Central amygdala micro-circuits mediate fear extinction.
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ABSTRACT:
SUBMITTER: Whittle N
PROVIDER: S-EPMC8260764 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Retrieval of fear extinction memory is associated with increased firing of neurons in the medial prefrontal cortex (mPFC). It is unknown, however, how extinction learning-induced changes in mPFC activity are relayed to target structures in the amygdala, resulting in diminished fear responses. Here, we show that fear extinction decreases the efficacy of excitatory synaptic transmission in projections from the mPFC to the basolateral nucleus of the amygdala (BLA), whereas inhibitory responses are not altered. In contrast, synaptic strength at direct mPFC inputs to intercalated neurons remains unchanged after extinction. Moreover, priming stimulation of mPFC projections induced heterosynaptic inhibition in auditory cortical inputs to the BLA. These synaptic mechanisms could contribute to the encoding of extinction memory by diminishing the ability of projections from the mPFC to drive BLA activity while retaining the ability of intercalated neurons to inhibit the output nuclei of the amygdala.
| S-EPMC3872173 | biostudies-literature
Project description:Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction.
| S-EPMC3125298 | biostudies-literature
Project description:Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy, which involves enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a cellular mechanism for fear extinction; however, a direct link between depotentiation and extinction has not yet been tested. To address this issue, we applied both ex vivo and in vivo approaches to rats in which fear memory had been consolidated. A unique form of depotentiation reversed conditioning-induced potentiation at thalamic input synapses onto the LA (T-LA synapses) ex vivo. Extinction returned the enhanced T-LA synaptic efficacy observed in conditioned rats to baseline and occluded the depotentiation. Consistently, extinction reversed conditioning-induced enhancement of surface expression of AMPAR subunits in LA synaptosomal preparations. A GluR2-derived peptide that blocks regulated AMPAR endocytosis inhibited depotentiation, and microinjection of a cell-permeable form of the peptide into the LA attenuated extinction. Our results are consistent with the use of depotentiation to weaken potentiated synaptic inputs onto the LA during extinction and provide strong evidence that AMPAR removal at excitatory synapses in the LA underlies extinction.
| S-EPMC2409248 | biostudies-literature
Project description:Fear extinction is an active learning process whereby previously established conditioned responses to a conditioned stimulus are suppressed. Paradoxically, when extinction training is performed immediately following fear acquisition, the extinction memory is weakened. Here, we demonstrate that corticotrophin-releasing factor (CRF)-expressing neurons in the central amygdala (CeA) antagonize the extinction memory following immediate extinction training. CeA-CRF neurons transition from responding to the unconditioned stimulus to the conditioned stimulus during the acquisition of a fear memory that persists during immediate extinction training, but diminishes during delayed extinction training. Inhibition of CeA-CRF neurons during immediate extinction training is sufficient to promote enhanced extinction memories, and activation of these neurons following delay extinction training is sufficient to reinstate a previously extinguished fear memory. These results demonstrate CeA-CRF neurons are an important substrate for the persistence of fear and have broad implications for the neural basis of persistent negative affective behavioral states.
| S-EPMC6976644 | biostudies-literature
Project description:Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.
| S-EPMC4832021 | biostudies-literature
Project description:Anxiety disorders such as post-traumatic stress are characterized by an impaired ability to learn that cues previously associated with danger no longer represent a threat. However, the mechanisms underlying fear extinction remain unclear. We found that fear extinction in rats was associated with increased levels of synaptic inhibition in fear output neurons of the central amygdala (CEA). This increased inhibition resulted from a potentiation of fear input synapses to GABAergic intercalated amygdala neurons that project to the CEA. Enhancement of inputs to intercalated cells required prefrontal activity during extinction training and involved an increased transmitter release probability coupled to an altered expression profile of ionotropic glutamate receptors. Overall, our results suggest that intercalated cells constitute a promising target for pharmacological treatment of anxiety disorders.
