TY  - JOUR
AB  - DNA methylation of the FKBP5 gene is assumed to alter FKBP5 expression and hence the synthesis of the FK506 binding protein 51, a central element of a genomic negative feedback loop for glucocorticoid receptor signaling. The present study aimed to replicate and extend previously reported influences of FKBP5 genotypes, childhood maltreatment and depression on methylation levels of five CpG sites in intron 7 of the FKBP5 gene in a large population-based sample. Besides the single nucleotide polymorphism (SNP) rs1360780, associations of the FKBP5 methylation with 22 other, unlinked FKBP5 SNPs as well as associations between FKBP5 methylation levels and transcription levels were investigated. Using whole-blood methylation of 3965 subjects of the Study of Health in Pomerania (SHIP) reduced methylation levels in TT allele carriers of rs1360780 (OR = 0.975, p =.005) and currently depressed subjects (OR = 0.995, p = 0.005) were found. Further, an impact of two yet undescribed SNPs (rs6910300, rs7771727) on methylation levels was observed. However, main and interactive effects for childhood maltreatment and lifetime major depressive disorder observed in previous studies could not be replicated. Finally, FKBP5 methylation levels were not related to FKBP5 transcription levels in whole blood. Thus, the present study verified the associations of FKBP5 genotypes and state depression on the FKBP5 methylation levels of five CpG sites in intron 7. However, FKBP5 methylation of these five CpG sites could not be validated as a valuable clinical biomarker for biological long-term effects of childhood maltreatment or lifetime depression.
AU  - Klinger-König, J.*
AU  - Hertel, J.*
AU  - Van der Auwera, S.*
AU  - Frenzel, S.*
AU  - Pfeiffer, L.
AU  - Waldenberger, M.
AU  - Golchert, J.*
AU  - Teumer, A.*
AU  - Nauck, M.*
AU  - Homuth, G.*
AU  - Völzke, H.*
AU  - Grabe, H.J.*
C1  - 55441
C2  - 46363
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 930-938
TI  - Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression.
JO  - Neuropsychopharmacology
VL  - 44
IS  - 5
PB  - Nature Publishing Group
PY  - 2019
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Although sleep-dependent consolidation and its neurochemical underpinnings have been strongly researched, less is known about how consolidation during sleep affects subsequent learning. Since sleep enhances memory, it can be expected to pro-actively interfere with learning after sleep, in particular of similar materials. This pro-active interference should be enhanced by substances that benefit consolidation during sleep, such as D-cycloserine. We tested this hypothesis in two groups (Sleep, Wake) of young healthy participants receiving on one occasion D-cycloserine (175 mg) and on another occasion placebo, according to a double-blind balanced crossover design. Treatment was administered after participants had learned a set of word pairs (A-B list) and before nocturnal retention periods of sleep vs. wakefulness. After D-cycloserine blood plasma levels had dropped to negligible amounts, i.e., the next day in the evening, participants learned, in three sequential runs, new sets of word pairs. One list-to enhance interference-consisted of the same cue words as the original set paired with a new target word (A-C list) and the other of completely new cue words (D-E set). Unexpectedly, during post-retention learning the A-C interference list was generally better learned than the completely new D-E list, which suggests that consolidation of previously encoded similar material enhances memory integration rather than pro-active interference. Consistent with this view, new learning of word pairs was better after sleep than wakefulness. Similarly, D-cycloserine generally enhanced learning of new word pairs, compared to placebo. This effect being independent of sleep or wakefulness, leads us to speculate that D-cycloserine, in addition to enhancing sleep-dependent consolidation, might mediate a time-dependent process of active forgetting.
AU  - Asfestani, M.A.*
AU  - Braganza, E.*
AU  - Schwidetzky, J.*
AU  - Santiago, J.C.
AU  - Soekadar, S.*
AU  - Born, J.*
AU  - Feld, G.B.*
C1  - 54407
C2  - 45526
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 2292-2298
TI  - Overnight memory consolidation facilitates rather than interferes with new learning of similar materials-a study probing NMDA receptors.
JO  - Neuropsychopharmacology
VL  - 43
IS  - 11
PB  - Nature Publishing Group
PY  - 2018
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n =1522, age 32-72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient = 0.56 standard error (SE) = 0.10, p (Bonferroni) = 0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p =0.083) and a significant interaction among women (p =0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β= 0.005, SE=0.002, p= 0.021, n= 131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p= 0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders.
