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Mainstream theory suggests that the approximate number system supports our non-symbolic number abilities (e.g. estimating or comparing different sets of items). It is argued that this system can extract number independently of the visual cues present in the stimulus (diameter, aggregate surface, etc.). However, in a recent report we argue that this might not be the case. We showed that participants combined information from different visual cues to derive their answers. While numerosity comparison requires a rough comparison of two sets of items (smaller versus larger), numerosity estimation requires a more precise mechanism. It could therefore be that numerosity estimation, in contrast to numerosity comparison, might rely on the approximate number system. To test this hypothesis, we conducted a numerosity estimation experiment. We controlled for the visual cues according to current standards: each single visual property was not informative about numerosity. Nevertheless, the results reveal that participants were influenced by the visual properties of the dot arrays. They gave a larger estimate when the dot arrays consisted of dots with, on average, a smaller diameter, aggregate surface or density but a larger convex hull. The reliance on visual cues to estimate numerosity suggests that the existence of an approximate number system that can extract numerosity independently of the visual cues is unlikely. Instead, we propose that humans estimate numerosity by weighing the different visual cues present in the stimuli.

It is widely accepted that human and nonhuman species possess a specialized system to process large approximate numerosities. The theory of an evolutionarily ancient approximate number system (ANS) has received con- verging support from developmental studies, comparative experiments, neuroimaging, and computational modelling, and it is one of the most dominant and influential theories in numerical cognition. The existence of an ANS system is significant, as it is believed to be the building block of numerical development in general. The acuity of the ANS is related to future arithmetic achievements, and intervention strategies therefore aim to improve the ANS. Here we critically review current evidence supporting the existence of an ANS. We show that important shortcomings and confounds exist in the empirical studies on human and non-human animals as well as the logic used to build computational models that support the ANS theory. We conclude that rather than taking the ANS theory for granted, a more comprehensive explanation might be provided by a sensory-integration system that compares or estimates large approximate numerosities by integrating the different sensory cues comprising number stimuli.

Encoding and retrieval of contextual memories is initially mediated by sparsely activated neurons, so-called engram cells, in the hippocampus. Subsequent memory persistence is thought to depend on network-wide changes involving progressive contribution of cortical regions, a process referred to as systems consolidation. Using a viral-based TRAP (targeted recombination in activated populations) approach, we studied whether consolidation of contextual fear memory by neurons in the medial prefrontal cortex (mPFC) is modulated by memory strength and CREB function. We demonstrate that activity of a small subset of mPFC neurons is sufficient and necessary for remote memory expression, but their involvement depends on the strength of conditioning. Furthermore, selective disruption of CREB function in mPFC engram cells after mild conditioning impairs remote memory expression. Together, our data demonstrate that memory consolidation by mPFC engram cells requires CREB-mediated transcription, with the functionality of this network hub being gated by memory strength. Little is known about mechanisms that regulate the involvement of cortical engram cells in remote memory. Here, authors demonstrate that memory consolidation by mPFC engram cells requires CREB-mediated transcription, with the functionality of this network hub being gated by memory strength.

To investigate the difference in passive viewing and active processing of numerosity, we presented participants arrays of dots and concurrently measured their EEG. In the first condition, participants naïve to the subject under study passively viewed the dot-arrays. In the second condition, the participants were informed about the changes in numerosity and had to actively process numerosity. The visual properties of the dot-arrays were controlled and could therefore not explain possible numerosity related effects. The results revealed no numerosity related effects in the passive and active conditions. Instead, when the data was reorganised according to visual cue size (surface or diameter, etc.), strong effects of the visual cues were present at lateral occipital and parietal electrode sites. These electrode sites and time windows correspond to the ERP components often suggested to support numerosity processes. Furthermore, a larger central–parietal P3 amplitude effect was present for active versus passive numerosity processing. This result was not influenced by numerosity itself and could not be explained by response processing. It therefore appears to reflect general cognitive processes. Together, our results show that we do not (automatically) extract numerosity from a visual scene during passive or active processing of numerosity. Instead, these results are consistent with the notion that we rely on the continuous sensory properties of numerosity stimuli to make numerosity judgments. ► Sensory processes explain previous neural responses to numerosity. ► N2 amplitude increased with the size of the visual cues present in numerosity. ► Numerosity is not (automatically) extracted from a visual scene. ► Passive versus active numerosity processing evoked P3 amplitude effects.

An enigma in studies of neuropsychiatric disorders is how to translate polygenic risk into disease biology. For schizophrenia, where > 145 significant GWAS loci have been identified and only a few genes directly implicated, addressing this issue is a particular challenge. We used a combined cellomics and proteomics approach to show that polygenic risk can be disentangled by searching for shared neuronal morphology and cellular pathway phenotypes of candidate schizophrenia risk genes. We first performed an automated high-content cellular screen to characterize neuronal morphology phenotypes of 41 candidate schizophrenia risk genes. The transcription factors Tcf4 and Tbr1 and the RNA topoisomerase Top3b shared a neuronal phenotype marked by an early and progressive reduction in synapse numbers upon knockdown in mouse primary neuronal cultures. Proteomics analysis subsequently showed that these three genes converge onto the syntaxin-mediated neurotransmitter release pathway, which was previously implicated in schizophrenia, but for which genetic evidence was weak. We show that dysregulation of multiple proteins in this pathway may be due to the combined effects of schizophrenia risk genes Tcf4, Tbr1, and Top3b. Together, our data provide new biological functions for schizophrenia risk genes and support the idea that polygenic risk is the result of multiple small impacts on common neuronal signaling pathways.

