Publications by authors named "Oliver Ambrée"

35 Publications

Social Defeat Modulates T Helper Cell Percentages in Stress Susceptible and Resilient Mice.

Int J Mol Sci 2019 Jul 17;20(14). Epub 2019 Jul 17.

Department of Psychiatry, University of Münster, 48149 Münster, Germany.

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4 and CD8 T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (T) and decreased gene expression levels of TGF-β. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4 cells (CD4-PPARγ), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγ controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses T cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20143512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678569PMC
July 2019

Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner.

Brain Struct Funct 2019 Jul 10;224(6):2213-2230. Epub 2019 Jun 10.

Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1/A9, 48149, Munster, Germany.

The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7 mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7 mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00429-019-01898-6DOI Listing
July 2019

Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress.

Front Behav Neurosci 2018 13;12:141. Epub 2018 Jul 13.

Department of Psychiatry, University of Münster, Münster, Germany.

Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6C monocytes and higher numbers of spleen-derived CD11b cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45 CD11b cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2) Ly6C monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6C monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnbeh.2018.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053497PMC
July 2018

Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress.

Neuropsychopharmacology 2018 05 7;43(6):1308-1316. Epub 2017 Nov 7.

Department of Psychiatry, University of Münster, Münster, Germany.

DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5-HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5-HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2017.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916353PMC
May 2018

Swing Boat: Inducing and Recording Locomotor Activity in a Model of Alzheimer's Disease.

Front Behav Neurosci 2017 30;11:159. Epub 2017 Aug 30.

Institute of Neuropathology, University Hospital MünsterMünster, Germany.

Recent studies indicate that physical activity can slow down progression of neurodegeneration in humans. To date, automated ways to induce activity have been predominantly described in rodent models. To study the impact of activity on behavior and survival in adult , we aimed to develop a rotating tube device "swing boat" which is capable of monitoring activity and sleep patterns as well as survival rates of flies. For the purpose of a first application, we tested our device on a transgenic fly model of Alzheimer's disease (AD). Activity of flies was recorded in a climate chamber using the Activity Monitoring (DAM) System connected to data acquisition software. Locomotor activity was induced by a rotating tube device "swing boat" by repetitively tilting the tubes for 30 min per day. A non-exercising group of flies was used as control and activity and sleep patterns were obtained. The GAL4-/UAS system was used to drive pan-neuronal expression of human Aβ42 in flies. Immunohistochemical stainings for Aβ42 were performed on paraffin sections of adult fly brains. Daily rotation of the fly tubes evoked a pronounced peak of activity during the 30 min exercise period. Pan-neuronal expression of human Aβ42 in flies caused abnormalities in locomotor activity, reduction of life span and elevated sleep fragmentation in comparison to wild type flies. Furthermore, the formation of amyloid accumulations was observed in the adult fly brain. Gently induced activity over 12 days did not evoke prominent effects in wild type flies but resulted in prolongation of median survival time by 7 days (32.6%) in Aβ42-expressing flies. Additionally, restoration of abnormally decreased night time sleep (10%) and reduced sleep fragmentation (28%) were observed compared to non-exercising Aβ42-expressing flies. On a structural level no prominent effects regarding prevalence of amyloid aggregations and RNA expression were detected following activity induction. The rotating tube device successfully induced activity in flies shown by quantitative activity analysis. Our setup enabled quantitative analysis of activity and sleep patterns as well as of survival rates. Induced activity in a model of Alzheimer's disease improved survival and ameliorated sleep phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnbeh.2017.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582087PMC
August 2017

Altered B Cell Homeostasis in Patients with Major Depressive Disorder and Normalization of CD5 Surface Expression on Regulatory B Cells in Treatment Responders.

J Neuroimmune Pharmacol 2018 03 13;13(1):90-99. Epub 2017 Sep 13.

Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Pro-inflammatory activity and cell-mediated immune responses have been widely observed in patients with major depressive disorder (MDD). Besides their well-known function as antibody-producers, B cells play a key role in inflammatory responses by secreting pro- and anti-inflammatory factors. However, homeostasis of specific B cell subsets has not been comprehensively investigated in MDD. In this study, we characterized circulating B cells of distinct developmental steps including transitional, naïve-mature, antigen-experienced switched, and non-switched memory cells, plasmablasts and regulatory B cells by multi-parameter flow cytometry. In a 6-weeks follow-up, circulating B cells were monitored in a small group of therapy responders and non-responders. Frequencies of naïve lgDCD27 B cells, but not lgDCD27 memory B cells, were reduced in severely depressed patients as compared to healthy donors (HD) or mildly to moderately depressed patients. Specifically, B cells with immune-regulatory capacities such as CD1dCD5 B cells and CD24CD38 transitional B cells were reduced in MDD. Also Bm1-Bm5 classification in MDD revealed reduced Bm2' cells comprising germinal center founder cells as well as transitional B cells. We further found that reduced CD5 surface expression on transitional B cells was associated with severe depression and normalized exclusively in clinical responders. This study demonstrates a compromised peripheral B cell compartment in MDD with a reduction in B cells exhibiting a regulatory phenotype. Recovery of CD5 surface expression on transitional B cells in clinical response, a molecule involved in activation and down-regulation of B cell responses, further points towards a B cell-dependent process in the pathogenesis of MDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11481-017-9763-4DOI Listing
March 2018

The effect of childhood trauma on serum BDNF in bipolar depression is modulated by the serotonin promoter genotype.

