A Neural Switch for Active and Passive Fear

Gozzi, Alessandro; Jain, Apar; Giovannelli, Alessandro; Bertollini, Cristina; Crestan, Valerio; Schwarz, Adam J.; Tsetsenis, Theodoros; Ragozzino, Davide; Gross, Cornelius; Bifone, Angelo

doi:10.1016/j.neuron.2012.02.007

Cited by 35 publications

(56 citation statements)

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“…As CS presentation continues, the freezing rate progressively declines due to extinction and/or habituation processes (Myers and Davis, 2007). However, CS presentation can also elicit proactive behaviors (Gozzi et al, 2010) considered as attempts to actively cope with the danger source (Koolhaas et al, 1999;Blanchard et al, 2001;De Boer and Koolhaas, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…They were then exposed to the tone [conditioned stimulus (CS)] for 8 min preceded by a 2 min pre-tone. Freezing (i.e., lack of movements except those associated with breathing) and active coping (i.e., digging, rearing and wall-sniffing/rearing) were scored (De Boer and Koolhaas, 2003;Gozzi et al, 2010) by an experimenter blind to mouse genotypes and expressed as a percentage of time. To ensure that the observed behaviors were specifically induced by the CS, the maximal freezing and active coping percentage times per minute induced by the tone were compared to pre-tone levels for each mouse, revealing a consistent and robust increase of both behaviors during CS presentation ( p Ͻ 0.001 for all genotypes, paired t test, data not shown).…”

Section: Fear Conditioningmentioning

confidence: 99%

“…However, most studies in fear conditioning only rely on the analysis of passive coping behaviors. Gozzi et al (2010) recently reported that conditioned freezing in mice (i.e., passive coping) was inhibited to favor active coping by pharmacogenetic manipulations of amygdalar activity, suggesting that inhibition of conditioned freezing may reflect not only a quantitative attenuation of fear but also a qualitative change of fear response.…”

Section: Introductionmentioning

confidence: 99%

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Bimodal Control of Fear-Coping Strategies by CB₁Cannabinoid Receptors

Metna-Laurent¹,

Soria-Gómez²,

Verrier³

et al. 2012

J. Neurosci.

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To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB 1 ) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB 1 receptors in CB 1 Ϫ/Ϫ mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB 1 receptors from cortical glutamatergic neurons. CB 1 receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB 1 receptor agonist ⌬ 9 -tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB 1 receptors in the amygdala of CB 1 Ϫ/Ϫ mice restored the normal switch between the two coping strategies. These data strongly suggest that CB 1 receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear.

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Section: Resultsmentioning

confidence: 99%

Section: Fear Conditioningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bimodal Control of Fear-Coping Strategies by CB₁Cannabinoid Receptors

Metna-Laurent¹,

Soria-Gómez²,

Verrier³

et al. 2012

J. Neurosci.

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“…The majority of fear responses are organized in the medial division of the central nucleus of the amygdala which sends projections to various anatomical regions that mediate behavioral expressions of fear (Davis and Whalen 2001). While these projections have been known for some time now, studies have begun to identify circuits within the central nucleus that govern whether active or passive fear responses are expressed (e.g., Gozzi et al 2010). Other recent work has identified specific cell types in the central nucleus which favor the expression of passive fear behavior (i.e., freezing), while other cell types drive the expression of active fear responses (Yu et al 2016;Fadok et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Response-specific sex difference in the retention of fear extinction

Voulo

Parsons

2017

Learn. Mem.

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Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction in male and female rats using both fear-potentiated startle and freezing behavior as measures. Rats were trained to fear cues that predicted the occurrence of shock and then subsequently exposed to an extinction training procedure where the cue was presented repeatedly in the absence of shock. Retention of the extinction memory was assessed the next day. Our results showed that females exhibited less retention of fear extinction, but only when measured by fear-potentiated startle. Our results highlight the importance of using multiple indices of fear behavior, particularly when comparing sexes on measures of extinction learning.Not all individuals who experience trauma during their lifetime will develop post-traumatic stress disorder (PTSD). One of the greatest risk factors for developing this disorder is being female, with the lifetime prevalence rate twice as high for women as it is for men (Kessler et al. 1995;Kilpatrick et al. 2013). Fear conditioning studies in rodents allow us to study the behavioral and neural mechanisms that may underlie PTSD (Parsons and Ressler 2013), yet very few fear conditioning studies in rodents have used females as subjects (Lebron-Milad and Milad 2012). Despite the increased prevalence of PTSD and other fear and anxiety-based disorders in females, nonhuman animal studies testing for sex differences in fear conditioning have largely failed to capture this difference.Fear conditioning studies typically use a procedure in which a discrete cue (e.g., auditory stimulus) signals the occurrence of an aversive stimulus, usually a brief shock. Under normal circumstances, animals learn to fear the discrete cue associated with shock and will also learn to fear the context (i.e., place) in which shock occurs. A handful of studies have directly compared animals of both sexes on tests of cued and contextual fear conditioning. Some of these reports have shown that while males and females exhibit equivalent levels of fear conditioning to discrete cues (Maren et al. 1994;Baran et al. 2009;Milad et al. 2009a;Barker and Galea 2010;Gruene et al. 2015a;Fenton et al. 2016), males often show evidence of better contextual conditioning (Maren et al. 1994;Chang et al. 2009;Barker and Galea 2010). Other studies have tested for sex differences in fear extinction learning, a form of learning through which animals learn to inhibit responding to cues that once signaled an aversive event. Over the last several years, the study of fear extinction has received considerable attention (Milad and Quirk 2012) due in part to the fact that humans with PTSD display impaired extinction (Milad et al. 2009b;Norrholm et al. 2011). Recent findings in rodents are mixed with regard t...

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“…However, the role of the Imp may not be confined only to fear expression. In fact, SLp-Imp neurons through inhibition of the cholinergic basal forebrain may switch the fear response from freezing to risk assessment and exploration (Gozzi et al, 2010). Likewise, Cp-Imp neurons may provide an important inhibitory drive onto CEc/l neurons and in turn affect the output of CEm neurons.…”

Section: Distinct Role Of Itc Clusters In Different Fear Statesmentioning

confidence: 99%