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  • 1
    Keywords: brain ; EXPRESSION ; MODEL ; MODELS ; SYSTEM ; COHORT ; GENE ; PROTEIN ; transcription ; DRUG ; MICE ; RESPONSES ; MECHANISM ; TRANSCRIPTION FACTOR ; RATS ; mechanisms ; BINDING ; ALPHA ; CREB ; ELEMENT ; ELEMENT-BINDING PROTEIN ; ISOFORM ; MUTANT ; NERVOUS-SYSTEM ; NO ; TARGETED MUTATION ; DECREASE ; STRESS ; MUTATION ; MODULATION ; REGION ; REGIONS ; Jun ; INVOLVEMENT ; BEHAVIOR ; FOOD ; LACKING ; BINDING PROTEIN ; molecular ; BINDING-PROTEIN ; MOLECULAR-MECHANISM ; DEPENDENCE ; NEURONS ; KNOCKOUT MICE ; ADDICTION ; CERULEUS ; conditioned place preference ; emotional behavior ; locus coeruleus ; LOCUS-COERULEUS NEURONS ; MOLECULAR-MECHANISMS ; NEURAL PLASTICITY ; opiate addiction ; OPIATE-WITHDRAWAL
    Abstract: The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Creb / (NesCre)). A genetically defined cohort of the previously described hypomorphic Creb / (alphaDelta) mice, in which the two major transcriptionally active isoforms (alpha and Delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb / mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb / mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine
    Type of Publication: Journal article published
    PubMed ID: 15029152
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  • 2
    Keywords: brain ; EXPRESSION ; Germany ; human ; GENE ; transcription ; MICE ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; MARKER ; PHOSPHORYLATION ; ASSOCIATION ; polymorphism ; CAMP ; ELEMENT-BINDING PROTEIN ; PATTERNS ; CYCLIC-AMP ; molecular ; PATTERN ; LIGHT ; analysis ; MEDICINE ; CIRCADIAN CLOCK ; MAJOR DEPRESSION ; SUPRACHIASMATIC-NUCLEI
    Abstract: Activation of the transcription factor CREB by Ser142 phosphorylation is implicated in synchronizing circadian rhythmicity, which is disturbed in many depressive patients. Hence, one could assume that emotional behaviour and neuroendocrinological markers would be altered in CREBS142A mice, in which serine 142 is replaced by alanine, preventing phosphorylation at this residue. Moreover, associations of CREB Ser142 and seasonal affective disorder (SAD) might be detectable by the analysis of single-nucleotide polymorphisms (SNPs) in the CREB gene close to the Ser142 residue in SAD patients. However, neither CREBS142A mice demonstrate features of depression, nor there is evidence for an association of SAD with the CREB genotypes. Nevertheless, in humans there is an association of a global seasonality score and circadian rhythmicity with the CREB genotypes in healthy control probands, but not SAD patients. This parallels the phenotype of CREBS142A mice, presenting alterations of circadian rhythm and light-induced entrainment. Thus it is reasonable to assume that CREB Ser142 represents a molecular switch in mice and men, which is responsible for the (dys)regulation of circadian rhythms. (C) 2007 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17574346
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  • 3
    Abstract: Recent clinical evidence for the effectiveness of new antipsychotic drugs that specifically target glutamate receptors has rekindled interest in the glutamatergic system regarding pathophysiology and treatment of schizophrenia. The glutamatergic hypothesis of schizophrenia was triggered by the clinical/behavioural observation that NMDA receptor antagonists can induce psychosis in humans and abnormal behaviour with schizophrenia-like symptoms in animals. Initial models focused on NMDA receptor hypofunction as a potential pathogenetic mechanism. More recent genetic and pharmacological studies revealed that malfunction of other components of the glutamatergic system might also be relevant in explaining specific symptoms of this complex disease. Here, we review mutant mouse models with relevance for schizophrenia. These rodent models, in which specific glutamate receptor subtypes or various components of their intracellular transduction machinery are genetically altered, permit a detailed dissection of the contribution of different components of the glutamate system in inducing schizophrenia-like behaviours. They may provide insight into the pathophysiology of schizophrenia and prove useful in the development of new therapeutics.