Neurosci Lett 2017 Aug 25;656:177-181. Epub 2017 Jul 25.

Department of Psychiatry, University of Münster, Münster, Germany.

In healthy humans, both childhood trauma and the short form of the serotonin promoter transporter genotype (5-HTTLPR) are associated with lower levels of brain-derived neurotrophic factor (BDNF). In subjects with bipolar disorder (BD), lower levels of BDNF and a higher degree of childhood trauma were observed compared with healthy controls. However, is still unknown if the functional 5-HTTLPR polymorphisms exerts an effect on both abnormalities. In 40 inpatients affected by a major depressive episode in the course of BD, we genotyped 5-HTTLPR, measured serum BDNF with ELISA, and assessed early adversities by the childhood trauma questionnaire (CTQ). Data were analyzed in the context of the general linear model correcting for age, sex, ongoing lithium treatment, severity of current depression, and CTQ minimization/denial scores to investigate the effect of 5-HTTLPR polymorphism and childhood trauma on BDNF levels. Early trauma were negatively associated with BDNF serum levels (higher CTQ scores, lower BDNF; p=0.0019). 5-HTTLPR l/l homozygotes showed significantly higher BDNF levels than 5-HTTLPR*s carriers (30.57±6.13 vs 26.82±6.41; p=0.0309). A separate-slopes analysis showed that 5-HTTLPR significantly influenced the relationship between early trauma and adult BDNF (interaction of 5-HTTLPR with CTQ scores: p=0.0023), due to a significant relationship between trauma and BDNF in 5-HTTLPR*s carriers, but not among l/l homozygotes. Putatively detrimental effects of childhood trauma exposure on adult BDNF serum levels are influenced by 5-HTTLPR genotype in patients affected by BD. Possible mechanisms include epigenetic modulation of BDNF gene expression, due to different reactivity to stressors in 5-HTTLPR genotype groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2017.07.043DOI Listing
August 2017

SMAD dependent signaling plays a detrimental role in a fly model of SMARCB1-deficiency and the biology of atypical teratoid/rhabdoid tumors.

J Neurooncol 2017 02 20;131(3):477-484. Epub 2017 Jan 20.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.

Atypical teratoid/rhabdoid tumors (ATRT) are highly malignant brain tumors arising in young children. The majority of ATRT is characterized by inactivation of the chromatin remodeling complex member SMARCB1 (INI1/hSNF5). Little is known, however, on downstream pathways involved in the detrimental effects of SMARCB1 deficiency which might also represent targets for treatment. Using Drosophila melanogaster and the Gal4-UAS system, modifier screens were performed in order to identify the role of SMAD dependent signaling in the lethal phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. Expression and functional role of human homologs was next investigated in ATRT tumor samples and SMARCB1-deficient rhabdoid tumor cells. The lethal phenotype associated with snr1 knockdown in Drosophila melanogaster could be shifted to later stages of development upon additional knockdown of several decapentaplegic pathway members including Smox, and Med. Similarly, the transforming growth factor beta (TGFbeta) receptor type I kinase inhibitor SB431542 ameliorated the detrimental effect of snr1 knockdown in the fruit fly. Examination of homologs of candidate decapentaplegic pathway members in human SMARCB1-deficent ATRT samples revealed SMAD3 and SMAD6 to be over-expressed. In SMARCB1-deficent rhabdoid tumor cells, siRNA-mediated silencing of SMAD3 or SMAD6 expression reduced TGFbeta signaling activity and resulted in decreased proliferation. Similar results were obtained upon pharmacological inhibition of TGFbeta signaling using SB431542. Our data suggest that SMAD dependent signaling is involved in the detrimental effects of SMARCB1-deficiency and provide a rationale for the investigation of TGFbeta targeted treatments in ATRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-016-2326-3DOI Listing
February 2017

Environmental enrichment and physical exercise revert behavioral and electrophysiological impairments caused by reduced adult neurogenesis.

Hippocampus 2017 01 18;27(1):36-51. Epub 2016 Oct 18.

Department of Psychiatry, Laboratory of Molecular Psychiatry, University of Münster, Münster, Germany.

