@article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126845}, pages = {573-579}, year = {2012}, abstract = {RATIONALE: The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. OBJECTIVES: Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. METHODS: We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. RESULTS: Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. CONCLUSIONS: Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129936}, pages = {573-579}, year = {2012}, abstract = {Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{ClineCostaNunesCespuglioetal.2015, author = {Cline, Brandon H. and Costa-Nunes, Joao P. and Cespuglio, Raymond and Markova, Natalyia and Santos, Ana I. and Bukhman, Yury V. and Kubatiev, Aslan and Steinbusch, Harry W. M. and Lesch, Klaus-Peter and Strekalova, Tatyana}, title = {Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression}, series = {Frontiers in Behavioral Neuroscience}, volume = {9}, journal = {Frontiers in Behavioral Neuroscience}, number = {37}, doi = {10.3389/fnbeh.2015.00037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143992}, year = {2015}, abstract = {Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naive DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naive animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.}, language = {en} } @article{BrevikvanDonkelaarWeberetal.2016, author = {Brevik, Erlend J and van Donkelaar, Marjolein M. J. and Weber, Heike and S{\´a}nchez-Mora, Cristina and Jacob, Christian and Rivero, Olga and Kittel-Schneider, Sarah and Garcia-martinez, Iris and Aebi, Marcel and van Hulzen, Kimm and Cormand, Bru and Ramos-Quiroga, Josep A and Lesch, Klaus-Peter and Reif, Andreas and Ribases, Marta and Franke, Barbara and Posserud, Maj-Britt and Johansson, Stefan and Lundervold, Astri J. and Haavik, Jan and Zayats, Tetyana}, title = {Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder}, series = {American Journal of Medical Genetics Part B-Neuropsychiatric Genetics}, volume = {171B}, journal = {American Journal of Medical Genetics Part B-Neuropsychiatric Genetics}, number = {5}, organization = {IMAGE Consortium}, doi = {10.1002/ajmg.b.32434}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188116}, pages = {733-747}, year = {2016}, abstract = {Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40\%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders.}, language = {en} } @article{BoddenRichterSchreiberetal.2015, author = {Bodden, Carina and Richter, S. Helene and Schreiber, Rebecca S. and Kloke, Vanessa and Gerß, Joachim and Palme, Rupert and Lesch, Klaus-Peter and Lewejohann, Lars and Kaiser, Sylvia and Sachser, Norbert}, title = {Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype}, series = {Frontiers in Behavioral Neuroscience}, volume = {9}, journal = {Frontiers in Behavioral Neuroscience}, number = {47}, doi = {10.3389/fnbeh.2015.00047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143723}, year = {2015}, abstract = {Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered.}, language = {en} } @article{AraragiMlinarBaccinietal.2013, author = {Araragi, Naozumi and Mlinar, Boris and Baccini, Gilda and Gutknecht, Lise and Lesch, Klaus-Peter and Corradetti, Renato}, title = {Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis}, series = {Frontiers in Neuropharmacology}, journal = {Frontiers in Neuropharmacology}, doi = {10.3389/fphar.2013.00097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97098}, year = {2013}, abstract = {Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.}, language = {en} }