AU  - Emeny, R.T.
AU  - Baumert, J.J.
AU  - Zannas, A.S.*
AU  - Kunze, S.
AU  - Wahl, S.
AU  - Iurato, S.*
AU  - Knauer-Arloth, J.
AU  - Erhardt, A.*
AU  - Balsevich, G.*
AU  - Schmidt, M.V.*
AU  - Weber, P.*
AU  - Kretschmer, A.
AU  - Pfeiffer, L.
AU  - Kruse, J.*
AU  - Strauch, K.
AU  - Roden, M.*
AU  - Herder, C.*
AU  - Koenig, W.*
AU  - Gieger, C.
AU  - Waldenberger, M.
AU  - Peters, A.
AU  - Binder, E.B.*
AU  - Ladwig, K.-H.
C1  - 51192
C2  - 43111
CY  - London
SP  - 342-353
TI  - Anxiety associated increased CpG methylation in the promoter of Asb1: A translational approach evidenced by epidemiological and clinical studies and a murine model.
JO  - Neuropsychopharmacology
VL  - 43
IS  - 2
PB  - Nature Publishing Group
PY  - 2018
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18-30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information.
AU  - Feld, G.B.*
AU  - Wilhem, I.*
AU  - Benedict, C.*
AU  - Rüdel, B.*
AU  - Klameth, C.*
AU  - Born, J.
AU  - Hallschmid, M.
C1  - 47402
C2  - 39297
CY  - London
SP  - 1540-1550
TI  - Central nervous insulin signaling in sleep-associated memory formation and neuroendocrine regulation.
JO  - Neuropsychopharmacology
VL  - 41
IS  - 6
PB  - Nature Publishing Group
PY  - 2016
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Reward sensitivity and possible alterations in the dopaminergic-reward system are associated with obesity. We therefore aimed to investigate the influence of dopamine depletion on food-reward processing. We investigated 34 female subjects in a randomized placebo controlled, within-subject design (body mass index (BMI) = 27.0 kg/m(2) +/- 4.79 SD; age = 28 years +/- 4.97 SD) using an acute phenylalanine/tyrosine depletion drink representing dopamine depletion and a balanced amino acid drink as the control condition. Brain activity was measured with functional magnetic resonance imaging during a 'wanting' and 'liking' rating of food items. Eating behavior-related traits and states were assessed on the basis of questionnaires. Dopamine depletion resulted in reduced activation in the striatum and higher activation in the superior frontal gyms independent of BMI. Brain activity during the wanting task activated a more distributed network than during the liking task This network included gustatory, memory, visual, reward, and frontal regions. An interaction effect of dopamine depletion and the wanting/liking task was observed in the hippocampus. The interaction with the covariate BMI was significant in motor and control regions but not in the striatum. Our results support the notion of altered brain activity in the reward and prefrontal network with blunted dopaminergic action during food-reward processing. This effect is, however, independent of BMI, which contradicts the reward-deficiency hypothesis. This hints to the hypothesis suggesting a different or more complex mechanism underlying the dopaminergic reward function in obesity.
AU  - Frank, S.*
AU  - Veit, R.
AU  - Sauer, H.*
AU  - Enck, P.*
AU  - Friederich, H.*
AU  - Unholzer, T.*
AU  - Bauer, U.*
AU  - Linder, K.*
AU  - Heni, M.
AU  - Fritsche, A.
AU  - Preissl, H.
C1  - 48529
C2  - 41178
CY  - London
SP  - 1551-1559
TI  - Dopamine depletion reduces food-related reward activity independent of BMI.
JO  - Neuropsychopharmacology
VL  - 41
IS  - 6
PB  - Nature Publishing Group
PY  - 2016
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine which activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.
AU  - Patrício, P.*
AU  - Mateus-Pinheiro, A.*
AU  - Irmler, M.
AU  - Alves, N.D.*
AU  - Machado-Santos, A.R.*
AU  - Morais, M.*
AU  - Correia, J.S.*
AU  - Korostynski, M.*
AU  - Piechota, M.*
AU  - Stoffel, R.*
AU  - Beckers, J.
AU  - Bessa, J.M.*
AU  - Almeida, O.F.*
AU  - Sousa, N.*
AU  - Pinto, L.*
C1  - 31785
C2  - 34763
SP  - 338-349
TI  - Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus.
