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Singh RK, Kumar S, Kumar S, Shukla A, Kumar N, Patel AK, Yadav LK, Kaushalendra, Antiwal M, Acharya A. Potential implications of protein kinase Cα in pathophysiological conditions and therapeutic interventions. Life Sci 2023; 330:121999. [PMID: 37536614 DOI: 10.1016/j.lfs.2023.121999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/31/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
PKCα is a molecule with many functions that play an important role in cell survival and death to maintain cellular homeostasis. Alteration in the normal functioning of PKCα is responsible for the complicated etiology of many pathologies, including cancer, cardiovascular diseases, kidney complications, neurodegenerative diseases, diabetics, and many others. Several studies have been carried out over the years on this kinase's function, and regulation in normal physiology and pathological conditions. A lot of data with antithetical results have therefore accumulated over time to create a complex framework of physiological implications connected to the PKCα function that needs comprehensive elucidation. In light of this information, we critically analyze the multiple roles played by PKCα in basic cellular processes and their molecular mechanism during various pathological conditions. This review further discusses the current approaches to manipulating PKCα signaling amplitude in the patient's favour and proposed PKCα as a therapeutic target to reverse pathological states.
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Affiliation(s)
- Rishi Kant Singh
- Lab of Hematopoiesis and Leukemia, KSBS, Indian Institute of Technology, Delhi, New Delhi 110016, India; Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Sanjay Kumar
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Sandeep Kumar
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Alok Shukla
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Naveen Kumar
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Anand Kumar Patel
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Lokesh Kumar Yadav
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Kaushalendra
- Department of Zoology, Pachhunga University College Campus, Mizoram University, Aizawl 796001, India
| | - Meera Antiwal
- Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Arbind Acharya
- Cancer Immunology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, India.
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Kumar S, Kesavan R, Sistla SC, Penumadu P, Natarajan H, Chakradhara Rao US, Nair S, Vasuki V, Kundra P. Predictive models for fentanyl dose requirement and postoperative pain using clinical and genetic factors in patients undergoing major breast surgery. Pain 2023; 164:1332-1339. [PMID: 36701226 DOI: 10.1097/j.pain.0000000000002821] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/03/2022] [Indexed: 01/27/2023]
Abstract
ABSTRACT Fentanyl exhibits interindividual variability in its dose requirement due to various nongenetic and genetic factors such as single nucleotide polymorphisms (SNPs). This study aims to develop and cross-validate robust predictive models for postoperative fentanyl analgesic requirement and other related outcomes in patients undergoing major breast surgery. Data regarding genotypes of 10 candidate SNPs, cold pain test (CPT) scores, pupillary response to fentanyl (PRF), and other common clinical characteristics were recorded from 257 patients undergoing major breast surgery. Predictive models for 24-hour fentanyl requirement, 24-hour pain scores, and time for first analgesic (TFA) in the postoperative period were developed using 4 different algorithms: generalised linear regression model, linear support vector machine learning (SVM-Linear), random forest (RF), and Bayesian regularised neural network. The variant genotype of OPRM1 (rs1799971) and higher CPT scores were associated with higher 24-hour postoperative fentanyl consumption, whereas higher PRF and history of hypertension were associated with lower fentanyl requirement. The variant allele of COMT (rs4680) and higher CPT scores were associated with 24-hour postoperative pain scores. The variant genotype of CTSG (rs2070697), higher intraoperative fentanyl use, and higher CPT scores were associated with significantly lower TFA. The predictive models for 24-hour postoperative fentanyl requirement, pain scores, and TFA had R-squared values of 0.313 (SVM-Linear), 0.434 (SVM-Linear), and 0.532 (RF), respectively. We have developed and cross-validated predictive models for 24-hour postoperative fentanyl requirement, 24-hour postoperative pain scores, and TFA with satisfactory performance characteristics and incorporated them in a novel web application.
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Affiliation(s)
- Shathish Kumar
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Ramasamy Kesavan
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Sarath Chandra Sistla
- Department of General Surgery, Sri Manakula Vinayagar Medical College and Hospital (SMVMCH), Puducherry, India
| | - Prasanth Penumadu
- Department of Surgical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Harivenkatesh Natarajan
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Uppugunduri S Chakradhara Rao
- CANSEARCH Research Platform in Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Sreekumaran Nair
- Department of Biostatistics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Venkatesan Vasuki
- ICMR-Vector Control Research Centre, Department of Health Research, Ministry of Health and Family Welfare, GOI, Medical Complex, Puducherry, India
| | - Pankaj Kundra
- Department of Anaesthesiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
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Human cerebellum and corticocerebellar connections involved in emotional memory enhancement. Proc Natl Acad Sci U S A 2022; 119:e2204900119. [PMID: 36191198 PMCID: PMC9564100 DOI: 10.1073/pnas.2204900119] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Enhanced memory for emotional stimuli is crucial for survival, but it may also contribute to the development and maintenance of fear-related disorders in case of highly aversive experiences. This large-scale functional brain imaging study identifies the cerebellum and cerebellar–cerebral connections involved in the phenomenon of superior memory for emotionally arousing visual information. These findings expand knowledge on the role of the cerebellum in complex cognitive and emotional processes and may be relevant for the understanding of psychiatric disorders with aberrant emotional circuitry, such as posttraumatic stress disorder or autism spectrum disorder. Emotional information is better remembered than neutral information. Extensive evidence indicates that the amygdala and its interactions with other cerebral regions play an important role in the memory-enhancing effect of emotional arousal. While the cerebellum has been found to be involved in fear conditioning, its role in emotional enhancement of episodic memory is less clear. To address this issue, we used a whole-brain functional MRI approach in 1,418 healthy participants. First, we identified clusters significantly activated during enhanced memory encoding of negative and positive emotional pictures. In addition to the well-known emotional memory–related cerebral regions, we identified a cluster in the cerebellum. We then used dynamic causal modeling and identified several cerebellar connections with increased connection strength corresponding to enhanced emotional memory, including one to a cluster covering the amygdala and hippocampus, and bidirectional connections with a cluster covering the anterior cingulate cortex. The present findings indicate that the cerebellum is an integral part of a network involved in emotional enhancement of episodic memory.
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Cannon-Albright LA, Romesser J, Teerlink CC, Thomas A, Meyer LJ. Evidence for excess familial clustering of Post Traumatic Stress Disorder in the US Veterans Genealogy resource. J Psychiatr Res 2022; 150:332-337. [PMID: 34953562 DOI: 10.1016/j.jpsychires.2021.12.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/22/2021] [Accepted: 12/10/2021] [Indexed: 10/19/2022]
Abstract
A genealogy of the United States has been record-linked to National Veteran's Health Administration (VHA) patient data to allow non-identifiable analysis of familial clustering. This genealogy, including over 70 million individuals linked to over 1 million VHA patients, is the largest such combined resource reported. Analysis of familial clustering among VHA patients diagnosed with Post Traumatic Stress Disorder (PTSD) allowed a test of the hypothesis of an inherited contribution to PTSD. PTSD is associated strongly with military service and extended familial clustering data have not previously been presented. PTSD-affected VHA patients with genealogy data were identified by presence of an ICD diagnosis code in the VHA medical record in at least 2 different years. The Genealogical Index of Familiality (GIF) method was used to compare the average relatedness of VHA patients diagnosed with PTSD with their expected average relatedness, estimated from randomly selected sets of matched linked VHA patient controls. Relative risks for PTSD were estimated in first-, second-, and third-degree relatives of PTSD patients who were also VHA patients, using sex and age-matched rates for PTSD estimated from all linked VHA patients. Significant excess pairwise relatedness, and significantly elevated risk for PTSD in first-, second-, and third-degree relatives was observed; multiple high-risk extended PTSD pedigrees were identified. The analysis provides evidence for excess familial clustering of PTSD and identified high-risk PTSD pedigrees. These results support an inherited contribution to PTSD predisposition and identify a powerful resource of high-risk PTSD pedigrees for predisposition gene identification.
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Affiliation(s)
- Lisa A Cannon-Albright
- Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA; Huntsman Cancer Institute, Salt Lake City, UT, USA.
| | - Jennifer Romesser
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
| | - Craig C Teerlink
- Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
| | - Alun Thomas
- Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
| | - Lawrence J Meyer
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA; Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA.
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OUP accepted manuscript. Hum Mol Genet 2022; 31:2236-2261. [DOI: 10.1093/hmg/ddac029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 11/12/2022] Open
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Soubh AA, El-Gazar AA, Mohamed EA, Awad AS, El-Abhar HS. Further insights for the role of Morin in mRTBI: Implication of non-canonical Wnt/PKC-α and JAK-2/STAT-3 signaling pathways. Int Immunopharmacol 2021; 100:108123. [PMID: 34560511 DOI: 10.1016/j.intimp.2021.108123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 08/01/2021] [Accepted: 08/01/2021] [Indexed: 12/24/2022]
Abstract
The slightly available data about the pathogenesis process of mild repetitive traumatic brain injury (mRTBI) indicates to the necessity of further exploration of mRTBI consequences. Several cellular changes are believed to contribute to the cognitive disabilities, and neurodegenerative changes observed later in persons subjected to mRTBI. We investigated glial fibrillary acidic protein (GFAP), the important severity related biomarker, where it showed further increase after multiple trauma compared to single one. To authenticate our aim, Morin (10 mg/kg loading dose, then twice daily 5 mg/kg for 7 days), MK-801 (1 mg/kg; i.p) and their combination were used. The results obtained has shown that all the chosen regimens opposed the upregulated dementia markers (Aβ1-40,p(Thr231)Tau) and inflammatory protein contents/expression of p(Ser53s6)NF-κBp65, TNF-α, IL-6,and IL-1β and the elevated GFAP in immune stained cortex sections. Additionally, they exerted anti-apoptotic activity by decreasing caspase-3 activity and increasing Bcl-2 contents. Saving brain tissues was evident after these therapeutic agents via upregulating the non-canonical Wnt-1/PKC-α cue and IL-10/p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 signaling pathway to confirm enhancement of survival pathways on the molecular level. Such results were imitated by correcting the injury dependent deviated behavior, where Morin alone or in combination enhanced behavior outcome. On one side, our study refers to the implication of two survival signaling pathways; viz.,the non-canonical Wnt-1/PKC-α and p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 in single and repetitive mRTBI along with distorted dementia markers, inflammation and apoptotic process that finally disrupted behavior. On the other side, intervention through affecting all these targets by Morin alone or with MK-801 affords a promising neuroprotective effect.
