SorCS1-mediated sorting in dendrites maintains neurexin axonal surface polarization required for synaptic function.

The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The membrane trafficking mechanisms by which neurons control surface polarization of synaptic receptors remain poorly understood. The sorting receptor Sortilin-related CNS expressed 1 (SorCS1) is a critical regulator of trafficking of neuronal receptors, including the presynaptic adhesion molecule neurexin (Nrxn), an essential synaptic organizer. Here, we show that SorCS1 maintains a balance between axonal and dendritic Nrxn surface levels in the same neuron. Newly synthesized Nrxn1α traffics to the dendritic surface, where it is endocytosed. Endosomal SorCS1 interacts with the Rab11 GTPase effector Rab11 family-interacting protein 5 (Rab11FIP5)/Rab11 interacting protein (Rip11) to facilitate the transition of internalized Nrxn1α from early to recycling endosomes and bias Nrxn1α surface polarization towards the axon. In the absence of SorCS1, Nrxn1α accumulates in early endosomes and mispolarizes to the dendritic surface, impairing presynaptic differentiation and function. Thus, SorCS1-mediated sorting in dendritic endosomes controls Nrxn axonal surface polarization required for proper synapse development and function.

Regional Specificity of GABAergic Regulation of Cross-Modal Plasticity in Mouse Visual Cortex after Unilateral Enucleation.

In adult mice, monocular enucleation (ME) results in an immediate deactivation of the contralateral medial monocular visual cortex. An early restricted reactivation by open eye potentiation is followed by a late overt cross-modal reactivation by whiskers (Van Brussel et al., 2011). In adolescence (P45), extensive recovery of cortical activity after ME fails as a result of suppression or functional immaturity of the cross-modal mechanisms (Nys et al., 2014). Here, we show that dark exposure before ME in adulthood also prevents the late cross-modal reactivation component, thereby converting the outcome of long-term ME into a more P45-like response. Because dark exposure affects GABAergic synaptic transmission in binocular V1 and the plastic immunity observed at P45 is reminiscent of the refractory period for inhibitory plasticity reported by Huang et al. (2010), we molecularly examined whether GABAergic inhibition also regulates ME-induced cross-modal plasticity. Comparison of the adaptation of the medial monocular and binocular cortices to long-term ME or dark exposure or a combinatorial deprivation revealed striking differences. In the medial monocular cortex, cortical inhibition via the GABAA receptor α1 subunit restricts cross-modal plasticity in P45 mice but is relaxed in adults to allow the whisker-mediated reactivation. In line, in vivo pharmacological activation of α1 subunit-containing GABAA receptors in adult ME mice specifically reduces the cross-modal aspect of reactivation. Together with region-specific changes in glutamate acid decarboxylase (GAD) and vesicular GABA transporter expression, these findings put intracortical inhibition forward as an important regulator of the age-, experience-, and cortical region-dependent cross-modal response to unilateral visual deprivation. SIGNIFICANCE STATEMENT: In adult mice, vision loss through one eye instantly reduces neuronal activity in the visual cortex. Strengthening of remaining eye inputs in the binocular cortex is followed by cross-modal adaptations in the monocular cortex, in which whiskers become a dominant nonvisual input source to attain extensive cortical reactivation. We show that the cross-modal component does not occur in adolescence because of increased intracortical inhibition, a phenotype that was mimicked in adult enucleated mice when treated with indiplon, a GABAA receptor α1 agonist. The cross-modal versus unimodal responses of the adult monocular and binocular cortices also mirror regional specificity in inhibitory alterations after visual deprivation. Understanding cross-modal plasticity in response to sensory loss is essential to maximize patient susceptibility to sensory prosthetics.

Retinal lesions induce fast intrinsic cortical plasticity in adult mouse visual system.

Neuronal activity plays an important role in the development and structural-functional maintenance of the brain as well as in its life-long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post-lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy-based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region- and cell-type-specific contributions to functional recovery, up to microcircuit level.

