Gq neuromodulation of BLA parvalbumin interneurons induces burst firing and mediates fear-associated network and behavioral state transition in mice

Xin Fu,Jonathan P Fadok,Pantelis Antonoudiou,Jeffrey G Tasker,Jamie Maguire,Chandrashekhar D Borkar,Grant L Weiss,Eric Teboul

doi:10.1038/s41467-022-28928-y

Xin Fu, Jonathan P Fadok + Show 6 more

Open Access

https://doi.org/10.1038/s41467-022-28928-y

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Abstract

Patterned coordination of network activity in the basolateral amygdala (BLA) is important for fear expression. Neuromodulatory systems play an essential role in regulating changes between behavioral states, however the mechanisms underlying this neuromodulatory control of transitions between brain and behavioral states remain largely unknown. We show that chemogenetic Gq activation and α1 adrenoreceptor activation in mouse BLA parvalbumin (PV) interneurons induces a previously undescribed, stereotyped phasic bursting in PV neurons and time-locked synchronized bursts of inhibitory postsynaptic currents and phasic firing in BLA principal neurons. This Gq-coupled receptor activation in PV neurons suppresses gamma oscillations in vivo and in an ex vivo slice model, and facilitates fear memory recall, which is consistent with BLA gamma suppression during conditioned fear expression. Thus, here we identify a neuromodulatory mechanism in PV inhibitory interneurons of the BLA which regulates BLA network oscillations and fear memory recall.

Highlights

Patterned coordination of network activity in the basolateral amygdala (BLA) is important for fear expression
Stimulation of Gq signaling in BLA PV interneurons by the activation of exogenous Gq-coupled designer receptors or endogenous α1A adrenoreceptors generated phasic firing in the PV interneurons, which resulted in synchronized phasic bursts of IPSCs and phasic firing in BLA principal neurons
Two weeks after virus injections, wholecell voltage clamp recordings were performed in putative BLA principal cells in amygdala slices in the presence of glutamate AMPA-receptor (DNQX, 20 μM) and NMDA-receptor antagonists (APV, 40 μM) to isolate inhibitory postsynaptic currents (IPSCs) (Fig. 1c)

Summary

Results

Chemogenetic Gq activation in BLA PV interneurons stimulates repetitive bursts of IPSCs. Following the blockade of glutamatergic transmission with DNQX (20 μM) and APV (40 μM) and CCK basket cellmediated transmission with the CB1 agonist WIN 55,212-2 (1 μM), we found that serotonin (100 μM) induced repetitive bursts of IPSCs that were inhibited by the P/Q calcium channel blocker, ω-agatoxin (0.5 μM), and by an antagonist of the Gqcoupled 5-HT2A receptor, MDL 100907 (1 μM) (Supplementary Fig. 4) These data suggest that serotonin stimulates a phasic synaptic output from PV interneurons, and indicate that Gq activation of PV interneurons serves as a general cellular mechanism for different neuromodulators to regulate BLA neural circuit activity under different emotional states. Like PV neuron-specific Gq activation, intra-BLA infusion of NE (10 mM, 0.3 μL) reduced fast gamma power and trended

40-70 Hz saline

Discussion

Methods

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