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Affiliation(s)
- Ayman A Soubh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Amira A El-Gazar
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, October 6 University, Giza, Egypt
| | - Eman A Mohamed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Azza S Awad
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Hanan S El-Abhar
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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Fondren AH, Banducci AN, Cox R, Contractor AA. Processing of Positive Memories Technique among Clients Reporting Traumatic Experiences: A Case Series. Clin Case Stud 2021. [DOI: 10.1177/15346501211035841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Many current treatments for posttraumatic stress disorder (PTSD) emphasize processing and engaging with trauma memories as the key mechanism of therapeutic change. However, promising emerging research indicates links between PTSD symptoms and positive memories. Processing positive memories, to therapeutically impact health outcomes for trauma-exposed individuals, may have several benefits, including (a) increasing access to positive coping mechanisms via activating positive affect and thoughts; (b) addressing avoidance of positive affect and thoughts; and (c) honing skills that will aid in the eventual processing of trauma memories. The present article demonstrates the utility and effects of a novel Processing of Positive Memories Technique (PPMT) with three clients who reported a history of traumatic experiences. We outline the procedures of a 5-session PPMT, that incorporates symptom assessment, detailed imaginal experiencing of positive memories, and processing of associated positive values, affect, strengths, and thoughts. We utilize longitudinal assessment data to demonstrate the clinical benefits of PPMT, such as less PTSD severity, improved mood (e.g., less negative affect), and greater self-esteem. Finally, we discuss treatment considerations based on unique client factors and treatment modalities (i.e., in-person vs. video telehealth).
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Affiliation(s)
- Alana H. Fondren
- Department of Psychology, University of North Texas, Denton, TX, USA
| | - Anne N. Banducci
- The National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA
- Boston University School of Medicine, Boston, MA, USA
| | - Randall Cox
- Department of Psychology, University of North Texas, Denton, TX, USA
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Singh RK, Kumar S, Tomar MS, Verma PK, Kumar A, Kumar S, Kumar N, Singh JP, Acharya A. Putative role of natural products as Protein Kinase C modulator in different disease conditions. ACTA ACUST UNITED AC 2021; 29:397-414. [PMID: 34216003 DOI: 10.1007/s40199-021-00401-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 05/25/2021] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Protein kinase C (PKC) is a promising drug target for various therapeutic areas. Natural products derived from plants, animals, microorganisms, and marine organisms have been used by humans as medicine from prehistoric times. Recently, several compounds derived from plants have been found to modulate PKC activities through competitive binding with ATP binding site, and other allosteric regions of PKC. As a result fresh race has been started in academia and pharmaceutical companies to develop an effective naturally derived small-molecule inhibitor to target PKC activities. Herein, in this review, we have discussed several natural products and their derivatives, which are reported to have an impact on PKC signaling cascade. METHODS All information presented in this review article regarding the regulation of PKC by natural products has been acquired by a systematic search of various electronic databases, including ScienceDirect, Scopus, Google Scholar, Web of science, ResearchGate, and PubMed. The keywords PKC, natural products, curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, protocatechuic acid, tannic acid, PKC modulators from marine organism, bryostatin, staurosporine, midostaurin, sangivamycin, and other relevant key words were explored. RESULTS The natural products and their derivatives including curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, bryostatin, staurosporine, and midostaurin play a major role in the management of PKC activity during various disease progression. CONCLUSION Based on the comprehensive literature survey, it could be concluded that various natural products can regulate PKC activity during disease progression. However, extensive research is needed to circumvent the challenge of isoform specific regulation of PKC by natural products.
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Affiliation(s)
- Rishi Kant Singh
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | | | - Munendra Singh Tomar
- Department of Pharmaceutical Science, School of Pharmacy, University of Colorado, Denver, USA
| | | | - Amit Kumar
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | - Sandeep Kumar
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | - Naveen Kumar
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | - Jai Prakash Singh
- Department of Panchkarma, Institute of Medical Science, BHU, Varanasi, India, 221005
| | - Arbind Acharya
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India.
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Contractor AA, Weiss NH, Forkus SR. Moderating effects of dysregulation and fear of positive emotions on the relationship between posttraumatic stress disorder symptoms and positive memory count. J Clin Psychol 2021; 77:701-721. [PMID: 32844395 PMCID: PMC7878328 DOI: 10.1002/jclp.23046] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 07/14/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES We examined moderating effects of positive emotion dysregulation and fear of positive emotions in the relation between posttraumatic stress disorder (PTSD) severity and positive memory count. METHOD Participants were 205 trauma-exposed community individuals (Mage = 35.44; 61.50% female). RESULTS Moderation analyses indicated interaction effects of PTSD severity with nonacceptance of positive emotions (b = -0.01, p = .002) and difficulties with goal-directed behaviors when experiencing positive emotions (b = -0.01, p = .006) on positive memory count. CONCLUSIONS Greater PTSD severity was associated with more specific positive memories when individuals reported less nonacceptance of positive emotions and fewer difficulties engaging in goal-directed behaviors in the context of positive emotions. Greater PTSD severity was associated with fewer specific positive memories when individuals reported greater nonacceptance of positive emotions and greater difficulties engaging in goal-directed behaviors in the context of positive emotions. Results support addressing positive emotion dysregulation in memory-focused interventions for PTSD.
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Affiliation(s)
| | - Nicole H. Weiss
- Department of Psychology, University of Rhode Island, RI, USA
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Bian YY, Yang LL, Zhang B, Li W, Li ZJ, Li WL, Zeng L. Identification of key genes involved in post-traumatic stress disorder: Evidence from bioinformatics analysis. World J Psychiatry 2020; 10:286-298. [PMID: 33392005 PMCID: PMC7754529 DOI: 10.5498/wjp.v10.i12.286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 10/06/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Post-traumatic stress disorder (PTSD) is a serious stress-related disorder.
AIM To identify the key genes and pathways to uncover the potential mechanisms of PTSD using bioinformatics methods.
METHODS Gene expression profiles were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified by using GEO2R. Gene functional annotation and pathway enrichment were then conducted. The gene-pathway network was constructed with Cytoscape software. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was applied for validation, and text mining by Coremine Medical was used to confirm the connections among genes and pathways.
RESULTS We identified 973 DEGs including 358 upregulated genes and 615 downregulated genes in PTSD. A group of centrality hub genes and significantly enriched pathways (MAPK, Ras, and ErbB signaling pathways) were identified by using gene functional assignment and enrichment analyses. Six genes (KRAS, EGFR, NFKB1, FGF12, PRKCA, and RAF1) were selected to validate using qRT-PCR. The results of text mining further confirmed the correlation among hub genes and the enriched pathways. It indicated that these altered genes displayed functional roles in PTSD via these pathways, which might serve as key signatures in the pathogenesis of PTSD.
CONCLUSION The current study identified a panel of candidate genes and important pathways, which might help us deepen our understanding of the underlying mechanism of PTSD at the molecular level. However, further studies are warranted to discover the critical regulatory mechanism of these genes via relevant pathways in PTSD.
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Affiliation(s)
- Yao-Yao Bian
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Li-Li Yang
- School of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
- Jingwen Library, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Bin Zhang
- Digestive Department, Ningbo Hospital of Traditional Chinese Medicine, Ningbo 315200, Zhejiang Province, China
| | - Wen Li
- School of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Zheng-Jun Li
- Management School, University of St Andrews, St Andrews KY16 9AJ, United Kingdom
- College of Health Economics Management, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Wen-Lin Li
- Jingwen Library, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Li Zeng
- School of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
- Jingwen Library, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Expression of Pea3 protein subfamily members in hippocampus and potential regulation following neuronal stimulation. Neurosci Lett 2020; 738:135348. [PMID: 32891673 DOI: 10.1016/j.neulet.2020.135348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023]
Abstract
Pea3 proteins belong to a subfamily of the E-twentysix (ETS) domain superfamily of transcription factors, which play various roles during development. Polyoma Enhancer-Activator 3 (Pea3) proteins Pea3, ERM and Er81 are particularly involved in tissues with branching morphogenesis, including kidney, lung, mammary gland and nervous system development. A recent transcriptomic study on novel targets of Pea3 transcription factor revealed various axon guidance and nervous system development related targets, supporting a role of Pea3 proteins in motor neuron connectivity, as well as novel targets in signaling pathways involved in synaptic plasticity. This study focuses on the expression of Pea3 family members in hippocampal neurons, and regulation of putative Pea3 targets in Pea3-overexpressing cell lines and following induction of long-term potentiation or seizure in vivo. We show that Pea3 proteins are expressed in hippocampus in both neuronal and non-neuronal cells, and that Pea3 represses Elk-1 but activates Prkca and Nrcam expression in hippocampal cell lines. We also show that mRNA and protein levels of Pea3 family members are differentially regulated in the dentate gyrus and CA1 region upon MECS stimulation, but not upon LTP induction.