Health care expenditures among long-term survivors of pediatric solid tumors: Results from the French Childhood Cancer Survivor Study (FCCSS) and the French network of cancer registries (FRANCIM).

BACKGROUND: Childhood cancer survivors (CCS) may require lifelong medical care due to late effects of cancer treatments. Little is known about of their healthcare utilization and expenditures at long-term especially in publicly funded health care system. We aim to estimate and describe the health care expenditures among long-term CCS in France. METHODS: A total of 5319 five-year solid CCS diagnosed before the age of 21 between 1945 and 2000 in France were identified in the French Childhood Cancer Survivors Study cohort (FCCSS) and the French cancer registry. Information about health care expenditure was taken from the French national health data system between 2011 and 2016, and was described according to survivors' characteristics. Generalized linear models were used to determine associations between health care expenditures and survivors' characteristics. RESULTS: Mean annual amount of healthcare expenditures was € 4,255. Expenditures on hospitalizations and pharmacy represents 60% of total expenditures. Mean annual of healthcare expenditures were higher at increasing age, among women survivors (€ 4,795 vs € 3,814 in men) and in central nervous system (CNS) tumor survivors (€ 7,116 vs € 3,366 in lymphoma and € 3,363 in other solid tumor survivors). CONCLUSIONS: Childhood cancer survivorship is associated with a substantial economic burden in France. We found that female gender and CNS primary cancer were associated with increased healthcare expenditures.

Long-term hospitalisations in survivors of paediatric solid tumours in France.

The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006-2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49 (95% confidence interval [CI] 2.46-2.52) and the RBDR was 3.49 (95% CI 3.46-3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy (risk ratio [RR] 1.62, 95% CI 1.53-1.70), radiotherapy (RR 2.11, 95% CI 1.99-2.24) or both (RR 2.59, 95% CI 2.46-2.73) had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS.

Secreted amyloid-ß precursor protein functions as a GABABR1a ligand to modulate synaptic transmission.

Amyloid-ß precursor protein (APP) is central to the pathogenesis of Alzheimer's disease, yet its physiological function remains unresolved. Accumulating evidence suggests that APP has a synaptic function mediated by an unidentified receptor for secreted APP (sAPP). Here we show that the sAPP extension domain directly bound the sushi 1 domain specific to the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a). sAPP-GABABR1a binding suppressed synaptic transmission and enhanced short-term facilitation in mouse hippocampal synapses via inhibition of synaptic vesicle release. A 17-amino acid peptide corresponding to the GABABR1a binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized Thy1-GCaMP6s mice. Our findings identify GABABR1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABABR1a function to modulate synaptic transmission.

5-HTR2A and 5-HTR3A but not 5-HTR1A antagonism impairs the cross-modal reactivation of deprived visual cortex in adulthood.

Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross-modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury. Serotonin (5-HT) is known to modulate sensory information processing and integration, but its impact on cortical reorganization after sensory loss, remains largely unexplored. To address this issue, we assessed the involvement of 5-HT in ME-induced cross-modal plasticity and the 5-HT receptor (5-HTR) subtype used. We first focused on establishing the impact of ME on the total 5-HT concentration measured in the visual cortex and in the somatosensory barrel field. Next, the changes in expression as a function of post-ME recovery time of the monoamine transporter 2 (vMAT2), which loads 5-HT into presynaptic vesicles, and of the 5-HTR1A and 5-HTR3A were assessed, in order to link these temporal expression profiles to the different types of cortical plasticity induced by ME. In order to accurately pinpoint which 5-HTR exactly mediates ME-induced cross-modal plasticity, we pharmacologically antagonized the 5-HTR1A, 5-HTR2A and 5-HTR3A subtypes. This study reveals brain region-specific alterations in total 5-HT concentration, time-dependent modulations in vMAT2, 5-HTR1A and 5-HTR3A protein expression and 5-HTR antagonist-specific effects on the post-ME plasticity phenomena. Together, our results confirm a role for 5-HTR1A in the early phase of binocular visual cortex plasticity and suggest an involvement of 5-HTR2A and 5-HTR3A but not 5-HTR1A during the late cross-modal recruitment of the medial monocular visual cortex. These insights contribute to the general understanding of 5-HT function in cortical plasticity and may encourage the search for improved rehabilitation strategies to compensate for sensory loss.

