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

The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood. We combined transgenic mice, in vivo transsynaptic circuit-dissecting anatomical approaches, optogenetics, pharmacological methods, and...

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Published in:Biological psychiatry (1969) 2024-04, Vol.95 (8), p.732-744
Main Authors: Zhu, Yi, Xie, Shi-Ze, Peng, Ai-Bing, Yu, Xiao-Dan, Li, Chun-Yue, Fu, Jia-Yu, Shen, Chen-Jie, Cao, Shu-Xia, Zhang, Ying, Chen, Jiadong, Li, Xiao-Ming
Format: Article
Language:English
Subjects:
Animals
Basolateral Nuclear Complex
Bed nucleus of stria terminalis
Central Amygdaloid Nucleus
Central lateral amygdala
Context fear
Fear - physiology
Fear memory
Mice
Neurons - physiology
Opioid receptor
Septal Nuclei
Tone fear
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Summary:The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood. 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. 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 PKCδCeL-vBNST pathway specifically reduced context fear memory, whereas the SSTCeL-vBNST pathway mainly reduced tone fear memory. Intriguingly, optogenetic manipulation of vBNST neurons that received the projection from PKCδCeL neurons exerted bidirectional regulation of context fear, whereas manipulation of vBNST neurons that received the projection from SSTCeL 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 PKCδCeL-vBNST or SSTCeL-vBNST pathway successfully restored context or tone fear memory reduction induced by prolonged activation of the circuits. Together, these findings establish a functional role for distinct CeL-vBNST circuits in the differential regulation and appropriate maintenance of fear.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2023.08.022