From SCIENCE: Fear memory in mice is erased by experimental killing of a subpopulation of lateral amygdala neurons

Science 13 March 2009: Vol. 323. no. 5920, pp. 1492 - 1496 DOI: 10.1126/science.1164139

For article, click here.

For podcast interview with author, click here.

Reports

Selective Erasure of a Fear Memory

Jin-Hee Han,^1,2,3 Steven A. Kushner,^1,4 Adelaide P. Yiu,^1,2 Hwa-Lin (Liz) Hsiang,^1,2 Thorsten Buch,⁵ Ari Waisman,⁶ Bruno Bontempi,⁷ Rachael L. Neve,⁸ Paul W. Frankland,^1,2,3 Sheena A. Josselyn^1,2,3*

¹ Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
² Institute of Medical Sciences, University of Toronto, Toronto, ON, M5G 1X8, Canada.
³ Department of Physiology, University of Toronto, Toronto, ON, M5G 1X8, Canada.
⁴ Department of Psychiatry, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands.
⁵ Department of Pathology, University of Zurich, CH-8057 Zurich, Switzerland.
⁶ I.Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, 55131 Mainz, Germany.
⁷ Centre de Neurosciences Intégratives et Cognitives, CNRS UMR5228 and University of Bordeaux 1, 33405 Talence, France.
⁸ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

^* To whom correspondence should be addressed. E-mail: sheena.josselyn@sickkids.ca

Is schizophrenia caused by alterations in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics?

Click here for a link to this article.

Molecular Psychiatry advance online publication 3 March 2009; doi: 10.1038/mp.2009.18

Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function

P R Maycox¹, F Kelly², A Taylor², S Bates², J Reid², R Logendra³, M R Barnes³, C Larminie³, N Jones², M Lennon⁴, C Davies¹, J J Hagan¹, C A Scorer¹, C Angelinetta⁵, T Akbar⁵, S Hirsch⁵, A M Mortimer^5,6, T R E Barnes⁵ and J de Belleroche⁵

1. Psychiatry CEDD, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
2. Genetic and Proteomic Sciences, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
3. Computational Biology, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
4. Statistical Sciences, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
5. Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
6. Academic Unit of Psychiatry, University of Hull, Hull, UK

Correspondence: Professor J de Belleroche, Neurogenetics Group, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London W12 0NN, UK. E-mail: j.belleroche@imperial.ac.uk

Received 20 October 2008; Revised 27 January 2009; Accepted 28 January 2009; Published online 3 March 2009.

Abstract

Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.

Is the neurogenesis hypothesis of depression and antidepressant action only applicable to the young?

Click here for a link to this article.

Molecular Psychiatry advance online publication 13 January 2009; doi: 10.1038/mp.2008.147

Ageing abolishes the effects of fluoxetine on neurogenesis

S Couillard-Despres¹, C Wuertinger¹, M Kandasamy¹, M Caioni¹, K Stadler¹, R Aigner¹, U Bogdahn¹ and L Aigner^1,2

1. Department of Neurology, University of Regensburg, Regensburg, Germany
2. Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria

Correspondence: Dr S Couillard-Despres, Department of Neurology, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg D-93053, Germany. E-mail: sebastien.couillard-despres@klinik.uni-regensburg.de

Received 9 July 2008; Revised 26 November 2008; Accepted 15 December 2008; Published online 13 January 2009.

Abstract

Depression constitutes a widespread condition observed in elderly patients. Recently, it was found that several drugs employed in therapies against depression stimulate hippocampal neurogenesis in young rodents and nonhuman primates. As the rate of neurogenesis is dramatically reduced during ageing, we examined the influences of ageing on neurogenic actions of antidepressants. We tested the impact of fluoxetine, a broadly used antidepressant, on hippocampal neurogenesis in mice of three different age groups (100, 200 and over 400 days of age). Proliferation and survival rate of newly generated cells, as well as the percentage of cells that acquired a neuronal phenotype were analyzed in the hippocampus of mice that received fluoxetine daily in a chronic manner. Surprisingly, the action of fluoxetine on neurogenesis was decreasing as a function of age and was only significant in young animals. Hence, fluoxetine increased survival and the frequency of neuronal marker expression in newly generated cells of the hippocampus in the young adult group (that is 100 days of age) only. No significant effects on neurogenesis could be detected in fluoxetine-treated adult and elderly mice (200 and over 400 days of age). The data indicate that the action of fluoxetine on neurogenesis is highly dependent on the age of the treated individual. Although the function of neurogenesis in the clinical manifestation of depression is currently a matter of speculation, this study clearly shows that the therapeutic effects of antidepressants in elderly patients are not mediated by neurogenesis modulation.