It is well known that adult neurogenesis occurs in two distinct regions, the subgranular zone of the dentate gyrus and the subventricular zone along the walls of the lateral ventricles. Until now, the contribution of these newly born neurons to behavior and cognition is still uncertain. The current study tested the functional impacts of diminished hippocampal neurogenesis on emotional and cognitive functions in transgenic Gfap-tk mice. Our results showed that anxiety-related behavior evaluated both in the elevated plus maze as well as in the open field, social interaction in the sociability test, and spatial working memory in the spontaneous alternation test were not affected. On the other hand, recognition and emotional memory in the object recognition test and contextual fear conditioning, and hippocampal long-term potentiation were impaired in transgenic mice. Furthermore, we evaluated whether environmental enrichment together with physical exercise could improve or even restore the level of adult neurogenesis, as well as the behavioral functions. Our results clearly demonstrated that environmental enrichment together with physical exercise successfully elevated the overall number of progenitor cells and young neurons in the dentate gyrus of transgenic mice. Furthermore, it led to a significant improvement in object recognition memory and contextual fear conditioning, and reverted impairments in hippocampal long-term potentiation. Thus, our results confirm the importance of adult neurogenesis for learning and memory processes and for hippocampal circuitry in general. Environmental enrichment and physical exercise beneficially influenced adult neurogenesis after it had been disrupted and most importantly recovered cognitive functions and long-term potentiation. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hipo.22669DOI Listing
January 2017

Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice.

Behav Brain Res 2016 11 25;314:87-95. Epub 2016 Jul 25.

Department of Psychiatry, University of Münster, Münster, Germany; Cluster of Excellence EXC 1003, Cells in Motion, University of Münster, Münster, Germany.

Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/-)) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2016.07.041DOI Listing
November 2016

Cytokine levels in major depression are related to childhood trauma but not to recent stressors.

Psychoneuroendocrinology 2016 11 15;73:24-31. Epub 2016 Jul 15.

Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.

Background: Major depressive disorder (MDD) is a stress-related psychiatric disorder. A subgroup of MDD patients is characterized by increased inflammatory activation. We aimed to investigate whether increased inflammation particularly occurs in MDD patients with a history of stressful early or later life experiences.

Methods: Serum levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in N=214 MDD patients and N=180 healthy controls (HC). Childhood trauma (Childhood Trauma Questionnaire - CTQ), adverse life events of the past 12 months (List of Threatening Experiences Questionnaire - LTE-Q), and perceived stress in the past month (Perceived Stress Scale - PSS) were analyzed with regard to cytokine levels.

Results: Pro-inflammatory cytokine levels were not related to global scores of adverse events or perceived stress covering different time points ranging from childhood to the past month. However, in the subgroup of traumatized MDD patients, higher severity of childhood sexual abuse was associated with higher levels of both IL-6 and TNF-α in a linear fashion.

Conclusions: Our data suggest a linear relationship between childhood sexual abuse and increased pro-inflammatory cytokine levels in MDD patients, while more recent stressful life events were not related to these inflammatory markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psyneuen.2016.07.205DOI Listing
November 2016

Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder.

J Affect Disord 2016 Sep 24;202:1-9. Epub 2016 May 24.

Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.

Background: Bipolar Disorder (BD) is associated with elevated biomarkers of cell-mediated immune activation and inflammation and with signs of widespread disruption of white matter (WM) integrity in adult life. Consistent findings in animal models link WM damage in inflammatory diseases of the brain and serum levels of cytokines.

Methods: With an exploratory approach, we tested the effects of 22 serum analytes, including pro- and anti-inflammatory cytokines and neurotrophic/hematopoietic factors, on DTI measures of WM microstructure in a sample of 31 patients with a major depressive episode in course of BD. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA).

Results: The inflammation-related cytokines TNF-α, IL-8, IFN-γ and IL-10, and the growth factors IGFBP2 and PDGF-BB, shared the same significant associations with lower FA, and higher MD and RD, in large overlapping networks of WM fibers mostly located in the anterior part of the brain and including corpus callosum, cingulum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, uncinate, forceps, corona radiata, thalamic radiation, internal capsule.

Conclusions: Higher RD is thought to signify increased space between fibers, suggesting demyelination or dysmyelination. The pattern of higher RD and MD with lower FA suggests that inflammation-related cytokine and growth factor levels inversely associate with integrity of myelin sheaths. The activated inflammatory response system might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2016.05.047DOI Listing
September 2016

Stem Cell Factor (SCF) is a putative biomarker of antidepressant response.

J Neuroimmune Pharmacol 2016 06 23;11(2):248-58. Epub 2016 Apr 23.

Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.

Growth factors involved in neurogenesis and neuroplasticity could play a role in biological processes that drive depression recovery. Combined total sleep deprivation and morning light therapy (TSD + LT) can acutely reverse depressive symptoms, thus allowing to investigate the neurobiological correlates of antidepressant response. We tested if changes on plasma levels of Brain Derived Neurotrophic Factor (BDNF), S100 calcium binding protein B (S100-B), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Vascular Endothelial Growth Factor (VEGF) are associated with response to TSD + LT in 26 inpatients affected by a major depressive episode in the course of bipolar disorder. Regional grey matter (GM) volumes were assessed at baseline, and BOLD fMRI neural responses to a moral valence decision task were recorded before and after treatment. 61.5 % of patients responded to treatment. SCF plasma levels increased significantly more in responders, and correlated with GM volumes in frontal and parietal cortical areas. The pattern of change of SCF also associated with both GM volumes and changes of BOLD fMRI neural responses in the anterior cingulate and medial prefrontal cortex. SCF is both a hematopoietic growth factor and a neurotrophic factor, involved in neuron-neuron and neuron-(micro) glia interactions, fostering neuronal growth and an anti-inflammatory milieu. We correlated SCF levels with antidepressant response and with functional and structural MRI measures in cortical areas that are involved in the cognitive generation and control of affect. SCF may be a candidate growth factor that contributes to neurotrophic and immune effects that are involved in the process of remission/recovery from depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11481-016-9672-yDOI Listing
June 2016

