CATECHOLAMINERGIC MODULATION OF PREFRONTAL-LATERAL HYPOTHALAMIC CIRCUIT IN STRESS AND ANXIETY

Stress and anxiety help animals adapt to challenging environments, but when dysregulated, they contribute to numerous psychiatric disorders. The medial prefrontal cortex (mPFC) is involved in regulating stress and anxiety and exerts top-down control over subcortical regions, including the lateral hypothalamus (LH). Both norepinephrine and dopamine dynamics respond to stress and modulate neuronal activity in mPFC and LH. Yet it remains unclear how prefrontal–hypothalamic circuit mediates stress- and anxiety-related adaptations, and how catecholamines shape this interaction.
To dissect the role of vmPFC-LH projections, we performed calcium imaging of these projections during innate stress- and anxiety-related behaviours of mice. We then employed dual-site, dual-color fibre photometry of GRAB sensors to simultaneously monitor norepinephrine and dopamine activity in vmPFC and LH. Furthermore, we combined TRAP labelling, retrograde tracing and in situ hybridisation to characterize the molecular identity of stress-responsive LH-projecting neurons in vmPFC.
Our data revealed that vmPFC-LH projections are functionally engaged during stress- and anxiety-related responses, preferentially signalling behaviours relevant to the current challenge. Stress-responsive LH-projecting vmPFC neurons expressed receptors for both norepinephrine and dopamine, positioning them to integrate neuromodulatory signals during stress. Dual-site photometry revealed that norepinephrine dynamics were coordinated across vmPFC and LH, tracking anxiety, stress-induced anxiety, and anxiety-relieving behaviours. Dopamine signals also responded to stress and anxiety but displayed greater regional specialization. Together, these findings identify the vmPFC–LH pathway as a catecholamine-sensitive circuit that supports adaptive behavioural responses to stress and anxiety.
We gratefully acknowledge support by the ERC consolidator grant HypFeedNet, DFG CRC1451, EXC2030-CECAD.