    Type of Publication: Journal article published
    PubMed ID: 19651155
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  • 4
    Abstract: Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.
    Type of Publication: Journal article published
    PubMed ID: 11970866
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  • 5
    Keywords: IN-VIVO ; sensitivity ; AMYGDALA ; CORTICOTROPIN-RELEASING-FACTOR ; POSTTRAUMATIC-STRESS-DISORDER ; EXTINCTION ; GLUCOCORTICOID-RECEPTOR GENE ; MEDIAL PREFRONTAL CORTEX ; ANXIETY-RELATED BEHAVIOR ; PTSD
    Abstract: BACKGROUND: Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis.MethodIn this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. RESULTS: Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala-prefrontal connectivity. CONCLUSIONS: This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.
    Type of Publication: Journal article published
    PubMed ID: 22410078
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  • 6
    Abstract: The gene tailless is a member of the superfamily of genes that encode transcription factors of the ligand-activated nuclear receptor type, and is expressed in the invertebrate and vertebrate brain. In mice, its transcripts are restricted to the periventricular zone of the forebrain, the site of origin of neurons and glia. Here we use homologous recombination to generate mice that lack a functional tailless protein. Homozygous mutant mice are viable at birth, indicating that tailless is not required for prenatal survival; however, adult mutant mice show a reduction in the size of rhinencephalic and limbic structures, including the olfactory, infrarhinal and entorhinal cortex, amygdala and dentate gyrus. Both male and female mice are more aggressive than usual and females lack normal maternal instincts. These animals therefore enable a molecular approach to be taken towards understanding the genetic architecture and morphogenesis of the forebrain.
    Type of Publication: Journal article published
    PubMed ID: 9394001
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  • 7
    Keywords: brain ; RECEPTOR ; EXPRESSION ; MODEL ; GENE ; METABOLISM ; MICE ; TIME ; RESPONSES ; MESSENGER-RNA ; DISORDER ; MEMORY ; fear conditioning ; hormone ; PLASMA ; STRESS ; inactivation ; NETHERLANDS ; CORTICOSTERONE ; RECEPTORS ; BEHAVIOR ; DISORDERS ; MS ; mineralocorticoid receptor ; FOREBRAIN ; EVENTS ; USA ; GLUCOCORTICOID-RECEPTORS ; ANXIETY ; Emotion ; INDIVIDUAL-DIFFERENCES ; Unconditioned behavior
    Abstract: The stress hormone corticosterone acts via two receptor types in the brain: the mineralocorticoid (MR) and the glucocorticoid receptor (GR). Both receptors are involved in processing of stressful events. A disbalance of MR:GR functions is thought to promote stress-related disorders. Here we studied the effect of stress on emotional and cognitive behaviors in mice with forebrain-specific inactivation of the MR gene (MRCaMKCre. 4 months old; and control littermates). MRCaMKCre mice responded to prior stress (5 min of restraint) with higher arousal and less locomotor activity in an exploration task. A fear conditioning paradigm allowed assessing in one experimental procedure both context- and cue-related fear. During conditioning, MRCaMKCre mice expressed more cue-related freezing. During memory test, contextual freezing remained potentiated, while control mice distinguished between cue (more freezing) and context episodes (less freezing) in the second memory test. At this time, plasma corticosterone levels of MRCaMKCre mice were 40% higher than in controls. We conclude that control of emotional arousal and adaptive behaviors is lost in the absence of forebrain MR, and thus, anxiety-related responses are and remain augmented. We propose that such a disbalance in MR:GR functions in MRCaMKCre mice provides the conditions for an animal model for anxiety-related disorders. (C) 2009 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19447109
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  • 8
    Keywords: brain ; CELLS ; EXPRESSION ; PATHWAY ; MICE ; MOUSE ; CELL-DEATH ; TUMOR-SUPPRESSOR GENE ; CRE RECOMBINASE ; ANIMAL-MODELS ; MAMMALIAN TARGET ; neurodegeneration ; mTOR ; NIGROSTRIATAL SYSTEM ; MOTOR DEFICITS ; NUCLEOLAR DISRUPTION