| S-EPMC2847017 | biostudies-literature
Project description:The memory of fear extinction is context dependent: fear that is suppressed in one context readily renews in another. Understanding of the underlying neuronal circuits is, therefore, of considerable clinical relevance for anxiety disorders. Prefrontal cortical and hippocampal inputs to the amygdala have recently been shown to regulate the retrieval of fear memories, but the cellular organization of these projections remains unclear. By using anterograde tracing in a transgenic rat in which neurons express a dendritically-targeted PSD-95:Venus fusion protein under the control of a c-fos promoter, we found that, during the retrieval of extinction memory, the dominant input to active neurons in the lateral amygdala was from the infralimbic cortex, whereas the retrieval of fear memory was associated with greater hippocampal and prelimbic inputs. This pattern of retrieval-related afferent input was absent in the central nucleus of the amygdala. Our data show functional anatomy of neural circuits regulating fear and extinction, providing a framework for therapeutic manipulations of these circuits.
| S-EPMC3479515 | biostudies-literature
Project description:The central amygdala (Ce), particularly its medial sector (CeM), is the main output station of the amygdala for conditioned fear responses. However, there is uncertainty regarding the nature of CeM control over conditioned fear. The present study aimed to clarify this question using unit recordings in rats. Fear conditioning caused most CeM neurons to increase their conditioned stimulus (CS) responsiveness. The next day, CeM cells responded similarly during the recall test, but these responses disappeared as extinction of conditioned fear progressed. In contrast, the CS elicited no significant average change in central lateral (CeL) firing rates during fear conditioning and a small but significant reduction during the recall test. Yet, cell-by-cell analyses disclosed large but heterogeneous CS-evoked responses in CeL. By the end of fear conditioning, roughly equal proportions of CeL cells exhibited excitatory (CeL(+)) or inhibitory (CeL(-)) CS-evoked responses (?10%). The next day, the proportion of CeL(-) cells tripled with no change in the incidence of CeL(+) cells, suggesting that conditioning leads to overnight synaptic plasticity in an inhibitory input to CeL(-) cells. As in CeM, extinction training caused the disappearance of CS-evoked activity in CeL. Overall, these findings suggest that conditioned freezing depends on increased CeM responses to the CS. The large increase in the incidence of CeL(-) but not CeL(+) cells from conditioning to recall leads us to propose a model of fear conditioning involving the potentiation of an extrinsic inhibitory input (from the amygdala or elsewhere) to CeL, ultimately leading to disinhibition of CeM neurons.
| S-EPMC3080118 | biostudies-literature
Project description:The empathic ability to vicariously experience the other's fearful situation, a process called observational fear (OF), is critical to survive in nature and function in society. OF can be facilitated by both prior similar fear experience in the observer and social familiarity with the demonstrator. However, the neural circuit mechanisms of experience-dependent OF (Exp OF) remain unknown. Here, we demonstrate that hippocampal-basolateral amygdala (HPC-BLA) circuits in mice without involving the anterior cingulate cortex, considered a center of OF, mediate Exp OF. Dorsal HPC neurons generate fear memory engram cells in BLA encoding prior similar fear experiences, which are essential for Exp OF. On the other hand, ventral HPC neurons respond to the familiar demonstrator's aversive situation during Exp OF, which reactivates the fear memory engram cells in BLA to elicit Exp OF. Our study provides new insights into the memory engram-dependent perception-action coupling that underlies empathic behaviors like Exp OF.
| S-EPMC9035063 | biostudies-literature
Project description:BACKGROUND: Prolonged re-exposure to a fear-eliciting cue in the absence of an aversive event extinguishes the fear response to the cue, and has been clinically used as an exposure therapy. Arc (also known as Arg3.1) is implicated in synaptic and experience-dependent plasticity. Arc is regulated by the transcription factor cAMP response element binding protein, which is upregulated with and necessary for fear extinction. Because Arc expression is also activated with fear extinction, we hypothesized that Arc expression is required for fear extinction. FINDINGS: Extinction training increased the proportion of Arc-labeled cells in the basolateral amygdala (BLA). Arc was transcribed during latter part of extinction training, which is possibly associated with fear extinction, as well as former part of extinction training. Intra-BLA infusions of Arc antisense oligodeoxynucleotide (ODN) before extinction training impaired long-term but not short-term extinction memory. Intra-BLA infusions of Arc antisense ODN 3 h after extinction training had no effect on fear extinction. CONCLUSION: Our findings demonstrate that Arc is required for long-term extinction of conditioned fear and contribute to the understanding of extinction as a therapeutic manner.
| S-EPMC4022082 | biostudies-other