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Contractor AA, Banducci AN, Jin L, Keegan FS, Weiss NH. Effects of processing positive memories on posttrauma mental health: A preliminary study in a non-clinical student sample. J Behav Ther Exp Psychiatry 2020; 66:101516. [PMID: 31634724 PMCID: PMC6923756 DOI: 10.1016/j.jbtep.2019.101516] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 08/07/2019] [Accepted: 09/22/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Although trauma research and therapy primarily focus on traumatic memories, recent evidence indicates positive memory processes play a role in the etiology/maintenance of posttraumatic stress disorder (PTSD) symptom severity. We examined the effects of a novel positive memory processing technique on PTSD symptom severity, depression symptom severity, affect, posttrauma cognitions, and self-esteem. METHODS Sixty-five trauma-exposed participants were randomly assigned to one of three conditions (narrating/processing vs. writing/processing two specific positive memories, or a time-matched control) and completed self-report measures pre- and post-task (T0). About one week later, participants repeated their assigned task condition and completed self-report measures pre- and post-task (T1). We conducted mixed ANOVAs to examine the impact of the technique on study variables over time. RESULTS The narrating condition had significant decreases in PTSD symptom severity, posttrauma cognitions, and negative affect from T0 pre-task to T1 post-task; and significant increases in positive affect from T0 pre-to-post-task and from T1 pre-to-post-task. The writing condition had significant increases in positive affect from T0 pre-to-post-task, but a significant decrease from T0 post-task to T1 post-task; and significant decreases in negative affect from T0 pre-to-post-task with an increase from T0 post-task to T1 post-task. LIMITATIONS Use of self-report measures, non-clinical convenience sample with less gender/ethnic/racial diversity, small sample size, methodological differences in time frames for measures, and no examination of follow-up effects. CONCLUSIONS Narrating and processing specific positive memories had a beneficial impact on PTSD symptom severity, posttrauma maladaptive cognitions, and affect; such results provide an impetus to examine positive memory interventions in trauma clinical work.
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Affiliation(s)
| | - Anne N Banducci
- The National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA; Boston University School of Medicine, Boston, MA, USA
| | - Ling Jin
- Department of Psychology, University of North Texas, Denton, TX, USA
| | - Fallon S Keegan
- Department of Psychology, University of North Texas, Denton, TX, USA
| | - Nicole H Weiss
- Department of Psychology, University of Rhode Island, Kingston, RI, USA
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Contractor AA, Greene T, Dolan M, Weiss NH, Armour C. Relation between PTSD symptom clusters and positive memory characteristics: A network perspective. J Anxiety Disord 2020; 69:102157. [PMID: 31751918 PMCID: PMC6960352 DOI: 10.1016/j.janxdis.2019.102157] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/02/2019] [Accepted: 11/02/2019] [Indexed: 01/03/2023]
Abstract
Positive memory characteristics relate to posttraumatic stress disorder (PTSD) severity. We utilized a network approach to examine relations between PTSD clusters (intrusions, avoidance, negative alterations in cognitions and mood [NACM], alterations in arousal and reactivity [AAR]) and positive memory characteristics (count, accessibility, valence, vividness, coherence, time perspective, sensory details). We identified differential relations between PTSD clusters and positive memory characteristics, and central/bridging symptoms. Participants were an Amazon Mechanical Turk-recruited sample of 206 individuals (Mage = 35.36; 61.20% females). We estimated a regularized Gaussian Graphic Model comprising four nodes representing the PTSD clusters and six nodes representing positive memory characteristics. Regarding cross-community relations, AAR (highest node strength) was negatively associated with positive memory count, valence, coherence, and accessibility; avoidance was positively and negatively associated with positive memory vividness and count respectively. The NACM-AAR and intrusion-avoidance edges were significantly stronger than most edges. From the PTSD community, AAR and avoidance had the highest bridge strength and bridge expected influence respectively; from the positive memory community, coherence and vividness had the highest bridge strength and bridge expected influence respectively. Results indicate the potential pivotal role of AAR, avoidance, coherence, and vividness in the PTSD-positive memory relation, which renders them assessment/treatment targets pending further investigation.
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Affiliation(s)
| | - Talya Greene
- Department of Community Mental Health, University of Haifa, Israel
| | - Megan Dolan
- Department of Psychology, University of North Texas, Denton, TX, USA
| | - Nicole H. Weiss
- Department of Psychology, University of Rhode Island, RI, TX, USA
| | - Cherie Armour
- School of Psychology, Queens University Belfast, Northern Ireland, UK
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14
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Conrad D, Wilker S, Schneider A, Karabatsiakis A, Pfeiffer A, Kolassa S, Freytag V, Vukojevic V, Vogler C, Milnik A, Papassotiropoulos A, J.‐F. de Quervain D, Elbert T, Kolassa I. Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts. Psychophysiology 2020; 57:e13288. [PMID: 30328613 PMCID: PMC7379258 DOI: 10.1111/psyp.13288] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 12/17/2022]
Abstract
The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.
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Affiliation(s)
- Daniela Conrad
- Clinical Psychology and NeuropsychologyUniversity of KonstanzKonstanzGermany
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Sarah Wilker
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Anna Schneider
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Alexander Karabatsiakis
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Anett Pfeiffer
- Clinical Psychology and NeuropsychologyUniversity of KonstanzKonstanzGermany
| | | | - Virginie Freytag
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
| | - Vanja Vukojevic
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Department Biozentrum, Life Sciences Training FacilityUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Christian Vogler
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Annette Milnik
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Andreas Papassotiropoulos
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Department Biozentrum, Life Sciences Training FacilityUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Dominique J.‐F. de Quervain
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
- Division of Cognitive NeuroscienceUniversity of BaselBaselSwitzerland
| | - Thomas Elbert
- Clinical Psychology and NeuropsychologyUniversity of KonstanzKonstanzGermany
| | - Iris‐Tatjana Kolassa
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
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15
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Contractor AA, Caldas SV, Dolan M, Banducci AN, Jin L. Exploratory examination of clinician perspectives on positive memories and post‐traumatic stress disorder interventions. COUNSELLING & PSYCHOTHERAPY RESEARCH 2019. [DOI: 10.1002/capr.12267] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
| | | | - Megan Dolan
- Department of Psychology University of North Texas Denton TX USA
| | - Anne N. Banducci
- VA Boston Healthcare System Boston MA USA
- Boston University School of Medicine Boston MA USA
| | - Ling Jin
- Department of Psychology University of North Texas Denton TX USA
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16
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Littlejohn BP, Price DM, Neuendorff DA, Carroll JA, Vann RC, Riggs PK, Riley DG, Long CR, Welsh TH, Randel RD. Prenatal transportation stress alters genome-wide DNA methylation in suckling Brahman bull calves. J Anim Sci 2018; 96:5075-5099. [PMID: 30165450 PMCID: PMC6276578 DOI: 10.1093/jas/sky350] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 08/27/2018] [Indexed: 12/11/2022] Open
Abstract
The objective of this experiment was to identify genome-wide differential methylation of DNA in young prenatally stressed (PNS) bull calves. Mature Brahman cows (n = 48) were transported for 2-h periods at 60 ± 5, 80 ± 5, 100 ± 5, 120 ± 5, and 140 ± 5 d of gestation or maintained as nontransported Controls (n = 48). Methylation of DNA from white blood cells from a subset of 28-d-old intact male offspring (n = 7 PNS; n = 7 Control) was assessed via reduced representation bisulfite sequencing. Samples from PNS bulls contained 16,128 CG, 226 CHG, and 391 CHH (C = cytosine; G = guanine; H = either adenine, thymine, or cytosine) sites that were differentially methylated compared to samples from Controls. Of the CG sites, 7,407 were hypermethylated (at least 10% more methylated than Controls; P ≤ 0.05) and 8,721 were hypomethylated (at least 10% less methylated than Controls; P ≤ 0.05). Increased DNA methylation in gene promoter regions typically results in decreased transcriptional activity of the region. Therefore, differentially methylated CG sites located within promoter regions (n = 1,205) were used to predict (using Ingenuity Pathway Analysis software) alterations to canonical pathways in PNS compared with Control bull calves. In PNS bull calves, 113 pathways were altered (P ≤ 0.05) compared to Controls. Among these were pathways related to behavior, stress response, metabolism, immune function, and cell signaling. Genome-wide differential DNA methylation and predicted alterations to pathways in PNS compared with Control bull calves suggest epigenetic programming of biological systems in utero.
