Chronobiology and ASD: Investigation of Melatonin Rhythm, Sleep, Inflammatory Mediators, and Sensory Processing

• Grant number: 25/03212-6
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2025
• End date: September 30, 2028
• Field of knowledge: Health Sciences - Medicine
• Agreement: Instituto Jô Clemente
• Principal Investigator: Luciana Pinato
• Grantee: Luciana Pinato
• Host Institution: Faculdade de Filosofia e Ciências (FFC). Universidade Estadual Paulista (UNESP). Campus de Marília. Marília , SP, Brazil
• City of the host institution: Marília
• Associated researchers: Aila Narene Dahwache Criado Rocha ; Celia Maria Giacheti ; Erika Cecon ; Sanseray da Silveira Cruz Machado ; Vanderlei Amadeu da Rocha

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction, communication, and behavior, as well as sensory processing deficits (DSM-5-TR). Among the symptoms of ASD, the high prevalence of sleep disorders stands out, with negative consequences for behavioral changes, mood instability, sensory processing, and neurocognitive functions. Melatonin, a neurohormone produced at night by the pineal gland, plays a key role in regulating biological rhythms, particularly the sleep-wake cycle, through the activation of G protein-coupled receptors, MTNR1A (MT1) and MTNR1B (MT2). Its synthesis depends on the sequential action of the enzymes aralkylamine N-acetyltransferase (AANAT) and acetylserotonin-O-methyltransferase (ASMT), whose mutations may compromise hormone production. Several studies have reported abnormal melatonin concentrations in individuals with ASD, with alterations observed in more than 60% of cases (Melke et al., 2008, PMID 17505466; Tordjman et al., 2012, PMID 22613035). In some individuals, single nucleotide polymorphisms (SNPs) in the ASMT gene have been identified, associated with the complete inhibition of melatonin biosynthesis. A previous study by our group showed that 40% of individuals with ASD do not exhibit the daily rhythm of the urinary metabolite 6-sulfatoxymelatonin (aMT6s), while 60% presented a rhythm but with a significant reduction in nocturnal excretion and an increase in diurnal excretion (da Silveira Cruz-Machado et al., 2021, PMID 33421193). The same study found that elevated levels of tumor necrosis factor (TNF), but not interleukin 6 (IL-6), correlated with altered aMT6s excretion, suggesting that the inflammatory state may contribute to the chronobiological dysfunction in ASD, including sleep difficulties (da Silveira Cruz-Machado et al., 2021, PMID 33421193, reviewed by Pinato et al., 2019, PMID 31682208). Thus, both genetic dysfunctions in the circadian machinery and systemic inflammatory processes appear to contribute to the chronobiological disorders associated with ASD. In this context, the identification of biomarkers associated with chronobiological alterations in ASD using non-invasive methods based on salivary and urinary samples, along with scales and actigraphy, represents a promising approach for research and clinical practice, allowing the monitoring of this population, which is more vulnerable to invasive procedures. Therefore, this study aims to investigate chronobiological signatures in children with different levels of ASD support, analyzing the daily rhythm of melatonin-including its biosynthesis and genetic variants in its receptors-as well as inflammatory markers, sleep patterns, locomotor activity, sensory processing, and quality of life, and their interactions with environmental factors and associated individual characteristics. (AU)