Distinct Circuits From the Central Lateral Amygdala to the Ventral Part of the Bed Nucleus of Stria Terminalis Regulate Different Fear Memory

Abstract

Background: The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood.

Methods: We combined transgenic mice, in vivo transsynaptic circuit-dissecting anatomical approaches, optogenetics, pharmacological methods, and electrophysiological recording to investigate the involvement of specific extended amygdala circuits in different fear memory.

Results: We identified the projections from central lateral amygdala (CeL) protein kinase C δ (PKCδ)-positive neurons and somatostatin (SST)-positive neurons to GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons in the ventral part of the bed nucleus of stria terminalis (vBNST). Prolonged optogenetic activation or inhibition of the PKCδ^CeL-vBNST pathway specifically reduced context fear memory, whereas the SST^CeL-vBNST pathway mainly reduced tone fear memory. Intriguingly, optogenetic manipulation of vBNST neurons that received the projection from PKCδ^CeL neurons exerted bidirectional regulation of context fear, whereas manipulation of vBNST neurons that received the projection from SST^CeL neurons could bidirectionally regulate both context and tone fear memory. We subsequently demonstrated the presence of δ and κ opioid receptor protein expression within the CeL-vBNST circuits, potentially accounting for the discrepancy between prolonged activation of GABAergic circuits and inhibition of downstream vBNST neurons. Finally, administration of an opioid receptor antagonist cocktail on the PKCδ^CeL-vBNST or SST^CeL-vBNST pathway successfully restored context or tone fear memory reduction induced by prolonged activation of the circuits.

Conclusions: Together, these findings establish a functional role for distinct CeL-vBNST circuits in the differential regulation and appropriate maintenance of fear.

Keywords: Bed nucleus of stria terminalis; Central lateral amygdala; Context fear; Fear memory; Opioid receptor; Tone fear.