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Abstract:
Psychiatric disorders are the rising medical challenge of the 21st century due to their recent rise in prevalence, world-spread incidence, and burden on patients? life. Among all psychiatric disorders, stress-related psychiatric disorders rank the highest for societal burden. This category
includes disorders characterized by a strong influence of stress exposure onto their onset and progression, such as depression and anxiety disorders.
Stress-related psychiatric disorders clinically manifest in women and men with different incidence, symptoms, comorbidities, impact on quality of life, and treatment efficacy and compliance. While these aspects have been thoroughly characterised in the recent years from a clinical point of view, we still lack a lot of information on how sex is able to shapes so many aspects of these disorders and how it interacts with main environmental factors that influences them: stress.
Molecularly speaking, sex has been shown to impact on the stress response of several brain
regions. Good evidence suggests that some of these sex differences might stem by sex-specific
response at a cell type level. This thesis aims to verify this hypothesis in the adult mouse paraventricular nucleus of the hypothalamus using single-cell RNA-sequencing. As such, we generated a large single-cell RNA-sequencing dataset using the latest technology from male and
female mice that either did not experience any stress (controls) or experienced acute restraint stress with or without a previous experience of chronic mild stress. We combined bioinformatic and molecular approaches to characterise the transcriptional response to acute stress, and
describe how it differs between cell types, how it is shaped by sex, and how it is impacted by previous chronic stress exposure.
We showed that the transcriptional response to acute stress is strongly cell-type- and sex-specific with limited overlap between different cells and different sexes. We identified circulating hormones as a source for some of these sex-difference, especially for the GABAergic neurons. We further characterized the impact of chronic stress exposure in changing these transcriptional signatures, identifying a different degree of change based on the cell type and the sex. We also identified the oligodendrocytes as the cell type whose response to acute stress is the most affected by a previous exposure to chronic stress. Ultimately, we further characterized the basal transcriptional and morphological sex differences of oligodendrocytes that likely resulted in different responses and different developmental states after stress.
Altogether, this thesis describes a new rich dataset and provides evidence for cell-type-specific contributions to the sex dimorphisms in stress. It also identifies several cell types of interest --} such as AVP neurons, tanycytes, GABAergic neurons, and oligodendrocytes {-- worth of further investigation to better understand sex differences in the stress response. Finally, we also provide an interactive and easily accessible platform for anyone to explore the dataset and ask their own
set of research questions. This work contributes to the general understanding of sex differences at a molecular level, providing new target cell types and genes of interest for future translational studies with the ultimate goal of enabling personalized medicine in stress-related disorders in the near future.
