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Effects of hM4Di activation in CamKII basolateral amygdala neurons and CNO treatment on sensory-specific vs. general PIT: refining PIT circuits and considerations for using CNO

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Abstract

Background

Pavlovian stimuli can influence instrumental behaviors via phenomena such as Pavlovian-to-instrumental transfer (PIT). PIT arises via dissociable processes as sensory-specific PIT (SS-PIT) and general PIT. The basolateral amygdala (BLA) mediates SS-PIT, but not general PIT. However, the specific BLA neuronal populations involved are unknown.

Aims

To determine the contribution of glutamatergic BLA neurons to the expression of SS-PIT and to the recall of sensory-specific properties of stimulus-outcome associations.

Methods

BLA neurons were transduced with virus containing either GFP or hM4Di, driven by the CamKII promoter. Rats were then tested for SS and general PIT and subsequently for expression of Pavlovian outcome devaluation effects and conditioned taste aversion following injections of vehicle or clozapine-N-oxide (CNO, the hM4Di agonist).

Results

CNO selectively blocked SS-PIT in the hM4Di-expressing group, but not controls, without altering expression of Pavlovian outcome devaluation or sensory-specific taste aversion in either group. Unexpectedly, CNO disrupted general PIT in both groups.

Conclusions

CamKII BLA neurons mediate the expression of SS-PIT by enabling Pavlovian stimuli to trigger recall of the correct action-outcome associations rather than by mediating recall of the sensory-specific properties of the stimulus-outcome association. Separately, our data demonstrate that CNO alone is sufficient to disrupt affective, but not sensory-specific processes, an effect that was not due to generalized motor disruption. This non-specific effect on general PIT may be related to CNO-induced shifts in internal state. Together, these data identify BLA CamKII neurons as critical for the expression of SS-PIT and reveal important considerations for using CNO to study general affective motivation.

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Acknowledgments

Viruses plasmids were obtained from Addgene as gifts from Bryan Roth (Addgene plasmid # 50469; http://n2t.net/addgene:50469; RRID: Addgene_50469; Addgene plasmid # 50477; http://n2t.net/addgene:50477; RRID: Addgene_50477). CNO was provided by the Drug Supply program of the National Institute on Drug Abuse.

Data accessibility

All data are freely available upon request. Please contact the corresponding author.

Funding

This work was supported by NIH-NIDDK 1F31-DK111194-01 awarded to RCD, Whitehall Foundation Grant 2017-12-98 and NIH-R21DA043190 awarded to CEB, and NIH-R01DK106188 and NIH-R01DK115526 awarded to CRF.

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Contributions

RCD designed and executed the experiments, analyzed data, and wrote the manuscript. BEC generated the viruses and wrote the manuscript. CRF designed experiments, analyzed data, and wrote the manuscript. All authors have read and approve the manuscript.

Corresponding author

Correspondence to Carrie R. Ferrario.

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The authors declare that they have no conflicts of interest.

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Derman, R.C., Bass, C.E. & Ferrario, C.R. Effects of hM4Di activation in CamKII basolateral amygdala neurons and CNO treatment on sensory-specific vs. general PIT: refining PIT circuits and considerations for using CNO. Psychopharmacology 237, 1249–1266 (2020). https://doi.org/10.1007/s00213-020-05453-8

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  • DOI: https://doi.org/10.1007/s00213-020-05453-8

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