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Affiliation(s)
- Brittni P Littlejohn
- Texas A&M AgriLife Research & Extension Center, Overton, TX
- Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX
| | - Deborah M Price
- Texas A&M AgriLife Research & Extension Center, Overton, TX
- Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX
| | | | | | - Rhonda C Vann
- Mississippi Agricultural and Forestry Experiment Station, Mississippi State University, Raymond, MS
| | - Penny K Riggs
- Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX
| | - David G Riley
- Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX
| | - Charles R Long
- Texas A&M AgriLife Research & Extension Center, Overton, TX
- Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX
| | - Thomas H Welsh
- Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX
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17
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Wilker S, Schneider A, Conrad D, Pfeiffer A, Boeck C, Lingenfelder B, Freytag V, Vukojevic V, Vogler C, Milnik A, Papassotiropoulos A, J.-F. de Quervain D, Elbert T, Kolassa S, Kolassa IT. Genetic variation is associated with PTSD risk and aversive memory: Evidence from two trauma-Exposed African samples and one healthy European sample. Transl Psychiatry 2018; 8:251. [PMID: 30467376 PMCID: PMC6250662 DOI: 10.1038/s41398-018-0297-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 09/26/2018] [Accepted: 10/18/2018] [Indexed: 11/11/2022] Open
Abstract
The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p ≤ 1 × 10-5) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail.
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Affiliation(s)
- Sarah Wilker
- Clinical & Biological Psychology, Ulm University, Ulm, Germany.
| | - Anna Schneider
- Clinical & Biological Psychology, Ulm University, Ulm, Germany.
| | - Daniela Conrad
- Clinical & Biological Psychology, Ulm University, Ulm, Germany. .,Clinical Psychology and Neuropsychology, University of Konstanz, Konstanz, Germany.
| | - Anett Pfeiffer
- 0000 0001 0658 7699grid.9811.1Clinical Psychology and Neuropsychology, University of Konstanz, Konstanz, Germany
| | - Christina Boeck
- 0000 0004 1936 9748grid.6582.9Clinical & Biological Psychology, Ulm University, Ulm, Germany
| | - Birke Lingenfelder
- 0000 0001 0658 7699grid.9811.1Clinical Psychology and Neuropsychology, University of Konstanz, Konstanz, Germany
| | - Virginie Freytag
- 0000 0004 1937 0642grid.6612.3Division of Molecular Neuroscience, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland
| | - Vanja Vukojevic
- 0000 0004 1937 0642grid.6612.3Division of Molecular Neuroscience, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Psychiatric University Clinics, University of Basel, Basel, Switzerland
| | - Christian Vogler
- 0000 0004 1937 0642grid.6612.3Division of Molecular Neuroscience, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Psychiatric University Clinics, University of Basel, Basel, Switzerland
| | - Annette Milnik
- 0000 0004 1937 0642grid.6612.3Division of Molecular Neuroscience, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Psychiatric University Clinics, University of Basel, Basel, Switzerland
| | - Andreas Papassotiropoulos
- 0000 0004 1937 0642grid.6612.3Division of Molecular Neuroscience, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Psychiatric University Clinics, University of Basel, Basel, Switzerland
| | - Dominique J.-F. de Quervain
- 0000 0004 1937 0642grid.6612.3Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Psychiatric University Clinics, University of Basel, Basel, Switzerland ,0000 0004 1937 0642grid.6612.3Division of Cognitive Neuroscience, University of Basel, Basel, Switzerland
| | - Thomas Elbert
- 0000 0001 0658 7699grid.9811.1Clinical Psychology and Neuropsychology, University of Konstanz, Konstanz, Germany
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18
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Contractor AA, Brown LA, Caldas SV, Banducci AN, Taylor DJ, Armour C, Shea MT. Posttraumatic stress disorder and positive memories: Clinical considerations. J Anxiety Disord 2018; 58:23-32. [PMID: 30025253 DOI: 10.1016/j.janxdis.2018.06.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 06/02/2018] [Accepted: 06/22/2018] [Indexed: 12/31/2022]
Abstract
Encoding and retrieval difficulties, and avoidance of both traumatic and positive memories, are associated with posttraumatic stress disorder (PTSD) symptoms. However, most PTSD research and clinical work has solely examined the role of traumatic memories in the maintenance/resolution of PTSD symptoms. This review provides a comprehensive discussion of the literature on positive memories and PTSD. First, we review theories and evidence on the relations between trauma, PTSD, and memory processes (particularly positive memories). Next, we propose a conceptual model that integrates evidence from experimental and positive/memory-based intervention research and highlights hypothesized mechanisms underlying the potential effectiveness of targeting positive memories in PTSD interventions. Specifically, we discuss how targeting positive memories could (1) increase positive affect and reduce negative affect, (2) correct negative cognitions, (3) increase specificity of retrieving autobiographical memories, and (4) be effectively integrated/sequenced with and enhance the effects of trauma-focused interventions. Lastly, we suggest clinical research avenues for investigating the relations between positive memories and PTSD, to possibly alter the current PTSD intervention paradigm focused only on traumatic memories. Overall, our proposed model drawing from experimental and intervention research, and outlining potential effects of targeting positive memories to reduce PTSD severity, needs further empirical investigation.
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Affiliation(s)
| | - Lily A Brown
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - Daniel J Taylor
- Department of Psychology, University of North Texas, Denton, TX, USA
| | - Cherie Armour
- Institute of Mental Health Sciences, School of Psychology, Ulster University, Northern Ireland, UK
| | - M Tracie Shea
- Providence Veterans Affairs Medical Center, Providence, USA; Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, USA
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19
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The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats. PLoS One 2018; 13:e0198256. [PMID: 29870545 PMCID: PMC5988320 DOI: 10.1371/journal.pone.0198256] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 05/16/2018] [Indexed: 01/14/2023] Open
Abstract
Enzastaurin is a Protein Kinase C-β selective inhibitor that was developed to treat cancers. Protein Kinase C-β is an important enzyme for a variety of neuronal functions; in particular, previous rodent studies have reported deficits in spatial and fear-conditioned learning and memory with lower levels of Protein Kinase C-β. Due to Enzastaurin's mechanism of action, the present study investigated the consequences of Enzastaurin exposure on learning and memory in 12-month-old Fischer-344 male rats. Rats were treated daily with subcutaneous injections of either vehicle or Enzastaurin, and behaviorally tested using the spatial reference memory Morris Water Maze. Rats treated with Enzastaurin exhibited decreased overnight retention and poorer performance on the latter testing day, indicating a mild, but significant, memory impairment. There were no differences during the probe trial indicating that all animals were able to spatially localize the platform to the proper quadrant by the end of testing. RNA isolated from the hippocampus was analyzed using Next Generation Sequencing (Illumina). No statistically significant transcriptional differences were noted. Our findings suggest that acute Enzastaurin treatment can impair hippocampal-based learning and memory performance, with no effects on transcription in the hippocampus. We propose that care should be taken in future clinical trials that utilize Protein Kinase C-ß inhibitors, to monitor for possible cognitive effects, future research should examine if these effects are fully reversible.
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20
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Naß J, Efferth T. Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder. Curr Neuropharmacol 2018; 15:831-860. [PMID: 27834145 PMCID: PMC5652029 DOI: 10.2174/1570159x15666161111113514] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 09/23/2016] [Accepted: 11/08/2016] [Indexed: 12/26/2022] Open
Abstract
Background: Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment. Methods: We conducted a systematic review on SNPs in genes related to PTSD pathology and development of targeted pharmacological treatment options based on PubMed database searches. We focused on clinical trials with military personnel. Results: SNPs in 22 human genes have been linked to PTSD. These genes encode proteins acting as neurotransmitters and receptors, downstream signal transducers and metabolizing enzymes. Pharmacological inhibitors may serve as drug candidates for PTSD treatment, e.g. β2 adrenoreceptor antagonists, dopamine antagonists, partial dopamine D2 receptor agonists, dopamine β hydroxylase inhibitors, fatty acid amid hydrolase antagonists, glucocorticoid receptor agonists, tropomyosin receptor kinase B agonists, selective serotonin reuptake inhibitors, catechol-O-methyltransferase inhibitors, gamma-amino butyric acid receptor agonists, glutamate receptor inhibitors, monoaminoxidase B inhibitors, N-methyl-d-aspartate receptor antagonists. Conclusion: The combination of genetic and pharmacological research may lead to novel target-based drug developments with improved specificity and efficacy to treat PTSD. Specific SNPs may be identified as reliable biomarkers to assess individual disease risk. Focusing on soldiers suffering from PTSD will not only help to improve treatment options for this specific group, but for all PTSD patients and the general population.