Prenatal immune activation in mice blocks the effects of environmental enrichment on exploratory behavior and microglia density.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jun 14;67:10-20. Epub 2016 Jan 14.

Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, Germany. Electronic address:

Adverse environmental factors including prenatal maternal infection are capable of inducing long-lasting behavioral and neural alterations which can enhance the risk to develop schizophrenia. It is so far not clear whether supportive postnatal environments are able to modify such prenatally-induced alterations. In rodent models, environmental enrichment influences behavior and cognition, for instance by affecting endocrinologic, immunologic, and neuroplastic parameters. The current study was designed to elucidate the influence of postnatal environmental enrichment on schizophrenia-like behavioral alterations induced by prenatal polyI:C immune stimulation at gestational day 9 in mice. Adult offspring were tested for amphetamine-induced locomotion, social interaction, and problem-solving behavior as well as expression of dopamine D1 and D2 receptors and associated molecules, microglia density and adult neurogenesis. Prenatal polyI:C treatment resulted in increased dopamine sensitivity and dopamine D2 receptor expression in adult offspring which was not reversed by environmental enrichment. Prenatal immune activation prevented the effects of environmental enrichment which increased exploratory behavior and microglia density in NaCl treated mice. Problem-solving behavior as well as the number of immature neurons was affected by neither prenatal immune stimulation nor postnatal environmental enrichment. The behavioral and neural alterations that persist into adulthood could not generally be modified by environmental enrichment. This might be due to early neurodevelopmental disturbances which could not be rescued or compensated for at a later developmental stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2016.01.005DOI Listing
June 2016

Deficiencies of the T and natural killer cell system in major depressive disorder: T regulatory cell defects are associated with inflammatory monocyte activation.

Brain Behav Immun 2016 May 8;54:38-44. Epub 2015 Dec 8.

Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.

Background: In a previous study, we found an up-regulated inflammatory monocyte gene expression profile in major depressive disorder (MDD) patients aged ⩾ 28 years and a down-regulated inflammatory gene expression profile in MDD patients aged<28 years. In the same sample of patients, we aimed to investigate immune dysregulation in the lymphocyte arm of the immune system, particularly in the context of the described monocyte (de-)activation states.

Methods: From deep frozen leukocytes, circulating percentages of monocytes, lymphocytes, B, T, and natural killer (NK) cells, and various functional subsets of T and T helper (Th) cells (Th1, Th2, Th17, and natural T regulatory cells) were measured in N=50 MDD patients and N=58 age- and gender-matched healthy controls (HC). In addition, serum levels of interleukin (IL)-6, sCD25, IL-7, IL-3, SCF, IGF-BP2, and EGF were evaluated.

Results: MDD patients were in general characterized by an impaired maturation of Th2 cells, Th17 cells, and NK cells and by decreased serum levels of IL-7 and sCD25. MDD patients aged ⩾ 28 years additionally exhibited decreased percentages of CD4(+)CD25(high)FoxP3(+) T regulatory cells, next to signs of the above described partial T cell defects. Natural T regulatory cells were inversely associated with the pro-inflammatory state of the monocytes (r=-.311; p=.034) that characterized this patient subgroup.

Conclusions: Deficiencies of the NK and T (regulatory) cell system and inflammatory monocyte immune activation co-occur as partly interrelated phenomena within the same MDD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2015.12.003DOI Listing
May 2016

S100B Serum Levels Predict Treatment Response in Patients with Melancholic Depression.

Int J Neuropsychopharmacol 2015 Sep 12;19(3):pyv103. Epub 2015 Sep 12.

Department of Psychiatry, University of Münster, Germany (Dr Ambrée, Ms Grosse, Dr Alferink, Dr Rothermundt, and Dr Arolt); Department of Psychiatry, Erasmus Medical Center Rotterdam, The Netherlands (Drs Bergink and Birkenhäger); Radiology Morphological Solutions, Rotterdam, The Netherlands (Ms Grosse); Department of Immunology, Erasmus Medical Center Rotterdam, The Netherlands (Dr Drexhage); Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany (Dr Alferink); Department of Psychiatry, St. Rochus-Hospital, Telgte, Oberhausen, Germany (Dr Rothermundt).

