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Molecular Psychiatry

Daniel Durstewitz, Georgia Koppe, Andreas Meyer-Lindenberg
Machine and deep learning methods, today's core of artificial intelligence, have been applied with increasing success and impact in many commercial and research settings. They are powerful tools for large scale data analysis, prediction and classification, especially in very data-rich environments ("big data"), and have started to find their way into medical applications. Here we will first give an overview of machine learning methods, with a focus on deep and recurrent neural networks, their relation to statistics, and the core principles behind them...
February 15, 2019: Molecular Psychiatry
Marco Colizzi, Nathalie Weltens, Philip McGuire, David Lythgoe, Steve Williams, Lukas Van Oudenhove, Sagnik Bhattacharyya
The neurobiological mechanisms underlying the association between cannabis use and acute or long-lasting psychosis are not completely understood. While some evidence suggests altered striatal dopamine may underlie the association, direct evidence that cannabis use affects either acute or chronic striatal dopamine is inconclusive. In contrast, pre-clinical research suggests that cannabis may affect dopamine via modulation of glutamate signaling. A double-blind, randomized, placebo-controlled, crossover design was used to investigate whether altered striatal glutamate, as measured using proton magnetic resonance spectroscopy, underlies the acute psychotomimetic effects of intravenously administered delta-9-tetrahydrocannabinol (Δ9-THC; 1...
February 15, 2019: Molecular Psychiatry
Stuart J Ritchie, W David Hill, Riccardo E Marioni, Gail Davies, Saskia P Hagenaars, Sarah E Harris, Simon R Cox, Adele M Taylor, Janie Corley, Alison Pattie, Paul Redmond, John M Starr, Ian J Deary
Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing...
February 13, 2019: Molecular Psychiatry
Junghee Jin, Dionnet L Bhatti, Ko-Woon Lee, Lucian Medrihan, Jia Cheng, Jing Wei, Ping Zhong, Zhen Yan, Cassandra Kooiker, Claire Song, Jung-Hyuck Ahn, Gerald J Obermair, Amy Lee, Jodi Gresack, Paul Greengard, Yong Kim
Genetic polymorphisms of the L-type voltage-gated calcium channel (VGCC) are associated with psychiatric disorders including major depressive disorder. Alterations of S100A10 (p11) level are also implicated in the etiology of major depressive disorder. However, the existence of an endogenous regulator in the brain regulating p11, L-type VGCC, and depressive behavior has not been known. Here we report that Ahnak, whose function in the brain has been obscure, stabilizes p11 and Anxa2 proteins in the hippocampus and prefrontal cortex in the rodent brain...
February 13, 2019: Molecular Psychiatry
Iakovos Lazaridis, Ourania Tzortzi, Moritz Weglage, Antje Märtin, Yang Xuan, Marc Parent, Yvonne Johansson, Janos Fuzik, Daniel Fürth, Lief E Fenno, Charu Ramakrishnan, Gilad Silberberg, Karl Deisseroth, Marie Carlén, Konstantinos Meletis
Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively...
February 12, 2019: Molecular Psychiatry
A B Niculescu, H Le-Niculescu, D F Levey, K Roseberry, K C Soe, J Rogers, F Khan, T Jones, S Judd, M A McCormick, A R Wessel, A Williams, S M Kurian, F A White
We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis...
February 12, 2019: Molecular Psychiatry
Mari Sild, Linda Booij
Anorexia nervosa (AN) and other eating disorders continue to constitute significant challenges for individual and public health. AN is thought to develop as a result of complex interactions between environmental triggers, psychological risk factors, sociocultural influences, and genetic vulnerability. Recent research developments have highlighted a novel potentially relevant component in the AN etiology-activity of the histone deacetylase 4 (HDAC4) gene that has emerged in several recent studies related to AN...
February 11, 2019: Molecular Psychiatry
Thiago C Genaro-Mattos, Luke B Allen, Allison Anderson, Keri A Tallman, Ned A Porter, Zeljka Korade, Károly Mirnics
Mutations in both copies in the gene encoding 7-dehydrocholesterol reductase (DHCR7) cause Smith-Lemli-Opitz Syndrome (SLOS), which is characterized by a toxic elevation in 7-dehydrocholesterol (7-DHC). Aripiprazole (ARI) exposure, independent of genetic mutations, also leads to elevation of 7-DHC. We investigated the combined effect of a single-copy Dhcr7+/- mutation and maternal ARI exposure on the developing offspring brain. We generated a time-pregnant mouse model where WT and Dhcr7+/ - embryos were maternally exposed to ARI or vehicle (VEH) from E12 to E19 (5 mg/kg)...