JO  - Neuropsychopharmacology
VL  - 40
IS  - 2
PY  - 2015
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies using baseline gene expression profiles have provided mixed results, our approach was to use an in vivo dexamethasone challenge test and to compare glucocorticoid receptor (GR)-mediated changes in gene expression between depressed patients and healthy controls. Whole genome gene expression data (baseline and following GR-stimulation with 1.5 mg dexamethasone p.o.) from two independent cohorts were analyzed to identify gene expression pattern that would predict case and control status using a training (N=18 cases/18 controls) and a test cohort (N=11/13). Dexamethasone led to reproducible regulation of 2670 genes in controls and 1151 transcripts in cases. Several genes, including FKBP5 and DUSP1, previously associated with the pathophysiology of major depression, were found to be reliable markers of GR-activation. Using random forest analyses for classification, GR-stimulated gene expression outperformed baseline gene expression as a classifier for case and control status with a correct classification of 79.1 vs 41.6% in the test cohort. GR-stimulated gene expression performed best in dexamethasone non-suppressor patients (88.7% correctly classified with 100% sensitivity), but also correctly classified 77.3% of the suppressor patients (76.7% sensitivity), when using a refined set of 19 genes. Our study suggests that in vivo stimulated gene expression in peripheral blood cells could be a promising molecular marker of altered GR-functioning, an important component of the underlying pathology, in patients suffering from depressive episodes.
AU  - Menke, A.*
AU  - Knauer-Arloth, J.*
AU  - Pütz, B.*
AU  - Weber, P.*
AU  - Klengel, T.*
AU  - Mehta, D.*
AU  - Gonik, M.*
AU  - Rex-Haffner, M.*
AU  - Rubel, J.*
AU  - Uhr, M.*
AU  - Lucae, S.*
AU  - Deussing, J.M.
AU  - Müller-Myhsok, B.*
AU  - Holsboer, F.*
AU  - Binder, E.B.*
C1  - 7514
C2  - 29773
SP  - 1455-1464
TI  - Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients.
JO  - Neuropsychopharmacology
VL  - 37
IS  - 6
PB  - Nature Publishing Group
PY  - 2012
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic-pituitary-adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1(NestinCre)) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1(NestinCre) mice as compared with control animals. Crhr1(NestinCre) mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.
AU  - Molander, A.*
AU  - Vengeliene, V.*
AU  - Heilig, M.*
AU  - Wurst, W.
AU  - Deussing, J.M.*
AU  - Spanagel, R.*
C1  - 6845
C2  - 29349
SP  - 1047-1056
TI  - Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking.
JO  - Neuropsychopharmacology
VL  - 37
IS  - 4
PB  - American College of Neuropsychopharmacology
PY  - 2012
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Persistent dreadful memories and hyperarousal constitute prominent psychopathological features of posttraumatic stress disorder (PTSD). Here, we used a contextual fear conditioning paradigm to demonstrate that conditional genetic deletion of corticotropin-releasing hormone (CRH) receptor 1 within the limbic forebrain in mice significantly reduced remote, but not recent, associative and non-associative fear memories. Per os treatment with the selective CRHR1 antagonist DMP696 (3 mg/kg) attenuated consolidation of remote fear memories, without affecting their expression and retention. This could be achieved, if DMP696 was administered for 1 week starting as late as 24 h after foot shock. Furthermore, by combining electrophysiological recordings and western blot analyses, we demonstrate a delayed-onset and long-lasting increase in AMPA receptor (AMPAR) GluR1-mediated signaling in the dentate gyrus (DG) of the dorsal hippocampus 1 month after foot shock. These changes were absent from CRHR1-deficient mice and after DMP696 treatment. Inactivation of hippocampal GluR1-containing AMPARs by antisense oligonucleotides or philantotoxin 433 confirmed the behavioral relevance of AMPA-type glutamatergic neurotransmission in maintaining the high levels of remote fear in shocked mice with intact CRHR1 signaling. We conclude that limbic CRHR1 receptors enhance the consolidation of remote fear memories in the first week after foot shock by increasing the expression of Ca(2+)-permeable GluR1-containing AMPARs in the DG. These findings suggest both receptors as rational targets for the prevention and therapy, respectively, of psychopathology associated with exaggerated fear memories, such as PTSD.
AU  - Thoeringer, C.K.*
AU  - Henes, K.*
AU  - Eder, M.*
AU  - Dahlhoff, M.*
AU  - Wurst, W.
