The Vanity of Dogmatizing

Book review: Beyond the formalist-realist divide: The role of politics in judging. Brian Z. Tamanaha. Princeton University Press. 2010. Pp. xii + 252. Reviewed by Marc O. DeGirolami

Rethinking Professor Westbrook\u27s Two Thoughts about Insider Preferences

status: publishe

Post-weaning housing conditions influence freezing during contextual fear conditioning in adult rats

The present study aimed to investigate the influence of housing conditions on contextual fear memory malleability. Male Wistar rats were housed in enriched, standard, or impoverished conditions after weaning and remained in these conditions throughout the entire experiment. After six weeks into those housing conditions, all animals underwent a 3-day protocol including contextual fear conditioning (day 1), memory reactivation followed by systemic administration of midazolam or vehicle (day 2), and a retention test (day 3). Percentage freezing was used as a behavioral measure of contextual fear. There was no evidence for an effect of housing conditions on the sensitivity of contextual fear memory to amnestic effects of post-reactivation midazolam administration, and no indication for amnestic effects of post-reactivation midazolam overall (including in the standard group). The inability to replicate previous demonstrations of post-reactivation amnesia using the same protocol underscores the subtle nature of post-reactivation pharmacological memory interference. Notably, impoverished housing resulted in a decrease in contextual freezing during contextual fear conditioning, reactivation and retention testing, compared to enriched and standard housing conditions. This observation warrants caution when interpreting the results from experiments regarding effects of housing on fear memory processes, particularly when freezing is used as a measure of fear.Fil: Schroyens, Natalie. Katholikie Universiteit Leuven; BélgicaFil: Bender, Crhistian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Alfei Palloni, Joaquin Matías. Katholikie Universiteit Leuven; BélgicaFil: Molina, Víctor Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Luyten, Laura. Katholikie Universiteit Leuven; BélgicaFil: Beckers, Tom. Katholikie Universiteit Leuven; Bélgic

Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors

Apparent Reconsolidation Interference Without Generalized Amnesia

- Raw Data - Excluded animal

Limited replicability of drug-induced amnesia after contextual fear memory retrieval in rats

A series of failures to replicate amnesia for contextual fear memories in rats by systemic administration of several drugs after memory retrieval

Pharmacological induction of post-reactivation amnesia for contextual fear memory in rats

This project contains the data and preregistration related to Schroyens, N., Bender, C. L., Alfei, J. M., Molina, V. A., Luyten, L., & Beckers, T. (2019). Post-weaning housing conditions influence freezing during contextual fear conditioning in adult rats. Behavioural Brain Research, 359, 172–180. https://doi.org/10.1016/j.bbr.2018.10.04

Recovery of generalized fear memory after experimentally induced amnesia challenges the reconsolidation blockade account of forgetting.

status: publishe

Apparent Reconsolidation Interference Without Generalized Amnesia

Abstract Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.status: publishe

Inducing post-reactivation amnesia of contextual fear memory in rats (presentation)

status: publishe