Theranostics 2019; 9(23):7051-7071. doi:10.7150/thno.34655 This issue Cite

Research Paper

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

Jinlan Zhao1*, Li Ying1*, Yutong Liu1, N Liu4, Genghong Tu1, Mengjuan Zhu1, Yue Wu1, Bin Xiao1, Liuzhen Ye1, Juan Li2, Fukun Guo5, Lin Zhang2✉, Huijun Wang3✉, Lu Zhang1✉

1. Key Laboratory of Functional Proteomics of Guangdong Province, Key Laboratory of Mental Health of the Ministry of Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
2. Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Tissue Construction and Detection, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
3. School of Forensic Medicine, Southern Medical University, Guangzhou 510515, China
4. Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
5. Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, OH, USA
* These authors contributed equally.

Citation:
Zhao J, Ying L, Liu Y, Liu N, Tu G, Zhu M, Wu Y, Xiao B, Ye L, Li J, Guo F, Zhang L, Wang H, Zhang L. Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens. Theranostics 2019; 9(23):7051-7071. doi:10.7150/thno.34655. https://www.thno.org/v09p7051.htm
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Abstract

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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.

Keywords: Rac1, nucleus accumbens, spine plasticity, METH addiction, drug reward memory


Citation styles

APA
Zhao, J., Ying, L., Liu, Y., Liu, N., Tu, G., Zhu, M., Wu, Y., Xiao, B., Ye, L., Li, J., Guo, F., Zhang, L., Wang, H., Zhang, L. (2019). Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens. Theranostics, 9(23), 7051-7071. https://doi.org/10.7150/thno.34655.

ACS
Zhao, J.; Ying, L.; Liu, Y.; Liu, N.; Tu, G.; Zhu, M.; Wu, Y.; Xiao, B.; Ye, L.; Li, J.; Guo, F.; Zhang, L.; Wang, H.; Zhang, L. Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens. Theranostics 2019, 9 (23), 7051-7071. DOI: 10.7150/thno.34655.

NLM
Zhao J, Ying L, Liu Y, Liu N, Tu G, Zhu M, Wu Y, Xiao B, Ye L, Li J, Guo F, Zhang L, Wang H, Zhang L. Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens. Theranostics 2019; 9(23):7051-7071. doi:10.7150/thno.34655. https://www.thno.org/v09p7051.htm

CSE
Zhao J, Ying L, Liu Y, Liu N, Tu G, Zhu M, Wu Y, Xiao B, Ye L, Li J, Guo F, Zhang L, Wang H, Zhang L. 2019. Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens. Theranostics. 9(23):7051-7071.

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