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Affiliation(s)
- Janine Naß
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz. Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz. Germany
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21
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Lu WH, Yeh NH, Huang YS. CPEB2 Activates GRASP1 mRNA Translation and Promotes AMPA Receptor Surface Expression, Long-Term Potentiation, and Memory. Cell Rep 2017; 21:1783-1794. [DOI: 10.1016/j.celrep.2017.10.073] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 09/15/2017] [Accepted: 10/19/2017] [Indexed: 01/09/2023] Open
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22
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Heck A, Milnik A, Vukojevic V, Petrovska J, Egli T, Singer J, Escobar P, Sengstag T, Coynel D, Freytag V, Fastenrath M, Demougin P, Loos E, Hartmann F, Schicktanz N, Delarue Bizzini B, Vogler C, Kolassa IT, Wilker S, Elbert T, Schwede T, Beisel C, Beerenwinkel N, de Quervain DJF, Papassotiropoulos A. Exome sequencing of healthy phenotypic extremes links TROVE2 to emotional memory and PTSD. Nat Hum Behav 2017. [DOI: 10.1038/s41562-017-0081] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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23
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Bergholz LM, Subic-Wrana C, Heylmann D, Beutel ME, Wiltink J, Kaina B. DNA damage in lymphocytes of patients suffering from complex traumatization. DNA Repair (Amst) 2017; 52:103-109. [PMID: 28254426 DOI: 10.1016/j.dnarep.2017.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 12/21/2016] [Accepted: 02/07/2017] [Indexed: 11/19/2022]
Abstract
It has been shown that complex childhood traumatization (CCT) increases the risk for severe somatic and mental disorders. However, the somatic pathways linking maladaptive affect regulation and disease are not understood. Here we tested the hypothesis that traumatic stress is linked to the induction of DNA damage. We isolated peripheral lymphocytes (PBLCs) from blood of healthy donors and patients suffering from CCT. Cells were immobilised on slides and stained with anti-phosphohistone 2AX (γH2AX). The number of γH2AX foci, which are an accepted surrogate marker of DNA double-strand breaks (DSBs), was determined and set in relation to the patient characteristics. We show that CCT patients (HS) have higher levels of DSBs in PBLCs than healthy volunteers (CG) and psychiatric patients without CCT (LS) (HS: 0.88±0.46 foci/cell; LS: 0.31±0.23 foci/cell; CG: 0.15±0.10 foci/cell). The difference between HS and control group was highly significant (p<0.001). Insecure-dismissing attachment as a psychological marker was related to an increase in the γH2AX foci in all groups, but especially in the CCT patients. There was no significant correlation in the γH2AX level to potential external genotoxic influences such as smoking and alcohol consumption. In PBLCs, spontaneous occurring γH2AX foci partially colocalized with 53BP1 and pATM, supporting the notion they represent DSBs. Overall, our data indicate that complex traumatization is a source of genotoxic stress that can cause systemic DNA damage, pointing to the importance of emotional early life experiences for the genetically determined health status in later life periods. The finding of CCT to be interrelated to genomic instability opens new opportunities for a deeper understanding of the link between emotional stress, DNA damage and somatic disorders.
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Affiliation(s)
- Liana M Bergholz
- Institute of Toxicology, University Medical Center, Mainz, Germany; Clinic for Psychosomatic Medicine and Psychotherapy, University Medical Center, Mainz, Germany
| | - Claudia Subic-Wrana
- Clinic for Psychosomatic Medicine and Psychotherapy, University Medical Center, Mainz, Germany
| | - Daniel Heylmann
- Institute of Toxicology, University Medical Center, Mainz, Germany
| | - Manfred E Beutel
- Clinic for Psychosomatic Medicine and Psychotherapy, University Medical Center, Mainz, Germany
| | - Jörg Wiltink
- Clinic for Psychosomatic Medicine and Psychotherapy, University Medical Center, Mainz, Germany
| | - Bernd Kaina
- Institute of Toxicology, University Medical Center, Mainz, Germany.
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A Deletion Variant of the α2b-Adrenoceptor Modulates the Stress-Induced Shift from "Cognitive" to "Habit" Memory. J Neurosci 2017; 37:2149-2160. [PMID: 28115477 DOI: 10.1523/jneurosci.3507-16.2017] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 12/21/2016] [Accepted: 01/17/2017] [Indexed: 11/21/2022] Open
Abstract
Stress induces a shift from hippocampus-based "cognitive" toward dorsal striatum-based "habitual" learning and memory. This shift is thought to have important implications for stress-related psychopathologies, including post-traumatic stress disorder (PTSD). However, there is large individual variability in the stress-induced bias toward habit memory, and the factors underlying this variability are completely unknown. Here we hypothesized that a functional deletion variant of the gene encoding the α2b-adrenoceptor (ADRA2B), which has been linked to emotional memory processes and increased PTSD risk, modulates the stress-induced shift from cognitive toward habit memory. In two independent experimental studies, healthy humans were genotyped for the ADRA2B deletion variant. After a stress or control manipulation, participants completed a dual-solution learning task while electroencephalographic (Study I) or fMRI measurements (Study II) were taken. Carriers compared with noncarriers of the ADRA2B deletion variant exhibited a significantly reduced bias toward habit memory after stress. fMRI results indicated that, whereas noncarriers of the ADRA2B deletion variant showed increased functional connectivity between amygdala and putamen after stress, this increase in connectivity was absent in carriers of the deletion variant, who instead showed overall enhanced connectivity between amygdala and entorhinal cortex. Our results indicate that a common genetic variation of the noradrenergic system modulates the impact of stress on the balance between cognitive and habitual memory systems, most likely via altered amygdala orchestration of these systems.SIGNIFICANCE STATEMENT Stressful events have a powerful effect on human learning and memory. Specifically, accumulating evidence suggests that stress favors more rigid dorsal striatum-dependent habit memory, at the expense of flexible hippocampus-dependent cognitive memory. Although this shift may have important implications for understanding mental disorders, such as post-traumatic stress disorder, little is known about the source of individual differences in the sensitivity for the stress-induced bias toward habit memory. We report here that a common genetic variation of the noradrenergic system, a known risk factor for post-traumatic stress disorder, modulates the stress-induced shift from cognitive to habit memory, most likely through altered crosstalk between the hippocampus and dorsal striatum with the amygdala, a key structure in emotional memory.
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Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene. Eur J Hum Genet 2017; 25:446-451. [PMID: 28051079 DOI: 10.1038/ejhg.2016.196] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 11/24/2016] [Accepted: 12/06/2016] [Indexed: 11/08/2022] Open
Abstract
Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score >12 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant single-nucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N=908) and in individuals from the Rotterdam Study (N=212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs887797 mapping to the protein kinase C alpha (PRKCA) gene odds ratio (OR)possNP=2.41 (95% CI 1.74-3.34, P=1.29 × 10-7). This SNP has been found to be associated with multiple sclerosis and encodes a functional variant affecting splicing and expression of the PRKCA gene. The PRKCA gene has been associated with long-term potentiation, synaptic plasticity, chronic pain and memory in the literature, making this a biologically relevant finding.
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26
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Wang Y, Yao Y, Nie H, He X. Implication of protein kinase C of the left intermediate medial mesopallium in memory impairments induced by early prenatal morphine exposure in one-day old chicks. Eur J Pharmacol 2016; 795:94-100. [PMID: 27940175 DOI: 10.1016/j.ejphar.2016.12.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 12/02/2016] [Accepted: 12/06/2016] [Indexed: 02/06/2023]
Abstract
Previously we reported that prenatal morphine exposure during embryonic days 5-8 can cause cognitive deficits of one-trial passive avoidance learning (PAL) in one-day old chicks. Because protein kinase C (PKC) has been associated with memory capacity, we investigated the effects of prenatal morphine exposure on PKC isoforms expression in the left intermediate medial mesopallium (IMM) of chick brain at a time when memory tests were performed at 30, 120 and 360min respectively following training in PAL paradigm. We found that the level of PKCα in the membrane fractions in left IMM was decreased but that in the cytosol fractions showed a increased trend in prenatally morphine-exposed chicks with impaired long-term memory (120 and 360min). Moreover, the translocation of PKC δ from cytosol to membrane in left IMM was shown in prenatal morphine group which had significantly impaired long-term memory at 360min after training. Furthermore, there were no statistical differences between the two groups regarding the expressions of PKCα and PKC δ in the membrane fraction, although their levels in the cytosol fraction of prenatal morphine group which showed impaired intermediate-term memory at 30min after training, were quite different from that of prenatal saline group. Taken together, these results indicate that PKCα and PKC δ in the left IMM are differentially involved in the impairments of long-term memory induced by prenatal morphine exposure. Neither PKCα nor PKC δ in left IMM may be associated with the disruption of intermediate-term memory of chicks prenatally exposed to morphine.
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Affiliation(s)
- Ying Wang
- School of Medical Humanities, Tianjin Medical University, Tianjin, PR China
| | - Yang Yao
- Department of Clinical Biochemistry, School of Medical Laboratory, Tianjin Medical University, Tianjin, PR China
| | - Han Nie
- College of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, PR China
| | - Xingu He
- School of Medical Humanities, Tianjin Medical University, Tianjin, PR China.
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27
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Stratta P, Sanità P, Bonanni RL, de Cataldo S, Angelucci A, Rossi R, Origlia N, Domenici L, Carmassi C, Piccinni A, Dell'Osso L, Rossi A. Clinical correlates of plasma brain-derived neurotrophic factor in post-traumatic stress disorder spectrum after a natural disaster. Psychiatry Res 2016; 244:165-70. [PMID: 27479108 DOI: 10.1016/j.psychres.2016.07.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/26/2016] [Accepted: 07/09/2016] [Indexed: 12/30/2022]
Abstract
Clinical correlates of plasma Brain-Derived Neurotrophic Factor (BDNF) have been investigated in a clinical population with Post Traumatic Stress Disorder (PTSD) symptoms and healthy control subjects who survived to the L'Aquila 2009 earthquake. Twenty-six outpatients and 14 control subjects were recruited. Assessments included: Structured Clinical Interview for DSM-IV Axis-I disorders Patient Version, Trauma and Loss Spectrum-Self Report (TALS-SR) for post-traumatic spectrum symptoms. Thirteen patients were diagnosed as Full PTSD and 13 as Partial PTSD. The subjects with full-blown PTSD showed lower BDNF level than subjects with partial PTSD and controls. Different relationship patterns of BDNF with post-traumatic stress spectrum symptoms have been reported in the three samples. Our findings add more insight on the mechanisms regulating BDNF levels in response to stress and further proofs of the utility of the distinction of PTSD into full and partial categories.
