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 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.

Zhu Y ，Xie SZ ，Peng AB ，Yu XD ，Li CY ，Fu JY ，Shen CJ ，Cao SX ，Zhang Y ，Chen J ，Li XM ... -  《-》

Cell-type specific parallel circuits in the bed nucleus of the stria terminalis and the central nucleus of the amygdala of the mouse.

Ye J ，Veinante P 《-》

CART neuropeptide modulates the extended amygdalar CeA-vBNST circuit to gate expression of innate fear.

Innate fear is critical for the survival of animals and is under tight homeostatic control. Deregulation of innate fear processing is thought to underlie pathological phenotypes including, phobias and panic disorders. Although central processing of conditioned fear has been extensively studied, the circuitry and regulatory mechanisms subserving innate fear remain relatively poorly defined. In this study, we identify cocaine- and amphetamine-regulated transcript (CART) neuropeptide signaling in the central amygdala (CeA) - ventral bed nucleus of stria terminalis (vBNST) axis as a key modulator of innate fear expression. 2,4,5-trimethyl-3-thiazoline (TMT), a component of fox faeces, induces a freezing response whose intensity is regulated by the extent of CART-signaling in the CeA neurons. Abrogation of CART activity in the CeA attenuates the freezing response and reduces activation of vBNST neurons. Conversely, ectopically elevated CART signaling in the CeA potentiates the fear response concomitant with enhanced vBNST activation. We show that local levels of CART signaling modulate the activation of CeA neurons by NMDA receptor-mediated glutamatergic inputs, in turn, regulating activity in the vBNST. This study identifies the extended amygdalar CeA-vBNST circuit as a CART modulated axis encoding innate fear. CART signaling regulates the glutamatergic excitatory drive in the CeA-vBNST circuit, in turn, gating the expression of the freezing response to TMT.

Rale A ，Shendye N ，Bodas DS ，Subhedar N ，Ghose A ... -  《-》

Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early-Life Anxious Temperament.

Children exhibiting extreme anxious temperament (AT) are at an increased risk for developing anxiety and depression. Our previous mechanistic and neuroimaging work in young rhesus monkeys linked the central nucleus of the amygdala to AT and its underlying neural circuit. Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT's molecular underpinnings by focusing on neurons from the lateral division of the central nucleus of the amygdala (CeL). RNA sequencing identified numerous AT-related CeL transcripts, and we used immunofluorescence (n = 3) and tract-tracing (n = 2) methods in a different sample of monkeys to examine the expression, distribution, and projection pattern of neurons expressing one of these transcripts. We found 555 AT-related transcripts, 14 of which were confirmed with high statistical confidence (false discovery rate < .10), including protein kinase C delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared its distribution with that of the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis. These findings demonstrate that CeL PKCδ is associated with primate anxiety, provides evidence of a CeL to laterodorsal bed nucleus of the stria terminalis circuit that may be relevant to understanding human anxiety, and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.

Kovner R ，Souaiaia T ，Fox AS ，French DA ，Goss CE ，Roseboom PH ，Oler JA ，Riedel MK ，Fekete EM ，Fudge JL ，Knowles JA ，Kalin NH ... -  《-》

Somatostatin neurons in the central amygdala mediate anxiety by disinhibition of the central sublenticular extended amygdala.

Fear and anxiety are two defensive emotional states evoked by threats in the environment. Fear can be initiated by either imminent or future threats, but experimentally, it is typically studied as a phasic response initiated by imminent danger that subsides when the threats is removed. In contrast, anxiety is a sustained response, initiated by imagined or potential threats. The central amygdala (CeA) is a key structure active during both fear and anxiety but thought to engage different neural systems. Fear responses are triggered by activation of somatostatin (SOM) expressing neurons in the lateral division of the CeA (CeL), and downstream projections from the medial division. Anxiety responses engage the central extended amygdala that includes the CeA, central sublenticular extended amygdala (SLEAc) and bed nucleus of the stria terminalis, but the nature of connections between these regions is not understood. Here using a combination of tract tracing, electrophysiology, and behavioral analysis in mice, we show that a population of SOM+ neurons in the CeL project to the SLEAc where they inhibit local GABAergic interneurons. Optogenetic activation of this input to the SLEAc has no effect on movement, but is anxiogenic in both open field and elevated plus maze. Our results define the inhibitory connections between CeL and SLEAc and establish a specific CeL to SLEAc projection as a circuit element in mediating anxiety.

Sun Y ，Qian L ，Xu L ，Hunt S ，Sah P ... -  《-》