TY - THES A1 - Weißflog, Lena T1 - Molecular Genetics of Emotional Dysregulation in Attention-Deficit/Hyperactivity Disorder T1 - Molekulargenetik emotionaler Dysregulation bei Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom N2 - Attention-deficit/hyperactivity disorder (ADHD) is a genetically complex childhood onset neurodevelopmental disorder which is highly persistent into adulthood. Several chromo-somal regions associated with this disorder were identified previously in genome-wide linkage scans, association (GWA) and copy number variation (CNV) studies. In this work the results of case-control and family-based association studies using a can-didate gene approach are presented. For this purpose, possible candidate genes for ADHD have been finemapped using mass array-based SNP genotyping. The genes KCNIP4, CDH13 and DIRAS2 have been found to be associated with ADHD and, in addition, with cluster B and cluster C personality disorders (PD) which are known to be related to ADHD. Most of the associations found in this work would not withstand correction for multiple testing. However, a replication in several independent populations has been achieved and in conjunction with previous evidence from linkage, GWA and CNV studies, it is assumed that there are true associations between those genes and ADHD. Further investigation of DIRAS2 by quantitative real-time PCR (qPCR) revealed expression in the hippocampus, cerebral cortex and cerebellum of the human brain and a significant increase in Diras2 expression in the mouse brain during early development. In situ hybrid-izations on murine brain slices confirmed the results gained by qPCR in the human brain. Moreover, Diras2 is expressed in the basolateral amygdala, structures of the olfactory system and several other brain regions which have been implicated in the psychopatholo-gy of ADHD. In conclusion, the results of this work provide further support to the existence of a strong genetic component in the pathophysiology of ADHD and related disorders. KCNIP4, CDH13 and DIRAS2 are promising candidates and need to be further examined to get more knowledge about the neurobiological basis of this common disease. This knowledge is essential for understanding the molecular mechanisms underlying the emergence of this disorder and for the development of new treatment strategies. N2 - Bei Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom (ADHS) handelt es sich um eine ge-netisch komplexe neuronale Entwicklungsstörung, die im Kindesalter einsetzt und eine hohe Persistenz ins Erwachsenenalter aufweist. Mehrere chromosomale Regionen zeigten eine Assoziation mit dieser Erkrankung in genomweiten Kopplungsanalysen, Assoziations- (GWA) und Copie Number Variation (CNV) Studien. In dieser Arbeit werden die Ergebnisse von Fall-Kontroll- und Familien-basierten Assozia-tionsstudien, basierend auf der Annahme bestimmter Kandidatengene, vorgestellt. Die möglichen Kandidatengene wurden mit Hilfe eines massenspektrometrischen Verfahrens für SNP Genotypisierungen untersucht. Für die Gene KCNIP4, CDH13 und DIRAS2 konnte eine Assoziation mit ADHS und zudem mit Persönlichkeitsstörungen gefunden werden. Die meisten der in dieser Arbeit berichteten Assoziationen würden einer Korrektur für multiples Testen nicht standhalten. Dennoch kann von einer tatsächlichen Assoziation dieser Gene mit ADHS ausgegangen werden da eine Replikation in verschiedenen unab-hängigen Stichproben stattgefunden hat und zudem vorangegangene Kopplungsanalysen, GWA und CNV Studien auf eine Assoziation hindeuten. Die weitere Untersuchung des DIRAS2 Gens mit Hilfe von quantitativer real-time PCR (qPCR) ergab eine Expression des Gens im Hippocampus, dem zerebralen Kortex und dem Kleinhirn des Menschen. Zudem wurde ein signifikanter Anstieg der Diras2 Expression im murinen Gehirn während der frühen Entwicklungsstadien beobachtet. In situ Hybridisie-rungen auf Maushirnschnitten bestätigten die Ergebnisse der qPCR im menschlichen Ge-hirn. Außerdem wird Diras2 in der basolateralen Amygdala, in Komponenten des olfakto-rischen Systems und in mehreren anderen Hirnarealen, die vermutlich an der Pathologie von ADHS beteiligt sind, exprimiert. Zusammenfassend untermauern die Ergebnisse dieser Arbeit die Tatsache dass eine star-ke genetische Komponente an der Entstehung von ADHS beteiligt ist. KCNIP4, CDH13 und DIRAS2 sind vielversprechende Kandidatengene und sollten weiter untersucht werden um nähere