Adolescent alcohol use: an interaction of parenting and dopamine D2 genotype?

Click here for a link to this article.

Molecular Psychiatry advance online publication 24 February 2009; doi: 10.1038/mp.2009.4

Interaction between dopamine D2 receptor genotype and parental rule-setting in adolescent alcohol use: evidence for a gene-parenting interaction

C S van der Zwaluw¹, R C M E Engels¹, A A Vermulst¹, B Franke^2,3, J Buitelaar³, R J Verkes³ and R H J Scholte¹

1. Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
2. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3. Department of Psychiatry, Radboud University Nijmegen Medical Centre, Donders Centre for Neuroscience, Nijmegen, The Netherlands

Correspondence: CS van der Zwaluw, Behavioral Science Institute, Radboud University Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands. E-mail: C.vanderZwaluw@bsi.ru.nl

Received 22 September 2008; Revised 3 December 2008; Accepted 18 December 2008; Published online 24 February 2009.

Abstract

Association studies investigating the link between the dopamine D2 receptor gene (DRD2) and alcohol (mis)use have shown inconsistent results. This may be due to lack of attention for environmental factors. High levels of parental rule-setting are associated with lower levels of adolescent alcohol use and delay of initiation of drinking. We tested whether DRD2 TaqI A (rs1800497) genotype interacts with alcohol-specific parenting practices in predicting the uptake of regular adolescent alcohol use. Non-regular drinkers were selected from a Dutch, nationwide sample of 428 adolescents (mean age 13.4 years at baseline) and participated in a prospective, community-based study with three annual waves. Parental rule-setting was directly and inversely related to adolescent alcohol use over time. For DRD2 genotype no significant main effect was found. DRD2 genotype interacted with parental rule-setting on adolescent alcohol use over time: adolescents, with parents highly permissive toward alcohol consumption and carrying a genotype with the DRD2 A1 (rs1800497T) allele, used significantly more alcohol over time than adolescents without these characteristics. The DRD2 genotype may pose an increased risk for alcohol use and abuse, depending on the presence of environmental risk factors, such as alcohol-specific parenting.

Prenatal cigarette exposure and genes: a pathway to sociopathy

Click here for a link to this article.

Molecular Psychiatry advance online publication 3 March 2009; doi: 10.1038/mp.2009.22

Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior

L S Wakschlag¹, E O Kistner², D S Pine³, G Biesecker¹, K E Pickett⁴, A D Skol⁵, V Dukic², R J R Blair³, B L Leventhal¹, N J Cox⁵, J L Burns¹, K E Kasza², R J Wright⁶ and E H Cook Jr¹

1. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
2. Department of Health Studies, University of Chicago, Chicago, IL, USA
3. Laboratory of Affective & Developmental Neurosciences, NIMH Intramural Research Program, Bethesda, MD, USA
4. Department of Health Sciences, University of York, York, England
5. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
6. Channing Laboratory, Harvard University Medical School, Boston, MA, USA

Correspondence: Dr LS Wakschlag, Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Road, MC747, Chicago, IL 60608, USA. E-mail: lwakschlag@psych.uic.edu

Received 2 October 2008; Revised 29 January 2009; Accepted 3 February 2009; Published online 3 March 2009.

Abstract

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene–environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene exposure interactions may shape behavior through associated changes in brain function.

Angiotensin receptor gene polymorphisms and 2-year change in hyperintense lesion volume in men

Click here for a link to this article.

