Intercalated amygdala clusters orchestrate a switch in fear state

Hagihara, Kazuki; Bukalo, Olena; Zeller, Martin; Aksoy‐Aksel, Ayla; Karalis, Nikolaos; Limoges, Aaron; Rigg, Tanner; Campbell, Tiffany L.; Mendez, Adriana; Weinholtz, Chase A.; Mahn, Mathias; Zweifel, Larry S.; Palmiter, Richard D.; Ehrlich, Ingrid; Lüthi, Andreas; Holmes, Andrew

doi:10.1038/s41586-021-03593-1

Cited by 90 publications

(85 citation statements)

References 59 publications

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“…Indeed, recent work has demonstrated that pathway-specific inputs from intercalated neurons in the basolateral amygdala to discrete components of dorsal and ventral PFC may differentially regulate feedback to gate continued fear or its extinction (Hagihara et al, 2021). If this is the case, then persistent increases in fear-associated excitability in vmPFC of ELS animals may not be due to an inability to detect threats, but rather for a PFC-amygdala network to cooperatively use error-related feedback to update cues to a new and less-threatening state.…”

Section: Discussionmentioning

confidence: 99%

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

Bercum

Gomez

Saddoris

2021

Preprint

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Stress experienced early in development can have profound influences on developmental trajectories and ultimately behaviors in adulthood. Potent stressors during brain maturation can profoundly disrupt prefrontal cortical areas in particular, which can set the stage for prefrontal-dependent alterations in fear regulation and risk of drug abuse in adulthood. Despite these observations, few studies have investigated in vivo signaling in prefrontal signals in animals with a history of early life stress (ELS). Here, rats with ELS experience on PND3-5 were then tested on a conditioned suppression paradigm during adulthood. During conditioned suppression, electrophysiological recordings were made in the ventral medial prefrontal cortex (vmPFC) during presentations of a fear-associated cues that resolved both single-unit activity and local field potentials (LFPs). Relative to unstressed controls, ELS-experienced rats showed greater fear-related suppression of lever pressing. During presentations of the fear-associated cue (CS+), neurons in the vmPFC of ELS animals showed a significant increase in the probability of excitatory encoding relative to controls, and excitatory phasic responses in the ELS animals were reliably of higher magnitude than Controls. In contrast, vmPFC neurons in ELS subjects better discriminated between the shock-associated CS+ and the neutral ("safe") CS- cue than Controls. LFPs recorded in the same locations revealed that high gamma band (65-95 Hz) oscillations were strongly potentiated in Controls during presentation of the fear-associated CS+ cue, but this potentiation was abolished in ELS subjects. Notably, no other LFP spectra differed between ELS and Controls for either the CS+ or CS-. Collectively, these data suggest that ELS experience alters the neurobehavioral functions of PFC in adulthood that are critical for processing fear regulation. As such, these alterations may also provide insight into to increased susceptibility to other PFC-dependent processes such as risk-based choice, motivation, and regulation of drug use and relapse in ELS populations.

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Section: Discussionmentioning

confidence: 99%

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

Bercum

Gomez

Saddoris

2021

Preprint

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“…Importantly, no work directly links variation in circuitry function to aberrant expression of threat-anticipatory responses in anxiety. Given cross-species findings, we hypothesize that excessive threat-anticipatory responding in anxiety relates to function within this “defensive response” circuitry, including cortical-subcortical connections that drive the selection, maintenance, and regulation of imminence-specific defensive responses ( Mobbs, 2018 ; Robinson et al, 2019 ; Hagihara et al, 2021 ; Myers-Schulz and Koenigs, 2012 ; Halladay and Blair, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Threat imminence reveals links among unfolding of anticipatory physiological response, cortical-subcortical intrinsic functional connectivity, and anxiety

Abend

Ruiz

Bajaj

et al. 2022

Neurobiology of Stress

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Excessive expression of fear responses in anticipation of threat occurs in anxiety, but understanding of underlying pathophysiological mechanisms is limited. Animal research indicates that threat-anticipatory defensive responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from basic neuroscience research in animals on threat imminence could guide mechanistic research in humans mapping abnormal function in this circuitry to aberrant defensive responses in pathological anxiety. 50 pediatric anxiety patients and healthy-comparisons (33 females) completed an instructed threat-anticipation task whereby cues signaled delivery of painful (threat) or non-painful (safety) thermal stimulation. Temporal changes in skin-conductance indexed anxiety effects on anticipatory responding as function of threat imminence. Multivariate network analyses of resting-state functional connectivity data from a subsample were used to identify intrinsic-function correlates of anticipatory-response dynamics, within a specific, distributed network derived from translational research on defensive responding. By considering threat imminence, analyses revealed specific anxiety effects. Importantly, pathological anxiety was associated with excessive deployment of anticipatory physiological response as threat, but not safety, outcomes became more imminent. Magnitude of increase in threat-anticipatory physiological responses corresponded with magnitude of intrinsic connectivity within a cortical-subcortical circuit. Moreover, more severe anxiety was associated with stronger associations between anticipatory physiological responding and connectivity that ventromedial prefrontal cortex showed with hippocampus and basolateral amygdala, regions implicated in animal models of anxiety. These findings link basic and clinical research, highlighting variations in intrinsic function in conserved defensive circuitry as a potential pathophysiological mechanism in anxiety.