    Abstract: Parkinson's disease (PD) is a progressive age-related movement disorder that results primarily from the selective loss of midbrain dopaminergic (DA) neurons. Symptoms of PD can be induced by genetic mutations or by DA neuron-specific toxins. A specific ablation of an essential factor controlling ribosomal RNA transcription, TifIa, in adult mouse DA neurons represses mTOR signaling and leads to progressive neurodegeneration and PD-like phenotype. Using an inducible Cre system in adult mice, we show here that the specific ablation of Pten in adult mouse DA neurons leads to activation of mTOR pathway and is neuroprotective in genetic (TifIa deletion) and neurotoxin-induced (MPTP or 6OHDA) mouse models of PD. Adult mice with DA neuron-specific Pten deletion exhibit elevated expression of tyrosine hydroxylase, a rate-limiting enzyme in the dopamine biosynthesis pathway, associated with increased striatal dopamine content, and increased mRNA levels of Foxa2, Pitx3, En1, Nurr1, and Lmx1b-the essential factors for maintaining physiological functions of adult DA neurons. Pten deletion attenuates the loss of tyrosine hydroxylase-positive cells after 6OHDA treatment, restores striatal dopamine in TifIa-knockout and MPTP-treated mice, and rescues locomotor impairments caused by TifIa loss. Inhibition of Pten-dependent functions in adult DA neurons may represent a promising PD therapy.-Domanskyi, A., Geissler, C., Vinnikov, I. A., Alter, H., Schober, A., Vogt, M. A., Gass, P., Parlato, R., Schutz, G. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models.
    Type of Publication: Journal article published
    PubMed ID: 21593433
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  • 9
    Keywords: brain ; EXPRESSION ; transcription ; TRANSGENIC MICE ; BEHAVIOR ; secretion ; CORTICOTROPIN-RELEASING-FACTOR ; IMPAIRED STRESS-RESPONSE ; ELEVATED PLUS-MAZE ; ADRENOCORTICAL REGULATION
    Abstract: The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune and nervous system responses and ensure an adequate profile of transcription. In the brain, Gr has been proposed to modulate emotional behaviour, cognitive functions and addictive states. Previously, these aspects were not studied in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth (F.T., C.K. and G.S., unpublished data). Therefore, we generated tissue-specific mutations of this gene using the Cre/loxP -recombination system. This allowed us to generate viable adult mice with loss of Gr function in selected tissues. Loss of Gr function in the nervous system impairs hypothalamus-pituitary-adrenal (HPA)-axis regulation, resulting in increased glucocorticoid (GC) levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.
    Type of Publication: Journal article published
    PubMed ID: 10471508
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  • 10
    Abstract: The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PAC1) is a G-protein-coupled receptor binding the strongly conserved neuropeptide PACAP with 1000-fold higher affinity than the related peptide vasoactive intestinal peptide. PAC1-mediated signaling has been implicated in neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we generated two different mutant mouse strains, harboring either a complete or a forebrain-specific inactivation of PAC1. Mutants from both strains show a deficit in contextual fear conditioning, a hippocampus-dependent associative learning paradigm. In sharp contrast, amygdala-dependent cued fear conditioning remains intact. Interestingly, no deficits in other hippocampus-dependent tasks modeling declarative learning such as the Morris water maze or the social transmission of food preference are observed. At the cellular level, the deficit in hippocampus-dependent associative learning is accompanied by an impairment of mossy fiber long-term potentiation (LTP). Because the hippocampal expression of PAC1 is restricted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated signaling at the mossy fiber synapse is involved in both LTP and hippocampus-dependent associative learning.
    Type of Publication: Journal article published
    PubMed ID: 11466423
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