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

Abstract

BACKGROUND: Brain defensive mechanisms evolved to maintain low levels of state anxiety. However, risk factors such as stress exposure shifts 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. METHODS: We used chronic social defeat stress (CSD) 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 CSD. We performed in vivo fiber photometry recordings to track inputs onto basolateral amygdala. Array tomography and electron microscopy were used to unravel the structural composition of VTA-BLA synapses. RESULTS: We identified the VTA as a source of glutamatergic inputs to the BLA potentiated by stress. In turn, inputs from mPFC were not potentiated. BLA-projecting VTA glutamatergic neurons are activated by social stress, increasing their excitability and synaptic strength. In vivo potentiation of VTA glutamatergic inputs in the BLA is sufficient to increase anxiety. We showed that stress-induced synaptic strengthening is mediated by insertion of GluA1-containing AMPA receptors. Impeding GluA1 subunit trafficking in BLA neurons with VTA upstream inputs prevents stress-induced increase in synaptic firing and anxiety. CONCLUSIONS: Potentiation of VTA inputs increases synaptic integration, enhancing amygdala activity and promoting maladaptive anxiety. Understanding the impact of amygdala hyperactivity could lead to targeted therapies, restoring circuit balance and offering new precision medicine approaches for anxiety disorders.