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“…The ITCs consist of several dispersed clusters located around the basolateral complex of the amygdala (BLA) ( Millhouse, 1986 ; Busti et al, 2011 ). Two main ITC clusters are situated along the intermediate capsule, a dorsal medio-paracapsular (mpITC) and a larger ventrally located (vmITC) cluster ( Millhouse, 1986 ; Kaoru et al, 2010 ; Busti et al, 2011 ; Hagihara et al, 2021 ). The vmITC is critically involved in the formation and/or recall of fear extinction memory ( Likhtik et al, 2008 ; Amano et al, 2010 ; Hagihara et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Two main ITC clusters are situated along the intermediate capsule, a dorsal medio-paracapsular (mpITC) and a larger ventrally located (vmITC) cluster ( Millhouse, 1986 ; Kaoru et al, 2010 ; Busti et al, 2011 ; Hagihara et al, 2021 ). The vmITC is critically involved in the formation and/or recall of fear extinction memory ( Likhtik et al, 2008 ; Amano et al, 2010 ; Hagihara et al, 2021 ). In contrast, the mpITC was found to be active during the expression of fear ( Busti et al, 2011 ; Huang et al, 2014 ; Kwon et al, 2015 ; Hagihara et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…The vmITC is critically involved in the formation and/or recall of fear extinction memory ( Likhtik et al, 2008 ; Amano et al, 2010 ; Hagihara et al, 2021 ). In contrast, the mpITC was found to be active during the expression of fear ( Busti et al, 2011 ; Huang et al, 2014 ; Kwon et al, 2015 ; Hagihara et al, 2021 ). The vmITC has been proposed to be directly inhibited by the mpITC leading to disinhibition of the CeM and facilitation of fear responses ( Royer et al, 2000 ; Busti et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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Fear Memory Retrieval Is Associated With a Reduction in AMPA Receptor Density at Thalamic to Amygdala Intercalated Cell Synapses

Seewald

Schönherr

Hörtnagl

et al. 2021

Front. Synaptic Neurosci.

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The amygdala plays a crucial role in attaching emotional significance to environmental cues. Its intercalated cell masses (ITC) are tight clusters of GABAergic neurons, which are distributed around the basolateral amygdala complex. Distinct ITC clusters are involved in the acquisition and extinction of conditioned fear responses. Previously, we have shown that fear memory retrieval reduces the AMPA/NMDA ratio at thalamic afferents to ITC neurons within the dorsal medio-paracapsular cluster. Here, we investigate the molecular mechanisms underlying the fear-mediated reduction in the AMPA/NMDA ratio at these synapses and, in particular, whether specific changes in the synaptic density of AMPA receptors underlie the observed change. To this aim, we used a detergent-digested freeze-fracture replica immunolabeling technique (FRIL) approach that enables to visualize the spatial distribution of intrasynaptic AMPA receptors at high resolution. AMPA receptors were detected using an antibody raised against an epitope common to all AMPA subunits. To visualize thalamic inputs, we virally transduced the posterior thalamic complex with Channelrhodopsin 2-YFP, which is anterogradely transported along axons. Using face-matched replica, we confirmed that the postsynaptic elements were ITC neurons due to their prominent expression of μ-opioid receptors. With this approach, we show that, following auditory fear conditioning in mice, the formation and retrieval of fear memory is linked to a significant reduction in the density of AMPA receptors, particularly at spine synapses formed by inputs of the posterior intralaminar thalamic and medial geniculate nuclei onto identified ITC neurons. Our study is one of the few that has directly linked the regulation of AMPA receptor trafficking to memory processes in identified neuronal networks, by showing that fear-memory induced reduction in AMPA/NMDA ratio at thalamic-ITC synapses is associated with a reduced postsynaptic AMPA receptor density.

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Intercalated amygdala clusters orchestrate a switch in fear state

Cited by 90 publications

References 59 publications

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

Threat imminence reveals links among unfolding of anticipatory physiological response, cortical-subcortical intrinsic functional connectivity, and anxiety

Fear Memory Retrieval Is Associated With a Reduction in AMPA Receptor Density at Thalamic to Amygdala Intercalated Cell Synapses

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