Social Stress Increases Anxiety by GluA1-Dependent Synaptic Strengthening of Ventral Tegmental Area Inputs to the...

Brain defensive mechanisms evolved to maintain low levels of state anxiety. However, risk factors such as stress exposure shift activity within defensive circuits, resulting in increased anxiety. The amygdala is a crucial node for maintaining adaptive anxiety levels, and amygdala hyperactivity can lead to pathological anxiety through mechanisms that are not well understood.

We used chronic social defeat stress (CSDS) in mice. We combined anatomical tracing methods, patch-clamp recordings, and optogenetics to probe how synaptic inputs from the ventral tegmental area (VTA) to the basolateral amygdala (BLA) are affected by CSDS. We performed in vivo fiber photometry recordings to track inputs onto the BLA. Array tomography and electron microscopy were used to unravel the structural composition of VTA-BLA synapses.

We identified the VTA as a source of glutamatergic inputs to the BLA potentiated by stress. Inputs from the medial prefrontal cortex were not potentiated. BLA-projecting VTA glutamatergic neurons were activated by social stress, which increased their excitability and synaptic strength. In vivo potentiation of VTA glutamatergic inputs in the BLA was sufficient to increase anxiety. We showed that stress-induced synaptic strengthening was mediated by insertion of GluA1-containing AMPA receptors. Impeding GluA1 subunit trafficking in BLA neurons with VTA upstream inputs prevented stress-induced increase in synaptic firing and anxiety.

Potentiation of VTA inputs increased synaptic integration, thereby enhancing amygdala activity and promoting maladaptive anxiety. Understanding the impact of amygdala hyperactivity may lead to targeted therapies that restore circuit balance and offer new precision medicine approaches for anxiety disorders.