Decoding the cellular landscape of biological stress in the human brain.

Adversity exposure leading to a dysfunctional biological stress response represents a significant risk factor underlying psychiatric disorder aetiology for many individuals. Yet our understanding of how different cell types within stress-responsive brain circuits differentially contribute to psychiatric risk remains limited, particularly in the human brain. Our lab, the Mental Illness, Neurobiology and Disorders of Stress (MINDS) Laboratory, has been addressing this knowledge gap through large-scale analyses of postmortem human brain specimens from individuals with major psychiatric disorders who experienced high levels of adversity in their lives. We have a focus on examining targets and pathways involved in HPA axis and glucocorticoid-mediated signalling in the human brain at single-cell resolution. Through integration of single-cell and spatial molecular data with advanced histological approaches to evaluate cellular morphology, we have identified cell-type-specific vulnerability patterns to the biological consequences of adversity exposure. Our findings demonstrate how different populations respond to adversity through coordinated molecular and morphological changes that affect synaptic function and stability. This approach exemplifies the potential for combining new spatial omics and traditional histological approaches to achieve precision medicine in psychiatry, by revealing specific cellular targets for therapeutic intervention. Our work facilitates a shift from broad neurotransmitter-based interventions towards targeted therapeutic strategies for stress-related psychiatric disorders. These advances provide a foundation for developing more effective treatments tailored to the underlying cellular pathology in individual patients with stress-related mental illness.