Amygdala-hippocampus somatostatin interneuron beta-synchrony underlies a cross-species biomarker of emotional state.

Emotional responses arise from limbic circuits including the hippocampus and amygdala. In the human brain, beta-frequency communication between these structures correlates with self-reported mood and anxiety. However, both the mechanism and significance of this biomarker as a readout vs. driver of emotional state remain unknown. Here, we show that beta-frequency communication between ventral hippocampus and basolateral amygdala also predicts anxiety-related behavior in mice, both on long timescales (∼30 min) and immediately preceding behavioral choices. Genetically encoded voltage indicators reveal that this biomarker reflects synchronization between somatostatin interneurons across both structures. Indeed, synchrony between these neurons dynamically predicts approach-avoidance decisions, and optogenetically shifting the phase of synchronization by just 25 ms is sufficient to bidirectionally modulate anxiety-related behaviors. Thus, back-translation establishes a human biomarker as a causal determinant (not just predictor) of emotional state, revealing a novel mechanism whereby interregional synchronization that is frequency, phase, and cell type specific controls emotional processing.