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Electrosurgery. To avoid harming the patient or damaging the neurostimulation system, do not use monopolar electrosurgery devices on patients with implanted neurostimulation systems. Before using an electrosurgery device, place the device in Surgery Mode using the patient controller app or clinician programmer app. Confirm the neurostimulation system is functioning correctly after the procedure.
Electrosurgery. To avoid harming the patient or damaging the neurostimulation system, do not use monopolar electrosurgery devices on patients with implanted neurostimulation systems. If use of electrocautery is necessary, place the neurostimulator in Surgery mode using the clinician programmer app or the patient controller app before using an electrosurgery device.
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.
Here, we tested the role of Gq neuromodulation of BLA PV interneurons in controlling network states and regulating conditioned fear expression. Our findings reveal molecular and cellular mechanisms for emotional brain-state transitions whereby Gq signaling reconfigures BLA PV interneuron activity patterns, which tunes BLA network oscillations and facilitates conditioned fear expression. Stimulation of Gq signaling in BLA PV interneurons by the activation of exogenous Gq-coupled designer receptors (hM3D) 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. Gq activation via hM3D or α1A adrenergic receptors in BLA PV interneurons suppressed BLA gamma oscillations in ex vivo slices and in vivo. Selective rescue of α1A adrenergic signaling or activation of hM3D receptors in BLA PV interneurons in global α1A adrenoreceptor knockout mice enhanced conditioned fear expression. These findings reveal a role for Gq neuromodulation of BLA PV interneurons in the coordination of BLA network states underlying fear memory expression.
PV interneurons are critically involved in the generation of gamma-frequency oscillations, which are phase-locked to PV neuron action potentials during tonic high-frequency spiking activity1,15,16. As Gq activation in PV interneurons generated phasic action potentials in PV cells and synchronized repetitive IPSC bursts in principal cells of the BLA, we postulated that Gq activation of PV cells may reconfigure pattern generation among BLA networks and alter potential gamma-frequency network coordination. To address this, we first recorded the spiking responses in BLA PV interneurons and principal cells to PV neuron Gq activation during tonic high-frequency spiking activity.
Our findings reveal a PV cell type-specific neuromodulatory mechanism for BLA network coordination of emotionally salient brain-state transitions. Activation of Gq signaling in PV interneurons via hM3D-Gq and α1A adrenoreceptors generated a highly stereotyped phasic bursting pattern of activity that drove repetitive, synchronized bursts of IPSCs and spikes in postsynaptic BLA principal neurons. Gq-DREADD and α1A receptor activation in BLA PV neurons decreased gamma oscillatory power. Finally, BLA PV-Gq signaling enhanced retrieval of auditory cue-conditioned fear memory, consistent with the suppression of BLA gamma oscillations.
In contrast to the canonical electrophysiological property of PV interneurons to fire sustained high-frequency action potentials upon depolarization, we observed repetitive bursts of action potentials in PV interneurons in response to α1A and hM3D receptor-induced Gq activation. The PV neuron phasic bursting was dependent on a postsynaptic intrinsic Gq signaling mechanism, and not mediated by local circuits or depolarization-induced activation, since it was not suppressed by blocking ionotropic glutamate and GABA receptors and was not induced with sustained photostimulation of BLA PV neurons. This revealed an important role for Gq neuromodulation in changing the operational mode of PV interneurons from tonic activation to alternating cycles of activation and inhibition, via an intrinsic mechanism independent of depolarization and fast chemical synaptic transmission. Further studies will be necessary to determine the signaling mechanisms downstream from Gq responsible for inducing the intrinsic oscillatory activity in the PV interneurons.
Parvalbumin interneurons are critically involved in the generation of gamma-frequency oscillations in the cortex and hippocampus1,14,15,16,17. Mechanistic studies in these structures indicate that tonic PV neuron activity provides inhibitory signaling to principal neurons that drives local gamma rhythm generation, demonstrated by phase locking of PV neuron activity to the gamma cycle15,16 and by optogenetic activation and inhibition of PV neuron activity14,17,18. Like in cortical structures, PV basket cells densely target the perisomatic region and PV chandelier cells project to the axons of BLA principal neurons to tightly regulate amygdalar output10,11,26,27,47,48. Therefore, altering BLA PV activity patterns is likely to have a robust effect on BLA network oscillations and amygdala output. We found that Gq activation in BLA PV neurons transformed the tonic activity pattern of PV neurons into a bursting pattern of action potentials and inhibitory synaptic inputs to BLA principal cells. This activity pattern transition in turn induced a phasic pattern of activation in local principal cells. Consistent with tonic PV neuron activity promoting gamma oscillations, transforming PV neuron tonic activity to phasic activity by either chemogenetic manipulation or α1A adrenoreceptor activation decreased gamma oscillatory power locally in the BLA both ex vivo and in vivo.
Given the influence of BLA noradrenergic signaling on promoting fear states49, we examined what significance the PV neuron α1A adrenoreceptor-mediated reorganization of BLA network activity has in fear conditioning. Genetic re-expression of α1A adrenoreceptors and hM3D-Gq activation in PV interneurons bilaterally in the BLA of Adra1a global knockout mice enhanced conditioned fear expression. Therefore, the Gq-mediated transition in BLA PV interneuron patterned output appears important for promoting BLA fear state transitions. Conditioned fear expression is associated with BLA potentiation of theta and suppression of fast gamma oscillatory power7. Our data demonstrating that Gq signaling via α1A adrenoreceptor and hM3D receptor activation in BLA PV interneurons desynchronizes gamma oscillations and may work cooperatively with other local interneurons (e.g., CCK interneurons) to potentiate theta network activity, reveal a potential critical role for Gq neuromodulation of BLA PV cells in the expression of fear memory.
Thousands of G protein-coupled receptors converge onto four main classes of known Gα proteins50. In addition to α1A adrenoreceptor-mediated Gq activation of PV interneurons, we also found that Gq-coupled 5-HT2A serotonergic receptors generated a similar pattern of repetitive bursts of IPSCs in BLA principal neurons. Others have reported that acetylcholine also drives repetitive IPSC bursts in pyramidal neurons of the frontal cortex, possibly through the activation of Gq-coupled M1 muscarinic receptors51, although whether this response is also mediated by PV interneuron activation is not known. Notably, PV interneurons in the hippocampus and BLA stimulated by CCK activation of Gi/o-coupled CCKB receptors52,53,54,55 generate tonic IPSCs in principal neurons. Thus, different neurotransmitters acting on their cognate Gq-coupled receptors have a similar effect on neural activity through activation of the same signaling pathway, whereas the neuromodulatory excitation of PV interneurons via different GPCR signaling mechanisms induces distinct output patterns. If the patterned bursts of IPSCs is a generalized PV neuron output mode following activation of Gq-coupled receptors by different neuromodulators, then the specificity of the neuromodulatory regulation must lie in other spatiotemporal properties of the neuromodulatory inputs, such as the timing of the inputs and the somato-dendritic distribution of the synapses or synaptic receptors. Then again, the convergence of disparate neuromodulatory inputs onto the Gq signaling pathway to generate a similar patterned PV neuron output may represent a redundancy of neuromodulatory systems to achieve a common salient network outcome, the desynchronization of BLA circuits in the gamma-frequency band, under different environmental conditions. Just as different representations of intrinsic membrane ionic currents in individual neurons and synaptic strengths in neural circuits can be tuned homeostatically to achieve target network outputs56, so may neuromodulatory inputs be activated variably, alone or in combination, to arrive at a particular desired brain state. 1e1e36bf2d