A hippocampal Cdk5 pathway regulates extinction of contextual fear

Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.National Institutes of Health (U.S.) (Grant NS051874)Alexander von Humboldt-Stiftung (German Research Foundation Fellowship)European Neuroscience Institute Goettinge

Phosphorylation of hippocampal Erk-1/2, Elk-1, and p90-Rsk-1 during contextual fear conditioning: Interactions between Erk-1/2 and Elk-1

The phosphorylation of proteins involved in the MAP kinase signal transduction pathway was investigated during associative learning of C57BL/6J mice. Context-dependent fear conditioning, consisting of a single exposure of mice to a context followed by foot shock, was employed as a learning paradigm. Control groups consisted of mice exposed to context only or an immediate shock in the context. Coincident up-regulation of phosphorylated Erk-1/2 and Elk-1 was observed in the CA3 hippocampal subfield and dentate gyrus 30 min after fear conditioning but not after the control paradigms. Phosphorylated Erk-1/2 and Elk-1 were associated and predominantly colocalized in the mossy fibers. In vitro kinase assays showed that hippocampal Erk-1/2 phosphorylates Elk-1. Notably, Elk-1 in turn enhances the phosphorylation of Erk-1/2 and its downstream target p90Rsk-1. Increased phosphorylation and nuclear translocation of p90Rsk-1 was also demonstrated in the CA3 hippocampal area in vivo during contextual fear conditioning. The observed interactions between hippocampal Elk-1 and Erk-1/2 proteins may affect the consolidation of contextual memories through activation of the downstream nuclear targets of Erk-1/2, such as p90Rsk-1, without requiring nuclear translocation of Elk-1 and Erk-1/2

Cyclin-dependent kinase 5 is required for associative learning

Transient stressful experiences may persistently facilitate associative and nonassociative learning, possibly through alterations of gene expression. Here we identify, by subtractive hybridization, differential expression of the Cdk5 gene in response to stress. The Cdk5 protein is selectively induced in the fibers of septohippocampal cholinergic neurons but not in other regions of prominent Cdk5 production. This upregulation is accompanied by increased Cdk5 kinase activity, which is blocked completely by the Cdk5 inhibitor butyrolactone I. Microinjection of butyrolactone I into the lateral septum and hippocampus prevents the acquisition of conditioned context-dependent fear as well as its stress-induced facilitation. By demonstrating that a transient increase of Cdk5 activity within the septohippocampal system is required for associative learning, an important novel role of Cdk5 has been identified

Perinatal exposure to bisphenol A increases adult mammary gland progesterone response and cell number

Bisphenol A [BPA, 2,2,-bis (hydroxyphenyl) propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor kB ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer. © 2011 by The Endocrine Society.Swiss Science Foundation (NRP50); Swiss Federal Public Health Offic

Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis

To investigate the impact of single or repeated episodes of reversible demyelination on long-term locomotor performance and neuroaxonal integrity, and to analyze the myelin proteome after remyelination and during aging

Adaptation of DIN technical reports "Bridges" to Eurocodes. Part 1: Adaptation of the DIN technical report 101 "Effects on Bridges" to Eurocodes - a sustainable load model for road traffic loads; Part 2: Adjustment of DIN-Fachbericht 102 "Concrete Bridges" to the final Eurocodes; Part 3: Adjustment of DIN-Fachbericht 103 "Steel Bridges" to the final Eurocodes; Part 4: Adjustment of DIN-Fachbericht 104 "Composite Bridges" to the final Eurocodes

Die gegenwärtigen DIN-Fachberichte basieren auf den ENV-Fassungen der Eurocodes unter Berücksichtigung der nationalen Regelungen. Bis zur Einführung der Europäischen Normen mit den zugehörigen Nationalen Anwendungsdokumenten werden in Deutschland Brücken auf der Grundlage der DIN-Fachberichte 101 "Einwirkungen auf Brücken", 102 "Betonbrücken", 103 "Stahlbrücken" und 104 "Verbundstahlbrücken" in den Ausgaben 03:2009 berechnet, bemessen und konstruiert. Aus der Anwendung der DIN-Fachberichte für den Brückenbau seit 2003 liegen überwiegend positive Erfahrungen vor. Mit ihrer Anwendung wurde ein hoher Qualitätsstandard sicher gestellt. Insgesamt soll mit der Einführung der EN-Normen das bisher in Deutschland erreichte hohe Qualitätsniveau im Brückenbau gehalten werden. Das Schwerverkehrsaufkommen auf den Straßen in Deutschland ist in den letzten Jahrzehnten überproportional angewachsen, und auch für die Zukunft werden weitere Steigerungen prognostiziert. Die Festlegungen aktueller Verkehrslastmodelle für Straßenbrücken beruhen auf Messungen aus der Mitte der 1980er Jahre. Im Vergleich dazu wurde durch neuere Verkehrserfassungen eine Verdopplung des Schwerverkehrsaufkommens festgestellt. Aus diesem Grund war es erforderlich, die Verkehrslasten auf Straßenbrücken hinsichtlich des aktuellen und des zukünftigen Schwerverkehrs zu überprüfen und anzupassen. Mit der geplanten Einführung der Eurocodes im Brückenbau werden im Vergleich zu den derzeitigen Regelwerken neben Änderungen bei den Straßenverkehrslasten auch Anpassungen zu den jeweiligen Eurocodes für die Bemessung von Brücken vorgeschlagen, um das gebotene Sicherheitsniveau einerseits sowie die Wirtschaftlichkeit andererseits zu wahren. Im Rahmen mehrerer Forschungsvorhaben wurden die Auswirkungen dieser Änderungen für Beton-, Stahl- und Stahlverbundbrücken untersucht.The current DIN Technical Reports are based on the European pre-standards (ENV) of the Eurocodes, taking national regulations into account. Pending the introduction of European Standards with corresponding National Application Documents, German bridges are being calculated, designed and constructed on the basis of the DIN Technical Reports 101 "Actions on Bridges", 102 "Concrete Bridges", 103 "Steel Bridges" and 104 "Composite Bridges" in editions 03:2009. The application of the DIN Technical Reports for bridge building, since 2003, has resulted in predominantly positive experiences. A high level of quality was ensured with the applications. On the overall, the introduction of the EN Standards is to uphold the high level of quality in bridge building achieved in Germany. The volume of the heavy load traffic on the road network in Germany has increased disproportionally in the last decades; further increases are predicted for the future. The regulations for the current traffic load models for road bridges are based on traffic measurements from the mid-80s. In comparison to those data, a doubling of the heavy load traffic volume could be determined from actual traffic measurements. For this reason it was necessary to control the traffic load model for road bridges in consideration of the actual and future heavy load traffic volume and, if necessary, to adapt the load model. In comparison with the current regulations, the intended implementation of the Eurocodes for bridge construction in Germany will propose several changes regarding traffic loads, as well as adaptations of the respective Eurocodes for the design of bridges, in order to maintain both the existing level of safety and economic efficiency. Within the framework of several research projects, the impact these changes will have on concrete, steel and composite bridges, was investigated