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Rat primary cortical neurons are the preferred cell model to study this process as they can maintain their functional attributes, including functional synapses, and simulate the behavior of neuronal cells in vivo. In this study, we employed Fourier transform infrared (FTIR) spectroscopy to monitor the molecular transformations that occur during the differentiation of rat cortical neurons. Partial least squares regression (PLS-R) analysis from the 1800\u20131500 cm\u22121 region further allows the identification of the spectroscopic profile of early and late differentiation stages, highlighting the technique\u2019s ability to detect subtle molecular changes. Further peak intensity analysis revealed significant changes in the cells\u2019 metabolome during differentiation; it was possible to observe remodeling of protein secondary structures and an increase in protein phosphorylation levels, which can imply activation of signaling pathways essential for neuronal differentiation and maturation. Concomitantly, lipid-associated spectral regions demonstrated increased levels of total lipids, lipid esters, and longer acyl chains and decreased unsaturation levels, alterations that can be linked to membrane expansion throughout neuronal differentiation. These findings underscore FTIR spectroscopy as a valuable tool for studying neuronal differentiation, offering insights into the conformational and metabolic shifts underlying the formation of mature neuronal phenotypes.<\/jats:p>","DOI":"10.3390\/ijms26168027","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T07:50:46Z","timestamp":1755676246000},"page":"8027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spectroscopic Profile of Metabolome Dynamics During Rat Cortical Neuronal Differentiation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-0666","authenticated-orcid":false,"given":"Id\u00e1lia","family":"Almeida","sequence":"first","affiliation":[{"name":"Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-1809","authenticated-orcid":false,"given":"Filipa","family":"Martins","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3191-7121","authenticated-orcid":false,"given":"Brian J.","family":"Goodfellow","sequence":"additional","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0595-5821","authenticated-orcid":false,"given":"Alexandra","family":"Nunes","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5862-5797","authenticated-orcid":false,"given":"Sandra","family":"Rebelo","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0168-0102(02)00062-7","article-title":"Axon specification in hippocampal neurons","volume":"43","author":"Fukata","year":"2002","journal-title":"Neurosci. 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