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Affiliation(s)
- Paolo Stratta
- Department of Mental Health, ASL 1, L'Aquila, Italy.
| | - Patrizia Sanità
- General Pathology and Immunology Laboratory, Department Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | | | | | - Adriano Angelucci
- General Pathology and Immunology Laboratory, Department Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Rodolfo Rossi
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | | | - Luciano Domenici
- Neuroscience Institute, CNR, Pisa, Italy; Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Claudia Carmassi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Armando Piccinni
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Liliana Dell'Osso
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alessandro Rossi
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
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Ryan J, Chaudieu I, Ancelin ML, Saffery R. Biological underpinnings of trauma and post-traumatic stress disorder: focusing on genetics and epigenetics. Epigenomics 2016; 8:1553-1569. [PMID: 27686106 DOI: 10.2217/epi-2016-0083] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Certain individuals are more susceptible to stress and trauma, as well as the physical and mental health consequences following such exposure, including risk for post-traumatic stress disorder (PTSD). This differing vulnerability is likely to be influenced by genetic predisposition and specific characteristics of the stress itself (nature, intensity and duration), as well as epigenetic mechanisms. In this review we provide an overview of research findings in this field. We highlight some of the key genetic risk factors identified for PTSD, and the evidence that epigenetic processes might play a role in the biological response to trauma, as well as being potential biomarkers of PTSD risk. We also discuss important considerations for future research in this area.
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Affiliation(s)
- Joanne Ryan
- Cancer & Disease Epigenetics Group, Murdoch Children's Research Institute, Royal Childrens Hospital, Parkville 3052, Victoria, Australia.,Department of Paediatrics, The University of Melbourne, Parkville 3052, Victoria, Australia.,Inserm, U1061, University of Montpellier, Montpellier F-34093, France.,Department of Epidemiology & Preventive Medicine, School of Public Health & Preventive Medicine, Monash University, Prahran 3004, Australia
| | - Isabelle Chaudieu
- Inserm, U1061, University of Montpellier, Montpellier F-34093, France
| | | | - Richard Saffery
- Cancer & Disease Epigenetics Group, Murdoch Children's Research Institute, Royal Childrens Hospital, Parkville 3052, Victoria, Australia.,Department of Paediatrics, The University of Melbourne, Parkville 3052, Victoria, Australia
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29
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Shimshoni JA, Winkler I, Golan E, Nutt D. Neurochemical binding profiles of novel indole and benzofuran MDMA analogues. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:15-24. [PMID: 27650729 DOI: 10.1007/s00210-016-1297-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 09/02/2016] [Indexed: 12/11/2022]
Abstract
3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,c and NEα2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,c receptors as compared to MDMA.
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Affiliation(s)
- Jakob A Shimshoni
- Department of Toxicology, Kimron Veterinary Institute, Bet Dagan, Israel.
| | | | | | - David Nutt
- Neuropsychopharmacology Unit, Imperial College London, London, UK
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Lebois LAM, Wolff JD, Ressler KJ. Neuroimaging genetic approaches to Posttraumatic Stress Disorder. Exp Neurol 2016; 284:141-152. [PMID: 27109180 DOI: 10.1016/j.expneurol.2016.04.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 04/10/2016] [Accepted: 04/20/2016] [Indexed: 12/16/2022]
Abstract
Neuroimaging genetic studies that associate genetic and epigenetic variation with neural activity or structure provide an opportunity to link genes to psychiatric disorders, often before psychopathology is discernable in behavior. Here we review neuroimaging genetics studies with participants who have Posttraumatic Stress Disorder (PTSD). Results show that genes related to the physiological stress response (e.g., glucocorticoid receptor and activity, neuroendocrine release), learning and memory (e.g., plasticity), mood, and pain perception are tied to neural intermediate phenotypes associated with PTSD. These genes are associated with and sometimes predict neural structure and function in areas involved in attention, executive function, memory, decision-making, emotion regulation, salience of potential threats, and pain perception. Evidence suggests these risk polymorphisms and neural intermediate phenotypes are vulnerabilities toward developing PTSD in the aftermath of trauma, or vulnerabilities toward particular symptoms once PTSD has developed. Work distinguishing between the re-experiencing and dissociative sub-types of PTSD, and examining other PTSD symptom clusters in addition to the re-experiencing and hyperarousal symptoms, will further clarify neurobiological mechanisms and inconsistent findings. Furthermore, an exciting possibility is that genetic associations with PTSD may eventually be understood through differential intermediate phenotypes of neural circuit structure and function, possibly underlying the different symptom clusters seen within PTSD.
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Affiliation(s)
- Lauren A M Lebois
- Department of Depression and Anxiety, McLean Hospital, Belmont, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States
| | - Jonathan D Wolff
- Department of Depression and Anxiety, McLean Hospital, Belmont, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States
| | - Kerry J Ressler
- Department of Depression and Anxiety, McLean Hospital, Belmont, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States.
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31
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Papassotiropoulos A, de Quervain DJF. Genetics of human memory functions in healthy cohorts. Curr Opin Behav Sci 2015. [DOI: 10.1016/j.cobeha.2015.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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32
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Lucke-Wold BP, Turner RC, Logsdon AF, Simpkins JW, Alkon DL, Smith KE, Chen YW, Tan Z, Huber JD, Rosen CL. Common mechanisms of Alzheimer's disease and ischemic stroke: the role of protein kinase C in the progression of age-related neurodegeneration. J Alzheimers Dis 2015; 43:711-724. [PMID: 25114088 PMCID: PMC4446718 DOI: 10.3233/jad-141422] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Ischemic stroke and Alzheimer's disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.
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Affiliation(s)
- Brandon P. Lucke-Wold
- Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Ryan C. Turner
- Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Aric F. Logsdon
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, USA
| | - James W. Simpkins
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Daniel L. Alkon
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA
| | - Kelly E. Smith
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, USA
| | - Yi-Wen Chen
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Zhenjun Tan
- Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Jason D. Huber
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, USA
| | - Charles L. Rosen
- Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA
- The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
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The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder. Neurobiol Stress 2015; 1:89-99. [PMID: 25436222 PMCID: PMC4244027 DOI: 10.1016/j.ynstr.2014.10.002] [Citation(s) in RCA: 210] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Research on the neurobiology of the stress response in animals has led to successful new treatments for Post-Traumatic Stress Disorder (PTSD) in humans. Basic research has found that high levels of catecholamine release during stress rapidly impair the top-down cognitive functions of the prefrontal cortex (PFC), while strengthening the emotional and habitual responses of the amygdala and basal ganglia. Chronic stress exposure leads to dendritic atrophy in PFC, dendritic extension in the amygdala, and strengthening of the noradrenergic (NE) system. High levels of NE release during stress engage low affinity alpha-1 adrenoceptors, (and likely beta-1 adrenoceptors), which rapidly reduce the firing of PFC neurons, but strengthen amygdala function. In contrast, moderate levels of NE release during nonstress conditions engage higher affinity alpha-2A receptors, which strengthen PFC, weaken amygdala, and regulate NE cell firing. Thus, either alpha-1 receptor blockade or alpha-2A receptor stimulation can protect PFC function during stress. Patients with PTSD have signs of PFC dysfunction. Clinical studies have found that blocking alpha-1 receptors with prazosin, or stimulating alpha-2A receptors with guanfacine or clonidine can be useful in reducing the symptoms of PTSD. Placebo-controlled trials have shown that prazosin is helpful in veterans, active duty soldiers and civilians with PTSD, including improvement of PFC symptoms such as impaired concentration and impulse control. Open label studies suggest that guanfacine may be especially helpful in treating children and adolescents who have experienced trauma. Thus, understanding the neurobiology of the stress response has begun to help patients with stress disorders.
Research in animals has revealed how prefrontal cortex goes “off-line” during stress. Prefrontal cortical function is protected by α2A-, but impaired by α1-adrenoceptors. Based on this research, α1 blockers and α2A agonists are now in use to treat PTSD.
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Progress towards understanding the genetics of posttraumatic stress disorder. J Anxiety Disord 2014; 28:873-83. [PMID: 25445077 DOI: 10.1016/j.janxdis.2014.09.014] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/16/2014] [Indexed: 01/12/2023]
Abstract
Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene-environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.
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Wilker S, Elbert T, Papassotiropoulos A, de Quervain DJF, Kolassa IT. Response to: further support for an association between the memory-related gene WWC1 and posttraumatic stress disorder: results from the Detroit Neighborhood Health Study. Biol Psychiatry 2014; 76:e27-8. [PMID: 24947540 DOI: 10.1016/j.biopsych.2014.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 05/01/2014] [Indexed: 12/01/2022]
Affiliation(s)
- Sarah Wilker
- Clinical & Biological Psychology, Institute for Psychology & Education, University of Ulm, Ulm, Germany.
| | - Thomas Elbert
- Clinical Psychology & Behavioural Neuroscience, University of Konstanz, Konstanz, Germany
| | | | | | - Iris-Tatjana Kolassa
- Clinical & Biological Psychology, Institute for Psychology & Education, University of Ulm, Ulm, Germany
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36
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Holz N, Boecker R, Buchmann AF, Blomeyer D, Baumeister S, Hohmann S, Jennen-Steinmetz C, Wolf I, Rietschel M, Witt SH, Plichta MM, Meyer-Lindenberg A, Schmidt MH, Esser G, Banaschewski T, Brandeis D, Laucht M. Evidence for a Sex-Dependent MAOA× Childhood Stress Interaction in the Neural Circuitry of Aggression. Cereb Cortex 2014; 26:904-14. [PMID: 25331606 DOI: 10.1093/cercor/bhu249] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOA× CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.
