Periodic Reporting for period 4 - SPANUMBRA (Number-space associations in the brain)
Berichtszeitraum: 2024-05-01 bis 2025-04-30
Human abilities for symbolic, formal arithmetic are rooted on an evolutionarily ancient and largely conserved Approximate Number System (ANS) mechanism. This ANS deals with both discrete (numerousness) and continuous (size, time, space) quantities. Moreover, evidence suggests that the numerical (discrete) features of a stimulus can interact with the spatial, continuous features. This is shown in mapping of numerical magnitudes with a left-to-right spatial orientation (mental number line) and others numerical-spatial associations (NSA). These NSA are pervasive in human behavior and important to health (e.g. dyscalculia is thought to be associated with impairment of the mental number line). NSA have been shown to occur in human newborns and in non-human animals and SPANUMBRA aims to investigate how in the brain discrete and continuous quantities are implemented and how they interact in NSA in different animal models (domestic chicks and zebrafish) and in human neonates and infants in order to provide ann overall framework on the developmental, neural and genetic origins of these phenomena. The project aims to investigate also the role of the experience in the development of NSA in newly-hatched chicks and in human neonates and infants before, during, and after the exposure to experienced-driven specific NSA associations and, in order to investigate the role of culture in shaping/reinforcing NSA, in traditional societies that lack formal mathematical systems. The study of the neural basis of the numerical and continuous quantities cognition and of their interaction will combine neurobiological techniques (immediate early gene expression in chicks and zebrafish) and non-invasive methods (EEG in human neonates). The genetic bases of NSA will be also investigated using transgenic lines of zebrafish, in order to understand the role of candidate genes implicated in the development of dyscalculia thus providing important societal consequences for the project.
The work performed and the main achievement in the project can be summarized as follows. First, we used our animal model systems to identify brain regions involved in the processing of discrete (countable) and continuous (spatial) quantities or magnitudes, as well as the circuitry by which associations between numerosities and space may occur. We were successful in this enterprise for we have identified specific brain regions that show selective activities to the different kind of magnitudes (e.g. the caudal nidopallium and the Wullst in the chick and the caudal part of the dorso-central division and habenula of the zebrafish pallium; see Messina et al 2021 Cereb Cortex; Lorenzi et al Heliyon 2024).
We also conducted work at the level of single neurons, discovering by single cell recording in chicks number neurons in the caudal nidopallium (Kobylkov et al PNAS 2022) and at the level of whole brain using light-sheet microscopy in the larval zebrafish in the midbrain and forebrain (Luu et al 2024, bioRxiv). Most interestingly we found an orderly appearance of number neurons during development in the zebrafish larvae, a finding linking SNA with the ordinal representation of numerosity as occuring during development. Second, we explored in work with chicks, zebrafish, pre-scholar babies and human adults the role of learning (and culture in humans) and of biological mechanisms in the development of the mental number line. The main findings (mostly already published - e.g. Eccher et al Nature Comm 2025; Potrick et al 2024 Heliyon; Sheardown et al Proc R Soc B, 2022) revealed a major role of biological mechanisms, that we also explored with our UK partner Caroline Brennan of Queen Mary Univ. London in transgenic lines of fish showing deficits mimicking discalculya, Torres et al, subm). Furthermore, our theory that explain SNA in terms of a valence hypothesis for division of function in the left and right side of the brain has been successfully tested in zebrafish (Potrich et al in prep) and also, in collaboration with another lab, in monkeys (Annichiarico et al in prep). Our interest for the societal and applied aspects of neurodevelopmental disorders of number cognition prompted us to develop novel tests for larval zebrafish, both wildtype (Adam et al, Anim Cogn 2024) and transgenic lines (Adam et al in prep), as well as the development of a screening and rehabilitation method for the early detection and treatment of developmental dyscalculia in children, in the form of an entertaining, tablet-based gaming environment. New theoretical work on brain asymmetry has been also generated thanks to the impetus provided by the empirical work done in the project (Vallortigara and Vitiello, 2024 R Soc Open Sci).
With more than fifty published papers on major scientific journals I believe the aims of the project have been fully and successfully accomplished. Exploitation and dissemination has been also intense, with participation of PI and group members to several conferences, science festival, and television events and newspapers pieces.