Background: There is an ongoing search for biomarkers in psychiatry, for example, as diagnostic tools or predictors of treatment response. The neurotrophic factor S100 calcium binding protein B (S100B) has been discussed as a possible predictor of antidepressant response in patients with major depression, but also as a possible biomarker of an acute depressive state. The aim of the present study was to study the association of serum S100B levels with antidepressant treatment response and depression severity in melancholically depressed inpatients.

Methods: After a wash-out period of 1 week, 40 inpatients with melancholic depression were treated with either venlafaxine or imipramine. S100B levels and Hamilton Depression Rating Scale (HAM-D) scores were assessed at baseline, after 7 weeks of treatment, and after 6 months.

Results: Patients with high S100B levels at baseline showed a markedly better treatment response defined as relative reduction in HAM-D scores than those with low baseline S100B levels after 7 weeks (P=.002) and 6 months (P=.003). In linear regression models, S100B was a significant predictor for treatment response at both time points. It is of interest to note that nonresponders were detected with a predictive value of 85% and a false negative rate of 7.5%. S100B levels were not associated with depression severity and did not change with clinical improvement.

Conclusions: Low S100B levels predict nonresponse to venlafaxine and imipramine with high precision. Future studies have to show which treatments are effective in patients with low levels of S100B so that this biomarker will help to reduce patients' burden of nonresponding to frequently used antidepressants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ijnp/pyv103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815471PMC
September 2015

Normal cerebellar development in S100B-deficient mice.

Cerebellum 2015 Apr;14(2):119-27

Division of Neurophysiology, Biocenter Grindel, Martin-Luther-King-Pl. 3, D-20146, Hamburg, Germany.

The calcium-binding protein S100B has been shown to support neuron proliferation, migration and neurite growth in vitro, while the significance of S100B for neuronal development in vivo is controversial. We have investigated the effect of S100B deficiency on cerebellar development in S100B knockout mice at an age of 5 and 10 days after birth (P5 and P10). This time range covers important developmental steps in the cerebellum such as granule cell proliferation and migration, as well as dendritic growth of Purkinje cells. Bergmann glial cells contain a particularly high concentration of S100B and serve as scaffold for both migrating granule cells and growing Purkinje cell dendrites. This renders the postnatal cerebellum ideal as a model system to study the importance of S100B for glial and neuronal development. We measured the length of Bergmann glial processes, the width of the external granule cell layer as a measure of granule cell proliferation, the decrease in width of the external granule cell layer between P5 and P10 as a measure of granule cell migration, and the length of Purkinje cell dendrites in wild-type and S100B knockout mice. None of these parameters showed significant differences between wild-type and knockout mice. In addition, wild-type and knockout mice performed equally in locomotor behaviour tests. The results indicate that S100B-deficient mice have normal development of the cerebellum and no severe impairment of motor function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-014-0606-zDOI Listing
April 2015

Clinical characteristics of inflammation-associated depression: Monocyte gene expression is age-related in major depressive disorder.

Brain Behav Immun 2015 Feb 20;44:48-56. Epub 2014 Aug 20.

Department of Psychiatry and Psychotherapy, University of Münster, Germany.

Increased inflammatory activation might only be present in a subgroup of depressed individuals in which immune processes are especially relevant to disease development. We aimed to analyze demographic, depression, and trauma characteristics of major depressive disorder (MDD) patients with regard to inflammatory monocyte gene expression. Fifty-six naturalistically treated MDD patients (32 ± 12 years) and 57 healthy controls (HC; 31 ± 11 years) were analyzed by the Inventory of Depressive Symptomatology (IDS) and by the Childhood Trauma Questionnaire (CTQ). We determined the expression of 38 inflammatory and immune activation genes including the glucocorticoid receptor (GR)α and GRβ genes in purified CD14(+) monocytes using quantitative-polymerase chain reaction (RT-qPCR). Monocyte gene expression was age-dependent, particularly in MDD patients. Increased monocyte gene expression and decreased GRα/β ratio were only present in MDD patients aged ⩾ 28 years. Post hoc analyses of monocyte immune activation in patients <28 years showed two subgroups: a subgroup with a severe course of depression (recurrent type, onset <15 years) - additionally characterized by panic/arousal symptoms and childhood trauma - that had a monocyte gene expression similar to HC, and a second subgroup with a milder course of the disorder (73% first episode depression, onset ⩾15 years) - additionally characterized by the absence of panic symptoms - that exhibited a strongly reduced inflammatory monocyte activation compared to HC. In conclusion, monocyte immune activation was not uniformly raised in MDD patients but was increased only in patients of 28 years and older.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2014.08.004DOI Listing
February 2015

Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B in bipolar offspring: a follow-up study from adolescence into adulthood.

Bipolar Disord 2015 Feb 17;17(1):39-49. Epub 2014 Jul 17.

Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.

Objectives: There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro-immune changes in a prospective study on children of patients with bipolar disorder.

Methods: Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1β (IL-1β), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls.

Results: During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages.

Conclusions: This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bdi.12231DOI Listing
February 2015

Serotonin transporter gene methylation is associated with hippocampal gray matter volume.

Hum Brain Mapp 2014 Nov 23;35(11):5356-67. Epub 2014 May 23.

