Genetic dissection of an amygdala microcircuit that gates conditioned fear

Haubensak, Wulf; Kunwar, Prabhat S.; Cai, Haijiang; Ciocchi, Stéphane; Wall, Nicholas R.; Ponnusamy, Ravikumar; Biag, Jonathan; Dong, Hong‐Wei; Deisseroth, Karl; Callaway, Edward M.; Fanselow, Michael S.; Lüthi, Andreas; Anderson, David J.

doi:10.1038/nature09553

Cited by 775 publications

(1,027 citation statements)

References 53 publications

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“…Others have shown that stimulating channelrhodopsinexpressing BLA terminals in the CeA produced an anxiolytic effect (Tye et al, 2011). The CeA is known to mediate conditioned fear and the acquisition of fear conditioning via inhibitory circuitry Haubensak et al, 2010;Wilensky et al, 2006). It is possible that ubiquitous expression of our construct was not sufficient to yield an obvious behavioral phenotype and may have affected the microcircuitry within the CeA itself.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States

Siuda

Al‐Hasani

McCall

et al. 2016

Neuropsychopharmacol

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Anxiety disorders are debilitating psychiatric illnesses with detrimental effects on human health. These heightened states of arousal are often in the absence of obvious threatening cues and are difficult to treat owing to a lack of understanding of the neural circuitry and cellular machinery mediating these conditions. Activation of noradrenergic circuitry in the basolateral amygdala is thought to have a role in stress, fear, and anxiety, and the specific cell and receptor types responsible is an active area of investigation. Here we take advantage of two novel cellular approaches to dissect the contributions of G-protein signaling in acute and social anxiety-like states. We used a chemogenetic approach utilizing the Gαs DREADD (rM3Ds) receptor and show that selective activation of generic Gαs signaling is sufficient to induce acute and social anxiety-like behavioral states in mice. Second, we use a recently characterized chimeric receptor composed of rhodopsin and the β 2 -adrenergic receptor (Opto-β 2 AR) with in vivo optogenetic techniques to selectively activate Gαs β-adrenergic signaling exclusively within excitatory neurons of the basolateral amygdala. We found that optogenetic induction of β-adrenergic signaling in the basolateral amygdala is sufficient to induce acute and social anxiety-like behavior. These findings support the conclusion that activation of Gαs signaling in the basolateral amygdala has a role in anxiety. These data also suggest that acute and social anxiety-like states may be mediated through signaling pathways identical to β-adrenergic receptors, thus providing support that inhibition of this system may be an effective anxiolytic therapy.

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Section: Discussionmentioning

confidence: 99%

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States

Siuda

Al‐Hasani

McCall

et al. 2016

Neuropsychopharmacol

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“…Combined with the hyperactivity seen in the PL and BA when extinction was poor (i.e., immediate), this suggests a complex network that extends from distinct mPFC populations to these very specific amygdala populations in mitigating the effect of extinction recency. However, more work is needed to determine the specificity of these microcircuits as the cell-type (PKCd+/2; glutamate/GABAergic receptor subtypes) and the precise afferents/efferents of these amygdala subregions are critically important in regulating fear expression and extinction Haubensak et al 2010;Dobi et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

et al. 2013

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An issue of increasing theoretical and translational importance is to understand the conditions under which learned fear can be suppressed, or even eliminated. Basic research has pointed to extinction, in which an organism is exposed to a fearful stimulus (such as a context) in the absence of an expected aversive outcome (such as a shock). This extinction process results in the suppression of fear responses, but is generally thought to leave the original fearful memory intact. Here, we investigate the effects of extinction during periods of memory lability on behavioral responses and on expression of the immediate -early gene c-Fos within fear conditioning and extinction circuits. Our results show that long-term extinction is impaired when it occurs during time periods during which the memory should be most vulnerable to disruption (soon after conditioning or retrieval). These behavioral effects are correlated with hyperactivation of medial prefrontal cortex and amygdala subregions associated with fear expression rather than fear extinction. These findings demonstrate that behavioral experiences during periods of heightened fear prevent extinction and prolong the conditioned fear response.

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“…Specifically, BLA neurons project to the lateral subdivision of the central amygdala, which sends GABAergic projections to the medial subdivision of the central amygdala (Haubensak et al, 2010). The fear response (ie, freezing) is controlled by projections from medial subdivision of the central amygdala to the periaqueductal grey (Fanselow, 1991).…”

Section: Neural Systems Involved In Fear Learningmentioning

confidence: 99%

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress

Perusini

Meyer

Long

et al. 2015

Neuropsychopharmacol

100

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Fear promotes adaptive responses to threats. However, when the level of fear is not proportional to the level of threat, maladaptive fear-related behaviors characteristic of anxiety disorders result. Post-traumatic stress disorder develops in response to a traumatic event, and patients often show sensitized reactions to mild stressors associated with the trauma. Stress-enhanced fear learning (SEFL) is a rodent model of this sensitized responding, in which exposure to a 15-shock stressor nonassociatively enhances subsequent fear conditioning training with only a single trial. We examined the role of corticosterone (CORT) in SEFL. Administration of the CORT synthesis blocker metyrapone prior to the stressor, but not at time points after, attenuated SEFL. Moreover, CORT co-administered with metyrapone rescued SEFL. However, CORT alone without the stressor was not sufficient to produce SEFL. In these same animals, we then looked for correlates of SEFL in terms of changes in excitatory receptor expression. Western blot analysis of the basolateral amygdala (BLA) revealed an increase in the GluA1 AMPA receptor subunit that correlated with SEFL. Thus, CORT is permissive to trauma-induced changes in BLA function.

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Genetic dissection of an amygdala microcircuit that gates conditioned fear

Cited by 775 publications

References 53 publications

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress

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