Respiratory-Limbic Coupling via a Thalamic Circuit Alleviates Anxiety

Breathing rhythms bidirectionally modulate affective states, yet the underlying neural pathways remain elusive. Here, we identified an ascending neural circuit that integrates respiratory patterning with affective state in male mice. This circuit originates from glutamatergic neurons in the preBötzinger complex (preBötC), projecting to the paraventricular thalamic nucleus (PVT) and subsequently targeting the central amygdala (CeA). We reveal that photostimulation of the preBötC→PVT circuit significantly alleviates acute restraint stress-induced anxiety-like phenotypes and reduces respiratory frequency variability. Conversely, inhibition of this circuit exacerbates anxiety-like phenotypes and respiratory dysfunction. These effects are significantly abolished by inhibition or ablation of PVT neurons projecting to the CeA. Additionally, this anxiolytic effect is mediated by PVT projections that preferentially excite centrolateral amygdala neurons, thereby inhibiting centromedial amygdala output. Translating these findings, we show that volitional slow breathing reduces anxiety in healthy humans and suppresses anxiety-related beta/high-gamma oscillations in the amygdala of epilepsy patients. This work delineates a conserved respiratory-limbic circuit that mechanistically explains the anxiolytic effect of controlled breathing.