Noninvasive tactile stimulation engaging a thalamic-amygdala circuit ameliorates mood dysfunction in mouse models of depression-like behavior

Disruption of excitatory/inhibitory (E/I) balance within the basolateral amygdala (BLA) is a critical feature of depressive and anxiety-like states, yet effective circuit-based therapies are lacking. Here, we demonstrate that tactile experience enrichment (TEE)-a noninvasive sensory stimulation-ameliorates depressive- and anxiety-like behaviors in multiple post-stroke depression (PSD) mouse models by engaging a thalamic-amygdala pathway from the reuniens nucleus (Re) to BLA inhibitory neurons (Re^Exc-BLA^Inh). Activation of this compensatory circuit re-establishes E/I balance in the BLA through feedforward inhibition of excitatory neurons, thereby bypassing the impaired medial prefrontal cortex-BLA pathway. Both chemogenetic activation of the Re^Exc-BLA^Inh pathway and TEE treatment in chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models similarly restore synaptic E/I balance and significantly improve emotional behaviors. These results define a lesion-bypassing circuit mechanism through which tactile input modulates amygdala function in mice and will motivate future studies of translational relevance.