February 11, 2019: Molecular Psychiatry
Jian-Guo Li, Jin Chiu, Domenico Praticò
Deficit in retromer complex function secondary to lower levels of one of its major components, the vacuolar protein sorting 35 (VPS35), has been reported in Alzheimer's disease (AD) brains. VPS35 genetic reduction results in increased Aβ levels and synaptic pathology in mouse models of the disease. However, whether restoration of its levels has an effect on the AD-like phenotype which includes Aβ plaques, tau tangles and memory impairments remain unknown. In this paper, we investigated the effect of VPS35 gene delivery into the central nervous system on the development of the neuropathology and behavioral deficits of the triple transgenic (3xTg) mice...
February 7, 2019: Molecular Psychiatry
David R Roalf, Angel Garcia de la Garza, Adon Rosen, Monica E Calkins, Tyler M Moore, Megan Quarmley, Kosha Ruparel, Cedric Huchuan Xia, Petra E Rupert, Theodore D Satterthwaite, Russell T Shinohara, Mark A Elliott, Ruben C Gur, Raquel E Gur
Abnormalities in brain white matter (WM) are reported in youth at-risk for psychosis. Yet, the neurodevelopmental time course of these abnormalities remains unclear. Thus, longitudinal diffusion-weighted imaging (DWI) was used to investigate WM abnormalities in youth at-risk for psychosis. A subset of individuals from the Philadelphia Neurodevelopmental Cohort (PNC) completed two DWI scans approximately 20 months apart. Youths were identified through structured interview as having subthreshold persistent psychosis risk symptoms (n = 46), and were compared to healthy typically developing participants (TD; n = 98)...
February 5, 2019: Molecular Psychiatry
A D Nelson, R N Caballero-Florán, J C Rodríguez Díaz, J M Hull, Y Yuan, J Li, K Chen, K K Walder, L F Lopez-Santiago, V Bennett, M G McInnis, L L Isom, C Wang, M Zhang, K S Jones, P M Jenkins
In the original version of this article, affiliation 3 was given as: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong, University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China". This has now been corrected to: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China".Additionally in the 'Data availability' section an incorrect accession code was given...
January 31, 2019: Molecular Psychiatry
Takuma Mori, Enas A Kasem, Emi Suzuki-Kouyama, Xueshan Cao, Xue Li, Taiga Kurihara, Takeshi Uemura, Toru Yanagawa, Katsuhiko Tabuchi
This article was originally published under standard licence, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.
January 31, 2019: Molecular Psychiatry
Hong Li, Ying Zhu, Yury M Morozov, Xiaoli Chen, Stephanie Cerceo Page, Matthew D Rannals, Brady J Maher, Pasko Rakic
The TCF4 gene is the subject of numerous and varied investigations of it's role in the genesis of neuropsychiatric disease. The gene has been identified as the cause of Pitt-Hopkins syndrome (PTHS) and it has been implicated in various other neuropsychiatric diseases, including schizophrenia, depression, and autism. However, the precise molecular mechanisms of the gene's involvement in neurogenesis, particularly, corticogenesis, are not well understood. Here, we present data showing that TCF4 is expressed in a region-specific manner in the radial glia and stem cells of transient embryonic zones at early gestational ages in both humans and mice...
January 31, 2019: Molecular Psychiatry
Yun Lei, Jiangong Wang, Dan Wang, Chen Li, Bin Liu, Xing Fang, Jingjing You, Ming Guo, Xin-Yun Lu
Sirtuin 1 (SIRT1), an NAD+ -dependent deacetylase, is a key regulator of cellular metabolism. Recent genome-wide association studies identified genetic variants of SIRT1 linked to major depressive disorders. SIRT1 is widely expressed in the brain; however, neuronal substrates that mediate SIRT1 action on depressive behaviors remain largely unknown. Here we show that selective deletion of SIRT1 in forebrain excitatory neurons causes depression-like phenotypes in male but not female mice. AAV-Cre-mediated SIRT1 knockdown in the medial prefrontal cortex (mPFC) of adult male mice induces depressive-like behaviors...
