Klaus-Peter Lesch

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (244)1171.74 Total impact

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    ABSTRACT: In line with the assumption that emotional-motivational deficits are one core dysfunction in ADHD, in one of our previous studies we observed a reduced reactivity towards pleasant pictures in adult ADHD patients as compared to controls. This was indicated by a lack of attenuation of the startle reflex specifically during pleasant pictures in ADHD patients. The first choice medical agents in ADHD, methylphenidate (MPH), is discussed to normalize these dysfunctions. However, experimental evidence in the sense of double-blind placebo-controlled study designs is lacking. Therefore, we investigated 61 adult ADHD patients twice, one time with placebo and one time with MPH with the same experimental design as in our study previously and assessed emotion processing during the presentation of pleasant, neutral and unpleasant pictures. We obtained startle reflex data as well as valence and arousal ratings in association with the pictures. As previously shown, ADHD patients showed a diminished startle attenuation during pleasant pictures while startle potentiation during unpleasant pictures was normal. Valence and arousal ratings unsuspiciously increased with increasing pleasantness and arousal of the pictures, respectively. There were no significant influences of MPH. The study replicates that ADHD patients show a reduced reactivity towards pleasant stimuli. MPH did not normalize this dysfunction. Possibly, MPH only influences emotions during more complex behavioural tasks that involve executive functions in adults with ADHD. Our results emphasize the importance for the use of double-blind placebo-controlled designs in psychopharmacological research.
    No preview · Article · Feb 2016 · Journal of Neural Transmission
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    ABSTRACT: Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreERT2 mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.
    No preview · Article · Feb 2016 · Scientific Reports
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    ABSTRACT: Brain Derived Neurotrophic Factor (BDNF) is a crucial regulator of neuronal development, organization and function and the val66met polymorphism in the BDNF gene has been associated with several (endo-) phenotypes of cognitive and affective processing. The BDNF met allele is considered a risk factor for anxiety and fear related phenotypes although findings are not entirely consistent. Here, the impact of BDNF val66met on two parameters of anxiety and stress was investigated in a series of studies. Acoustic startle responses were assessed in three adult samples (N1 = 117, N2 = 104, N3 = 116) as well as a children sample (N4 = 123). Cortisol increase in response to the Trier Social Stress Test (TSST) was measured in one adult sample (N3) and in the children sample (N4). The BDNF met allele was associated with enhanced cortisol responses in young adults (p = 0.039) and children (p = 0.013). On the contrary, BDNF met allele carriers showed a reduced acoustic startle response which reached significance in most samples (N1: p = 0.004; N2: p = 0.045; N3: n.s., N4: p = 0.043) pointing to differential effects of BDNF val66met on distinct endophenotypes of anxiety and stress-related responses. However, small effect sizes suggest substantial additional genetic as well as environmental contributors.
    No preview · Article · Dec 2015 · Psychoneuroendocrinology
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    ABSTRACT: Mood and anxiety disorders are prevalent conditions affecting one out of four people during lifetime. The development of high validity animal models to study these disorders has been a major challenge in the past. When considering experimental approaches for studying affective disorders, the social defeat paradigm has been shown to have etiological, predictive and face validity. Here, we explain the general principle of social defeat stress paradigms, with a strong focus on the resident-intruder model and compare different experimental settings as published to date. We discuss behavioral changes described in defeated animals as well as changes in the animal's physiological parameters. In addition, we provide an overview of the molecular adaptations that are found in animals subjected to defeat stress, with special attention to neural circuits and neuroendocrine signaling. Defeat produces specific behaviors resembling the signs and symptoms of humans with affective disorders, such as anhedonia, social avoidance, despair and anxiety. These can be linked to a wide range of physiological changes-ranging from cardiovascular changes to alterations in the immune system- or by disturbances in specific neurotransmitter systems, in particular serotonin and dopamine. The defeat stress model thus impacts on several functional domains of behavior and may mimic cardinal features of a multitude of psychiatric disorders including depression, post-traumatic stress disorder and schizophrenia. This manuscript critically reviews the core findings, strengths and limitation of the range of animal studies in this field and provides future perspectives.
