What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit.

The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms

Oxytocin is implicated in social memory deficits induced by early sensory deprivation in mice

Acknowledgements We thank Miss Jia-Yin and Miss Yu-Ling Sun for their help in breading the mice. Funding This work was supported by grants from the National Natural Science Foundation of China (81200933 to N.-N. Song; 81200692 to L. Chen; 81101026 to Y. Huang; 31528011 to B. Lang; 81221001, 91232724 and 81571332 to Y-Q. Ding), Zhejiang Province Natural Science Foundation of China (LQ13C090004 to C. Zhang), China Postdoctoral Science Foundation (2016 M591714 to C.-C. Qi), and the Fundamental Research Funds for the Central Universities (2013KJ049).Peer reviewedPublisher PD

Reaction to spatial novelty and exploratory strategies in baboons

Exploratory activity was examined in 4 young baboons with the aim of investigating the type of spatial coding (purely geometric and/or by taking into account the identity of the object) used for the configuration of objects. Animals were individually tested in an outdoor enclosure for their exploratory reactions (contact time and order of spontaneous visits) to changes brought about to a configuration of different objects. Two kinds of spatial changes were made: a modification (1) of the shape of the configuration (by displacement of one object) and (2) of the spatial arrangement without changing the initial shape (exchanging the location of two objects). In the second experiment, the effect of a spatial modification of the global geometry constituted by four identical objects was investigated. Finally, in the third experiment, a substitution of a familiar object with a novel one was performed without changing the objects' configuration. The baboons strongly reacted to geometrical modifications of the configuration. In contrast, they were less sensitive to modifications of local features that did not affect the initial spatial configuration. Analyses of spontaneous exploratory activities revealed two types of exploratory strategies (cyclic and back-and-forth). These data are discussed in relation to (1) the distinction between the encoding of geometric versus local spatial features and (2) the spatial function of exploratory activity

Cholinergic cells in the nucleus basalis of mice express the N-methyl-D-aspartate-receptor subunit NR2C and its replacement by the NR2B subunit enhances frontal and amygdaloid acetylcholine levels

It is known that glutamatergic and cholinergic systems interact functionally at the level of the cholinergic basal forebrain. The N-methyl-D-aspartate receptor (NMDA-R) is a multiprotein complex composed of NR1, NR2 and/or NR3 subunits. The subunit composition of NMDA-R of cholinergic cells in the nucleus basalis has not yet been investigated. Here, by means of choline acetyl transferase and NR2B or NR2C double staining, we demonstrate that mice express both the NR2C and NR2B subunits in nucleus basalis cholinergic cells.We generated NR2C-2B mutant mice in which an insertion of NR2B cDNA into the gene locus of the NR2C gene replaced NR2C by NR2B expression throughout the brain. This NR2C-2B mutant was used to examine whether a subunit exchange in cholinergic neurons would affect acetylcholine (ACh) content in several brain structures. We found increased ACh levels in the frontal cortex and amygdala in the brains of NR2C-2B mutant mice. Brain ACh has been implicated in neuroplasticity, novelty-induced arousal and encoding of novel stimuli. We therefore assessed behavioral habituation to novel environments and objects as well as object recognition in NR2C-2B subunit exchange mice. The behavioral analysis did not indicate any gross behavioral alteration in the mutant mice compared with the wildtype mice. Our results show that the NR2C by NR2B subunit exchange in mice affects ACh content in two target areas of the nucleus basalis.

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

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A habituation account of change detection in same/different judgments

We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation

A Laminar Cortical Model for 3D Perception of Slanted and Curved Surfaces and of 2D Images: Developement, attention, and Bistability

A model of laminar visual cortical dynamics proposes how 3D boundary and surface representations of slated and curved 3D objects and 2D images arise. The 3D boundary representations emerge from interactions between non-classical horizontal receptive field interactions with intracorticcal and intercortical feedback circuits. Such non-classical interactions contextually disambiguate classical receptive field responses to ambiguous visual cues using cells that are sensitive to angles and disparity gradients with cortical areas V1 and V2. These cells are all variants of bipole grouping cells. Model simulations show how horizontal connections can develop selectively to angles, how slanted surfaces can activate 3D boundary representations that are sensitive to angles and disparity gradients, how 3D filling-in occurs across slanted surfaces, how a 2D Necker cube image can be represented in 3D, and how bistable Necker cuber percepts occur. The model also explains data about slant aftereffects and 3D neon color spreading. It shows how habituative transmitters that help to control developement also help to trigger bistable 3D percepts and slant aftereffects, and how attention can influence which of these percepts is perceived by propogating along some object boundaries.Air Force Office of Scientific Research (F49620-01-1-0397, F49620-98-1-0108); Defense Advanced Research Projects Agency and the Office of Naval Research (N0014-95-1-0409, N00014-01-1-0624, N00014-95-1-0657); National Science Foundation (IIS-97-20333

Alice in wonderland syndrome. a clinical and pathophysiological review

Alice in Wonderland Syndrome (AIWS) is a perceptual disorder, principally involving visual and somesthetic integration, firstly reported by Todd, on the literary suggestion of the strange experiences described by Lewis Carroll in Alice in Wonderland books. Symptoms may comprise among others aschematia and dysmetropsia. This syndrome has many different etiologies; however EBV infection is the most common cause in children, while migraine affects more commonly adults. Many data support a strict relationship between migraine and AIWS, which could be considered in many patients as an aura or a migraine equivalent, particularly in children. Nevertheless, AIWS seems to have anatomical correlates. According to neuroimaging, temporoparietal- occipital carrefour (TPO-C) is a key region for developing many of AIWS symptoms. The final part of this review aims to find the relationship between AIWS symptoms, presenting a pathophysiological model. In brief, AIWS symptoms depend on an alteration of TPO-C where visual-spatial and somatosensory information are integrated. Alterations in these brain regions may cause the cooccurrence of dysmetropsia and disorders of body schema. In our opinion, the association of other symptoms reported in literature could vary depending on different etiologies and the lack of clear diagnostic criteria

A phenotypic and molecular characterization of the fmr1-tm1Cgr Fragile X mouse

Fragile X Syndrome is the most common form of\ud inherited mental retardation. It is also known for having\ud a substantial behavioral morbidity, including autistic features. In humans, Fragile X Syndrome is almost always\ud caused by inactivation of the X-linked FMR1 gene. A\ud single knockout mouse model, fmr1-tm1Cgr, exists. In\ud this report we further characterize the cognitive and\ud behavioral phenotype of the fmr1-tm1Cgr Fragile X\ud mouse through the use of F1 hybrid mice derived from\ud two inbred strains (FVB/NJ and C57BL/6J). Use of F1\ud hybrids allows focus on the effects of the fmr1-tm1Cgr\ud allele with reduced influence from recessive alleles\ud present in the parental inbred strains. We find that the\ud cognitive phenotype of fmr1-tm1Cgr mice, including\ud measures of working memory and learning set formation\ud that are known to be seriously impacted in humans with\ud Fragile X Syndrome, are essentially normal. Further testing of inbred strains supports this conclusion. Thus, any\ud fmr1-tm1Cgr cognitive deficit is surprisingly mild or\ud absent. There is, however, clear support presented for a\ud robust audiogenic seizure phenotype in all strains tested,\ud as well as increased entries into the center of an open\ud field. Finally, a molecular examination of the fmr1-tm1Cgr\ud mouse shows that, contrary to common belief, it is not a\ud molecular null. Implications of this finding for interpretation of the phenotype are discussed.\u