We also conducted work at the level of single neurons, discovering by single cell recording in chicks number neurons in the caudal nidopallium (Kobylkov et al PNAS 2022) and at the level of whole brain using light-sheet microscopy in the larval zebrafish in the midbrain and forebrain (Luu et al 2024, bioRxiv). Most interestingly we found an orderly appearance of number neurons during development in the zebrafish larvae, a finding linking SNA with the ordinal representation of numerosity as occuring during development. Second, we explored in work with chicks, zebrafish, pre-scholar babies and human adults the role of learning (and culture in humans) and of biological mechanisms in the development of the mental number line. The main findings (mostly already published - e.g. Eccher et al Nature Comm 2025; Potrick et al 2024 Heliyon; Sheardown et al Proc R Soc B, 2022) revealed a major role of biological mechanisms, that we also explored with our UK partner Caroline Brennan of Queen Mary Univ. London in transgenic lines of fish showing deficits mimicking discalculya, Torres et al, subm). Furthermore, our theory that explain SNA in terms of a valence hypothesis for division of function in the left and right side of the brain has been successfully tested in zebrafish (Potrich et al in prep) and also, in collaboration with another lab, in monkeys (Annichiarico et al in prep). Our interest for the societal and applied aspects of neurodevelopmental disorders of number cognition prompted us to develop novel tests for larval zebrafish, both wildtype (Adam et al, Anim Cogn 2024) and transgenic lines (Adam et al in prep), as well as the development of a screening and rehabilitation method for the early detection and treatment of developmental dyscalculia in children, in the form of an entertaining, tablet-based gaming environment. New theoretical work on brain asymmetry has been also generated thanks to the impetus provided by the empirical work done in the project (Vallortigara and Vitiello, 2024 R Soc Open Sci).
With more than fifty published papers on major scientific journals I believe the aims of the project have been fully and successfully accomplished. Exploitation and dissemination has been also intense, with participation of PI and group members to several conferences, science festival, and television events and newspapers pieces.
At least three aspects of our scientific work represent truly breakthroughs and/or very significant advancement beyond the state of the art.
The traditional view about the kind of number space association (NSA) represented by the so-called ‘mental number line’ was that it depends on human culture, namely that it is acquired by writing-reading habits. We challenged this view by showing that non-human animals and human newborns also show NSA and provided a different, mechanistic explanation for this phenomenon based on asymmetry of the brain. Furthermore we showed for the very first time that NSA could be observed also in a traditional and only oral society, lacking any formal arithmetic. This is clearly a breakthrough with respect to established knowledge. Similarly, it may appear obvious that cognition of number should rely on learning. But, most suprisingly, we found that neurons responding to number can be observed in the vertebrate brain in the absence of any previous specific experience. Contrary to the established belief that only one specific area can be devoted to number neurons we also found that there are multiple brain areas involved. Evidence for selectivity to numbers in the habenula in adult zebrafish by Immediate Early Gene Expression came as a true surprsise, which was then also confirmed by whole brain imaging in larval zebrafish. Moreover, thanks to the development of dedicated program and accurate experiments we documented straightforwardly that numerosity per se is encoded in the vertebrate brain, irrespective of continuous spatial quantities. The project has also important societal impact because poor numeracy is a most serious handicap for individual life chances and a major cost for society. Thus, major advances in our understanding of the neural and genetic basis of individual differences in numerical abilities ultimately aid development of new methods (such as those described in our project) for improving numeracy.
The traditional view about the kind of number space association (NSA) represented by the so-called ‘mental number line’ was that it depends on human culture, namely that it is acquired by writing-reading habits. We challenged this view by showing that non-human animals and human newborns also show NSA and provided a different, mechanistic explanation for this phenomenon based on asymmetry of the brain. Furthermore we showed for the very first time that NSA could be observed also in a traditional and only oral society, lacking any formal arithmetic. This is clearly a breakthrough with respect to established knowledge. Similarly, it may appear obvious that cognition of number should rely on learning. But, most suprisingly, we found that neurons responding to number can be observed in the vertebrate brain in the absence of any previous specific experience. Contrary to the established belief that only one specific area can be devoted to number neurons we also found that there are multiple brain areas involved. Evidence for selectivity to numbers in the habenula in adult zebrafish by Immediate Early Gene Expression came as a true surprsise, which was then also confirmed by whole brain imaging in larval zebrafish. Moreover, thanks to the development of dedicated program and accurate experiments we documented straightforwardly that numerosity per se is encoded in the vertebrate brain, irrespective of continuous spatial quantities. The project has also important societal impact because poor numeracy is a most serious handicap for individual life chances and a major cost for society. Thus, major advances in our understanding of the neural and genetic basis of individual differences in numerical abilities ultimately aid development of new methods (such as those described in our project) for improving numeracy.