Einblicke in die Neurobiologie dieser häufigen Erkrankung zu erhalten. Das dadurch erlangte Wissen ist notwendig um die molekularen Mechanismen die ADHS zu-grunde liegen zu verstehen und um neue Behandlungsstrategien entwickeln zu können. KW - Aufmerksamkeits-Defizit-Syndrom KW - Molekulargenetik KW - Assoziation KW - ADHD KW - genetics KW - association studies Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69345 ER - TY - JOUR A1 - Van den Hove, Daniel A1 - Jakob, Sissi Brigitte A1 - Schraut, Karla-Gerlinde A1 - Kenis, Gunter A1 - Schmitt, Angelika Gertrud A1 - Kneitz, Susanne A1 - Scholz, Claus-Jürgen A1 - Wiescholleck, Valentina A1 - Ortega, Gabriela A1 - Prickaerts, Jos A1 - Steinbusch, Harry A1 - Lesch, Klaus-Peter T1 - Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions JF - PLoS ONE N2 - Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-HttxPS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety-and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip (R) Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotypexPS manner, indicating a genexenvironment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice -particularly females-at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction. KW - Serotonin transporter polymorphism KW - Acute tryptophan depletion KW - Anxiety-like behavior KW - Long-term depression KW - Knock-out mice KW - Major depression KW - Interferon-alpha KW - Physiological functions KW - Restraint stress KW - Bipolar disorder Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135111 VL - 6 IS - 8 ER - TY - JOUR A1 - Song, Ning-Ning A1 - Xiu, Jian-Bo A1 - Huang, Ying A1 - Chen, Jia-Yin A1 - Zhang, Lei A1 - Gutknecht, Lise A1 - Lesch, Klaus Peter A1 - Li, He A1 - Ding, Yu-Qiang T1 - Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency JF - PLoS ONE N2 - The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreER(T2) mice were generated and crossed with Lmx1b(flox/flox) mice to obtain Pet1-CreER(T2); Lmx1b(flox/flox) mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2. KW - Molecular-genetics KW - Sonic hedgehog KW - Neurons KW - Mice KW - Brain KW - Expression KW - System KW - PET-1 KW - Transporter KW - Disorders Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133581 VL - 6 IS - 1 ER - TY - JOUR A1 - Riederer, Peter A1 - Laux, Gerd T1 - MAO-inhibitors in Parkinson's Disease JF - Experimental Neurobiology N2 - Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD. KW - selegiline KW - rasagiline KW - moclobemide KW - phenelzine KW - tranylcypromine KW - acetylcholine KW - Alzheimer disease KW - antidepressive agents KW - depression KW - freezing KW - head KW - indans KW - iron KW - levodopa KW - monoamine oxidase KW - monoamine oxidase inhibitors KW - Parkinson disease Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140930 VL - 20 IS - 1 ER - TY - JOUR A1 - Rantamäki, Tomi A1 - Vesa, Liisa A1 - Antila, Hanna A1 - Di Lieto, Antonio A1 - Tammela, Päivi A1 - Schmitt, Angelika A1 - Lesch, Klaus-Peter A1 - Rios, Maribel A1 - Castrén, Eero T1 - Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade JF - PLoS ONE N2 - Background: Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. Methodology: In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. Principal Findings: Using a chemical-genetic TrkB(F616A) mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf(-/-) knock-out mice (132.4+/-8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. Conclusions: The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain. KW - Serotonin transporter KW - Neuronal plasticity KW - Mood disorders KW - Messenger-RNA KW - Mouse-brain KW - Rat-brain KW - Activation KW - Depression KW - Mice KW - Insensitivity Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133746 VL - 6 IS - 6 ER - TY - JOUR A1 - Line, Samantha J. A1 - Barkus, Christopher A1 - Coyle, Clare A1 - Jennings, Katie A. A1 - Deacon, Robert M. A1 - Lesch, Klaus P. A1 - Sharp, Trevor A1 - Bannerman, David M. T1 - Opposing alterations in anxiety and species-typical behaviours in serotonin transporter overexpressor and knockout mice JF - European Neuropsychopharmacology N2 - Human gene association studies have produced conflicting findings regarding the relationship between the 5-HT transporter (5-HTT) and anxiety. In the present study genetically modified mice were utilised to examine the effects of changes in 5-HTT expression on anxiety. In addition, the influence of 5-HTT