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Number-space associations in the brain

Periodic Reporting for period 3 - SPANUMBRA (Number-space associations in the brain)

Reporting period: 2022-11-01 to 2024-04-30

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.
Up to now, we performed experiments on controlled-reared chicks using behavioral methods and early gene expression. We published a paper showing that numerical magnitude, rather than individual bias, explains spatial numerical association in newborn animals (Rugani et al (2020) eLife) and another paper investigating sex differences in spatial-numerical cognition (Lemaire et al. (2020) Learn Behav). We published two papers on top-level journals concerning the representation of zero and ‘absence’ (Szabó et al. (2022) eLife) and use of inference processes (Daisley et al (2021) Comms Biol). On the neurobiological side, we were able to record from single cells in young chicks showing the early presence of neurons selective sensitive to numbers in the nidopallium caudolaterale; the paper reporting these findings has published in a major scientific journal (Kobylkov et al., PNAS, 2022). More work has been done recently using single cell responses on the number of items needed to define a face (Kobylkov and Vallortigara G (2024) Front Neurosci) and the effects of light stimulation in embryo (Costalunnag et al iScience 2024; Lorenzi et al eLife, 2023).
In zebrafish we developed a new habituation/dishabituation test complemented by qPCR of early gene expression and in situ hybridation. In a first paper we showed involvement of thalamus and pallium (Messina et al. (2020) Sci. Rep.). Then we identified for the first time a region of the pallium (dorso-central in the more caudal part) showing population of neurons selectively sensitive to numerosity but not to other quantitative aspects of the stimuli (Messina et al. (2021) Cereb Cortex). We are now proceeding looking at the nuclei in the thalamus and tectum that connect to the pallium (and motoric control areas) using anterograde and retrograde tracers in order to identify the overall circuitry and how spatial extension and numerical aspects of stimuli are represented and interact to each other. A paper is in preparation.
We developed standardized techniques for presentation of numerical stimuli with control of continuous physical variables (Zanon et al. (2022) Behav Res Meth) and recently we used these to prove that fish are capable of ‘pure’ numerical cognition, with accurate controls of all continuous physical variables (Potrich et al. (2022) eLife).
We also investigated in zebrafish the distribution of pallial-expressed genes of relevance to numerical and other aspects of higher cognition, and found striking asymmetries (Messina et al. (2020) Eur. J. Neurosci.). We plan now to look at the possibilities to reveal these asymmetries in our behavioral tasks, looking at IEG expression separately in the two sides of the brain.
QMU developed transgenic lines for candidate genes for dyscalculia, a preliminary report testing numerical abilities in transgenic lines has been just submitted.
With QMU we also tested the ontogeny of numeracy using a group size preference (GSP) task in juvenile zebrafish. We found GSP from 21 days post-fertilization, though the systems involved in quantity representation do not operate separately from other cognitive mechanisms, suggesting that quantity processing in zebrafish may be the result of an interplay between attentional, cognitive and memory-related mechanisms as in humans (Sheardown et al (2022) Proc R Soc London B). Studies with human babies and infants were delayed because the pandemics prevented access to the hospital labs; we have now continued this part studying infants and comparing them with adults. Meanwhile, we completed the study on mental number line a traditional society, the Himba of Namibia, and submitted the paper to a major scientific journal.
Finally, we published several reviews and theoretical papers on topics related to the project, i.e. Miletto-Petrazzini et al. (2020) Front. Neuroanat.; Bortot et al. (2020) Biochem. Biophys. Res. Comm.; Lorenzi et al. (2021) Front. Psychol (Vallortigara et al (2022). Cur Dir Psycho Sci,; Messina et al (2021). Animals, 11: 3072); Messina et al (2022) Front Neuroanat; Kobylkov et al (2023) Bio Systems).
Some remarkable findings were obtained up to now with the project: (i) we identified for the first time single cells responding to numerosities in a young vertebrate (the newborn domestic chick); (ii) we identified for the first time localized specific populations of neurons that respond to as space extension (size) and numerosity in the pallium of zebrafish; (iii) we proved response to pure numerosity with control of all continuous spatial variables in a fish brain; (iv) we characterize the ontogeny of development of numeracy in zebrafish larvae.
All these findings open the door to subsequent work we plan to carry on to reveal neural circuitry and to perform genetic analyses at a level that would have had no precedent in more traditional models for studies of numerical and association between number and spatial aspects of the stimuli.
We are confident to obtain in the remaining part of the project further results about connectivity of pallial areas with others regions (in particular the thalamus and the tectum) as well as patterns of asymmetry of response, particularly in gene expression that will ensure further progress in our understanding of number and number/space associations. Furthermore, we expect to have indications by transgenic lines of zebrafish about candidate genes involved in numerical cognition and its disturbances (e.g. developmental dyscalculia).
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