Molecular Psychiatry advance online publication 10 March 2009; doi: 10.1038/mp.2009.26

The preliminary data were presented at the 2008 Annual Meeting of the American Association for Geriatric Psychiatry in Orlando, Florida on 17 March 2008.

W D Taylor^1,2, D C Steffens^1,2, A Ashley-Koch^3,4, M E Payne^1,2, J R MacFall^5,2, C F Potocky^3,4 and K R R Krishnan^1,2,6

1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
2. The Neuropsychiatric Imaging Research Laboratory, Duke University Medical Center, Durham, NC, USA
3. Department of Medicine, Duke University Medical Center, Durham, NC, USA
4. The Duke Center for Human Genetics, Duke University Medical Center, Durham, NC, USA
5. Department of Radiology, Duke University Medical Center, Durham, NC, USA
6. The Duke-NUS Graduate Medical School Singapore, Singapore

Correspondence: Dr WD Taylor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, DUMC Box 3903, Durham, NC 27710, USA. E-mail: Taylo066@mc.duke.edu

Received 20 October 2008; Revised 9 January 2009; Accepted 11 February 2009; Published online 10 March 2009.

Abstract

This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A, respectively. 137 depressed and 94 non-depressed participants aged 60 years were enrolled. Standard clinical evaluations were performed on all participants and blood samples obtained for genotyping. 1.5-T MRI (magnetic resonance imaging) data were obtained at baseline and approximately 2 years later. These scans were processed using a semi-automated segmentation process, which allowed for the calculation of WML volume at each time point. Statistical models were tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension (HTN) with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without HTN. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene–gene or gene–depression interactions were observed. Our results parallel earlier observed gender differences of the relationship between other renin–angiotensin system polymorphisms and HTN. Further work is needed to determine whether these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and whether antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.

Irritability as a symptom of major depression

Go here for a link to the journal article.

Molecular Psychiatry advance online publication 10 March 2009; doi: 10.1038/mp.2009.20

The importance of irritability as a symptom of major depressive disorder: results from the National Comorbidity Survey Replication

M Fava¹, I Hwang², A J Rush^3,4, N Sampson², E E Walters² and R C Kessler²

1. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
2. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA
3. Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
4. Department of Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

Correspondence: Dr R Kessler, Department of Health Care Policy, Harvard Medical School, 180 Longwood Ave, Boston, MA 2115, USA. E-mail: kessler@hcp.med.harvard.edu

Received 24 June 2008; Revised 27 January 2009; Accepted 28 January 2009; Published online 10 March 2009.

Abstract

Irritability is a diagnostic symptom of major depressive disorder (MDD) in children and adolescents but not in adults in both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) and International Classification of Diseases (ICD-10) systems. We explore the importance of irritability for subtyping adult DSM-IV MDD in the National Comorbidity Survey Replication (NCS-R), a national US adult household survey. The WHO Composite International Diagnostic Interview (CIDI) was used to assess prevalence of many DSM-IV disorders in the lifetime and in the year before interview (12-month prevalence). MDD was assessed conventionally (that is, requiring either persistent sadness or loss of interest), but with irritability included as one of the Criterion A symptoms. We also considered the possibility that irritability might be a diagnostic symptom of adult MDD (that is, detect cases who had neither sad mood nor loss of interest). Twelve-month MDD symptom severity was assessed with the Quick Inventory of Depressive Symptomatology and role impairment with the Sheehan Disability Scale. After excluding bipolar spectrum disorders, irritability during depressive episodes was reported by roughly half of respondents with lifetime DSM-IV MDD. Irritability in the absence of either sad mood or loss of interest, in comparison, was rare. Irritability in MDD was associated with early age of onset, lifetime persistence, comorbidity with anxiety and impulse-control disorders, fatigue and self-reproach during episodes, and disability. Irritability was especially common in MDD among respondents in the age range 18–44 and students. Further investigation is warranted of distinct family aggregation, risk factors and treatment response. Consideration should also be given to including irritability as a nondiagnostic symptom of adult MDD in DSM-V and ICD-11.