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Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y - Nat. Neurosci. (2013)

Bottom Line: However, the circuit-level adaptations mediating this plasticity remain elusive.We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving.As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

ABSTRACT
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

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LTD induction at BLA-NAc synapses selectively internalizes CP-AMPARs on withdrawal day 45(A–B) Example traces (A) and summarized results (B) showing that the LTD induction protocol induced a persistent reduction of the peak amplitudes of EPSCs at BLA-to-NAc shell synapses from cocaine-experienced, but not saline-experienced, rats. Arrows indicate the time points of application of LTD protocols. (C–F) Example EPSCs and the time course showing that BLA-to-NAc shell excitatory synapses, although highly sensitive to Naspm after withdrawal from cocaine (Fig. 3 E–I), became Naspm insensitive after LTD induction (E–G). In saline-experienced rats, EPSCs within this projection were Naspm-insensitive before (Fig. 3 E–I) or after LTD induction (C, D). (G) Summary showing that, at BLA-to-NAc synapses, LTD induction induced a persistent decrease in the peak amplitude of EPSCs, and that EPSCs lost their sensitivity to Naspm after LTD, suggesting a selectively reduction (internalization) of CP-AMPARs from these synapses. Error bar, s.e.m. ** p<0.01.
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Figure 6: LTD induction at BLA-NAc synapses selectively internalizes CP-AMPARs on withdrawal day 45(A–B) Example traces (A) and summarized results (B) showing that the LTD induction protocol induced a persistent reduction of the peak amplitudes of EPSCs at BLA-to-NAc shell synapses from cocaine-experienced, but not saline-experienced, rats. Arrows indicate the time points of application of LTD protocols. (C–F) Example EPSCs and the time course showing that BLA-to-NAc shell excitatory synapses, although highly sensitive to Naspm after withdrawal from cocaine (Fig. 3 E–I), became Naspm insensitive after LTD induction (E–G). In saline-experienced rats, EPSCs within this projection were Naspm-insensitive before (Fig. 3 E–I) or after LTD induction (C, D). (G) Summary showing that, at BLA-to-NAc synapses, LTD induction induced a persistent decrease in the peak amplitude of EPSCs, and that EPSCs lost their sensitivity to Naspm after LTD, suggesting a selectively reduction (internalization) of CP-AMPARs from these synapses. Error bar, s.e.m. ** p<0.01.

Mentions: We first verified the efficacy of this LTD protocol in brain slices. We virally expressed ChR2 in the BLA of rats trained to self-administer cocaine or saline (Fig. S1) and recorded EPSCs from BLA-to-NAc synapses on withdrawal day 45. The LTD protocol induced long-lasting depression of EPSCs in cocaine-trained but not saline-trained rats [training condition × LTD protocol interaction, F(57,855)=3.2, p<0.0001, Fig. 6A–B]. Furthermore, although EPSCs from cocaine-trained rats exhibited increased sensitivity to Naspm (Figs. 3E–I,S4), this effect was abolished after LTD induction [t(6)=0.4, p=0.7, Fig. 6C–G]. These results suggest that the AMPARs internalized by LTD induction were primarily CP-AMPARs, which were located at matured silent synapses.


Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y - Nat. Neurosci. (2013)

LTD induction at BLA-NAc synapses selectively internalizes CP-AMPARs on withdrawal day 45(A–B) Example traces (A) and summarized results (B) showing that the LTD induction protocol induced a persistent reduction of the peak amplitudes of EPSCs at BLA-to-NAc shell synapses from cocaine-experienced, but not saline-experienced, rats. Arrows indicate the time points of application of LTD protocols. (C–F) Example EPSCs and the time course showing that BLA-to-NAc shell excitatory synapses, although highly sensitive to Naspm after withdrawal from cocaine (Fig. 3 E–I), became Naspm insensitive after LTD induction (E–G). In saline-experienced rats, EPSCs within this projection were Naspm-insensitive before (Fig. 3 E–I) or after LTD induction (C, D). (G) Summary showing that, at BLA-to-NAc synapses, LTD induction induced a persistent decrease in the peak amplitude of EPSCs, and that EPSCs lost their sensitivity to Naspm after LTD, suggesting a selectively reduction (internalization) of CP-AMPARs from these synapses. Error bar, s.e.m. ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815713&req=5

Figure 6: LTD induction at BLA-NAc synapses selectively internalizes CP-AMPARs on withdrawal day 45(A–B) Example traces (A) and summarized results (B) showing that the LTD induction protocol induced a persistent reduction of the peak amplitudes of EPSCs at BLA-to-NAc shell synapses from cocaine-experienced, but not saline-experienced, rats. Arrows indicate the time points of application of LTD protocols. (C–F) Example EPSCs and the time course showing that BLA-to-NAc shell excitatory synapses, although highly sensitive to Naspm after withdrawal from cocaine (Fig. 3 E–I), became Naspm insensitive after LTD induction (E–G). In saline-experienced rats, EPSCs within this projection were Naspm-insensitive before (Fig. 3 E–I) or after LTD induction (C, D). (G) Summary showing that, at BLA-to-NAc synapses, LTD induction induced a persistent decrease in the peak amplitude of EPSCs, and that EPSCs lost their sensitivity to Naspm after LTD, suggesting a selectively reduction (internalization) of CP-AMPARs from these synapses. Error bar, s.e.m. ** p<0.01.
Mentions: We first verified the efficacy of this LTD protocol in brain slices. We virally expressed ChR2 in the BLA of rats trained to self-administer cocaine or saline (Fig. S1) and recorded EPSCs from BLA-to-NAc synapses on withdrawal day 45. The LTD protocol induced long-lasting depression of EPSCs in cocaine-trained but not saline-trained rats [training condition × LTD protocol interaction, F(57,855)=3.2, p<0.0001, Fig. 6A–B]. Furthermore, although EPSCs from cocaine-trained rats exhibited increased sensitivity to Naspm (Figs. 3E–I,S4), this effect was abolished after LTD induction [t(6)=0.4, p=0.7, Fig. 6C–G]. These results suggest that the AMPARs internalized by LTD induction were primarily CP-AMPARs, which were located at matured silent synapses.

Bottom Line: However, the circuit-level adaptations mediating this plasticity remain elusive.We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving.As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

ABSTRACT
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

Show MeSH
Related in: MedlinePlus