Department of Psychiatry, University of Münster, Münster, Germany; Department of Psychiatry, University of Marburg, Marburg, Germany.

Background: The serotonin transporter (5-HTT) and the 5-HTTLPR/rs25531 polymorphisms in its gene (SLC6A4) have been associated with depression, increased stress-response, and brain structural alterations such as reduced hippocampal volumes. Recently, epigenetic processes including SLC6A4 promoter methylation were shown to be affected by stress, trauma, or maltreatment and are regarded to be involved in the etiology of affective disorders. However, neurobiological correlates of SLC6A4 promoter methylation have never been studied or compared to genotype effects by means of human neuroimaging hitherto

Methods: Healthy subjects were recruited in two independent samples (N = 94, N = 95) to obtain structural gray matter images processed by voxel-based morphometry (VBM8), focusing on hippocampal, amygdala, and anterior cingulate gyrus gray matter structure. SLC6A4 promoter methylation within an AluJb element and 5-HTTLPR/rs25531 genotypes were analyzed in view of a possible impact on local gray matter volume

Results: Strong associations of AluJb methylation and hippocampal gray matter volumes emerged within each sample separately, which in the combined sample withstood most conservative alpha-corrections for the entire brain. The amygdala, insula, and caudate nucleus showed similar associations. The 5-HTTLPR/rs25531 showed no main effect on gray matter, and the effect of methylation rates on hippocampal structure was comparable among the genotype groups

Conclusions: Methylation within the AluJb appears to have strong effects on hippocampal gray matter volumes, indicating that epigenetic processes can alter brain structures crucially involved in stress-related disorders. Different ways of regulating SLC6A4 expression might involve exonization or transcription factor binding as potentially underlying mechanisms, which, however, is speculative and warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.22555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869452PMC
November 2014

Impaired spatial learning and reduced adult hippocampal neurogenesis in histamine H1-receptor knockout mice.

Eur Neuropsychopharmacol 2014 Aug 4;24(8):1394-404. Epub 2014 May 4.

Institute of Physiological Psychology, Heinrich-Heine University, Düsseldorf, Germany; Mental Health Research and Treatment Center, University of Bochum, Germany. Electronic address:

The histamine H1-receptor (H1R) is expressed in wide parts of the brain including the hippocampus, which is involved in spatial learning and memory. Previous studies in H1R knockout (H1R-KO) mice revealed deficits in a variety of learning and memory tasks. It was also proposed that H1R activation is crucial for neuronal differentiation of neural progenitors. Therefore, the aim of this study was to investigate negatively reinforced spatial learning in the water-maze and to assess survival and neuronal differentiation of newborn cells in the adult hippocampus of H1R-KO mice. H1R-KO and wild-type (WT) mice were subjected to the following sequence of tests: (a) cued version, (b) place learning, (c) spatial probe, (d) long-term retention and (e) reversal learning. Furthermore hippocampal neurogenesis in terms of survival and differentiation was assessed in H1R-KO and WT mice. H1R-KO mice showed normal cued learning, but impaired place and reversal learning as well as impaired long-term retention performance. In addition, a marked reduction of newborn neurons in the hippocampus but no changes in differentiation of neural progenitors into neuronal and glial lineage was found in H1R-KO mice. Our data suggest that H1R deficiency in mice is associated with pronounced deficits in hippocampus-dependent spatial learning and memory. Furthermore, we herein provide first evidence that H1R deficiency in the mouse leads to a reduced neurogenesis. However, the exact mechanisms for the reduced number of cells in H1R-KO mice remain elusive and might be due to a reduced survival of newborn hippocampal neurons and/or a reduction in cell proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2014.04.006DOI Listing
August 2014

S100B overexpression increases behavioral and neural plasticity in response to the social environment during adolescence.

J Psychiatr Res 2013 Nov 22;47(11):1791-9. Epub 2013 Aug 22.

Department of Psychiatry, University of Münster, Albert-Schweitzer-Campus 1, Building A9, D-48149 Münster, Germany; Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Münster, Germany.

Genetic variants as well as increased serum levels of the neurotrophic factor S100B are associated with different psychiatric disorders. However, elevated S100B levels are also related to a better therapeutic outcome in psychiatric patients. The functional role of elevated S100B in psychiatric disorders is still unclear. Hence, this study was designed in order to elucidate the differential effects of S100B overexpression in interaction with chronic social stress during adolescence on emotional behavior and adult neurogenesis. S100B transgenic and wild-type mice were housed either in socially stable or unstable environments during adolescence, between postnatal days 28 and 77. In adulthood, anxiety-related behavior in the open field, dark-light, and novelty-induced suppression of feeding test as well as survival of proliferating hippocampal progenitor cells were assessed. S100B transgenic mice revealed significantly reduced anxiety-related behavior in the open field compared to wild-types when reared in stable social conditions. In contrast, when transgenic mice grew up in unstable social conditions, their level of anxiety-related behavior was comparable to the levels of wild-type mice. In addition, S100B overexpressing mice from unstable housing conditions displayed higher numbers of surviving newborn cells in the adult hippocampus which developed into mature neurons. In conclusion, elevated S100B levels increase the susceptibility to environmental stimuli during adolescence resulting in more variable behavioral and neural phenotypes in adulthood. In humans, this increased plasticity might lead to both, enhanced risk for psychiatric disorders in negative environments and improved therapeutic outcome in positive environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2013.08.001DOI Listing
November 2013

Effect of acute stressor and serotonin transporter genotype on amygdala first wave transcriptome in mice.

