Fear extinction in 17 day old rats is dependent on metabotropic glutamate receptor 5 signaling

Ganella, Despina E.; Thangaraju, Pushbalela; Lawrence, Andrew J; Kim, Jee Hyun

doi:10.1016/j.bbr.2014.12.010

Cited by 22 publications

(34 citation statements)

References 23 publications

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“…CDPPB and VU29 were included as structurally distinct allosteric modulators from the same chemotype class, where CDPPB has been reported to be a PAM-agonist and VU29 a ‘pure’ PAM (Chen et al, 2007; Lindsley et al, 2004). CDPPB has previously been tested in vivo , showing efficacy in models of Huntington’s disease, fear extinction, psychosis and addiction (Cleva et al, 2011; Doria et al, 2015; Ganella et al, 2014; Gass et al, 2014; Uslaner et al, 2009). Recently, VU0409551 was described as a biased modulator on the basis that VU0409551 positively modulates mGlu 5 activity in vitro but does not enhance mGlu 5 modulation of NMDA current or NMDA receptor dependent plasticity in the hippocampus (Rook et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

et al. 2017

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Allosteric modulators, that exhibit no intrinsic agonist activity, offer the advantage of spatial and temporal fine-tuning of endogenous agonist activity, allowing the potential for increased selectivity, reduced adverse effects and improved clinical outcomes. Some allosteric ligands can differentially activate and/or modulate distinct signaling pathways arising from the same receptor, phenomena referred to as ’biased agonism’ and ’biased modulation’. Emerging evidence for CNS disorders with glutamatergic dysfunction suggests the metabotropic glutamate receptor subtype 5 (mGlu5) is a promising target. Current mGlu5 allosteric modulators have largely been classified based on modulation of intracellular calcium (iCa2+) responses to orthosteric agonists alone. We assessed eight mGlu5 allosteric modulators previously classified as mGlu5 PAMs or PAM-agonists representing four distinct chemotypes across multiple measures of receptor activity, to explore their potential for engendering biased agonism and/or modulation. Relative to the reference orthosteric agonist, DHPG, the eight allosteric ligands exhibited distinct biased agonism fingerprints for iCa2+ mobilization, IP1 accumulation and ERK1/2 phosphorylation in HEK293A cells stably expressing mGlu5 and in cortical neuron cultures. VU0424465, DPFE and VU0409551 displayed the most disparate biased signaling fingerprints in both HEK293A cells and cortical neurons that may account for the marked differences observed previously for these ligands in vivo. Select mGlu5 allosteric ligands also showed ‘probe dependence’ with respect to their cooperativity with different orthosteric agonists, as well as biased modulation for the magnitude of positive cooperativity observed. Unappreciated biased agonism and modulation may contribute to unanticipated effects (both therapeutic and adverse) when translating from recombinant systems to preclinical models.

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Section: Resultsmentioning

confidence: 99%

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

et al. 2017

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“…Accordingly, Kim and Richardson () characterize extinction in preweanling rats as inflexible and propose that preweanling rats either store a CS‐no US extinction memory in the amygdala (as compared to non‐localized storage in adult rats) or exhibit a form of extinction that “…involves unlearning of the original CS‐US association…due to the lack of involvement of the hippocampus and the vmPFC [ventromedial prefrontal cortex].” (p. 301). Recently, it has been hypothesized that both unlearning and learning are potentially involved in extinction with the proportion of each type of learning changing across development (Ganella & Kim, ; Ganella, Thangaraju, Lawrence, & Kim, in press).…”

Section: Discussionmentioning

confidence: 99%

A dissociation between recognition and reactivation: The renewal effect at 3 months of age

Cuevas

Learmonth

Rovee‐Collier

2015

Developmental Psychobiology

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Extinction allows organisms to adapt to an ever-changing environment. Despite its theoretical and applied significance, extinction has never been systematically studied with human infants. Using the operant mobile task, we examined whether 3-month-olds would exhibit evidence of original learning following extinction. In a recognition paradigm, infants exhibited renewal when tested in the acquisition context (ABA renewal) or a neutral context (ABC and AAB renewal) 1 day following extinction (Experiment 1a) and spontaneous recovery 3 days following extinction (Experiment 1b). In Experiments 2a-2b, we used a reminder paradigm to examine whether the extinguished response could be reinstated after the operant response had been forgotten. We failed, however, to find reinstatement of extinguished responding after spontaneous forgetting, regardless of the reminder and test contexts. We attributed this retention failure to competing responses at test. Although extinguished responding is recovered during infancy, this effect is elusive after the response has been forgotten.

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“…All chambers were equipped with a Med Associates VideoFreeze System (Med Associates, VT) and enclosed in a sound attenuating box with a near infrared (NIR) light source. The chambers were rectangular (31.8 cm × 25.4 cm × 26.7 cm) with stainless steel rods connected to stimulators to deliver electric shocks as previously described (Ganella, Thangaraju, Lawrence, & Kim, ). Each chamber was equipped with a speaker and a monochrome video camera with a NIR‐pass filter that recorded the behavior of the rats during experimental sessions.…”

Section: Methodsmentioning

confidence: 99%

A dissociation between renewal and contextual fear conditioning in juvenile rats

Park

Ganella

Kim

2017

Developmental Psychobiology

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We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning.

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Fear extinction in 17 day old rats is dependent on metabotropic glutamate receptor 5 signaling

Cited by 22 publications

References 23 publications

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

A dissociation between recognition and reactivation: The renewal effect at 3 months of age

A dissociation between renewal and contextual fear conditioning in juvenile rats

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