The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning.

The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95. Of note, BC1 KO mice show aberrant structural plasticity in response to whisker deprivation, impaired texture novel object recognition and altered social behavior. Thus, our study highlights a role for BC1 RNA in experience-dependent plasticity and learning in the mammalian adult neocortex, and provides insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders.Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors.

Visual system plasticity in mammals: the story of monocular enucleation-induced vision loss.

The groundbreaking work of Hubel and Wiesel in the 1960's on ocular dominance plasticity instigated many studies of the visual system of mammals, enriching our understanding of how the development of its structure and function depends on high quality visual input through both eyes. These studies have mainly employed lid suturing, dark rearing and eye patching applied to different species to reduce or impair visual input, and have created extensive knowledge on binocular vision. However, not all aspects and types of plasticity in the visual cortex have been covered in full detail. In that regard, a more drastic deprivation method like enucleation, leading to complete vision loss appears useful as it has more widespread effects on the afferent visual pathway and even on non-visual brain regions. One-eyed vision due to monocular enucleation (ME) profoundly affects the contralateral retinorecipient subcortical and cortical structures thereby creating a powerful means to investigate cortical plasticity phenomena in which binocular competition has no vote.In this review, we will present current knowledge about the specific application of ME as an experimental tool to study visual and cross-modal brain plasticity and compare early postnatal stages up into adulthood. The structural and physiological consequences of this type of extensive sensory loss as documented and studied in several animal species and human patients will be discussed. We will summarize how ME studies have been instrumental to our current understanding of the differentiation of sensory systems and how the structure and function of cortical circuits in mammals are shaped in response to such an extensive alteration in experience. In conclusion, we will highlight future perspectives and the clinical relevance of adding ME to the list of more longstanding deprivation models in visual system research.

Altered neuronal architecture and plasticity in the visual cortex of adult MMP-3-deficient mice.

Matrix metalloproteinases (MMPs) are Zn(2+)-dependent endopeptidases considered to be essential for normal brain development and neuroplasticity by modulating extracellular matrix proteins, receptors, adhesion molecules, growth factors and cytoskeletal proteins. Specifically, MMP-3 has recently been implicated in synaptic plasticity, hippocampus-dependent learning and neuronal development and migration in the cerebellum. However, the function(s) of this enzyme in the neocortex is understudied. Therefore, we explored the phenotypical characteristics of the neuronal architecture and the capacity for experience-dependent cortical plasticity in the visual cortex of adult MMP-3-deficient (MMP-3(-/-)) mice. Golgi-Cox stainings revealed a significant reduction in apical dendritic length and an increased number of apical obliques for layer V pyramidal neurons in the visual cortex of adult MMP-3(-/-) mice compared to wild-type (WT) animals. In addition, a significant upregulation of both phosphorylated and non-phosphorylated neurofilament protein (NF)-high, phosphorylated NF-medium, NF-low and α-internexin was detected in the visual cortex of MMP-3(-/-) mice. To assess the effect of MMP-3 deficiency on cortical plasticity, we monocularly enucleated adult MMP-3(-/-) mice and analyzed the reactivation of the contralateral visual cortex 7 weeks post-enucleation. In contrast to previous results in C57Bl/6J adult mice, activity remained confined to the binocular zone and did not expand into the monocular regions indicative for an aberrant open-eye potentiation. Permanent hypoactivity in the monocular cortex lateral and medial to V1 also indicated a lack of cross-modal plasticity. These observations demonstrate that genetic inactivation of MMP-3 has profound effects on the structural integrity and plasticity response of the visual cortex of adult mice.

Binocular pattern deprivation interferes with the expression of proteins involved in primary visual cortex maturation in the cat.

