Exploring Resilience and Vulnerability to Stress-Related Psychiatric Disorders in Neurodevelopment: A Multi-Omic Investigation of the Hypothalamus

• Grant number: 24/02495-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): September 01, 2024
• Effective date (End): August 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Andre de Souza Mecawi
• Grantee: Beatriz Andrade de Souza
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The environment directly interacts with the genome, promoting epigenetic signatures at different stages of life, intervening in gene expression, and shaping phenotypes associated with health or disease. Exposures to stressful factors during neurodevelopment can trigger epigenetic modifications related to DNA methylation, chromatin accessibility, and alterations in non-coding RNAs (ncRNA). Thus, the epigenetic signatures of each cell type can directly participate in determining vulnerability or resilience phenotypes to the development of stress-related psychiatric disorders (TPRE), such as anxiety and depression. The hypothalamus is a key region of the central nervous system (CNS) for the integration of somatic and neuropsychiatric responses, due to the synthesis and secretion of various neuropeptides such as vasopressin, oxytocin, and corticotropin-releasing hormone (CRH) that are proven to be related to the pathophysiology of TPREs. For example, stressful experiences in early childhood have been directly associated with permanent alterations in the expression of stress-related genes in the hypothalamic-pituitary-adrenal (HPA) axis. However, the role of genetic, epigenetic, and transcriptomic mechanisms in vulnerability or resilience patterns to TPREs remains poorly understood. We hypothesize that these patterns are associated with changes in epigenetic mechanisms, including chromatin accessibility, DNA methylation, and ncRNA expression, as well as transcriptomic responses in specific cell populations of the hypothalamus. Thus, this project aims to investigate the epigenetic and transcriptomic mechanisms of the hypothalamus in male and female Wistar rats subjected to maternal deprivation during the postnatal period. To this end, we will use a multi-omic approach (snATAC-seq and snRNA-seq) in single cells from the hypothalamus of adult rats (75 days old) control (group 1) and those subjected to maternal separation on the 3rd postnatal day and shown to be resilient (group 2) or vulnerable (group 3) to the development of TPRE. Additionally, we will conduct an analysis of methylation levels (methylome) in these same groups of animals in hypothalamic tissue. Finally, RT-qPCR, in situ hybridization (RNAscope), and immunofluorescence techniques to validate changes in ncRNA, mRNAs, and protein expression in the hypothalamus due to neonatal stress and assess their relationships with vulnerability or resilience patterns to the development of TPREs. We also intend to map the modifications, relating them to wide genomic research studies (GWAS) revealing connections between genetic variations, epigenetic modifications, and transcriptomic responses in different cell types. In addition to the mechanistic aspects addressed in this project, its clinical implications are promising: by identifying molecular markers associated with resilience and vulnerability to the development of TPREs, the possibility of preventive and personalized therapeutic strategies opens up, considering the genetic and environmental diversity of individuals. This project and the request for a doctoral scholarship are linked to the thematic aid proposal under evaluation by FAPESP (2023/13464-7).