expression on two innate “species-typical” behaviours (burrowing and marble burying) and body weight was explored. Across a range of models, 5-HTT overexpressing mice displayed reduced anxiety-like behaviour whilst 5-HTT knockout mice showed increased anxiety-like behaviour, compared to wildtype controls. In tests of species-typical behaviour 5-HTT overexpressing mice showed some facilitation whilst 5-HTT knockout mice were impaired. Reciprocal effects were also seen on body weight, as 5-HTT overexpressors were lighter and 5-HTT knockouts were heavier than wildtype controls. These findings show that variation in 5-HTT gene expression produces robust changes in anxiety and species-typical behaviour. Furthermore, the data add further support to findings that variation of 5-HTT expression in the human population is linked to changes in anxiety-related personality traits. KW - 5-HT KW - 5-HT transporter KW - Anxiety KW - Transgenic mice KW - Body weight Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141222 VL - 21 IS - 1 ER - TY - JOUR A1 - Herrmann, Martin J. A1 - Glotzbach, Evelyn A1 - Mühlberger, Andreas A1 - Gschwendtner, Kathrin A1 - Fallgatter, Andreas J. A1 - Pauli, Paul T1 - Prefrontal Brain Activation During Emotional Processing: A Functional Near Infrared Spectroscopy Study (fNIRS) JF - The Open Neuroimaging Journal N2 - The limbic system and especially the amygdala have been identified as key structures in emotion induction and regulation. Recently research has additionally focused on the influence of prefrontal areas on emotion processing in the limbic system and the amygdala. Results from fMRI studies indicate that the prefrontal cortex (PFC) is involved not only in emotion induction but also in emotion regulation. However, studies using fNIRS only report prefrontal brain activation during emotion induction. So far it lacks the attempt to compare emotion induction and emotion regulation with regard to prefrontal activation measured with fNIRS, to exclude the possibility that the reported prefrontal brain activation in fNIRS studies are mainly caused by automatic emotion regulation processes. Therefore this work tried to distinguish emotion induction from regulation via fNIRS of the prefrontal cortex. 20 healthy women viewed neutral pictures as a baseline condition, fearful pictures as induction condition and reappraised fearful pictures as regulation condition in randomized order. As predicted, the view-fearful condition led to higher arousal ratings than the view-neutral condition with the reappraise-fearful condition in between. For the fNIRS results the induction condition showed an activation of the bilateral PFC compared to the baseline condition (viewing neutral). The regulation condition showed an activation only of the left PFC compared to the baseline condition, although the direct comparison between induction and regulation condition revealed no significant difference in brain activation. Therefore our study underscores the results of previous fNIRS studies showing prefrontal brain activation during emotion induction and rejects the hypothesis that this prefrontal brain activation might only be a result of automatic emotion regulation processes. KW - fNIRS KW - Emotional processing KW - emotional regulation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97437 ER - TY - JOUR A1 - Haeussinger, Florian B. A1 - Heinzel, Sebastian A1 - Hahn, Tim A1 - Schecklmann, Martin A1 - Ehlis, Ann-Christine A1 - Fallgatter, Andreas J. T1 - Simulation of Near-Infrared Light Absorption Considering Individual Head and Prefrontal Cortex Anatomy: Implications for Optical Neuroimaging JF - PLoS ONE N2 - Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: (25.0 +/- 2.8) years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes (V(gray)) traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of (23.6 +/- 0.7) mm considering the deepest 5% of light. Of the detected photon packages scalp and bone absorbed (96.4 +/- 9: 7)% and V(gray) absorbed (3.1 +/- 1.8)% of the energy. The mean V(gray) volume (1.1 +/- 0.4)cm(3) was negatively correlated (r = - .76) with the SCD and frontal sinus volume (r = - .57) and was reduced by 41.5% in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD (r = .46) and the traversed frontal sinus volume (r = .43). Sulcal morphology had no significant impact on V(gray). Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance. KW - Beer-lambert law KW - Adult head KW - Human brain KW - Spectroscopy fnirs KW - Photon migration KW - Propagation KW - Scattering KW - Model KW - Tissues KW - Media Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142311 VL - 6 IS - 10 ER - TY - JOUR A1 - Goepel, Johanna A1 - Biehl, Stefanie C. A1 - Kissler, Johanna A1 - Paul-Jordanov, Isabelle T1 - Pro- and antisaccades in children elicited by visual and acoustic targets - does modality matter? JF - BMC Pediatrics N2 - Background: Children are able to inhibit a prepotent reaction to suddenly arising visual stimuli, although this skill is not yet as pronounced as it is in adulthood. However, up to now the inhibition mechanism to acoustic stimuli has been scarcely investigated Methods: Reflexive (prosaccade) and inhibitory (antisaccade) responses to visual and acoustic targets were examined with an eye tracker system in 31 children between seven and twelve years of age using a gap-overlap task and two target eccentricities. Results: Acoustically cued saccades had longer reaction times than visually cued saccades. A gap effect (i.e., shorter reaction time in the gap than the overlap condition) was only found for visually elicited saccades, whereas an eccentricity effect (i.e., faster saccades to more laterally presented targets - 12 degrees vs. 6 degrees or rather 90 degrees vs. 45 degrees) was only present in the acoustic condition. Longer reaction times of antisaccades compared to prosaccades were found only in the visual task. Across both tasks the typical pattern of elevated error rates in the antisaccade condition was found. Antisaccade errors declined with age, indicating an ongoing development of inhibitory functions. Conclusions: The present results lay the ground for further studies of acoustically triggered saccades in typically as well as atypically developing children and it might thus be possible to upgrade physiological diagnostic tools. KW - Saccadic eye-movements KW - Auditory targets KW - Voluntary control KW - Task-performance KW - Latency KW - Prosaccade KW - Vergence KW - Stimuli KW - GAP Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141807 VL - 11 IS - 116 ER - TY - JOUR A1 - Glotzbach, Evelyn A1 - Mühlberger, Andreas A1 - Gschwendtner, Kathrin A1 - Fallgatter, Andreas J A1 - Pauli, Paul A1 - Herrmann, Martin J T1 - Prefrontal Brain Activation During Emotional Processing: A Functional Near Infrared Spectroscopy Study (fNIRS) JF - The Open Neuroimaging Journal N2 - The limbic system and especially the amygdala have been identified as key structures in emotion induction and regulation. Recently research has additionally focused on the influence of prefrontal areas on emotion processing in the limbic system and the amygdala. Results from fMRI studies indicate that the prefrontal cortex (PFC) is involved not only in emotion induction but also in emotion regulation. However, studies using fNIRS only report prefrontal brain activation during emotion induction. So far it lacks the attempt to compare emotion induction and emotion regulation with regard to prefrontal activation measured with fNIRS, to exclude the possibility that the reported prefrontal brain activation in fNIRS studies are mainly caused by automatic emotion regulation processes. Therefore this work tried to distinguish emotion induction from regulation via fNIRS of the prefrontal cortex. 20 healthy women viewed neutral pictures as a baseline condition, fearful pictures as induction condition and reappraised fearful pictures as regulation condition in randomized order. As predicted, the view-fearful condition led to higher arousal ratings than the view-neutral condition with the reappraise-fearful condition in between. For the fNIRS results the induction condition showed an activation of the bilateral PFC compared to the baseline condition (viewing neutral). The regulation condition showed an activation only of the left PFC compared to the baseline condition, although the direct comparison between induction and regulation condition revealed no significant difference in brain activation. Therefore our study underscores the results of previous fNIRS studies showing prefrontal brain activation during emotion induction and rejects the hypothesis that this prefrontal brain activation might only be a result of automatic emotion regulation processes. KW - fNIRS KW - Emotional processing KW - emotional regulation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141714 VL - 5 ER -