PLoS One 2013 11;8(3):e58880. Epub 2013 Mar 11.

Department of Psychiatry, University of Muenster, Muenster, Germany.

The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058880PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594195PMC
December 2013

The question of pro-inflammatory immune activity in schizophrenia and the potential importance of anti-inflammatory drugs.

Mod Trends Pharmacopsychiatry 2013 27;28:100-16. Epub 2013 Feb 27.

Department of Psychiatry, University of Münster, Münster, Germany.

Throughout the last 20 years, numerous studies have indicated pro-inflammatory activity in patients with an acute schizophrenic episode. In this report, the most relevant findings concerning the cytokine systems in schizophrenia are demonstrated, together with recent studies on gene expression. Findings in humans are supplemented by observations from rodent models of schizophrenia. Furthermore, the current state of both neuroleptic and anti-inflammatory compounds on the immune system is reported, together with clinical data on the effects of anti-inflammatory medications on the course of the acute illness in patients with schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000343972DOI Listing
December 2014

Monoamine oxidase A gene DNA hypomethylation - a risk factor for panic disorder?

Int J Neuropsychopharmacol 2012 Oct 21;15(9):1217-28. Epub 2012 Mar 21.

Department of Psychiatry, University of Muenster, Germany.

The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Male subjects showed no or only very minor methylation with some evidence for relative hypomethylation at one CpG site in intron 1 in patients compared to controls. Female patients exhibited significantly lower methylation than healthy controls at 10 MAOA CpG sites in the promoter as well as in exon/intron 1, with significance surviving correction for multiple testing at four CpG sites (p≤0.001). Furthermore, in female subjects the occurrence of negative life events was associated with relatively decreased methylation, while positive life events were associated with increased methylation. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S146114571200020XDOI Listing
October 2012

Transgenic Alzheimer mice in a semi-naturalistic environment: more plaques, yet not compromised in daily life.

Behav Brain Res 2009 Jul 6;201(1):99-102. Epub 2009 Feb 6.

Department of Behavioural Biology, University of Münster, Münster, Germany.

The behaviour of transgenic animals modelling human diseases such as Alzheimer's disease (AD) is typically characterised in artificial apparatuses rather than labour-intensively observing their spontaneous behaviour in the home environment. Here we report on an in-depth behavioural characterisation of the day-to-day life of a murine model for AD living in a large (6.6 m(2)) semi-naturalistic indoor enclosure. In a genotype-blind investigation, 40 different behavioural patterns of wildtype and transgenic animals were recorded at early ages, before plaques can be found in the brains of the transgenic mice; and later in life, when these mice are known to exhibit AD-like plaques. Basal stress hormone levels (corticosterone) and cerebral amyloid-beta depositions were determined, and compared with individually and group-housed mice from non-enriched standard cages. Semi-naturalistically housed transgenics could not be differentiated from wildtypes by their behavioural profiles nor by basal levels of corticosterone. Surprisingly, the brains of these transgenics revealed an even more pronounced plaque load than controls from standard-housing conditions. Behavioural traits are known to involve gene-environment interactions. Here we show for the first time that despite high beta-amyloid plaque load the day-to-day life of AD mice is not compromised when the genetic predisposition interacts with a generous physically and socially enriched environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2009.01.037DOI Listing
July 2009

Reduction of cerebral oxidative stress following environmental enrichment in mice with Alzheimer-like pathology.

Brain Pathol 2010 Jan 7;20(1):166-75. Epub 2009 Jan 7.

Institute of Neuropathology, University Hospital, Muenster, Germany.

Oxidative stress is a key feature during progression of chronic neurodegenerative conditions such as Alzheimer's disease. In aging humans and animals, voluntary exercise lowers oxidative stress reactions. Additionally, recent work in our lab demonstrated that cognitive and physical stimulation (termed environmental enrichment) counteracts amyloid beta pathology, neurovascular dysfunction and behavioral symptoms in mice with Alzheimer-like disease. Based on these facts, we hypothesized that cognitive and physical activity can also protect against oxidative stress in Alzheimer-diseased brain. We, therefore, kept female TgCRND8 mice under standard and enriched housing from day 30 until 5 months of age. Environmental stimulation attenuated pro-oxidative processes and triggered anti-oxidative defense mechanisms as indicated by diminished biomarkers for reactive oxygen and nitrogen species, downregulation of pro-inflammatory and pro-oxidative mediators, decreased expression of pro-apoptotic caspases, and upregulation of SOD1 and SOD2. This study identifies a thus far undescribed antagonizing effect of environmental stimulation on Alzheimer's disease-related oxidative damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1750-3639.2008.00257.xDOI Listing
January 2010

Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology.