    No preview · Article · Oct 2015 · Neuroscience & Biobehavioral Reviews
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    ABSTRACT: Considerable evidence links dysfunction of serotonin (5-hydroxytryptamine, 5-HT) transmission to neurodevelopmental and psychiatric disorders characterized by compromised "social" cognition and emotion regulation. It is well established that the brain 5-HT system is under autoregulatory control by its principal transmitter 5-HT via its effects on activity and expression of 5-HT system-related proteins. To examine whether 5-HT itself also has a crucial role in the acquisition and maintenance of characteristic rhythmic firing of 5-HT neurons, we compared their intrinsic electrophysiological properties in mice lacking brain 5-HT, i.e. tryptophan hydroxylase-2 null mice (Tph2(-/-)) and their littermates, Tph2(+/-) and Tph2(+/+), by using whole-cell patch-clamp recordings in a brainstem slice preparation and single unit recording in anesthetized animals. We report that the active properties of dorsal raphe nucleus (DRN) 5-HT neurons in vivo (firing rate magnitude and variability; the presence of spike doublets) and in vitro (firing in response to depolarizing current pulses; action potential shape) as well as the resting membrane potential remained essentially unchanged across Tph2 genotypes. However, there were subtle differences in subthreshold properties, most notably, an approximately 25% higher input conductance in Tph2(-/-) mice compared with Tph2(+/-) and Tph2(+/+) littermates (p<0.0001). This difference may at least in part be a consequence of slightly bigger size of the DRN 5-HT neurons in Tph2(-/-) mice (approximately 10%, p<0.0001). Taken together, these findings show that 5-HT neurons acquire and maintain their signature firing properties independently of the presence of their principal neurotransmitter 5-HT, displaying an unexpected functional resilience to complete brain 5-HT deficiency.
    No preview · Article · Sep 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    ABSTRACT: Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1f-VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21-repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21-repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Jun 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics

  • No preview · Conference Paper · May 2015
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    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 naïve 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 naïve 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.
    Full-text · Article · Mar 2015 · Frontiers in Behavioral Neuroscience
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    ABSTRACT: Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals. Our study is cross-sectional and applies self-report questionnaires. Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
    Full-text · Article · Mar 2015 · PLoS ONE
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    ABSTRACT: Administration of neuropeptide S (NPS) elicits anxiolysis, arousal and higher activity in rodents. In humans, the NPS receptor (NPSR1) gene rs324981 A/T (Asn(107)Ile) polymorphism is associated with fear responses and anxiety. We have recently revealed an association of NPSR1 with impulsivity-related traits and psychopathology. In the present study the association of the NPSR1 genotype with impulsivity and attention-deficit/hyperactivity disorder (ADHD)-related symptoms was re-examined in two independent non-clinical cohorts. We used self-reports of two population-derived samples of the Estonian Psychobiological Study of Traffic Behaviour (EPSTB): a community car driving sample (n=491, MAge=37) and a driving school student sample (n=773, MAge=24). Impulsivity was measured with the Adaptive and Maladaptive Impulsivity Scale (AMIS) in both samples, and with the Barratt Impulsivity Scale (BIS) in driving schools only. For the latter sample, also measurement of ADHD symptoms was carried out with the Adult ADHD Self-Report Scale (ASRS). NPSR1 T-allele carriers had higher scores of impulsivity, motor restlessness and total ADHD scores. The effect on impulsivity originated from male participants but for ADHD symptoms the association was independent of sex. Thus we have confirmed in two additional population-derived samples that the T-allele of the NPSR1 rs324981 polymorphism is associated with increased impulsivity and ADHD-related traits. © The Author(s) 2015.
    No preview · Article · Mar 2015 · Journal of Psychopharmacology
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    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-HTT) 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.
    Full-text · Article · Mar 2015 · Frontiers in Behavioral Neuroscience
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    ABSTRACT: While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2(-/-)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2(-/-) males displayed increased impulsivity and high aggressiveness. Tph2(-/-) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2(-/-) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
    Full-text · Article · Feb 2015 · Psychopharmacology