AU  - Holsboer, F.*
AU  - Deussing, J.M.*
AU  - Moosmang, S.*
AU  - Wotjak, C.T.*
C1  - 6357
C2  - 29156
SP  - 787-796
TI  - Consolidation of remote fear memories involves corticotropin-releasing hormone (CRH) receptor type 1-mediated enhancement of AMPA receptor GluR1 signaling in the dentate gyrus.
JO  - Neuropsychopharmacology
VL  - 37
IS  - 3
PB  - Nature Publishing Group
PY  - 2012
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - There is considerable interest in examining the genes that may contribute to anxiety. We examined the function of ERK/MAPK in the acquisition of conditioned fear, as measured by fear-potentiated startle (FPS) in mice as a model for anticipatory anxiety in humans. We characterized the following for the first time in the mouse: (1) the expression of the ERK/MAPK signaling pathway components at the protein level in the lateral amygdala (LA); (2) the time course of activation of phospho-activated MAPK in the LA after fear conditioning; (3) if pharmacological inhibition of pMAPK could modulate the acquisition of FPS; (4) the cell-type specificity of pMAPK in the LA after fear conditioning. Using western blot and immunohistochemistry techniques and injecting the MEK inhibitor U0126 in the LA, we showed the following: (1) both MEK1/MEK2 and ERK1/ERK2 were co-expressed in the LA of the adult mouse brain; (2) there is a peak of pMAPK at 60 min after fear conditioning; (3) the ERK/MAPK signaling pathway activation is essential for the acquisition of an FPS response; (4) at 60 min, the pMAPK are exclusively neuronal and not glial. These results emphasize the importance of this signaling pathway in the acquisition of conditioned fear in the mouse. Given the widely held view that conditioned fear models the essential aspects of anxiety disorders, the results confirm the ERK/MAPK signaling pathway as a molecular target for the treatment of anxiety disorders in the clinic.
AU  - di Benedetto, B.
AU  - Kallnik, M.
AU  - Vogt Weisenhorn, D.M.
AU  - Falls, W.A.*
AU  - Wurst, W.
AU  - Hölter, S.M.
C1  - 146
C2  - 26079
SP  - 356-366
TI  - Activation of ERK/MAPK in the lateral amygdala of the mouse is required for acquisition of a fear-potentiated startle response.
JO  - Neuropsychopharmacology
VL  - 34
IS  - 2
PB  - Nature Publ. Group
PY  - 2009
SN  - 0893-133X
ER  - 

TY  - JOUR
AB  - Corticotropin-releasing factor (CRF) peptides and their receptors have crucial roles in behavioral and endocrine responses to stress. Dysregulation of CRF signaling has been linked to post-traumatic stress disorder, which is associated with increased startle reactivity in response to threat. Thus, understanding the mechanisms underlying CRF regulation of startle may identify pathways involved in this disorder. Here, we tested the hypothesis that both CRF1 and CRF2 receptors contribute to fear-induced increases in startle. Startle responses of wild type (WT) and mice with null mutations (knockout, KO) for CRF1 or CRF2 receptor genes were measured immediately after footshock (shock sensitization) or in the presence of cues previously associated with footshock (ie fear-potentiated startle, FPS). WT mice exhibited robust increases in startle immediately after footshock, which was dependent upon contextual cues. This effect was completely absent in CRF1 KO mice, and significantly attenuated in CRF2 KO mice. In contrast, CRF1 and CRF2 KO mice exhibited normal potentiation of startle by discrete conditioned cues. Blockade of both receptors via CRF1 receptor antagonist treatment in CRF2 KO mice also had no effect on FPS. These results support an additive model of CRF1 and CRF2 receptor activation effects on potentiated startle. These data also indicate that both CRF receptor subtypes contribute to contextual fear but are not required for discrete cued fear effects on startle reactivity. Thus, we suggest that either CRF1 or CRF2 could contribute to the increased startle observed in anxiety disorders with CRF system abnormalities.
AU  - Risbrough, V.B.*
AU  - Geyer, M.A.*
AU  - Hauger, R.L.*
AU  - Coste, S.*
AU  - Stenzel-Poore, M.*
AU  - Wurst, W.
AU  - Holsboer, F.*
C1  - 5846
C2  - 26031
SP  - 1494-1503
TI  - CRF1 and CRF2 receptors are required for potentiated startle to contextual but not discrete cues.
JO  - Neuropsychopharmacology
VL  - 34
IS  - 6
PB  - Nature Publ. Group
PY  - 2009
SN  - 0893-133X
ER  -