Y Zengqiang
Extracellular ATP is a widespread cell-to-cell signaling molecule in the brain, where it functions as a neuromodulator by activating glia and neurons. Although ATP exerts multiple effects on synaptic plasticity and neuro-glia interactions, as well as in mood disorders, the source and regulation of ATP release remain to be elaborated. Here, we define Calhm2 as an ATP-releasing channel protein based on in vitro and in vivo models. Conventional knockout and conditional astrocyte knockout of Calhm2 both lead to significantly reduced ATP concentrations, loss of hippocampal spine number, neural dysfunction and depression-like behaviors in mice, which can be significantly rescued by ATP replenishment...
November 28, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29180672/the-thalamic-reticular-nucleus-in-schizophrenia-and-bipolar-disorder-role-of-parvalbumin-expressing-neuron-networks-and-oxidative-stress
#10
P Steullet, J-H Cabungcal, S A Bukhari, M I Ardelt, H Pantazopoulos, F Hamati, T E Salt, M Cuenod, Kim Q Do, S Berretta
Growing evidence points to a disruption of cortico-thalamo-cortical circuits in schizophrenia (SZ) and bipolar disorder (BD). Clues for a specific involvement of the thalamic reticular nucleus (TRN) come from its unique neuronal characteristics and neural connectivity, allowing it to shape the thalamo-cortical information flow. A direct involvement of the TRN in SZ and BD has not been tested thus far. We used a combination of human postmortem and rodent studies to test the hypothesis that neurons expressing parvalbumin (PV neurons), a main TRN neuronal population, and associated Wisteria floribunda agglutinin-labeled perineuronal nets (WFA/PNNs) are altered in SZ and BD, and that these changes may occur early in the course of the disease as a consequence of oxidative stress...
November 28, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29180671/corticostriatal-circuit-defects-in-hoxb8-mutant-mice
#11
N Nagarajan, B W Jones, P J West, R E Marc, M R Capecchi
This corrects the article DOI: 10.1038/mp.2017.180.
November 28, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158585/child-abuse-associates-with-an-imbalance-of-oligodendrocyte-lineage-cells-in-ventromedial-prefrontal-white-matter
#12
A Tanti, J J Kim, M Wakid, M-A Davoli, G Turecki, N Mechawar
Child abuse (CA) is a major risk factor for depression, and strongly associates with suicidal behavior during adulthood. Neuroimaging studies have reported widespread changes in white matter integrity and brain connectivity in subjects with a history of CA. Although such observations could reflect changes in myelin and oligodendrocyte function, their cellular underpinnings have never been addressed. Using postmortem brain samples from depressed suicides with or without history of CA and matched controls (18 per group), we aimed to characterize the effects of CA on oligodendrocyte-lineage (OL) cells in the ventromedial prefrontal white matter...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158584/ketamine-enhances-structural-plasticity-in-mouse-mesencephalic-and-human-ipsc-derived-dopaminergic-neurons-via-ampar-driven-bdnf-and-mtor-signaling
#13
L Cavalleri, E Merlo Pich, M J Millan, C Chiamulera, T Kunath, P F Spano, G Collo
Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158583/patient-derived-ipscs-show-premature-neural-differentiation-and-neuron-type-specific-phenotypes-relevant-to-neurodevelopment
#14
E Yeh, D Q Dao, Z Y Wu, S M Kandalam, F M Camacho, C Tom, W Zhang, R Krencik, K A Rauen, E M Ullian, L A Weiss
Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAF(Q257R), the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158582/the-camp-responsive-element-binding-creb-1-gene-increases-risk-of-major-psychiatric-disorders
#15
X Xiao, C Zhang, M Grigoroiu-Serbanescu, L Wang, L Li, D Zhou, T-F Yuan, C Wang, H Chang, Y Wu, Y Li, D-D Wu, Y-G Yao, M Li
Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample)...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158581/improved-ethical-guidance-for-the-return-of-results-from-psychiatric-genomics-research
#16
G Lázaro-Muñoz, M S Farrell, J J Crowley, D M Filmyer, R A Shaughnessy, R C Josiassen, P F Sullivan
There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158580/ck2-regulates-5-ht4-receptor-signaling-and-modulates-depressive-like-behavior
#17
J Castello, B LeFrancois, M Flajolet, P Greengard, E Friedman, H Rebholz
The serotonergic neurotransmitter system has been widely implicated in the pathophysiology of mood-related disorders such as anxiety and major depressive disorder (MDD). The onset of therapeutic efficacy of traditional antidepressants is delayed by several weeks. The 5-HT4 receptor has emerged as a new therapeutic target since agonists of this receptor induce rapid antidepressant-like responses in rodents. Here we show that the 5-HT4 receptor is regulated by CK2, at transcriptional and post-transcriptional levels...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158579/rare-susceptibility-variants-for-bipolar-disorder-suggest-a-role-for-g-protein-coupled-receptors
#18
C Cruceanu, J-F Schmouth, S G Torres-Platas, J P Lopez, A Ambalavanan, E Darcq, F Gross, B Breton, D Spiegelman, D Rochefort, P Hince, J M Petite, J Gauthier, R G Lafrenière, P A Dion, C M Greenwood, B L Kieffer, M Alda, G Turecki, G A Rouleau
Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes. We explored this hypothesis by sequencing the exomes of affected individuals from 40 well-characterized multiplex families. We identified rare variants segregating with affected status in many interesting genes, and found an enrichment of deleterious variants in G protein-coupled receptor (GPCR) family genes, which are important drug targets...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158578/ketamine-and-its-metabolite-2r-6r-hydroxynorketamine-induce-lasting-alterations-in-glutamatergic-synaptic-plasticity-in-the-mesolimbic-circuit
#19
N Yao, O Skiteva, X Zhang, P Svenningsson, K Chergui
Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29158577/vgf-function-in-depression-and-antidepressant-efficacy
#20
C Jiang, W-J Lin, M Sadahiro, B Labonté, C Menard, M L Pfau, C A Tamminga, G Turecki, E J Nestler, S J Russo, S R Salton
Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes...
November 21, 2017: Molecular Psychiatry
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