Molecular Horizons - Dominic Kaul, PhD Exit Seminar

Severe psychological stress is a global issue - the World Health Organization estimates that over half of children globally are impacted by maltreatment. Severe stress is also the strongest environmental risk factor across major psychiatric disorders, which affect up to 35% of people over their lifetime. However, the cellular and molecular underpinnings of how stress raises risk to psychopathology are poorly understood, particularly in humans. Astrocytes are the most populous non-neuronal cell type in the brain. They are also highly sensitive to severe psychological stress, making them promising targets in the treatment of psychiatric disorders. However, previous examinations of astrocytes have failed to appreciate the diversity of these cells which is essential for precise targeting of this cell population. This presentation highlights approaches to understand astrocyte diversity using single nucleus and spatial transcriptomics, alongside histological analysis of postmortem human brain, and explores how a history of severe psychological stress can distinguish the brains of individuals who lived with a psychiatric disorder. Additionally, human pluripotent stem cell-derived astrocytes were examined to identify mechanisms by which human astrocytes respond to stress. These approaches converge on evidence that the role of astrocytes to regulate the synaptic environment are associated with stress in human contexts.