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      Profiling Trait Anxiety: Transcriptome Analysis Reveals Cathepsin B ( Ctsb) as a Novel Candidate Gene for Emotionality in Mice

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          Abstract

          Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait “anxiety”. We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, and also show signs of comorbid depression-like behavior.

          We identified and confirmed sex-independent differences in the basal expression of 13 candidate genes, using tissue from the entire brain, including coronin 7 ( Coro7), cathepsin B ( Ctsb), muscleblind-like 1 ( Mbnl1), metallothionein 1 ( Mt1), solute carrier family 25 member 17 ( Slc25a17), tribbles homolog 2 ( Trib2), zinc finger protein 672 ( Zfp672), syntaxin 3 ( Stx3), ATP-binding cassette, sub-family A member 2 ( Abca2), ectonucleotide pyrophosphatase/phosphodiesterase 5 ( Enpp5), high mobility group nucleosomal binding domain 3 ( Hmgn3) and pyruvate dehydrogenase beta ( Pdhb). Additionally, we confirmed brain region-specific differences in the expression of synaptotagmin 4 ( Syt4).

          Our identification of about 90 polymorphisms in Ctsb suggested that this gene might play a critical role in shaping our mouse model's behavioral endophenotypes. Indeed, the assessment of anxiety-related and depression-like behaviors of Ctsb knock-out mice revealed an increase in depression-like behavior in females.

          Altogether, our results suggest that Ctsb has significant effects on emotionality, irrespective of the tested mouse strain, making it a promising target for future pharmacotherapy.

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          Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation.

          Y. H. Yang (2002)
          There are many sources of systematic variation in cDNA microarray experiments which affect the measured gene expression levels (e.g. differences in labeling efficiency between the two fluorescent dyes). The term normalization refers to the process of removing such variation. A constant adjustment is often used to force the distribution of the intensity log ratios to have a median of zero for each slide. However, such global normalization approaches are not adequate in situations where dye biases can depend on spot overall intensity and/or spatial location within the array. This article proposes normalization methods that are based on robust local regression and account for intensity and spatial dependence in dye biases for different types of cDNA microarray experiments. The selection of appropriate controls for normalization is discussed and a novel set of controls (microarray sample pool, MSP) is introduced to aid in intensity-dependent normalization. Lastly, to allow for comparisons of expression levels across slides, a robust method based on maximum likelihood estimation is proposed to adjust for scale differences among slides.
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            Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c.

            C. Peters, Brian Bronk, B Svingen … (2000)
            TNF-alpha-induced apoptosis is thought to involve mediators from acidic vesicles. Cathepsin B (cat B), a lysosomal cysteine protease, has recently been implicated in apoptosis. To determine whether cat B contributes to TNF-alpha-induced apoptosis, we exposed mouse hepatocytes to the cytokine in vitro and in vivo. Isolated hepatocytes treated with TNF-alpha in the presence of the transcription inhibitor actinomycin D (AcD) accumulated cat B in their cytosol. Further experiments using cell-free systems indicated that caspase-8 caused release of active cat B from purified lysosomes and that cat B, in turn, increased cytosol-induced release of cytochrome c from mitochondria. Consistent with these observations, the ability of TNF-alpha/AcD to induce mitochondrial release of cytochrome c, caspase activation, and apoptosis of isolated hepatocytes was markedly diminished in cells from CatB(-/-) mice. Deletion of the CatB gene resulted in diminished liver injury and enhanced survival after treatment in vivo with TNF-alpha and an adenovirus construct expressing the IkappaB superrepressor. Collectively, these observations suggest that caspase-mediated release of cat B from lysosomes enhances mitochondrial release of cytochrome c and subsequent caspase activation in TNF-alpha-treated hepatocytes.
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              The stress system in depression and neurodegeneration: focus on the human hypothalamus.