Development of the brain involves the formation and maturation of numerous synapses. This process requires prominent changes of the synaptic proteome and potentially involves thousands of different proteins at every synapse. To date the proteome analysis of synapse development has been studied sparsely. Here, we analyzed the cortical synaptic membrane proteome of juvenile postnatal days 9 (P9), P15, P21, P27, adolescent (P35) and different adult ages P70, P140 and P280 of C57Bl6/J mice. Using a quantitative proteomics workflow we quantified 1560 proteins of which 696 showed statistically significant differences over time. Synaptic proteins generally showed increased levels during maturation, whereas proteins involved in protein synthesis generally decreased in abundance. In several cases, proteins from a single functional molecular entity, e.g., subunits of the NMDA receptor, showed differences in their temporal regulation, which may reflect specific synaptic development features of connectivity, strength and plasticity. SNARE proteins, Snap 29/47 and Stx 7/8/12, showed higher expression in immature animals. Finally, we evaluated the function of Cxadr that showed high expression levels at P9 and a fast decline in expression during neuronal development. Knock down of the expression of Cxadr in cultured primary mouse neurons revealed a significant decrease in synapse density.

Prior research suggests that the acuity of the approximate number system (ANS) predicts future mathematical abilities. Modelling the development of the ANS might therefore allow monitoring of children's mathematical skills and instigate educational intervention if necessary. A major problem however, is that our knowledge of the development of the ANS is acquired using fundamentally different paradigms, namely detection in infants versus discrimination in children and adults. Here, we question whether such a comparison is justified, by testing the adult ANS with both a discrimination and a detection task. We show that adults perform markedly better in the discrimination compared to the detection task. Moreover, performance on discrimination but not detection, correlated with performance on mathematics. With a second similar experiment, in which the detection task was replaced by a same-different task, we show that the results of experiment 1 cannot be attributed to differences in chance level. As only task instruction differed, the discrimination and the detection task most likely reflect differences at the decisional level. Future studies intending to model the development of the ANS should therefore rely on data derived from a single paradigm for different age groups. The same-different task appears a viable candidate, due to its applicability across age groups.

Studies investigating nonsymbolic numbers (e.g., dot arrays) are confronted with the problem that changes in numerosity are always accompanied by changes in the visual properties of the stimulus. It is therefore debated whether the visual properties of the stimulus rather than number can explain the results obtained in studies investigating nonsymbolic number processing. In this report, we present a program (available at http://titiagebuis.eu/Materials.html ; note that the program is designed to work with the Psychophysics Toolbox in MATLAB) that exports information about the visual properties of stimuli that co-vary with number (area extended, item size, total surface, density, and circumference). Consequently, insight into the relation between the visual properties of the stimulus and numerical distance can be achieved, and post hoc analyses can be conducted to directly reveal whether numerical distance or (some combinations of) the visual properties of a stimulus could be the most likely candidate underlying the results. Here, we report data that demonstrate the program’s usefulness for research on nonsymbolic number stimuli.

G-protein-coupled receptor 158 (Gpr158) is highly expressed in striatum, hippocampus and prefrontal cortex. It gained attention as it was implicated in physiological responses to stress and depression. Recently, Gpr158 has been shown to act as a pathway-specific synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure, and function. Although rodent Gpr158 expression is highest in CA3, considerable expression occurs in CA1 especially after the first postnatal month. Here, we combined hippocampal-dependent behavioral paradigms with subsequent electrophysiological and morphological analyses from the same group of mice to assess the effects of Gpr158 deficiency on CA1 physiology and function. We demonstrate deficits in spatial memory acquisition and retrieval in the Morris water maze paradigm, along with deficits in the acquisition of extinction memory in the passive avoidance test in Gpr158 KO mice. Electrophysiological recordings from CA1 pyramidal neurons revealed normal basal excitatory and inhibitory synaptic transmission, however, Schaffer collateral stimulation yielded dramatically reduced post-synaptic currents. Interestingly, intrinsic excitability of CA1 pyramidals was found increased, potentially acting as a compensatory mechanism to the reductions in Schaffer collateral-mediated drive. Both ex vivo and in vitro, neurons deficient for or with lowered levels of Gpr158 exhibited robust reductions in dendritic architecture and complexity, i.e., reduced length, surface, bifurcations, and branching. This effect was localized in the apical but not basal dendrites of adult CA1 pyramidals, indicative of compartment-specific alterations. A significant positive correlation between spatial memory acquisition and extent of complexity of CA1 pyramidals was found. Taken together, we provide first evidence of significant disruptions in hippocampal CA1 neuronal dendritic architecture and physiology, driven by Gpr158 deficiency. Importantly, the hippocampal neuronal morphology deficits appear to support the impairments in spatial memory acquisition observed in Gpr158 KO mice.

Leibovich et al. propose that continuous magnitudes and a number sense are used holistically to judge numerosity. We point out that their proposal is incomplete and implausible: incomplete, as it does not explain how continuous magnitudes are calculated; implausible, as it cannot explain performance in estimation tasks. We propose that we do not possess a number sense. Instead, we assume that numerosity judgments are accomplished by weighing the different continuous magnitudes constituting numerosity.