d-Cycloserine facilitates fear extinction in adolescent rats and differentially affects medial and lateral prefrontal cortex activation

Baker, Kathryn; McNally, Gavan P.; Richardson, Rick

doi:10.1016/j.pnpbp.2018.06.007

Cited by 13 publications

(9 citation statements)

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“…In regard to the lOFC, electrophysiological and inactivation studies have linked it to appetitive overexpectation ( Takahashi et al, 2009 ), but not to response inhibition when a conditioned cue is followed by reward omission ( Burke et al, 2009 , see also Chudasama et al, 2007 ). Our lOFC fear data are in line with these reports and join others ( Asok et al, 2013 ; Baker et al, 2018 ; Chang et al, 2018 ; Ray et al, 2018 ; Sarlitto et al, 2018 ; Trow et al, 2017 ; Zimmermann et al, 2018 ) in providing evidence that the lOFC has a role beyond the appetitive domain.…”

Section: Discussionsupporting

confidence: 91%

Different methods of fear reduction are supported by distinct cortical substrates

Lay

Pitaru

Boulianne

et al. 2020

eLife

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Understanding how learned fear can be reduced is at the heart of treatments for anxiety disorders. Tremendous progress has been made in this regard through extinction training in which the aversive outcome is omitted. However, current progress almost entirely rests on this single paradigm, resulting in a very specialized knowledgebase at the behavioural and neural level of analysis. Here, we used a dual-paradigm approach to show that different methods that lead to reduction in learned fear in rats are dissociated in the cortex. We report that the infralimbic cortex has a very specific role in fear reduction that depends on the omission of aversive events but not on overexpectation. The orbitofrontal cortex, a structure generally overlooked in fear, is critical for downregulating fear when novel predictions about upcoming aversive events are generated, such as when fear is inflated or overexpected, but less so when an expected aversive event is omitted.

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Section: Discussionsupporting

confidence: 91%

Different methods of fear reduction are supported by distinct cortical substrates

Lay

Pitaru

Boulianne

et al. 2020

eLife

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“…In contrast, we hypothesized that rats exposed to corticosterone during adolescence would show high levels of freezing at test, regardless of DCS or saline administration after extinction training. As three previous studies have demonstrated the effectiveness of DCS at enhancing extinction retention after 1 day of extinction training in nonstressed adolescents (Baker et al, 2018; Baker & Richardson, 2017; McCallum et al, 2010), we did not include water-exposed controls to replicate these findings in the current experiment. Instead, all animals were exposed to corticosterone treatment, with this occurring during either the juvenile period or adolescence.…”

Section: Resultsmentioning

confidence: 92%

“…Animals in Experiment 2 were injected with DCS or saline subcutaneously (nape of the neck; 1 mL/kg) immediately after extinction training. DCS (Sigma; C6880; 15 mg/kg; Baker et al, 2018; McCallum et al, 2010; Walker, Ressler, Lu, & Davis, 2002) was freshly dissolved in 0.9% sterile saline (wt/vol) on the day of use. Both DCS and saline solutions were kept on ice.…”

Section: Methodsmentioning

confidence: 99%

“…One approach is simply to give extended extinction training (essentially doubling the number of extinction trials; Baker & Richardson, 2017; Kim, Li, & Richardson, 2011; McCallum et al, 2010). A second approach is to combine extinction training with administration of the partial NMDA receptor agonist D-Cycloserine (DCS; Baker, McNally, & Richardson, 2018; McCallum et al, 2010). The finding that DCS can facilitate extinction retention in adolescents is interesting given that it has been shown to facilitate exposure-therapy in clinically anxious samples (e.g., Guastella et al, 2008; Otto et al, 2010; and Ressler et al, 2004; but see Mataix-Cols et al, 2017).…”

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confidence: 99%

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Timing is everything: Developmental differences in the effect of chronic corticosterone exposure on extinction retention.

Stylianakis¹,

Richardson²,

Baker³

2019

Behavioral Neuroscience

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Adolescence is noted as a time of “storm and stress.” In this developmental stage both rodents and humans exhibit an impairment in the extinction of learned fear; however, this impairment can be alleviated, at least in rodents, by increasing the amount of extinction training given or by administering the partial NMDA receptor agonist D-Cycloserine. In the present study we explored whether the benefits of these treatments would be reduced by chronic exogenous corticosterone (a commonly studied stress-related hormone). In 2 experiments, adolescent rats were given pairings of a white noise and shock (acquisition) and then given extinction training (white noise presented alone). In Experiment 1, adolescents exhibited impaired extinction retention even after 2 days of extinction training if they had been exposed to corticosterone in adolescence but not if the exposure occurred when they were juveniles. In Experiment 2, exposure to exogenous corticosterone in adolescence, but not during the juvenile period, reduced the efficacy of the pharmacological adjunct D-Cycloserine at enhancing extinction retention after 1 day of extinction training. Taken together, the results support the idea that adolescence is a time of particular susceptibility to elevated levels of the stress hormone corticosterone.

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“…Initial preclinical research has identified the glutamatergic N-methyl-D-aspartate (NMDA) as a highly promising candidate system 14 to facilitate extinction. For instance, the NMDA receptor partial agonist D-cycloserine (DCS) has been repeatedly demonstrated to improve extinction learning in rodents 14 , probably via augmenting prefrontal engagement 15 . However, translation into clinical utility has been limited by rapid attenuation of DCS-enhanced extinction with repeated administration 16 , and clinical trials reporting small 17 -or even detrimental 18 -effects when DCS was administered in combination with exposure therapy.…”

Section: Introductionmentioning

confidence: 99%

Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala

Zhou

Geng

et al. 2019

Preprint

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Recent translational research suggests a role of the renin-angiotensin (RA) system in threat extinction and underlying neuroplasticity; however, whether and how pharmacological modulation of the RA system influences physiological and neural manifestations of threat during extinction learning in humans is unclear. Here we report that pre-extinction administration of losartan, an angiotensin II type 1 receptor antagonist, accelerated attenuation of physiological threat expression. During early extinction, losartan enhanced threat-signal specific ventromedial prefrontal cortex (vmPFC) activation and its coupling with the basolateral amygdala. Multivoxel pattern analysis revealed that losartan reduced whole brain, particularly vmPFC, threat expression and voxel-wise mediation analyses further confirmed that losartanaccelerated extinction crucially involved vmPFC processing. Overall the results provide initial evidence for a critical role of the RA system in extinction learning in humans and suggest that adjunct losartan administration may facilitate the efficacy of extinction-based therapies.RCT Identifier: NCT03396523 (ClinicalTrials.gov)

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d-Cycloserine facilitates fear extinction in adolescent rats and differentially affects medial and lateral prefrontal cortex activation

Cited by 13 publications

References 50 publications

Different methods of fear reduction are supported by distinct cortical substrates

Different methods of fear reduction are supported by distinct cortical substrates

Timing is everything: Developmental differences in the effect of chronic corticosterone exposure on extinction retention.

Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala

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