BACKGROUND: Binocular pattern deprivation from eye opening (early BD) delays the maturation of the primary visual cortex. This delay is more pronounced for the peripheral than the central visual field representation within area 17, particularly between the age of 2 and 4 months [Laskowska-Macios, Cereb Cortex, 2014]. RESULTS: In this study, we probed for related dynamic changes in the cortical proteome. We introduced age, cortical region and BD as principal variables in a 2-D DIGE screen of area 17. In this way we explored the potential of BD-related protein expression changes between central and peripheral area 17 of 2- and 4-month-old BD (2BD, 4BD) kittens as a valid parameter towards the identification of brain maturation-related molecular processes. Consistent with the maturation delay, distinct developmental protein expression changes observed for normal kittens were postponed by BD, especially in the peripheral region. These BD-induced proteomic changes suggest a negative regulation of neurite outgrowth, synaptic transmission and clathrin-mediated endocytosis, thereby implicating these processes in normal experience-induced visual cortex maturation. Verification of the expression of proteins from each of the biological processes via Western analysis disclosed that some of the transient proteomic changes correlate to the distinct behavioral outcome in adult life, depending on timing and duration of the BD period [Neuroscience 2013;255:99-109]. CONCLUSIONS: Taken together, the plasticity potential to recover from BD, in relation to ensuing restoration of normal visual input, appears to rely on specific protein expression changes and cellular processes induced by the loss of pattern vision in early life.

Absence of system xc- in mice decreases anxiety and depressive-like behavior without affecting sensorimotor function or spatial vision.

There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based tests (rotarod, adhesive removal test, nest building test). Finally, due to the presence and potential functional relevance of system xc- in the eye, we investigated the visual acuity of system xc- deficient mice (optomotor test). Our results indicate that loss of system xc- does not affect motor or sensorimotor function, in either adult or aged mice, in any of the paradigms investigated. Similarly, loss of system xc- does not affect basic visual acuity, in either adult or aged mice. On the other hand, in the open field and light/dark tests, and forced swim and tail suspension tests respectively, we could observe significant anxiolytic and antidepressive-like effects in system xc- deficient mice that in certain cases (light/dark, forced swim) were age-dependent. These findings indicate that, under physiological conditions, nonvesicular glutamate release via system xc- mediates aspects of higher brain function related to anxiety and depression, but does not influence sensorimotor function or spatial vision. As such, modulation of system xc- might constitute the basis of innovative interventions in mood disorders.

Distinct and simultaneously active plasticity mechanisms in mouse hippocampus during different phases of Morris water maze training.

Although the Morris water maze (MWM) is the most frequently used protocol to examine hippocampus-dependent learning in mice, not much is known about the spatio-temporal dynamics of underlying plasticity processes. Here, we studied molecular and cellular hippocampal plasticity mechanisms during early and late phases of spatial learning in the MWM. Quantitative in situ hybridization for the immediate early genes zif268 and Homer1a (H1a) revealed phase-dependent differences in their expression between areas CA1 and CA3. During the initial learning phase, CA1 expression levels of the molecular plasticity marker H1a, but not of the activity reporter gene zif268, were related to task proficiency; whereas no learning-specific changes could be detected in CA3. Simultaneously, the ratio of surface-expressed NMDAR subunits NR2A and NR2B was downregulated as measured by acute slice biotinylation assay, while the total number of surface NMDARs was unaltered. When intrinsic 'somatic' and synaptic plasticity in the CA1-region of hippocampal slices were examined, we found that early learning promotes intrinsic neuronal plasticity as manifested by a reduction of spike frequency adaptation and postburst afterhyperpolarization. At the synaptic level, however, maintenance of long-term potentiation (LTP) in all learning groups was impaired which is most likely due to 'intrinsic' learning-induced LTP which occluded any further electrically induced LTP. Late learning, in contrast, was characterized by re-normalized H1a, NR2A and NR2B expression and neuronal firing, yet a further strengthening of learning-induced LTP. Together, our data support a precisely timed cascade of complex molecular and subcellular transformations occurring from early to late MWM learning.

