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      Hypothalamic-Pituitary-Adrenocortical System and Mood Disorders: Highlights from Mutant Mice

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          Abstract

          In recent years, refined molecular technologies and the generation of genetically engineered mice have allowed to specifically target individual genes involved in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Given the fundamental role of the corticotropin-releasing hormone (CRH) system in anxiety, stress-associated pathologies, and mood disorders, we describe genetic modifications of the genes that encode proteins integral to the CRH/CRH receptor system with particular emphasis on conditional gene-targeting strategies. The profile of results, consistent with current knowledge of CRH function from more traditional assays, indicates that enhancement of the CRH function is associated with an activation of the HPA system, an anxious phenotype, alterations in cognitive performance, reductions in food intake, and disturbances of autonomic functions. In general, blockade of CRH activity produces the opposite effects, namely an anxiety-reduced phenotype. Molecular genetic strategies for conditional inactivation or overexpression of the glucocorticoid receptor contribute to our understanding of the genetics of endocrine activity and behavior, the most complex form of biological organization. In addition, we introduce mice with a genetic manipulation in the function of the blood-brain barrier as an animal model for the study of neuroendocrine regulation and, in particular, of HPA system activity. By use of mice deficient for abcb1– (also called multidrug resistance gene 1, mdr1–) type P glycoproteins, it was shown most recently that abcb1-type P glycoproteins control the access of endogenous glucocorticoids into the central nervous system. Thus, the ABCB1-type P glycoprotein function exerts a profound influence on activity and regulation of the HPA system under both basal conditions and during stress. Taken together, these genetically engineered mice are valuable tools for increasing our understanding of HPA system dysregulation in anxiety and stress-related pathologies, including human affective disorders. The identification and detailed characterization of these molecular pathways will ultimately lead to the development of novel neuropharmacological intervention strategies.

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          Most cited references 52

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          Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety.

          The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune and nervous system responses and ensure an adequate profile of transcription. In the brain, Gr has been proposed to modulate emotional behaviour, cognitive functions and addictive states. Previously, these aspects were not studied in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth (F.T., C.K. and G.S., unpublished data). Therefore, we generated tissue-specific mutations of this gene using the Cre/loxP -recombination system. This allowed us to generate viable adult mice with loss of Gr function in selected tissues. Loss of Gr function in the nervous system impairs hypothalamus-pituitary-adrenal (HPA)-axis regulation, resulting in increased glucocorticoid (GC) levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.
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            Accessing genetic variation: genotyping single nucleotide polymorphisms.

             A-C Syvänen (2001)
            Understanding the relationship between genetic variation and biological function on a genomic scale is expected to provide fundamental new insights into the biology, evolution and pathophysiology of humans and other species. The hope that single nucleotide polymorphisms (SNPs) will allow genes that underlie complex disease to be identified, together with progress in identifying large sets of SNPs, are the driving forces behind intense efforts to establish the technology for large-scale analysis of SNPs. New genotyping methods that are high throughput, accurate and cheap are urgently needed for gaining full access to the abundant genetic variation of organisms.
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              Essential role for TrkB receptors in hippocampus-mediated learning.

              Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2004
                January 2004
                02 February 2004
                : 79
                : 1
                : 1-12
                Affiliations
                Max Planck Institute of Psychiatry, Munich, Germany
                Article
                76041 Neuroendocrinology 2004;79:1–12
                10.1159/000076041
                14755129
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 109, Pages: 12
                Categories
                Review Article: Transgenic Models in Neuroendocrinology

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