              G Meynen, Dick F. Swaab, Zhou Bao (2008)
              The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequently causes cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin (AVP) which potentiates the CRH effects. CRH neurons project not only to the median eminence but also into brain areas where they, e.g., regulate the adrenal innervation of the autonomic system and affect mood. The hypothalamo-neurohypophysial system is also involved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON) and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. The suprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmic changes of the stress system. Both centrally released CRH and increased levels of cortisol contribute to the signs and symptoms of depression. Symptoms of depression can be induced in experimental animals by intracerebroventricular injection of CRH. Depression is also a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing's syndrome. The AVP neurons in the hypothalamic PVN and SON are also activated in depression, which contributes to the increased release of ACTH from the pituitary. Increased levels of circulating AVP are also associated with the risk for suicide. The prevalence, incidence and morbidity risk for depression are higher in females than in males and fluctuations in sex hormone levels are considered to be involved in the etiology. About 40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor (ER)-alpha in the PVN, while estrogen-responsive elements have been found in the CRH gene promoter region, and estrogens stimulate CRH production. An androgen-responsive element in the CRH gene promoter region initiates a suppressing effect on CRH expression. The decreased activity of the SCN is the basis for the disturbances of circadian and circannual fluctuations in mood, sleep and hormonal rhythms found in depression. Neuronal loss was also reported in the hippocampus of stressed or corticosteroid-treated rodents and primates. Because of the inhibitory control of the hippocampus on the HPA-axis, damage to this structure was expected to disinhibit the HPA-axis, and to cause a positive feedforward cascade of increasing glucocorticoid levels over time. This 'glucocorticoid cascade hypothesis' of stress and hippocampal damage was proposed to be causally involved in age-related accumulation of hippocampal damage in disorders like Alzheimer's disease and depression. However, in postmortem studies we could not find the presumed hippocampal damage of steroid overexposure in either depressed patients or in patients treated with synthetic steroids.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 29 August 2011
                Volume: 6
                Issue: 8
                Electronic Location Identifier: e23604
                Affiliations
                [1 ]Max Planck Institute of Psychiatry, Munich, Germany
                [2 ]Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany
                [3 ]Affectis Pharmaceuticals, Martinsried, Germany
                [4 ]Max von Pettenkofer Institute, Ludwig Maximilians University, Munich, Germany
                [5 ]Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany
                Instituto Nacional de Câncer, Brazil
                Author notes

                Conceived and designed the experiments: LC LAB AS PW BP NA MB CG RW CK MP BH GR FH RL TR CP JMD. Performed the experiments: LC LAB AW KG AS PW BP NA MB CG RW CK MP. Analyzed the data: LC LAB AW KG AS PW BP MB CG RW MP. Contributed reagents/materials/analysis tools: PW BP CK MP GR TR CP FH RL JMD. Wrote the paper: LC LAB AW KG AS BP CK GR FH RL JMD.

                [¤a]

                Current address: Columbia University, New York, New York, United States of America

                [¤b]

                Current address: Department of Microbiology, Paris Lodron University, Salzburg, Austria

                Article
                Publisher ID: PONE-D-11-08886
                DOI: 10.1371/journal.pone.0023604
                PMC ID: 3163650
                PubMed ID: 21897848
                SO-VID: 1f66ae01-b84e-41d7-887f-3ed31abbaa12
                Copyright © Czibere et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 21 May 2011
                Date accepted : 20 July 2011
                Page count
                Pages: 12
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Computational Biology
                Subject: Molecular Genetics
                Subject: Gene Expression
                Subject: Microarrays
                Subject: Genetics
                Subject: Molecular Genetics
                Subject: Gene Identification and Analysis
                Subject: Gene Regulation
                Subject: Animal Genetics
                Subject: Gene Expression
                Subject: Gene Function
                Subject: Genetic Mutation
                Subject: Genetics of Disease
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Molecular Cell Biology
                Subject: Gene Expression
                Subject: Neuroscience
                Subject: Behavioral Neuroscience
                Subject: Molecular Neuroscience
                Subject: Neurobiology of Disease and Regeneration
                Subject: Medicine
                Subject: Mental Health
                Subject: Psychiatry
                Subject: Anxiety Disorders
                Subject: Mood Disorders
                Subject: Social and Behavioral Sciences
                Subject: Psychology
                Subject: Behavior
                Subject: Emotions

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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