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Affiliation(s)
- Nathalie Holz
- Department of Child and Adolescent Psychiatry and Psychotherapy
| | - Regina Boecker
- Department of Child and Adolescent Psychiatry and Psychotherapy
| | | | | | | | - Sarah Hohmann
- Department of Child and Adolescent Psychiatry and Psychotherapy
| | | | - Isabella Wolf
- Department of Child and Adolescent Psychiatry and Psychotherapy Department of Neuroimaging
| | | | | | - Michael M Plichta
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Germany
| | - Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Germany
| | | | - Günter Esser
- Department of Psychology, University of Potsdam, Potsdam, Germany
| | | | - Daniel Brandeis
- Department of Child and Adolescent Psychiatry and Psychotherapy Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland
| | - Manfred Laucht
- Department of Child and Adolescent Psychiatry and Psychotherapy Department of Psychology, University of Potsdam, Potsdam, Germany
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Khadka S, Narayanan B, Meda SA, Gelernter J, Han S, Sawyer B, Aslanzadeh F, Stevens MC, Hawkins KA, Anticevic A, Potenza MN, Pearlson GD. Genetic association of impulsivity in young adults: a multivariate study. Transl Psychiatry 2014; 4:e451. [PMID: 25268255 PMCID: PMC4199418 DOI: 10.1038/tp.2014.95] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 08/19/2014] [Accepted: 08/21/2014] [Indexed: 02/07/2023] Open
Abstract
Impulsivity is a heritable, multifaceted construct with clinically relevant links to multiple psychopathologies. We assessed impulsivity in young adult (N~2100) participants in a longitudinal study, using self-report questionnaires and computer-based behavioral tasks. Analysis was restricted to the subset (N=426) who underwent genotyping. Multivariate association between impulsivity measures and single-nucleotide polymorphism data was implemented using parallel independent component analysis (Para-ICA). Pathways associated with multiple genes in components that correlated significantly with impulsivity phenotypes were then identified using a pathway enrichment analysis. Para-ICA revealed two significantly correlated genotype-phenotype component pairs. One impulsivity component included the reward responsiveness subscale and behavioral inhibition scale of the Behavioral-Inhibition System/Behavioral-Activation System scale, and the second impulsivity component included the non-planning subscale of the Barratt Impulsiveness Scale and the Experiential Discounting Task. Pathway analysis identified processes related to neurogenesis, nervous system signal generation/amplification, neurotransmission and immune response. We identified various genes and gene regulatory pathways associated with empirically derived impulsivity components. Our study suggests that gene networks implicated previously in brain development, neurotransmission and immune response are related to impulsive tendencies and behaviors.
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Affiliation(s)
- S Khadka
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
| | - B Narayanan
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
| | - S A Meda
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
| | - J Gelernter
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
| | - S Han
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
- Department of Psychiatry, University of Iowa Carver
College of Medicine, Iowa City, IA, USA
| | - B Sawyer
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
| | - F Aslanzadeh
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
| | - M C Stevens
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
| | - K A Hawkins
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
| | - A Anticevic
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
| | - M N Potenza
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
- Department of Neurobiology, Yale University School of
Medicine, New Haven, CT, USA
| | - G D Pearlson
- Olin Neuropsychiatry Research Center/Institute of
Living, Hartford Healthcare, Hartford, CT, USA
- Department of Psychiatry, Yale University School of
Medicine, New Haven, CT, USA
- Department of Neurobiology, Yale University School of
Medicine, New Haven, CT, USA
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38
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McKinnon MC, Palombo DJ, Nazarov A, Kumar N, Khuu W, Levine B. Threat of death and autobiographical memory: a study of passengers from Flight AT236. Clin Psychol Sci 2014; 3:487-502. [PMID: 26167422 DOI: 10.1177/2167702614542280] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We investigated autobiographical memory in a group of passengers onboard a trans-Atlantic flight that nearly ditched at sea. The consistency of traumatic exposure across passengers, some of whom developed post-traumatic stress disorder (PTSD), provided a unique opportunity to assess verified memory for life-threatening trauma. Using the Autobiographical Interview, which separates episodic from non-episodic details, passengers and healthy controls (HCs) recalled three events: the airline disaster (or a highly negative event for HCs), the September 11, 2001 attacks, and a non-emotional event. All passengers showed robust mnemonic enhancement for episodic details of the airline disaster. Although neither richness nor accuracy of traumatic recollection was related to PTSD, production of non-episodic details for traumatic and non-traumatic events was elevated in PTSD passengers. These findings indicate a robust mnemonic enhancement for trauma that is not specific to PTSD. Rather, PTSD is associated with altered cognitive control operations that affect autobiographical memory in general.
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Affiliation(s)
- Margaret C McKinnon
- Department of Psychiatry and Behavioural Neurosciences, McMaster University ; Mood Disorders Program, St. Joseph's Healthcare Hamilton ; Homewood Research Institute
| | - Daniela J Palombo
- Rotman Research Institute, Baycrest Health Sciences ; Department of Psychology, University of Toronto
| | - Anthony Nazarov
- Department of Psychiatry and Behavioural Neurosciences, McMaster University ; Mood Disorders Program, St. Joseph's Healthcare Hamilton
| | - Namita Kumar
- Rotman Research Institute, Baycrest Health Sciences
| | - Wayne Khuu
- Rotman Research Institute, Baycrest Health Sciences
| | - Brian Levine
- Rotman Research Institute, Baycrest Health Sciences ; Department of Psychology, University of Toronto ; Department of Medicine (Neurology), University of Toronto
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The downside of strong emotional memories: How human memory-related genes influence the risk for posttraumatic stress disorder – A selective review. Neurobiol Learn Mem 2014; 112:75-86. [DOI: 10.1016/j.nlm.2013.08.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 08/27/2013] [Accepted: 08/28/2013] [Indexed: 11/19/2022]
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MacLeod CA, Donaldson DI. PRKCA polymorphism changes the neural basis of episodic remembering in healthy individuals. PLoS One 2014; 9:e98018. [PMID: 24842701 PMCID: PMC4026476 DOI: 10.1371/journal.pone.0098018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 04/28/2014] [Indexed: 11/21/2022] Open
Abstract
Everyday functioning relies on episodic memory, the conscious retrieval of past experiences, but this crucial cognitive ability declines severely with aging and disease. Vulnerability to memory decline varies across individuals however, producing differences in the time course and severity of memory problems that complicate attempts at diagnosis and treatment. Here we identify a key source of variability, by examining gene dependent changes in the neural basis of episodic remembering in healthy adults, targeting seven polymorphisms previously linked to memory. Scalp recorded Event-Related Potentials (ERPs) were measured while participants remembered words, using an item recognition task that requires discrimination between studied and unstudied stimuli. Significant differences were found as a consequence of a Single Nucleotide Polymorphism (SNP) in just one of the tested genes, PRKCA (rs8074995). Participants with the common G/G variant exhibited left parietal old/new effects, which are typically seen in word recognition studies, reflecting recollection-based remembering. During the same stage of memory retrieval participants carrying a rarer A variant exhibited an atypical pattern of brain activity, a topographically dissociable frontally-distributed old/new effect, even though behavioural performance did not differ between groups. Results replicated in a second independent sample of participants. These findings demonstrate that the PRKCA genotype is important in determining how episodic memories are retrieved, opening a new route towards understanding individual differences in memory.
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Affiliation(s)
- Catherine A. MacLeod
- Institute of Medical and Social Care Research, Bangor University, Bangor, Gwynedd, United Kingdom
- * E-mail:
| | - David I. Donaldson
- Psychology, School of Natural Sciences, University of Stirling, Stirling, United Kingdom
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Saroja SR, Kim EJ, Shanmugasundaram B, Höger H, Lubec G. Hippocampal monoamine receptor complex levels linked to spatial memory decline in the aging C57BL/6J. Behav Brain Res 2014; 264:1-8. [PMID: 24508236 DOI: 10.1016/j.bbr.2014.01.042] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 01/25/2014] [Accepted: 01/28/2014] [Indexed: 01/09/2023]
Abstract
Although a large series of reports on monoamine receptor (MAR) biochemistry and pharmacology in aging are available, work on MAR complexes rather than subunits is limited. It was the aim of the study to determine MAR complexes in hippocampi of three different age groups (3-12 and 18 months) in the mouse and to link MAR changes to spatial memory retrieval in the Morris water maze (MWM). MAR complexes were separated by blue native electrophoresis. Immunohistochemistry was performed in order to show the pattern of dopamine receptors and its colocalizations. D1R, D2R and 5-HT7R containing receptor complex levels were decreasing with age while 5-HT1AR-containing complex levels were increasing with age. D1R, 5-HT7R and 5-HT1AR were significantly correlating with the time spent in the target quadrant, representing retrieval in the MWM. D1R and D2R immunoreactivity was decreasing in an area-dependent pattern and D1R and D2R were colocalized. Individual monoamine receptors are linked to spatial memory retrieval and are modulated by age. The findings are relevant for interpretation of previous and design of future work on brain receptors, spatial memory and aging.