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    ABSTRACT: An association between metabolic abnormalities, hypercholesterolemia and affective disorders is now well recognized. Less well understood are the molecular mechanisms, both in brain and in the periphery, that underpin this phenomenon. In addition to hepatic lipid accumulation and inflammation, C57BL/6J mice fed a high-cholesterol diet (0.2%) to induce Non-Alcoholic Fatty Liver Disease (NAFLD), exhibited behavioural despair, anxiogenic changes, and hyperlocomotion under bright light. These abnormalities were accompanied by increased expression of transcript and protein for Toll-like receptor 4, a pathogen-associated molecular pattern (PAMP) receptor, in the prefrontal cortex and the liver. The behavioural changes and Tlr4 expression were reversed ten days after discontinuation of the high-cholesterol diet. Remarkably, the dietary fat content and body mass of experimental mice were unchanged, suggesting a specific role for cholesterol in the molecular and behavioural changes. Expression of Sert and Cox1 were unaltered. Together, our study has demonstrated for the first time that high consumption of cholesterol results in depression- and anxiety-like changes in C57BL/6J mice and that these changes are unexpectedly associated with the increased expression of TLR4, which suggests that TLR4 may have a distinct role in the CNS unrelated to pathogen recognition. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Brain Behavior and Immunity
  • Dominik P Kiser · Olga Rivero · Klaus-Peter Lesch
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    ABSTRACT: Neurodevelopmental disorders (NDDs) are defined by a wide variety of behavioural phenotypes, psychopathology and clinically informed categorical classifications. Diagnostic entities include intellectual disability (ID), the autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD). The aetiopathogenesis of these conditions and disorders involves an interaction between both genetic and environmental risk factors on the developmental trajectory. Despite their remarkable genetic heterogeneity and complexity of pathophysiological mechanisms, NDDs display an overlap in their phenotypic features, a considerable degree of comorbidity as well as sharing of genetic and environmental risk factors. This review aims to provide an overview of the genetics and epigenetic of NDDs. Recent evidence suggests a critical role of defined and tightly regulated neurodevelopmental programs running out of control in NDDs, most notably neuronal proliferation and migration, synapse formation and remodelling, as well as neural network configuration resulting in compromised systems connectivity and function. Moreover, the machinery of epigenetic programming, interacting with genetic liability, impacts many of those processes and pathways, thus modifying vulnerability of, and resilience to, NDDs. Consequently, the categorically defined entities of ID, ADHD and ASD are increasingly viewed as disorders on a multidimensional continuum of molecular and cellular deficiencies in neurodevelopment. As such, this range of NDDs displays a broad phenotypic diversity, which may be explained by a combination and interplay of underlying loss- and potential gain-of-function traits. In this overview, we discuss a backbone continuum concept of NDDs by summarizing pertinent findings in genetics and epigenetics. We also provide an appraisal of the genetic overlap versus differences, with a focus on genome-wide screening approaches for (epi)genetic variation. Finally, we conclude with insights from evolutionary psychobiology suggesting positive selection for discrete NDD-associated traits. © 2015 Association for Child and Adolescent Mental Health.
    No preview · Article · Feb 2015 · Journal of Child Psychology and Psychiatry
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    ABSTRACT: Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and molecular genetic approaches. A large multigenerational pedigree was ascertained within a Dagestan Genetic Heritage research program in a genetic isolate of indigenous ethnics. Clinical characteristics of the affected members were based on combining diagnoses from regional psychiatric hospitals with our own clinical assessment, using a Russian translation of the structured psychiatric interviews, the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies, based on DSM-IV criteria. Weber/CHLC 9.0 STRs set was used for multipoint parametric linkage analyses (Simwalk2.91). Next, we checked CNVs and LOH (based on Affymetrix SNP 5.0 data) in the linked with ID genomic regions with the aim to identify candidate genes associated with mutations in linked regions. The number of statistically significant (p ≤ 0.05) suggestive linkage peaks with 1.3 < LOD < 3.0 we detected in a total of 10 genomic regions: 1q41, 2p25.3-p24.2, 3p13-p12.1, 4q13.3, 10p11, 11q23, 12q24.22-q24.31, 17q24.2-q25.1, 21q22.13 and 22q12.3-q13.1. Three significant linkage signals with LOD >3 were obtained at 2p25.3-p24.2 under the dominant model, with a peak at 21 cM flanked by loci D2S2976 and D2S2952; at 12q24.22-q24.31 under the recessive model, with a peak at −120 cM flanked by marker D12S2070 and D12S395 and at 22q12.3 under the dominant model, with a peak at 32 cM flanked by marker D22S683 and D22S445. After a set of genes had been designated as possible candidates in these specific chromosomal regions,we conducted an exploratory search for LOH and CNV based on microarray data to detect structural genomic variants within five ID-linked regions with LOD scores between 2.0 and 3.9. In these selected regions we obtained 173 ROH segments and 98 CN segments. Further analysis of region 2p25.3-p24.2 revealed deletions within genes encoding MYTL, SNTG2 and TPO among five of 21 affected cases at 2p25.3-p24.2. In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500–6,472 kb) and for healthy control 682 kb (531–986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1. Seven of 21 affected pedigree members displayed segmental deletions at 22q12.3 that includes the gene LARGE. Eight affected pedigree members carried ROH segments and 6 CN segments at 10p11.23-p11.21 containing the genes ZEB1, c10orf68 and EPC1. Our linkage and structural genomic variation analyses in a remote highland genetic isolate with aggregation of ID demonstrated that even highly isolated single kindred ID has oligo/polygenic pathogenesis. The results obtained implicate 10 genomic regions linked with ID that contain some of previously reported candidate genes, including HRK, FBXW8, TESC, CDK2AP1 and SBNO1 at 12q24 that were shown in recent studies as associated with brain measures derived from MRI scans.
