The hypothalamus in major depressive disorder: a multiomics study of single-cell nuclei

• Grant number: 24/10829-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): August 01, 2024
• Effective date (End): July 31, 2025
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Camila Nascimento Mantelli
• Grantee: Vivian Sthefany Buarque
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/13345-2 - The hypothalamus in major depressive disorder: a multiomics single-nucleus study, AP.JP

Abstract

Major depression (MD) stands as one of the clinical conditions that greatly contribute to disability and suicide globally. The currently most accepted model for explaining the etiology of depression is the multifactorial model, in which alterations in the gene-environment interaction, mediated by epigenetic modifications, are observed. Within this context, the role of the hypothalamic-pituitary-adrenal (HPA) axis is highlighted as the principal neurobiological system controlling stress response, and it's among the most affected biological systems in MD. The hypothalamus serves as an integrative center for homeostasis, motivation, and social response based on interoceptive and exteroceptive information. Despite the well-established role of the HPA axis in MD, few studies have chosen the hypothalamus for analyses of morphological and biochemical modifications in individuals with this mental disorder. The limited studies point to modifications in specific cell types. Through single-cell sequencing, it is possible to assess information on genes and transcripts of specific cell types. Since chromatin modifications are tissue-specific, combining analyses of chromatin accessibility and the transcriptome further allows for the evaluation of the impact of epigenetic alterations on gene expression. This type of analysis becomes essential in the context of the hypothalamus, considering its complex anatomy. Our main goal is to identify epigenetic and transcriptional signatures in different nuclei of the hypothalamus and in various cell types (glia and neurons) in this brain region. To this end, we will perform a multi-omic analysis (ATAC-seq and RNA-seq) by sequencing the genetic material from hypothalamic cell nuclei of individuals with a history of depression and control subjects matched by sex and age (n=16 for each group). Bioinformatics and enrichment analyses will allow us to select targets that will be validated in histological sections of the hypothalamus (using in situ hybridization), as well as their functional relevance assessed in an animal model (Master's project). The ultimate goal is to discover new targets for the prevention and treatment (pharmacological and non-pharmacological) of MD.