Sunday, May 4, 2025
5/4/2025
Molecular and cellular characterization of the human brain across menopausal transition - Abstract The menopausal transition (MT) spans, on average, 2-8 years before the final menstrual period and is associated with significantly increased risk for major depressive disorder (MDD) and psychosis in women and other people with ovaries. While ovarian hormone shifts are strongly implicated in the increased psychiatric risk, the underlying biological mechanisms are unknown. Our previous studies in mice demonstrated that ovarian hormones dynamically change neuronal chromatin organization and gene expression in the ventral hippocampus, and we connected these molecular changes to changes in synaptic plasticity and anxiety-related behavior. Parallel ovarian hormone-induced changes in brain structure and activity have been found in the hippocampus of both mice and humans, but cellular and molecular studies in humans are lacking. Here, we hypothesize that the anterior hippocampus (aHIP), the analogous brain region critical for emotion regulation in humans, undergoes extensive changes in cellular composition and epigenome across the MT. We hypothesize that these changes are largely hormonally-driven, and could unmask genetic risk for depression and psychotic disorders in susceptible women. To address this question, we will work with a cohort of 42 postmortem human brains in which we defined the menopausal and hormonal status based on 39 putative menopausal biomarkers. The cohort includes three age groups: <40 years (“pre-menopausal”, N=10), 45-55 years (“peri-menopausal”, N=21), and >55 years (“post-menopausal”, N=11), consisting of individuals with MDD/depression (N=18) and control individuals or those without depressive symptoms (N=24). In Aim 1, we will perform single-nucleus multiome analysis of the human aHIP in pre-, peri-, and post-menopausal subjects, in order to define cellular clusters, gene expression, and chromatin states that shift in the aHIP across the MT. In Aim 2, we will perform Micro-C analysis of neuronal and non-neuronal cells of the aHIP in order to examine the MT-associated changes in the 3D genome, including chromosome compartments, topologically associating domains, loops, and enhancer- promoter interactions. Finally, in Aim 3, we will analyze the association of MT-sensitive gene regulatory regions with genetic risk loci for depression and schizophrenia, providing molecular mechanisms underlying enhanced psychiatric risk in women and other individuals undergoing MT. In summary, this project will allow us to characterize cellular and molecular changes in the human aHIP across MT using high-resolution, cutting-edge genomics techniques in uniquely curated brain tissue cohort. Our findings will open the path for the hormone status-informed, precision medicine approach in women’s mental health.
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