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Fear extinction is the well-known process of fear reduction through repeated re-exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state-of-the-art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub-cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed. ispartof: NEUROBIOLOGY OF LEARNING AND MEMORY vol:155 pages:113-126 ispartof: location:United States status: published

The blocking effect has inspired numerous associative learning theories and is widely cited in the literature. We recently reported a series of 15 experiments that failed to obtain a blocking effect in rodents. Based on those consistent failures, we claimed that there is a lack of insight into the boundary conditions for blocking. In his commentary, Soto (in press) argues that contemporary associative learning theory does provide a specific boundary condition for the occurrence of blocking, namely the use of same- versus different-modality stimuli. Given that in ten of our 15 experiments same-modality stimuli were used, he claims that our failure to observe a blocking effect is unsurprising. We cannot but disagree with that claim, because of theoretical, empirical, and statistical problems with his analysis. We also address two other possible reasons for a lack of blocking that are referred to in Soto's (in press) analysis, related to generalization and salience, and dissect the potential importance of both. While Soto's (in press) analyses raises a number of interesting points, we see more merit in an empirically guided analysis and call for empirical testing of boundary conditions on blocking.

© 2017 Elsevier Inc. The degree of generalization from a fearful context to other contexts is determined by precision of the original fear memory. Experiences before and after fear learning affect memory precision. Pre-exposure to a similar context before context conditioning results in increased generalization to the similar context. In contrast, exposure to the conditioning context after fear learning reduces fear generalization. In the current study we aimed to investigate whether the events before and after fear learning interact. We hypothesized that pre-exposure-induced enhanced generalization could be reduced by a return to the conditioning context. We found that, in contrast to previous findings, pre-exposure did not affect generalization. However, a reminder of the conditioning context reduced generalization to both a similar and a different context. The results stress the dynamic nature of emotional memory. ispartof: LEARNING AND MOTIVATION vol:63 pages:20-26 status: published

At the core of anxiety disorders lies the tendency to generalize fear from a threatening to a safe situation. A deeper understanding of the mechanisms that facilitate and restrain generalization in humans is therefore needed. Rodent studies showed that pre-exposure to a context that is similar to the threatening context enhanced generalization to the similar context. In Experiment 1 we replicated these animal findings in humans (US-expectancy). Studies on the underlying mechanisms showed that the pre-exposure representation was recalled during conditioning (due to similarity between the contexts) and the shock also became linked to the recalled representation, resulting in greater generalization. In Experiment 2 we developed a pre-exposure procedure that increased the ability to distinguish between the conditioned and pre-exposure contexts, such that presentation of the former would no longer result in recall of the latter. We then observed that overgeneralization (US-expectancy) was prevented. Pre-exposure did not affect generalization of skin conductance response or fear potentiated startle. Finally, exploratory analyses revealed that increased generalization (US-expectancy), if not prevented, could be reduced by a reminder of the conditioned context. Hence, we developed a prevention- and a treatment-strategy for overgeneralization. These findings may guide the development of new therapeutic strategies. ispartof: Scientific Reports vol:7 issue:1 ispartof: location:England status: published

© 2016 Macmillan Publishers Limited All rights reserved. This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/, Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies., This work was supported by grants from France Alzheimer (to DB) and LECMA/Alzheimer Forschung Initiative (to DB and CEM). DB and LVL got a Égide/Pessoa program EU exchange grant. Our laboratory is also supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), Inserm, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, Région Nord/Pas-de-Calais, FEDER, DN2M, ANR (ADONTAGE and ADORATAU, to DB) and FUI MEDIALZ. We thank the animal facility of IMPRT-IFR114 and M Besegher, I Brion, D Cappe, R Dehaynin, J Devassine, Y Lepage, C Meunier and D Taillieu for transgenic mouse production and animal care, as well as M Basquin, D Demeyer, S Eddarkaoui, H Obriot and M Schneider for support. CL holds a doctoral grant from Lille 2 University, and SB from Région Nord Pas de Calais and CHRU de Lille. VF holds a grant from Région Nord-Pas-de-Calais and Inserm. EF holds a post-doctoral grant from Région Nord-Pas-de-Calais (DN2M). LVL is an Investigator FCT (Fundação para a Ciência e Tecnologia, Portugal).

Cognitive and motor performances decline during aging. Although it is clear that such signs reflect synaptic compromise, the underlying mechanisms have not been defined. We found that the levels and activity of the synaptic plasticity modulators phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2) and phospholipase C? (PLC?) were substantially reduced in hippocampal synaptic membranes from old mice. In addition, these membranes contained reduced levels of the PI(4,5)P2-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS). Consistent with a cause-effect relationship, raising MARCKS levels in the brain of old mice led to increased synaptic membrane clustering of PI(4,5)P2 and to PLC? activation. MARCKS overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide resulted in enhanced long-term potentiation and improved memory. These results reveal one of the mechanisms involved in brain dysfunction during aging.

Although much information about metabotropic glutamate receptors (mGluRs) and their role in normal and pathologic brain function has been accumulated during the last decades, the role of group III mGluRs is still scarcely documented. Here, we examined mGluR4 knockout mice for types of behavior and synaptic plasticity that depend on either the hippocampus or the prefrontal cortex (PFC). We found improved spatial short- and long-term memory in the radial arm maze, which was accompanied by enhanced long-term potentiation (LTP) in hippocampal CA1 region. In contrast, LTP in the PFC was unchanged when compared with wild-type controls. Changes in paired-pulse facilitation that became overt in the presence of the GABAA antagonist picrotoxin indicated a function of mGluR4 in maintaining the excitation/inhibition balance, which is of crucial importance for information processing in the brain and the deterioration of these processes in neuropsychological disorders such as autism, epilepsy and schizophrenia.