A highly reproducible and straightforward method to perform in vivo ocular enucleation in the mouse after eye opening.

Enucleation or the surgical removal of an eye can generally be considered as a model for nerve deafferentation. It provides a valuable tool to study the different aspects of visual, cross-modal and developmental plasticity along the mammalian visual system(1-4). Here, we demonstrate an elegant and straightforward technique for the removal of one or both eyes in the mouse, which is validated in mice of 20 days old up to adults. Briefly, a disinfected curved forceps is used to clamp the optic nerve behind the eye. Subsequently, circular movements are performed to constrict the optic nerve and remove the eyeball. The advantages of this technique are high reproducibility, minimal to no bleeding, rapid post-operative recovery and a very low learning threshold for the experimenter. Hence, a large amount of animals can be manipulated and processed with minimal amount of effort. The nature of the technique may induce slight damage to the retina during the procedure. This side effect makes this method less suitable as compared to Mahajan et al. (2011)(5) if the goal is to collect and analyze retinal tissue. Also, our method is limited to post-eye opening ages (mouse: P10 - 13 onwards) since the eyeball needs to be displaced from the socket without removing the eyelids. The in vivo enucleation technique described in this manuscript has recently been successfully applied with minor modifications in rats and appears useful to study the afferent visual pathway of rodents in general.

Symbolic number abilities predict later approximate number system acuity in preschool children.

An ongoing debate in research on numerical cognition concerns the extent to which the approximate number system and symbolic number knowledge influence each other during development. The current study aims at establishing the direction of the developmental association between these two kinds of abilities at an early age. Fifty-seven children of 3-4 years performed two assessments at 7 months interval. In each assessment, children's precision in discriminating numerosities as well as their capacity to manipulate number words and Arabic digits was measured. By comparing relationships between pairs of measures across the two time points, we were able to assess the predictive direction of the link. Our data indicate that both cardinality proficiency and symbolic number knowledge predict later accuracy in numerosity comparison whereas the reverse links are not significant. The present findings are the first to provide longitudinal evidence that the early acquisition of symbolic numbers is an important precursor in the developmental refinement of the approximate number representation system.

The cross-modal aspect of mouse visual cortex plasticity induced by monocular enucleation is age dependent.

Monocular enucleation (ME) drastically affects the contralateral visual cortex, where plasticity phenomena drive specific adaptations to compensate for the unilateral loss of vision. In adult mice, complete reactivation of deprived visual cortex involves an early visually driven recovery followed by multimodal plasticity 3 to 7 weeks post ME (Van Brussel et al. [2011] Cereb. Cortex 21:2133-2146). Here, we specifically investigated the age dependence of the onset and the exact timing of both ME-induced reactivation processes by comparing cortical activity patterns of mice enucleated at postnatal day (P) 45, 90, or 120. A swifter open-eye potentiated reactivation characterized the binocular visual cortex of P45 mice. Nevertheless, even after 7 weeks, the reactivation remained incomplete, especially in the monocular cortex medial to V1. In comparison with P45, emergent cross-modal participation was demonstrated in P90 animals, although robust reactivation similar to enucleated adults (P120) was not achieved yet. Concomitantly, at 7 weeks post ME, somatosensory and auditory cortex shifted from a hypoactive state in P45 to hyperactivity in P120. Thus, we provide evidence for a presensitive period in which gradual recruitment of cross-modal recovery upon long-term ME coincides with the transition from adolescence to adulthood in mice.

Impact of language abilities on exact and approximate number skills development: evidence from children with specific language impairment.

