Single-cell genomics meets systems neuroscience: Insights from mapping the brain circuitry of stress

Responses to external and internal dangers is essential for survival and homeostatic regulation. Hypothalamic corticotropin-releasing hormone neurons (CRHNs) play a pivotal role in regulating neuroendocrine responses to fear and stress. In recent years, the application of neurogenetic tools, such as fiber photometry, chemogenetics and optogenetics, have provided new insights into the dynamic neuronal responses of CRHNs during stressful events, offering new perspectives into their functional significance in mediating neurobehavioural responses to stress. Transsynaptic viral tracers have facilitated the comprehensive mapping of neuronal inputs to CRHNs. Furthermore, the development and application of innovative single-cell genomic tools combined with viral tracing have begun to pave the way for a deeper understanding of the transcriptional profiles of neural circuit components, enabling molecular-anatomical circuit mapping. Here, I will discuss how these systems neuroscience approaches and novel single-cell genomic methods are advancing the molecular and functional mapping of stress neurocircuits, their associated challenges and future directions.