A Non-Canonical Cortico-Amygdala Inhibitory Loop.

Discriminating between auditory signals of different affective value is critical for the survival and success of social interaction of an individual. Anatomical, electrophysiological, imaging, and optogenetics approaches have established that the auditory cortex (AC) by providing auditory information to the lateral amygdala (LA) via long-range excitatory glutamatergic projections has an impact on sound-driven aversive/fear behavior. Here we test the hypothesis that the LA also receives GABAergic projections from the cortex. We addressed this fundamental question by taking advantage of optogenetics, anatomical, and electrophysiology approaches and directly examining the functional effects of cortical GABAergic inputs to LA neurons of the mouse (male/female) AC. We found that the cortex, via cortico-lateral-amygdala somatostatin neurons (CLA-SOM), has a direct inhibitory influence on the output of the LA principal neurons. Our results define a CLA long-range inhibitory circuit (CLA-SOM inhibitory projections → LA principal neurons) underlying the control of spike timing/generation in LA and LA-AC projecting neurons, and attributes a specific function to a genetically defined type of cortical long-range GABAergic neurons in CLA communication.SIGNIFICANCE STATEMENT It is very well established that cortical auditory inputs to the lateral amygdala are exclusively excitatory and that cortico-amygdala neuronal activity has been shown to be involved in sound-driven aversive/fear behavior. Here, for the first time, we show that the lateral amygdala receives long-range GABAergic projection from the auditory cortex and these form direct monosynaptic inhibitory connections onto lateral amygdala principal neurons. Our results define a cellular basis for direct inhibitory communication from auditory cortex to the lateral amygdala, suggesting that the timing and ratio of excitation and inhibition, two opposing forces in the mammalian cerebral cortex, can dynamically affect the output of the lateral amygdala, providing a general mechanism for fear/aversive behavior driven by auditory stimuli.