PURPOSE: Counting and exact arithmetic rely on language-based representations, whereas number comparison and approximate arithmetic involve approximate quantity-based representations that are available early in life, before the first stages of language acquisition. The objective of this study was to examine the impact of language abilities on the later development of exact and approximate number skills. METHOD: Twenty-eight 7- to 14-year-old children with specific language impairment (SLI) completed exact and approximate number tasks involving quantities presented symbolically and nonsymbolically. They were compared with age-matched (AM) and vocabulary-matched (VM) children. RESULTS: In the exact arithmetic task, the accuracy of children with SLI was lower than that of AM and VM controls and related to phonological measures. In the symbolic approximate tasks, children with SLI were less accurate than AM controls, but the difference vanished when their cognitive skills were considered or when they were compared with younger VM controls. In the nonsymbolic approximate tasks, children with SLI did not differ significantly from controls. Further, accuracy in the approximate number tasks was unrelated to language measures. CONCLUSIONS: Language impairment is related to reduced exact arithmetic skills, whereas it does not intrinsically affect the development of approximate number skills in children with SLI.

Differences in the acuity of the Approximate Number System in adults: the effect of mathematical ability.

It is largely admitted that processing numerosity relies on an innate Approximate Number System (ANS), and recent research consistently observed a relationship between ANS acuity and mathematical ability in childhood. However, studies assessing this relationship in adults led to contradictory results. In this study, adults with different levels of mathematical expertise performed two tasks on the same pairs of dot collections, based either on numerosity comparison or on cumulative area comparison. Number of dots and cumulative area were congruent in half of the stimuli, and incongruent in the other half. The results showed that adults with higher mathematical ability obtained lower Weber fractions in the numerical condition than participants with lower mathematical ability. Further, adults with lower mathematical ability were more affected by the interference of the continuous dimension in the numerical comparison task, whereas conversely higher-expertise adults showed stronger interference of the numerical dimension in the continuous comparison task. Finally, ANS acuity correlated with arithmetic performance. Taken together, the data suggest that individual differences in ANS acuity subsist in adulthood, and that they are related to mathematical ability.

AMIGO2 mRNA expression in hippocampal CA2 and CA3a.

AMIGO2, or amphoterin-induced gene and ORF (open reading frame) 2, belongs to the leucine-rich repeats and immunoglobulin superfamilies. The protein is a downstream target of calcium-dependent survival signals and, therefore, promotes neuronal survival. Here, we describe the mRNA distribution pattern of AMIGO2 throughout the mouse brain with special emphasis on the hippocampus. In the Ammon's horn, a detailed comparison between the subregional mRNA expression patterns of AMIGO2 and Pcp4 (Purkinje cell protein 4)--a known molecular marker of hippocampal CA2 (Cornu Ammonis 2)--revealed a prominent AMIGO2 mRNA expression level in both the CA2 and the CA3a (Cornu Ammonis 3a) subregion of the dorsal and ventral hippocampus. Since this CA2/CA3a region is particularly resistant to neuronal injury and neurotoxicity [Stanfield and Cowan (Brain Res 309(2):299­307 1984); Sloviter (J Comp Neurol 280(2):183­196 1989); Leranth and Ribak (Exp Brain Res 85(1):129­136 1991); Young and Dragunow (Exp Neurol 133(2):125­137 1995); Ochiishi et al. (Neurosci 93(3):955­967 1999)], we suggest that the expression pattern of AMIGO2 indeed fits with its involvement in neuroprotection.

Judgement of discrete and continuous quantity in adults: number counts!

Three experiments involving a Stroop-like paradigm were conducted. In Experiment 1, adults received a number comparison task in which large sets of dots, orthogonally varying along a discrete dimension (number of dots) and a continuous dimension (cumulative area), were presented. Incongruent trials were processed more slowly and with less accuracy than congruent trials, suggesting that continuous dimensions such as cumulative area are automatically processed and integrated during a discrete quantity judgement task. Experiment 2, in which adults were asked to perform area comparison on the same stimuli, revealed the reciprocal interference from number on the continuous quantity judgements. Experiment 3, in which participants received both the number and area comparison tasks, confirmed the results of Experiments 1 and 2. Contrasting with earlier statements, the results support the view that number acts as a more salient cue than continuous dimensions in adults. Furthermore, the individual predisposition to automatically access approximate number representations was found to correlate significantly with adults' exact arithmetical skills.