January 31, 2019: Molecular Psychiatry
Ida E Sønderby, Ómar Gústafsson, Nhat Trung Doan, Derrek P Hibar, Sandra Martin-Brevet, Abdel Abdellaoui, David Ames, Katrin Amunts, Michael Andersson, Nicola J Armstrong, Manon Bernard, Nicholas Blackburn, John Blangero, Dorret I Boomsma, Janita Bralten, Hans-Richard Brattbak, Henry Brodaty, Rachel M Brouwer, Robin Bülow, Vince Calhoun, Svenja Caspers, Gianpiero Cavalleri, Chi-Hua Chen, Sven Cichon, Simone Ciufolini, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E Curran, Anders M Dale, Shareefa Dalvie, Paola Dazzan, Eco J C de Geus, Greig I de Zubicaray, Sonja M C de Zwarte, Norman Delanty, Anouk den Braber, Sylvane Desrivières, Gary Donohoe, Bogdan Draganski, Stefan Ehrlich, Thomas Espeseth, Simon E Fisher, Barbara Franke, Vincent Frouin, Masaki Fukunaga, Thomas Gareau, David C Glahn, Hans Grabe, Nynke A Groenewold, Jan Haavik, Asta Håberg, Ryota Hashimoto, Jayne Y Hehir-Kwa, Andreas Heinz, Manon H J Hillegers, Per Hoffmann, Laurena Holleran, Jouke-Jan Hottenga, Hilleke E Hulshoff, Masashi Ikeda, Neda Jahanshad, Terry Jernigan, Christiane Jockwitz, Stefan Johansson, Gudrun A Jonsdottir, Erik G Jönsson, Rene Kahn, Tobias Kaufmann, Sinead Kelly, Masataka Kikuchi, Emma E M Knowles, Knut K Kolskår, John B Kwok, Stephanie Le Hellard, Costin Leu, Jingyu Liu, Astri J Lundervold, Arvid Lundervold, Nicholas G Martin, Karen Mather, Samuel R Mathias, Mark McCormack, Katie L McMahon, Allan McRae, Yuri Milaneschi, Clara Moreau, Derek Morris, David Mothersill, Thomas W Mühleisen, Robin Murray, Jan E Nordvik, Lars Nyberg, Loes M Olde Loohuis, Roel Ophoff, Tomas Paus, Zdenka Pausova, Brenda Penninx, Juan M Peralta, Bruce Pike, Carlos Prieto, Sara Pudas, Erin Quinlan, Daniel S Quintana, Céline S Reinbold, Tiago Reis Marques, Alexandre Reymond, Genevieve Richard, Borja Rodriguez-Herreros, Roberto Roiz-Santiañez, Jarek Rokicki, James Rucker, Perminder Sachdev, Anne-Marthe Sanders, Sigrid B Sando, Lianne Schmaal, Peter R Schofield, Andrew J Schork, Gunter Schumann, Jean Shin, Elena Shumskaya, Sanjay Sisodiya, Vidar M Steen, Dan J Stein, Stacy Steinberg, Lachlan Strike, Alexander Teumer, Anbu Thalamuthu, Diana Tordesillas-Gutierrez, Jessica Turner, Torill Ueland, Anne Uhlmann, Magnus O Ulfarsson, Dennis van 't Ent, Dennis van der Meer, Neeltje E M van Haren, Anja Vaskinn, Evangelos Vassos, G Bragi Walters, Yunpeng Wang, Wei Wen, Christopher D Whelan, Katharina Wittfeld, Margie Wright, Hidenaga Yamamori, Tetyana Zayats, Ingrid Agartz, Lars T Westlye, Sébastien Jacquemont, Srdjan Djurovic, Hreinn Stefánsson, Kári Stefánsson, Paul Thompson, Ole A Andreassen
Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%)...
January 31, 2019: Molecular Psychiatry
Krishna C Vadodaria, Yuan Ji, Michelle Skime, Apua Paquola, Timothy Nelson, Daniel Hall-Flavin, Callie Fredlender, Kelly J Heard, Yalin Deng, Amy T Le, Sonia Dave, Lianna Fung, Xinyi Li, Maria C Marchetto, Richard Weinshilboum, Fred H Gage
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters...
January 30, 2019: Molecular Psychiatry
Gustavo Sudre, Jennifer Frederick, Wendy Sharp, Ayaka Ishii-Takahashi, Aman Mangalmurti, Saadia Choudhury, Philip Shaw
There are now large-scale data on which common genetic variants confer risk for attention deficit hyperactivity disorder (ADHD). Here, we use mediation analyses to explore how cognitive and neural features might explain the association between common variant (polygenic) risk for ADHD and its core symptoms. In total, 544 participants participated (mean 21 years, 212 (39%) with ADHD), most with cognitive assessments, neuroanatomic imaging, and imaging of white matter tract microstructure. We found that polygenic risk for ADHD was associated with symptoms of hyperactivity-impulsivity but not inattention...
January 30, 2019: Molecular Psychiatry
Li Wang, Carolyn J Adamski, Vitaliy V Bondar, Evelyn Craigen, John R Collette, Kaifang Pang, Kihoon Han, Antrix Jain, Sung Y Jung, Zhandong Liu, Richard N Sifers, J Lloyd Holder, Huda Y Zoghbi
Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage...
January 29, 2019: Molecular Psychiatry
Nathalie Picard, Anne E Takesian, Michela Fagiolini, Takao K Hensch
Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine...
January 29, 2019: Molecular Psychiatry
Azahara M García-Serna, Eva Morales
Diverse studies have investigated the impact of prenatal exposure to vitamin D levels on brain development; however, evidence in humans has never been systematically reviewed. This article summarized evidence of the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits...
January 29, 2019: Molecular Psychiatry
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