Major Depressive Disorder (MDD) arises from a complex interaction between genetics and environmental influences such as stress, which leads to persistent changes in frontolimbic gene expression and cellular function. Although MDD has been predominantly studied in the context of neuronal function, emerging evidence indicates that dysregulation of glia may be equally important. In particular, astrocytes are key determinants of the neuronal microenvironment and can modulate synaptic efficacy through a wide range of secreted and contact-mediated signaling. Chronic stress can cause astrocytes to undergo broad transcriptomic changes, which can lead to loss of normal supportive functions, and gain of potentially neurotoxic qualities, both of which can be equally disruptive to the overall activity of surrounding circuitry. Understanding this astrocyte plasticity and how it contributes to the pathophysiology of inflammation-related psychiatric disease is a central question in this proposal. Our laboratory has implemented FANS coupled ATAC-seq to profile the cell type-specific regulatory landscape in human MDD orbitofrontal cortex (OFC), (Aim 1) a brain region that processes reward-based decision-making and may mediate anhedonic symptoms in MDD. Using this approach, I identified a key pioneer factor, ZBTB7A, which regulates chromatin structure specifically in astrocytes to facilitate feed-forward pro-inflammatory transcriptional cycles driven by NF-kB (with which ZBTB7A also directly interacts). In a series of studies utilizing astrocyte-specific viral manipulations, I found that overexpressing (OE) this chromatin remodeler in rodent OFC astrocytes was sufficient to induce aberrant expression of inflammatory genes, behavioral deficits, and neuronal hyperactivity in response to a mild stressor, compared to GFP- expressing mice. My findings indicate that OE of Zbtb7a in OFC astrocytes initiates a change in astrocyte phenotype that has selective, direct effects on neuronal transmission. However, understanding the specific impact of Zbtb7a OE on astrocyte plasticity, as well as the non-cell autonomous effects of astrocytic Zbtb7a OE requires expression profiling with single-cell resolution. Therefore, in Aim 2 I propose to perform single-nuclei RNA sequencing (snRNA-seq) on virally-infected OFC tissues from this same cohort of Zbtb7a OE animals vs. GFP in order to create a comprehensive cellular map and transcriptomic profile of cell-type specific changes across neural and glial populations in the OFC. I hypothesize that Zbtb7a OE induces key gene expression changes to elicit cell-autonomous maladaptive astrocyte phenotypes that reverse the normal adaptive role of astrocytes in responding to mild stress. In Aim 3, I will focus on identifying laboratories for my postdoctoral work, prioritizing expertise in multiplexed ?omics? profiling, circuit-specific approaches (including spatial transcriptomics), and electrophysiology, which will build on my current training to allow me to further investigate the role of astrocyte plasticity in psychiatric disease. Aim 3 will also emphasize strengthening essential professional development skills in order to facilitate my progress towards independent research.
|Effective start/end date||1/09/21 → 30/09/21|
- National Institute of Neurological Disorders and Stroke: $45,436.00
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