    Full-text · Article · Jan 2015 · Journal of Neural Transmission
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    ABSTRACT: Over the past years, certain "vulnerability genes" have been identified that play a key role in the development of mood and anxiety disorders. In particular, a low-expressing variant of the human serotonin transporter (5-HTT) gene has been described that renders individuals more susceptible to adverse experience and hence to the development of psychiatric diseases. However, some authors have recently argued that lower 5-HTT expression not only increases vulnerability to adverse experiences, but also enhances susceptibility to beneficial experiences, thus promoting phenotypic plasticity. The aim of the present study was to assess the effects of 5-HTT expression on susceptibility to beneficial experience in a hypothesis-driven experimental approach. Using a well-established rodent model for the human polymorphism, male heterozygous 5-HTT knockout (HET) and 5-HTT wildtype (WT) mice were either provided with the beneficial experience of cohabitation with a female (mating experience) or kept as naïve controls in single-housing conditions. Following the experimental treatment, they were tested for their anxiety-like behaviour and exploratory locomotion in three widely used behavioural tests. Interestingly, while cohabitation reduced anxiety-like behaviour and increased exploratory locomotion in the open field test in HET mice, it did not affect WT mice, pointing to a genotype-dependent susceptibility to the beneficial experience. Thus, our results might support the view of the low expressing version of the 5-HTT gene as a "plasticity" rather than a "vulnerability" variant. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jan 2015 · Behavioural Brain Research
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    ABSTRACT: Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. The present study - for the first time applying a multi-level epigenetic approach - investigates the role of OXTR gene methylation in categorical, dimensional and intermediate neuroendocrinological/neural network phenotypes of social anxiety. One-hundred and ten unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale, SPS; Social Interaction Anxiety Scale, SIAS), salivary cortisol response during the Trier Social Stress Test (TSST) and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3:8 809 437 was associated with (1) the categorical phenotype of SAD (p<0.001, Cohen's d=0.535), (2) increased SPS and SIAS scores (p<0.001), (3) increased cortisol response to the TSST (p=0.02), and (4) increased amygdala responsiveness during social phobia related word processing (right: pcorr<0.001; left: pcorr=0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system.Neuropsychopharmacology accepted article preview online, 07 January 2015. doi:10.1038/npp.2015.2.
    Full-text · Article · Jan 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    ABSTRACT: Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use.
    No preview · Article · Dec 2014 · Behavioural Pharmacology
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    ABSTRACT: Environmental factors can significantly affect disease prevalence, including neuropsychiatric disorders such as depression. The ratio of deuterium to protium in water shows substantial geographical variation, which could affect disease susceptibility. Thus the link between deuterium content of water and depression was investigated, both epidemiologically, and in a mouse model of chronic mild stress. We performed a correlation analysis between deuterium content of tap water and rates of depression in regions of the USA. Next, we used a 10-day chronic stress paradigm to test whether 2-week deuterium-depleted water treatment (91 ppm) affects depressive-like behavior and hippocampal structure. The effect of deuterium-depletion on sleep electrophysiology was also evaluated in naïve mice. There was a geographic correlation between a content of deuterium and the prevalence of depression across the USA. In the chronic stress model, depressive-like features were reduced in mice fed with deuterium-depleted water, and SERT expression was decreased in mice treated with deuterium-treated water compared with regular water. Five days of predator stress also suppressed proliferation in the dentate gyrus; this effect was attenuated in mice fed with deuterium-depleted water. Finally, in naïve mice, deuterium-depleted water treatment increased EEG indices of wakefulness, and decreased duration of REM sleep, phenomena that have been shown to result from the administration of selective serotonin reuptake inhibitors (SSRI). Our data suggest that the deuterium content of water may influence the incidence of affective disorder-related pathophysiology and major depression, which might be mediated by the serotoninergic mechanisms.
    Full-text · Article · Dec 2014 · Behavioural Brain Research
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    ABSTRACT: Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.
    Full-text · Article · Oct 2014 · Frontiers in Behavioral Neuroscience

Publication Stats

10k Citations
1,171.74 Total Impact Points


  • 2013-2015
    • Maastricht University
      Maestricht, Limburg, Netherlands
  • 1998-2015
    • University of Wuerzburg
      • • Division of Molecular Psychiatry
      • • Department of Psychiatry, Psychosomatics, and Psychotherapy
      • • Institute of Organic Chemistry
      Würzburg, Bavaria, Germany
  • 2012
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2011
    • The University of Edinburgh
      • Centre for Cognitive and Neural Systems
      Edinburgh, Scotland, United Kingdom
  • 2004-2009
    • National Institute of Mental Health (NIMH)
      • • Laboratory of Molecular Pathophysiology
      • • Laboratory of Clinical Science
      Maryland, United States
  • 1999
    • Loyola University
      New Orleans, Louisiana, United States
    • Ben-Gurion University of the Negev
      Be'er Sheva`, Southern District, Israel