Exp Neurol 2009 Mar 11;216(1):184-92. Epub 2008 Dec 11.

Institute of Neuropathology, University Hospital Muenster, Muenster, Germany.

Alzheimer's disease (AD) is accompanied by hippocampal neuronal loss and abnormal neurogenesis, both of which probably contributing to AD-related cognitive deficits. Mounting evidence indicates that cognitive and physical stimulation provided by environmental enrichment improves neurogenesis in healthy animals and counteracts beta-amyloid pathology in mouse models of AD. Here, we hypothesized that environmental enrichment has also an impact on hippocampal neurogenesis in mice with AD-like pathology. Therefore, TgCRND8 mice and wild type littermates were either housed under standard conditions or in an enriched environment for 4 months. Standard housed TgCRND8 mice revealed diminished hippocampal cell proliferation and reduced number of mature newborn neurons compared to wild type littermates under the same housing condition. However, environmental enrichment reversed this genotype effect. Here, we show that cognitive and physical stimulation is capable of increasing the number of newborn mature hippocampal neurons in transgenic mice to wild type levels. Moreover, the expression of various plasticity associated molecules was enhanced in transgenic mice due to enriched housing. This study identifies that environmental enrichment improves diminished cellular plasticity in AD brain, probably enhancing the brain capacity to better compensate for neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2008.11.027DOI Listing
March 2009

Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice.

Behav Brain Res 2008 Aug 14;191(1):43-8. Epub 2008 Mar 14.

Department of Behavioural Biology, University of Muenster, Badestr. 9, D-48149 Muenster, Germany.

After we could recently demonstrate a beneficial effect of environmental enrichment on AD-like brain pathology in female TgCRND8 mice [Ambrée O, Leimer U, Herring A, Görtz N, Sachser N, Heneka MT, et al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 2006;169:544-52] the present study focuses on the behavioural effects of environmental enrichment with special emphasis on learning and memory performance in this AD model. In the first experiment spontaneous exploration, locomotor activity and anxiety-related behaviour were assessed as the performance in learning tasks can be biased substantially by exploratory behavioural traits. In the second experiment spatial memory in the Barnes maze test and object recognition memory were examined. Regarding exploratory behaviour transgenic mice from standard housing condition were statistically indistinguishable from wild-type controls. Enrichment had comparable effects in both genotypes indicated by higher levels of exploration and locomotor activity. In transgenic mice the elevated plus-maze revealed less anxiety-related behaviour due to enrichment in contrast to wild-type mice that statistically did not differ in anxiety-related behaviour. Concerning learning and memory performance, cognitive deficits of standard housed transgenic mice could be demonstrated in both learning tasks. Surprisingly, in both housing conditions a significantly higher number of transgenic mice refused to explore any objects compared to wild-type mice. Furthermore, the Barnes maze test revealed deficits of the transgenic mice in spatial memory compared to wild-type mice whereas no effect of environmental enrichment was detectable. Thus environmental enrichment increased exploratory behaviour and decreased anxiety-related behaviour but could not clearly ameliorate deficits in learning and memory performance of TgCRND8 mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2008.03.006DOI Listing
August 2008

Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom?

Behav Brain Res 2008 Jun 8;190(1):74-84. Epub 2008 Feb 8.

Department of Behavioural Biology, University of Münster, Badestrasse 13, Münster, Germany.

Several studies on both humans and animals reveal benefits of physical exercise on brain function and health. A previous study on TgCRND8 mice, a transgenic model of Alzheimer's disease, reported beneficial effects of premorbid onset of long-term access to a running wheel on spatial learning and plaque deposition. Our study investigated the effects of access to a running wheel after the onset of Abeta pathology on behavioural, endocrinological, and neuropathological parameters. From day 80 of age, the time when Abeta deposition becomes apparent, TgCRND8 and wildtype mice were kept with or without running wheel. Home cage behaviour was analysed and cognitive abilities regarding object recognition memory and spatial learning in the Barnes maze were assessed. Our results show that, in comparison to Wt mice, Tg mice were characterised by impaired object recognition memory and spatial learning, increased glucocorticoid levels, hyperactivity in the home cage and high levels of stereotypic behaviour. Access to a running wheel had no effects on cognitive or neuropathological parameters, but reduced the amount of stereotypic behaviour in transgenics significantly. Furthermore, wheel-running was inversely correlated with stereotypic behaviour, suggesting that wheel-running may have stereotypic qualities. In addition, wheel-running positively correlated with plaque burden. Thus, in a phase when plaques are already present in the brain, it may be symptomatic of brain pathology, rather than protective. Whether or not access to a running wheel has beneficial effects on Alzheimer-like pathology and symptoms may therefore strongly depend on the exact time when the wheel is provided during development of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2008.02.005DOI Listing
June 2008