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Number-space associations in the brain

Periodic Reporting for period 2 - SPANUMBRA (Number-space associations in the brain)

Reporting period: 2021-05-01 to 2022-10-31

Evidence has shown that underlying the uniquely human abilities for symbolic mathematics lies an evolutionarily ancient and shared among animals Approximate Number System (ANS). This ANS deals with both discrete (numerousness) and continuous (size, time, space) quantities for it is well-known that the numerical features of a stimulus can interact with the spatial, continuous features. This is apparent in the tendency to map increasing numerical magnitudes with a left-to-right orientation. Importantly, these numerical-spatial associations (NSA) are pervasive in human behavior and have relevance to health (e.g. dyscalculia is thought to be associated with impaired understanding of the so-called «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 to provide a comprehensive and comparative perspective 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 with controlled-rearing experiments in which newly-hatched chicks will be exposed to correlated and anti-correlated discrete and continuous magnitudes. The development of NSA will be also studied in human neonates and infants before, during, and after the exposure to culture-specific NSA associations and, in order to investigate the role of culture in shaping/reinforcing NSA, studies with traditional societies with little developed 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 and fNIRS in human neonates). The genetic bases of NSA will be also investigated using transgenic lines of zebrafish, in order to understand the role of some genes implicated in the development of lateralization and in dyscalculia thus providing important potential societal consequences for the project.
During these 36 months of the project 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).
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.
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.
Our colleagues at QMU developed transgenic lines for candidate genes for dyscalculia, and we are currently rearing and growing up them; we plan to test these zebrafish lines when adults.
With our colleagues at 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 started this part studying infants and comparing them with adults. Meanwhile, we started data collection concerning a traditional society, the Himba, and their numerical-spatial associations.
Finally, we published some 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).
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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