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

Abstract

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.

Roles of palmitoylation in structural long-term synaptic plasticity

“…Rac1 has been shown to play important roles in both structural and functional aspects of learning, memory and forgetting in different experimental models [176][177][178][179]. During spinogenesis, studied in cultured rat hippocampal neurons, overexpression of Rac1 increased the size of dendritic spines and recruited AMPAR clusters to newly formed dendritic spines, enhancing excitatory synaptic transmission [180] and indicating that Rac1 contributes to modulation of both the morphology and function of spines [180,181].…”

Dynamic Changes of Cytoskeleton-Related Proteins Within Reward-Related Brain Regions in Morphine-Associated Memory

“…Most of the neurons within the striatum are medium spiny neurons. As previous studies have shown, drugs induced morphological changes of dendritic spines after withdrawal from chronic administration by means of modulating the actin cycle dynamic in the NAc (Zhao et al, 2019;Iino et al, 2020). Specifically, the underlying mechanisms are as follows.…”

Regulation of Cdc42 signaling by the dopamine D2 receptor in a mouse model of Parkinson’s disease

“…Lentiviruses containing constitutively active (Cdc42‐ca) and dominant negative Cdc42 (Cdc42‐dn) driven by the CMV promoter were combined with EGFP and constructed by Obio Technology Corp., Ltd. Control lentivirus expressed EGFP alone (Tu et al, 2019 ). Recombinant adeno‐associated virus serotype 2/9 (AAV 2/9) expressing mCherry/EYFP/EGFP alone or in combination with the Cre enzyme driven by the dopamine D1 receptor gene promoter ( Drd1 ) or dopamine D2 receptor gene promoter ( Drd2 ) was constructed by BrainVTA (Wuhan, China) (Tu et al, 2019 ; Zhao et al, 2019 ). All viruses’ constructs are listed in Table S3 .…”

“…All viruses’ constructs are listed in Table S3 . According to a previous study (Zhao et al, 2019 ), mice were anesthetized with 50 mg/kg pentobarbital sodium and positioned in a stereotaxic instrument. The skull was exposed, and holes were drilled above the CPu using standard procedures.…”

“…Recombinant adeno-associated virus serotype 2/9 (AAV 2/9) expressing mCherry/EYFP/EGFP alone or in combination with the Cre enzyme driven by the dopamine D1 receptor gene promoter (Drd1) or dopamine D2 receptor gene promoter (Drd2) was constructed by BrainVTA (Wuhan, China) (Tu et al, 2019;Zhao et al, 2019). All viruses' constructs are listed in Table S3.…”