Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.
Mol Psychiatry. 2012 Jan 31;
Authors: Hornig M, Briese T, Licinio J, Khabbaz RF, Altshuler LL, Potkin SG, Schwemmle M, Siemetzki U, Mintz J, Honkavuori K, Kraemer HC, Egan MF, Whybrow PC, Bunney WE, Lipkin WI
Abstract
In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.Molecular Psychiatry advance online publication, 31 January 2012; doi:10.1038/mp.2011.179.
PMID: 22290118 [PubMed - as supplied by publisher]
Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety.
Mol Psychiatry. 2012 Jan 31;
Authors: Sink KS, Walker DL, Freeman SM, Flandreau EI, Ressler KJ, Davis M
Abstract
The lateral division of the bed nucleus of the stria terminalis (BNST), which forms part of the circuitry regulating fear and anxiety, contains a large number of neurons expressing corticotropin releasing factor (CRF), a neuropeptide that has a prominent role in the etiology of fear- and anxiety-related psychopathologies. Stress increases CRF expression within BNST neurons, implicating these cells in stress- and anxiety-related behaviors. These experiments examined the effect of chronically enhanced CRF expression within BNST neurons on conditioned and unconditioned anxiety-related behavior by using a lentiviral vector containing a promoter that targets CRF gene overexpression (OE) to CRFergic cells. We found that BNST CRF-OE did not affect unconditioned anxiety-like responses in the elevated plus maze or basal acoustic startle amplitude. CRF-OE induced before training weakened sustained fear (conditioned anxiety); when induced after conditioning, CRF-OE increased expression of the conditioned emotional memory. Increased BNST CRF expression did not affect plasma corticosterone concentration but did decrease CRFR1 receptor density within the BNST and CRFR2 receptor density within the dorsal portion of the caudal dorsal raphe nucleus. These data raise the possibility that the observed behavioral effects may be mediated by enhanced CRF receptor signaling or compensatory changes in CRF receptor density within these structures. Together, these studies demonstrate that CRF neurons within the lateral BNST modulate conditioned anxiety-like behaviors and also suggest that enhanced CRF expression within these neurons may contribute to inappropriate regulation of emotional memories.Molecular Psychiatry advance online publication, 31 January 2012; doi:10.1038/mp.2011.188.
PMID: 22290119 [PubMed - as supplied by publisher]
The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D).
Mol Psychiatry. 2012 Jan 31;
Authors: Raison CL, Miller AH
Abstract
Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations. These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia. By shifting the adaptive context of depression risk alleles from relations with conspecifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function.Molecular Psychiatry advance online publication, 31 January 2012; doi:10.1038/mp.2012.2.
PMID: 22290120 [PubMed - as supplied by publisher]
Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism.
Mol Psychiatry. 2012 Jan 31;
Authors: Christakou A, Murphy CM, Chantiluke K, Cubillo AI, Smith AB, Giampietro V, Daly E, Ecker C, Robertson D, , Murphy DG, Rubia K
Abstract
Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato-thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto-striato-parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto-striato-cerebellar dysregulation in ASD.Molecular Psychiatry advance online publication, 31 January 2012; doi:10.1038/mp.2011.185.
PMID: 22290121 [PubMed - as supplied by publisher]
Antipsychotics activate the TGFβ pathway effector SMAD3.
Mol Psychiatry. 2012 Jan 31;
Authors: Cohen T, Sundaresh S, Levine F
Abstract
Although effective in treating an array of neurological disorders, antipsychotics are associated with deleterious metabolic side effects. Through high-throughput screening, we previously identified phenothiazine antipsychotics as modulators of the human insulin promoter. Here, we extended our initial finding to structurally diverse typical and atypical antipsychotics. We then identified the transforming growth factor beta (TGFβ) pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGFβ pathway, through a receptor distinct from the TGFβ receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. In vivo relevance was demonstrated by reanalysis of gene expression data from human brains treated with antipsychotics, which showed altered expression of SMAD3 responsive genes. This work raises the possibility that antipsychotics could be designed that retain beneficial CNS activity while lacking deleterious metabolic side effects.Molecular Psychiatry advance online publication, 31 January 2012; doi:10.1038/mp.2011.186.
PMID: 22290122 [PubMed - as supplied by publisher]
Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of δ-9-tetrahydrocannabinol on midbrain and striatal function.
Mol Psychiatry. 2012 Jan 31;
Authors: Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, Kambeitz J, Prata D, Williams S, Brammer M, Collier DA, McGuire PK
PMID: 22290123 [PubMed - as supplied by publisher]
An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model.
Mol Psychiatry. 2012 Jan 31;
Authors: Schmidt-Kastner R, van Os J, Esquivel G, Steinbusch HW, Rutten BP
Abstract
Investigating and understanding gene-environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia-hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia-hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia-hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.Molecular Psychiatry advance online publication, 31 January 2012; doi:10.1038/mp.2011.183.
PMID: 22290124 [PubMed - as supplied by publisher]
Authors: Bornstein SR, Ehrhart-Bornstein M, Androutsellis-Theotokis A, Eisenhofer G, Vukicevic V, Licinio J, Wong ML, Calissano P, Nisticò G, Preziosi P, Levi-Montalcini R
Abstract
Chromaffin cells probably are the most intensively studied of the neural crest derivates. They are closely related to the nervous system, share with neurons some fundamental mechanisms and thus were the ideal model to study the basic mechanisms of neurobiology for many years. The lessons we have learned from chromaffin cell biology as a peripheral model for the brain and brain diseases pertain more than ever to the cutting edge research in neurobiology. Here, we highlight how studying this cell model can help unravel the basic mechanisms of cell renewal and regeneration both in the central nervous system (CNS) and neuroendocrine tissue and also can help in designing new strategies for regenerative therapies of the CNS.Molecular Psychiatry advance online publication, 17 January 2012; doi:10.1038/mp.2011.176.
PMID: 22249377 [PubMed - as supplied by publisher]
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