The elusive nature of the blocking effect: 15 failures to replicate

With the discovery of the blocking effect, learning theory took a huge leap forward, because blocking provided a crucial clue that surprise is what drives learning. This in turn stimulated the development of novel association-formation theories of learning. Eventually, the ability to explain blocking became nothing short of a touchstone for the validity of any theory of learning, including propositional and other nonassociative theories. The abundance of publications reporting a blocking effect and the importance attributed to it suggest that it is a robust phenomenon. Yet, in the current article we report 15 failures to observe a blocking effect despite the use of procedures that are highly similar or identical to those used in published studies. Those failures raise doubts regarding the canonical nature of the blocking effect and call for a reevaluation of the central status of blocking in theories of learning. They may also illustrate how publication bias influences our perspective toward the robustness and reliability of seemingly established effects in the psychological literature

Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice

Stroobants S, Wolf H, Callaerts-Vegh Z, Dierks T, Lübke T, D'Hooge R. Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice. FRONTIERS IN BEHAVIORAL NEUROSCIENCE. 2018;12: 15.Fucosidosis is a lysosomal storage disorder (LSD) caused by lysosomal alpha-L-fucosidase deficiency. Insufficient alpha-L-fucosidase activity triggers accumulation of undegraded, fucosylated glycoproteins and glycolipids in various tissues. The human phenotype is heterogeneous, but progressive motor and cognitive impairments represent the most characteristic symptoms. Recently, Fuca1-deficient mice were generated by gene targeting techniques, constituting a novel animal model for human fucosidosis. These mice display widespread LSD pathology, accumulation of secondary storage material and neuroinflammation throughout the brain, as well as progressive loss of Purkinje cells. Fuca1-deficient mice and control littermates were subjected to a battery of tests detailing different aspects of motor, emotional and cognitive function. At an early stage of disease, we observed reduced exploratory activity, sensorimotor disintegration as well as impaired spatial learning and fear memory. These early markers of neurological deterioration were related to the respective stage of neuropathology using molecular genetic and immunochemical procedures. Increased expression of the lysosomal marker Lamp1 and neuroinflammation markers was observed throughout the brain, but appeared more prominent in cerebral areas in comparison to cerebellum of Fuca1-deficient mice. This is consistent with impaired behaviors putatively related to early disruptions of motor and cognitive circuits particularly involving cerebral cortex, basal ganglia, and hippocampus. Thus, Fuca1-deficient mice represent a practical and promising fucosidosis model, which can be utilized for pathogenetic and therapeutic studies

Failures to replicate blocking are surprising and informative : reply to Soto

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

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders

Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice

Although soluble oligomeric and protofibrillar assemblies of Aβ-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds ‘forward' in a near-irreversible manner from the monomeric Aβ peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward' Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward' Aβ protofibrils obtained from the aggregation of fresh Aβ monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Aβ-aggregates that could readily be activated by exposure to biological lipids

Genes given too tight a fit

status: publishe

Vogelzang en mensenspraak

Tijdens de ruim driehonderd miljoen jaar divergente evolutie is het brein van vogels er anders uit gaan zien dan dat van zoogdieren. Toch vindt een groep neurobiologen en ethologen dat zangvogels een goed modelorganisme bieden om de biopsychologische mechanismen van bepaalde aspecten van het menselijke gedrag te bestuderen. Zo zou het onderzoek van volgzang ons iets kunnen leren over de menselijke spraakstatus: publishe