Papel dos receptores de adenosina e impacto do consumo do seu antagonista cafeína na migração de neurónios corticais – lateralização no desenvolvimento do cérebro.

As detailed above, adenosine through the activation of A2AR controls both radial migration of cortical excitatory neurons (Alçada-Morais et al, 2021) and tangential migration of interneurons (Silva et al, 2013). However, while caffeine was shown to delay interneuron migration through the blockade of A2AR (Silva et al, 2013), our preliminary data showed that caffeine intake accelerated the migration of cortical principal neurons, opposite to the observed with A2AR antagonism (Fig.3). This observation demonstrates on one hand that the impact of caffeine in neuronal migration is more intricate and on the other hand that the regulation of radial migration by adenosine may be more complex and should entail the concerted action of other P1R, supported by eventual gradients of adenosine within the telencephalon and/or different sources of adenosine, in a region- and/or hemisphere-specific manner, since caffeine affected radial migration only in the right hemisphere (Fig. 3). This unilateral effect of caffeine also constitutes a paradigm-shifting finding since it indicates for the existence of a lateralization not only in brain function, but also in the mechanisms governing brain development. Hence, the comprehension of the role of adenosinergic signaling and their receptors and the impact of their antagonist caffeine in neuronal migration during corticogenesis is key to: 1) understand and prevent/correct any malfunction of this signaling system in corticogenesis, already associated with different pathological conditions (Turner et al, 2003; Rodrigues et al, 2019; Shi Nan-Rui et al, 2023; Kim et al, 2023); 2) address the clinical/societal need to evaluate the impact of the most consumed drug worldwide, caffeine, and, importantly different patterns of its consumption, in the development of brain cytoarchitecture, cortical network maturation, how it modifies brain function and eventually in the development of a higher susceptibility to neuropsychiatric and neurological conditions, taking into account the observed hemisphere-specific impact; and 3) consolidate the conceptual advance of the existence of a lateralisation not only in brain function, but also in the mechanisms governing brain development, and start to unravel the relationship between the well-established lateralisation in brain function and a lateralisation of brain development. This project is designed to tackle all these needs by aiming the following 7 main goals: AIM1 – Role of A1, A2B and A3 receptors in cortical radial migration and tangential migration (Task 1,2) AIM2 - Impact of inhibition of P1 receptors-driven control of neuronal migration in cortical cytoarchitecture and circuitry (Task 3) . AIM3 – Identification of extracellular ATP/adenosine gradients in the telencephalon (Task 4). AIM4 – Characterization of the impact of different patterns of caffeine-intake in radial migration, cortical network formation and brain function (Task 5). AIM5 – Identification of the adenosine receptor(s) targeted in the caffeine-induced effects on radial migration (Task 6). AIM6 – Evaluation of a lateralization of the effects of P1Rs and caffeine in corticogenesis (Task 1-6 by performing an hemisphere-specific analysis). AIM7 – Set up a retrospective and long-run prospective study correlating caffeine consumption and brain function, from brain performance to eventual disorders (Task 7).