Pde4b-regulated cAMP signaling pathway in the AUDGABA-S1TrSst circuit underlies acute-stress-induced anxiety-like behavior.

Abstract

Acute-stress-induced anxiety helps animals avoid danger, but the neural and molecular mechanisms controlling this behavior remain largely elusive. Here, we find that acute physical stress activates many neurons in the primary somatosensory cortex, trunk region (S1Tr). Single-cell sequencing reveals that the S1Tr c-fos-positive neurons activated by acute stress are largely GABAergic somatostatin (Sst) neurons. These S1Tr^Sst neurons desensitize during subsequent anxiety-like behavior tests. Inhibiting or inducing apoptosis of S1Tr^Sst neurons mimics acute-stress effects and induces anxiety, while activating these neurons reduces acute-stress-induced anxiety. S1Tr^Sst cells receive inputs from secondary auditory cortex, dorsal area (AUD) GABAergic neurons to modulate this anxiety. Spatial transcriptome sequencing and targeted Pde4b protein knockdown show that acute stress reduces Pde4b-regulated cAMP signaling in AUD^GABA-S1Tr^Sst projections, leading to decreased S1Tr^Sst neuron activity in subsequent behavioral tests. Our study reports a neural and molecular mechanism for acute-stress-induced anxiety, providing a basis for treating anxiety disorders.