Encoding of conditioned fear in central amygdala inhibitory circuits

Ciocchi, Stéphane; Herry, Cyril; Grenier, François; Wolff, Steffen B. E.; Letzkus, Johannes J.; Vlachos, Ioannis; Ehrlich, Ingrid; Sprengel, Rolf; Deisseroth, Karl; Stadler, Michael; Müller, Christian; Lüthi, Andreas

doi:10.1038/nature09559

Cited by 847 publications

(931 citation statements)

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“…Contemporary fear models posit that the basolateral amygdalar (basal and lateral nuclei) complex is interconnected with the central nucleus (CeA), which is thought to be the main amygdaloid output structure sending efferent fibers to various autonomic and somatomotor centers involved in mediating specific fear responses (7,28,29). In the present study, although freezing and 22-kHz USV were robustly elicited, the BLA stimulation was an ineffective US in supporting fear conditioning to tone and context CSs.…”

Section: Discussionmentioning

confidence: 46%

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

Kim¹,

Horovitz

Pellman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

132

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The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fearconditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hence, the present study investigated the functional relationship between the PAG and amygdala in two different settings, fear conditioning and naturalistic foraging, in rats. In fear conditioning, electrical stimulation of the dorsal PAG (dPAG) produced unconditional responses (URs) composed of brief activity bursts followed by freezing and 22-kHz ultrasonic vocalization. In contrast, stimulation of ventral PAG and the basolateral amygdalar complex (BLA) evoked freezing and/or ultrasonic vocalization. Whereas dPAG stimulation served as an effective unconditional stimulus for fear conditioning to tone and context conditional stimuli, neither ventral PAG nor BLA stimulation supported fear conditioning. The conditioning effect of dPAG, however, was abolished by inactivation of the BLA. In a foraging task, dPAG and BLA stimulation evoked only fleeing toward the nest. Amygdalar lesion/inactivation blocked the UR of dPAG stimulation, but dPAG lesions did not block the UR of BLA stimulation. Furthermore, in vivo recordings demonstrated that electrical priming of the dPAG can modulate plasticity of subiculum-BLA synapses, providing additional evidence that the amygdala is downstream of the dPAG. These results suggest that the dPAG conveys unconditional stimulus information to the BLA, which directs both innate and learned fear responses, and that brain stimulation-evoked behaviors are modulated by context. fear circuitry | learning and memory | long-term depression | long-term potentiation | synaptic plasticity D ecades of research involving various techniques have identified that the amygdala is essential for both innate and learned fear (1). Evidence indicates that neurons in the basolateral amygdalar complex (BLA) (basal and lateral nuclei) (2) are responsive to both the conditional stimulus (CS) and unconditional stimulus (US) (3, 4), undergo plastic changes during fear conditioning (5), and are necessary for producing fear responses (6, 7). Indeed, a recent study has shown that optogenetically induced depolarization of pyramidal neurons in the lateral amygdala (LA) can elicit a fear unconditional response (UR) and, when repeatedly paired with auditory CS, supports fear conditioning via Hebbian-like synaptic plasticity (8).However, stimulation-induced fear conditioning is not only achievable through the amygdala. Other studies have found that stimulation of the dorsal periaqueductal gray (dPAG) is an effective US in fear conditioning (9, 10). The PAG has long been implicated in generating defensive behaviors (11), and it has been suggested that its stimulation can support fear conditioning to a CS because it transmits the aversive US information to the LA (9, 12). Some have a...

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Section: Discussionmentioning

confidence: 46%

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

Kim¹,

Horovitz

Pellman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

132

View full text Add to dashboard Cite

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“…Thus, empirical determination of expression at different time points after initiation of expression may be of use. For example, it is not uncommon to perform experiments with mice 4 wk after viral delivery (e.g., by AAV), but many groups wait six or more weeks for opsin expression to reach distal axons of an infected cell (Ciocchi et al 2010;Witten et al 2010 Felix-Ortiz et al 2013;Kim et al 2013), though in cholinergic neurons virally infected at a young age, just 3 wk were reported to be effective for axonal expression .…”

Section: Cell-autonomous Side Effects Protein Expressionmentioning

confidence: 99%

Principles of designing interpretable optogenetic behavior experiments

2015

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Over the last decade, there has been much excitement about the use of optogenetic tools to test whether specific cells, regions, and projection pathways are necessary or sufficient for initiating, sustaining, or altering behavior. However, the use of such tools can result in side effects that can complicate experimental design or interpretation. The presence of optogenetic proteins in cells, the effects of heat and light, and the activity of specific ions conducted by optogenetic proteins can result in cellular side effects. At the network level, activation or silencing of defined neural populations can alter the physiology of local or distant circuits, sometimes in undesired ways. We discuss how, in order to design interpretable behavioral experiments using optogenetics, one can understand, and control for, these potential confounds.

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“…on generalization (e.g., Ciocchi et al, 2010;Kheirbek, Klemenhagen, Sahay, & Hen, 2012), human work on generalization of nonfear learning (e.g., Schechtman, Laufer, & Paz, 2010) or on the role of environmental factors in generalization (e.g., Pace-Shott et al, 2009) will not be considered here. Further, learning theory models of stimulus generalization and discrimination constitute a substantial literature that cannot be covered here due to space constraints (see, for example, McLaren & Mackintosh, 2002).…”

mentioning

confidence: 99%

Fear Generalization in Humans: Systematic Review and Implications for Anxiety Disorder Research

et al. 2015

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Fear generalization, in which conditioned fear responses generalize or spread to related stimuli, is a defining feature of anxiety disorders. The behavioral consequences of maladaptive fear generalization are that aversive experiences with one stimulus or event may lead one to regard other cues or situations as potential threats that should be avoided, despite variations in physical form. Theoretical and empirical interest in the generalization of conditioned learning dates to the earliest research on classical conditioning in nonhumans. Recently, there has been renewed focus on fear generalization in humans due in part to its explanatory power in characterizing disorders of fear and anxiety. Here, we review existing behavioral and neuroimaging empirical research on the perceptual and non-perceptual (conceptual and symbolic) generalization of fear and avoidance in healthy humans and patients with anxiety disorders. The clinical implications of this research for understanding the etiology and treatment of anxiety is considered and directions for future research described.

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Encoding of conditioned fear in central amygdala inhibitory circuits

Cited by 847 publications

References 47 publications

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

Principles of designing interpretable optogenetic behavior experiments

Fear Generalization in Humans: Systematic Review and Implications for Anxiety Disorder Research

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