Chronic Stress Causes Projection-Specific Adaptation of Amygdala Neurons via Small-Conductance Calcium-Activated Potassium Channel Downregulation

Abstract

Background

The role of the amygdala in mediating stress coping has been long appreciated. However, basolateral amygdala (BLA) projection neurons (PNs) are organized into discrete output circuits, and it remains unclear whether stress differentially impacts these circuits.

Methods

Mice were exposed to acute restraint stress or chronic restraint stress (CRS), and c-fos expression was measured as a proxy for neuronal activation in Retrobead retrogradely labeled dorsomedial prefrontal cortex–targeting PNs (BLA→dmPFC) and non-dmPFC-targeting PNs (BLA↛dmPFC). Next, the effects of CRS on neuronal firing and membrane potassium channel current were examined via ex vivo electrophysiology in these neuronal populations and correlated with anxiety-like behavior, as measured in the elevated plus maze and novel open field tests. Lastly, the ability of virus-mediated overexpression of subtype 2 of small-conductance, calcium-activated potassium (SK2) channel in BLA↛dmPFC PNs to negate the anxiety-related effects of CRS was assessed.

Results

BLA→dmPFC PNs were transiently activated after CRS, whereas BLA↛dmPFC showed sustained c-fos expression and augmented firing to external input. CRS led to a loss of SK2 channel–mediated currents in BLA↛dmPFC PNs, which correlated with heightened anxiety-like behavior. Virus-mediated maintenance of SK2 channel currents in BLA↛dmPFC PNs prevented CRS-induced anxiety-like behavior. Finally, CRS produced persistent activation of BLA PNs targeting the ventral hippocampus, and virally overexpressing SK2 channels in this projection population were sufficient to prevent CRS-induced anxiety-like behavior.

Conclusions

The current data reveal that chronic stress produces projection-specific functional adaptations in BLA PNs. These findings offer new insight into the neural circuits that contribute to stress-induced psychopathology.