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Modulation of methamphetamine memory reconsolidation by neural projection from basolateral amygdala to nucleus accumbens

Abstract

Drug-associated conditioned cues promote subjects to recall drug reward memory, resulting in drug-seeking and reinstatement. A consolidated memory becomes unstable after recall, such that the amnestic agent can disrupt the memory during the reconsolidation stage, which implicates a potential therapeutic strategy for weakening maladaptive memories. The basolateral amygdala (BLA) involves the association of conditioned cues with reward and aversive valences and projects the information to the nucleus accumbens (NAc) that mediates reward-seeking. However, whether the BLA-NAc projection plays a role in drug-associated memory reactivation and reconsolidation is unknown. We used methamphetamine (MeAM) conditioned place preference (CPP) to investigate the role of BLA-NAc neural projection in the memory reconsolidation. Two weeks before CPP training, we infused adeno-associated virus (AAV) carrying the designer receptor exclusively activated by designer drugs (DREADD) or control constructs. We infused clozapine-N-oxide (CNO) after the recall test to manipulate the neural activity of BLA-NAc projections in mice. We found that after recall, DREADD-mediated inhibition of BLA neurons projecting to the NAc core blunted consolidated MeAM-associated memory. Inhibition of BLA glutamatergic nerve terminals in the NAc core 1 h after recall disrupted consolidated MeAM-associated memory. However, inhibiting this pathway after the time window of reconsolidation failed to affect memory. Furthermore, under the condition without memory retrieval, DREADD-mediated activation of BLA-NAc core projection was required for amnesic agents to disrupt consolidated MeAM-associated memory. Our findings provide evidence that the BLA-NAc pathway activity is involved in the post-retrieval processing of MeAM-associated memory in CPP.

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Fig. 1: Anisomycin administration during reconsolidation disrupts MeAM-associated memory.
Fig. 2: Post-retrieval chemogenetic inhibition of the BLA neurons projecting to the NAc disrupts the consolidated MeAM-associated memory.
Fig. 3: Chemogenetic inhibition of nerve terminals of glutamatergic BLA neurons in the NAc core after retrieval disrupts the consolidated MeAM-associated memory.
Fig. 4: Delayed inhibition of BLA neuronal nerve terminals in the NAc core after the time window of memory reconsolidation fails to affect the consolidated MeAM-associated memory.
Fig. 5: Activating the glutamatergic BLA-NAc core pathway is sufficient for anisomycin to disrupt MeAM-associated memory.

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Acknowledgements

We thank Dr. Bryan Roth for gifts of chemogenetic constructs, and thank the Laboratory Animal Center, College of Medicine, National Cheng Kung University and Taiwan Animal Consortium for the technical support. We thank Dr. Li-Hsien Chen and the Bioimaging Core Facility of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan, for confocal technical support.

Funding

This study was supported by grants NHRI-EX109-10730NI from the National Health Research Institute and MOST110-2811-B-006-545, MOST109-2811-B-006-535, MOST110-2320-B-006-047, MOST110-2320-B-006-035, and MOST109-2320-B-006-064 from the Ministry of Science and Technology of Taiwan.

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JYL and CHC performed experiments and analyzed data. CLS designed some experiments and wrote the manuscript. YJY designed some experiments and analyzed some data. YQS performed some fluorescence experiments. CHC and PWG supervised JYL’s works, and PWG supervised YJY. CHC and PWG designed experiments and wrote the manuscript.

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Correspondence to Chih-Hua Chang or Po-Wu Gean.

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Li, JY., Yu, YJ., Su, CL. et al. Modulation of methamphetamine memory reconsolidation by neural projection from basolateral amygdala to nucleus accumbens. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01417-y

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