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The hypothalamus in major depressive disorder: a multiomics single-nucleus study

Abstract

Major depressive disorder (MMD) is one of the major clinical conditions that contribute to incapability and suicide worldwide. Individuals who live in underdeveloped countries have three times more chances of being depressed than those who live in developed countries. The most accepted model to explain the etiology of depression is the multifactorial model, in which, alterations in gene-environment interactions are found and are mediated by epigenetic modifications. In this context, the role of the hypothalamic-pituitary-adrenal axis (HPA axis) is highlighted since it is the most neurobiological system that controls the stress response, and it is among the main biological systems affected in MDD. Furthermore, the hypothalamus is a hub that integrates homeostasis, motivation, and social response according to interoceptive and exteroceptive information. Although the role of the HPA axis is consistently well-studied in MDD, few studies have elected the hypothalamus to analyze morphological and biochemical alterations in subjects with this mental disorder. Results from few studies point to modifications in specific cell types. Using single-cell sequencing, it is possible to evaluate cell-specific information regarding genes and transcripts. Such kind of analysis becomes essential in the context of the hypothalamus given its anatomical complexity. Our aim is the recognition of different epigenomic and transcriptomic signatures across the diverse nuclei and cell types (neurons and glial cells) of the hypothalamus. Additionally, we believe ha depressive subjects that lived in worsen socio-economic conditions and/or present cardiovascular and metabolic comorbidities may show specific molecular signatures. To answer this question, we will perform a multi-omic analysis (comprising both ATACseq and RNAseq) by sequencing genetic material from the nuclei of the hypothalamic cells of subjects with a history of MDD and age/sex-matched controls (n=16 for each group). This approach will give us information on cell-specific chromatin accessibility and transcriptomic changes occurring in MDD. As an exploratory analysis, we will evaluate molecular markers ha may be related to low education attainment, hypertension, diabetes mellitus, and obesity. After the characterization of the single-cell epigenomic and transcriptomic signatures related o MDD and its technical validation, we will use genetically modified mouse models (Cre/Loxp technology) associated with chemogenetics to evaluate the role of the hypothalamic cells in depressive-like symptoms. Our final goal is to discover novel targets for the prevention and treatment (pharmacological or non-pharmacological) of MDD, considering the different comorbidities and vulnerabilities of the Brazilian population. This top-down (from humans to animals) will allow us to uniquely map different etiologies of MDD and increased the interest for the development of public health strategies focused on the genetic and socio-economic peculiarities of the Brazilian and global population. (AU)

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