Mechanisms of fear learning and extinction: synaptic plasticity–fear memory connection

Luchkina, Natalia V.; Bolshakov, Vadim Y.

doi:10.1007/s00213-018-5104-4

Cited by 52 publications

(40 citation statements)

References 179 publications

(338 reference statements)

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“…Whether the old memory is suppressed or erased following extinction is still controversial. It is possible that the new memory acquisition and old memory erasure coexist during the extinction training 55. Recent studies investigating fear learning suggest that the inhibition mechanism is predominant during the early phase of extinction training, whereas the original fear memory is erased after repeated extinction training 56.…”

Section: Discussionmentioning

confidence: 99%

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Zhao¹,

Li²,

Liu³

et al. 2019

Theranostics

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Rationale: Repeated methamphetamine (METH) exposure induces long-term cognitive deficits and pathological drug-associated memory that can be disrupted by manipulating memory reconsolidation and extinction. The nucleus accumbens (NAc) is the key region of the brain reward system and predominantly consists of two subtypes of medium spiny neurons (MSNs) based on the expression of D1 or D2 dopamine receptors (D1-MSNs or D2-MSNs). Spine structural plasticity in the NAc is critical for the acquisition, reconsolidation and extinction of drug-associated memory. However, the molecular mechanisms underlying METH-associated memory and spine remodelling in each type of MSNs in the NAc remain unknown. Here, we explored whether Rac1 in the NAc mediates METH-associated contextual memory and spine remodelling.Methods: Pharmacological and genetic manipulations of Rac1 were used to investigate its role during the acquisition, reconsolidation and extinction of METH-associated contextual memory. Recombinant adeno-associated viruses expressing mCherry under the control of the dopamine D1 receptor gene promoter (Drd1-mCherry) or dopamine D2 receptor gene promoter (Drd2-mCherry) were used to specifically label D1-MSNs or D2-MSNs.Results: Using viral-mediated gene transfer, we demonstrated that decreased Rac1 activity was required for the acquisition of METH-associated contextual memory and the METH-induced increase in thin spine density, whereas increased Rac1 signalling was important for the extinction of METH-associated contextual memory and the related elimination of thin spines. Moreover, the increase of dendritic spines was both found in D1-MSNs and D2-MSNs during the acquisition process, but extinction training selectively decreased the spine density in D1-MSNs. Interestingly, Rac1 was responsible for METH-induced spine plasticity in D1-MSNs but not in D2-MSNs. Additionally, we found that microinjection of a Rac1 inhibitor or activator into the NAc was not sufficient to disrupt reconsolidation, and the pharmacological activation of Rac1 in the NAc facilitated the extinction of METH-associated contextual memory. Regarding cognitive memory, decreased Rac1 activity improved the METH-induced impairment in object recognition memory.Conclusion: Our findings indicate that Rac1 plays opposing roles in the acquisition and extinction of METH-associated contextual memory and reveal the cell-specific role of Rac1 in METH-associated spine remodelling, suggesting that Rac1 is a potential therapeutic target for reducing relapse in METH addiction and remediating METH-induced recognition memory impairment.

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Section: Discussionmentioning

confidence: 99%

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Zhao¹,

Li²,

Liu³

et al. 2019

Theranostics

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“…Appropriately, the section continues by considering the synaptic basis of fear extinction, beginning with a review by Luchkina and Bolshakov (2019), who make the case that synaptic plasticity is both necessary and sufficient for the learning of the original fear memory and the memory underlying extinction. The importance of the NMDA receptor (NMDAR) in synaptic plasticity and memory is well-established, but subtleties in the contributions of NMDARs with different subunit compositions presents challenges for the exploitation of NMDAR-mediated signalling as a therapeutic target, argue Radulovic et al (2019).…”

Section: New Mechanistic Insights Into the Psychopharmacology Of Extimentioning

confidence: 99%

Editorial: the psychopharmacology of extinction—from theory to therapy

Milton

Holmes

2019

Psychopharmacology

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“…Plasticity mechanisms in the amygdala and dorsal striatum are widely accepted as the likely substrates of fear conditioning 21 and procedural skill learning 22 , respectively. Surprisingly, it is still unclear whether plasticity in the NAc plays the same crucial role in cued approach learning.…”

Section: Introductionmentioning

confidence: 99%

NMDA receptor-dependent plasticity in the nucleus accumbens connects reward-predictive cues to approach responses

2019

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Learning associations between environmental cues and rewards is a fundamental adaptive function. Via such learning, reward-predictive cues come to activate approach to locations where reward is available. The nucleus accumbens (NAc) is essential for cued approach behavior in trained subjects, and cue-evoked excitations in NAc neurons are critical for the expression of this behavior. Excitatory synapses within the NAc undergo synaptic plasticity that presumably contributes to cued approach acquisition, but a direct link between synaptic plasticity within the NAc and the development of cue-evoked neural activity during learning has not been established. Here we show that, with repeated cue-reward pairings, cue-evoked excitations in the NAc emerge and grow in the trials prior to the detectable expression of cued approach behavior. We demonstrate that the growth of these signals requires NMDA receptor-dependent plasticity within the NAc, revealing a neural mechanism by which the NAc participates in learning of conditioned reward-seeking behaviors.

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Mechanisms of fear learning and extinction: synaptic plasticity–fear memory connection

Cited by 52 publications

References 179 publications

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Editorial: the psychopharmacology of extinction—from theory to therapy

NMDA receptor-dependent plasticity in the nucleus accumbens connects reward-predictive cues to approach responses

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