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Affiliation(s)
- Sivaprakasam R Saroja
- Department of Paediatrics, Medical University of Vienna, Währinger Gürtel 18, 1090 Vienna, Austria
| | - Eun-Jung Kim
- Department of Paediatrics, Medical University of Vienna, Währinger Gürtel 18, 1090 Vienna, Austria
| | | | - Harald Höger
- Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Brauhausgasse 34, A-2325 Himberg, Austria
| | - Gert Lubec
- Department of Paediatrics, Medical University of Vienna, Währinger Gürtel 18, 1090 Vienna, Austria.
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The "memory kinases": roles of PKC isoforms in signal processing and memory formation. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2014; 122:31-59. [PMID: 24484697 DOI: 10.1016/b978-0-12-420170-5.00002-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The protein kinase C (PKC) isoforms, which play an essential role in transmembrane signal conduction, can be viewed as a family of "memory kinases." Evidence is emerging that they are critically involved in memory acquisition and maintenance, in addition to their involvement in other functions of cells. Deficits in PKC signal cascades in neurons are one of the earliest abnormalities in the brains of patients suffering from Alzheimer's disease. Their dysfunction is also involved in several other types of memory impairments, including those related to emotion, mental retardation, brain injury, and vascular dementia/ischemic stroke. Inhibition of PKC activity leads to a reduced capacity of many types of learning and memory, but may have therapeutic values in treating substance abuse or aversive memories. PKC activators, on the other hand, have been shown to possess memory-enhancing and antidementia actions. PKC pharmacology may, therefore, represent an attractive area for developing effective cognitive drugs for the treatment of many types of memory disorders and dementias.
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Papassotiropoulos A, Gerhards C, Heck A, Ackermann S, Aerni A, Schicktanz N, Auschra B, Demougin P, Mumme E, Elbert T, Ertl V, Gschwind L, Hanser E, Huynh KD, Jessen F, Kolassa IT, Milnik A, Paganetti P, Spalek K, Vogler C, Muhs A, Pfeifer A, de Quervain DJF. Human genome-guided identification of memory-modulating drugs. Proc Natl Acad Sci U S A 2013; 110:E4369-74. [PMID: 24145423 PMCID: PMC3831994 DOI: 10.1073/pnas.1314478110] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory--a trait central to posttraumatic stress disorder--and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand-receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand-receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.
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Affiliation(s)
- Andreas Papassotiropoulos
- Department of Psychology, Division of Molecular Neuroscience
- Psychiatric University Clinics
- Transfaculty Research Platform
- Department Biozentrum, Life Sciences Training Facility, and
| | - Christiane Gerhards
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
| | - Angela Heck
- Department of Psychology, Division of Molecular Neuroscience
- Psychiatric University Clinics
- Transfaculty Research Platform
| | | | - Amanda Aerni
- Psychiatric University Clinics
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
| | - Nathalie Schicktanz
- Psychiatric University Clinics
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
| | - Bianca Auschra
- Department of Psychology, Division of Molecular Neuroscience
| | - Philippe Demougin
- Department of Psychology, Division of Molecular Neuroscience
- Department Biozentrum, Life Sciences Training Facility, and
| | - Eva Mumme
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
| | - Thomas Elbert
- Clinical Psychology and Neuropsychology, University of Konstanz, 78464 Konstanz, Germany
| | - Verena Ertl
- Clinical Psychology and Neuropsychology, University of Konstanz, 78464 Konstanz, Germany
| | - Leo Gschwind
- Department of Psychology, Division of Molecular Neuroscience
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
| | - Edveena Hanser
- Department of Psychology, Division of Molecular Neuroscience
- Department Biozentrum, Life Sciences Training Facility, and
| | - Kim-Dung Huynh
- Department of Psychology, Division of Molecular Neuroscience
- Department Biozentrum, Life Sciences Training Facility, and
| | - Frank Jessen
- Department of Psychiatry and Psychotherapy, University of Bonn Medical School, 53113 Bonn, Germany
| | - Iris-Tatjana Kolassa
- Clinical Psychology and Neuropsychology, University of Konstanz, 78464 Konstanz, Germany
- Clinical and Biological Psychology, Institute for Psychology and Education, University of Ulm, 89081 Ulm, Germany
| | - Annette Milnik
- Department of Psychology, Division of Molecular Neuroscience
- Department of Neurology, University of Magdeburg, 39120 Magdeburg, Germany; and
| | | | - Klara Spalek
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
| | - Christian Vogler
- Department of Psychology, Division of Molecular Neuroscience
- Psychiatric University Clinics
- Transfaculty Research Platform
| | | | | | - Dominique J.-F. de Quervain
- Psychiatric University Clinics
- Transfaculty Research Platform
- Department of Psychology, Division of Cognitive Neuroscience, University of Basel, 4055 Basel, Switzerland
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Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog Neurobiol 2013; 112:80-99. [PMID: 24211850 DOI: 10.1016/j.pneurobio.2013.10.005] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 10/16/2013] [Accepted: 10/17/2013] [Indexed: 12/21/2022]
Abstract
Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.
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Wilker S, Kolassa S, Vogler C, Lingenfelder B, Elbert T, Papassotiropoulos A, de Quervain DJF, Kolassa IT. The role of memory-related gene WWC1 (KIBRA) in lifetime posttraumatic stress disorder: evidence from two independent samples from African conflict regions. Biol Psychiatry 2013; 74:664-71. [PMID: 23582269 DOI: 10.1016/j.biopsych.2013.02.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 02/13/2013] [Accepted: 02/28/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common WWC1 alleles influence the risk for a lifetime diagnosis of PTSD. METHODS Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n = 392, Rwanda, and n = 399, Northern Uganda, respectively). Array-based single nucleotide polymorphism (SNP) genotyping was performed. The influence of WWC1 tagging SNPs and traumatic load on lifetime PTSD was estimated by means of logistic regression models with correction for multiple comparisons in the Rwandan sample. Replication analysis was performed in the independent Ugandan sample. RESULTS An association of two neighboring SNPs in almost complete linkage disequilibrium, rs10038727 and rs4576167, with lifetime PTSD was discovered in the Rwandan sample. Although each traumatic event added to the probability of lifetime PTSD in a dose-dependent manner in both genotype groups, carriers of the minor allele of both SNPs displayed a diminished risk (p = .007, odds ratio = .29 [95% confidence interval = .15-.54]). This effect was confirmed in the independent Ugandan sample. CONCLUSIONS This study reveals an association between two WWC1 SNPs and the likelihood of PTSD development, indicating that this memory-related gene might be involved in processes that occur in response to traumatic stress and influence the strengthening of fear memories.
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Affiliation(s)
- Sarah Wilker
- Clinical and Biological Psychology, Institute for Psychology and Education, University of Ulm, Ulm, Germany.
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Pignataro A, Middei S, Borreca A, Ammassari-Teule M. Indistinguishable pattern of amygdala and hippocampus rewiring following tone or contextual fear conditioning in C57BL/6 mice. Front Behav Neurosci 2013; 7:156. [PMID: 24194705 PMCID: PMC3810790 DOI: 10.3389/fnbeh.2013.00156] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 10/14/2013] [Indexed: 01/06/2023] Open
Abstract
Changes in neuronal connectivity occurring upon the formation of aversive memory were examined in C57BL/6 (C57) mice 24 h after they were trained for tone fear conditioning (TFC) and contextual fear conditioning (CFC). Although TFC and CFC are amenable to distinct learning systems each involving a specific neural substrate, we found that mice trained in the two protocols showed the same increase in spine density and spine size in class I basolateral amygdala (BLA) and in dorsal hippocampus CA1 pyramidal neurons. Our findings suggest that, because of their remarkably functional hippocampus, C57 mice might engage this region in any fear situation they face. These observations raise a point relevant to aversive memory studies, i.e., how the peculiarity of memory in certain individuals impacts on the components of the fear circuitry. It is suggested that enhanced connectivity in brain regions dispensable for specific forms of learning could considerably increase the resistance of aversive memory traces to treatments aimed at disrupting them.
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Affiliation(s)
- Annabella Pignataro
- 1Department of Experimental Neurology, Laboratory of Psicobiology, Santa Lucia Foundation Rome, Italy
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He Z, Cui L, He B, Ferguson SA, Paule MG. A common genetic mechanism underlying susceptibility to posttraumatic stress disorder. World J Neurol 2013; 3:14-24. [DOI: 10.5316/wjn.v3.i3.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 07/27/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
We hypothesize that susceptibility to post-traumatic stress disorder (PTSD) may be determined in part by aberrant microtubule-associated protein tau expression in neurons of critical brain structures. The following lines of evidence support this hypothesis. First, epidemiologic data suggest the involvement of genetic factors in the susceptibility to PTSD. Second, the common features of both abnormal tau expression and PTSD include amygdalar and hippocampal atrophy, upregulation of norepinephrine biosynthetic capacity in the surviving locus coeruleus neurons and dysfunction of N-methyl-D-aspartate-receptors. Finally, our experiments using rTg4510 mice, a model that over-expresses human mutant tau and develops age-dependent tauopathy, demonstrate that these animals display circling behavior thought to be related to states of anxiety. To detect the potential molecular mechanisms underlying PTSD episodes, laser-assisted/capture microdissection can be used with microarray analysis as an alternative approach to identify changes in gene expression in excitatory and/or inhibitory neurons in critical brain structures (i.e., hippocampus and amygdala) in response to the onset of PTSD.
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Gene linked to post-traumatic stress. Nature 2012. [DOI: 10.1038/nature.2012.10632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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