Lost in translation: no effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

Amanda R. de Oliveira; Adriano E. Reimer; Gregory J. Simandl; Sumedh S. Nagrale; Alik S. Widge

doi:10.1038/s41398-021-01448-x

Lost in translation: no effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

Amanda R. de Oliveira, Adriano E. Reimer, Gregory J. Simandl, Sumedh S. Nagrale, Alik S. Widge

Psychiatry & Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

The orbitofrontal cortex–ventromedial striatum (OFC–VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. Male Long-Evans rats implanted with optical fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC–VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after, and 1 h after each stimulation, 1 and 2 weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC–VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional set-shifting. OFC–VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the stimulation protocol altered OFC–VMS synaptic weighting. In sum, although we induced physiological changes in the OFC–VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. This suggests possible limitations to translation of mouse findings to species higher on the phylogenetic chain.

Original language	English (US)
Article number	315
Journal	Translational psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01448-x
State	Published - Jun 2021

Bibliographical note

Funding Information:
We would like to thank the University Imaging Centers, University of Minnesota (https://med.umn.edu/uic) for performing the tissue clearing, microscopy, and image processing for the PEGASOS protocol. We thank Dr. Sarah Heilbronner for assistance with the PEGASOS image processing. We thank Dr. Susanne Ahmari for several rounds of helpful discussion in both design and interpretation of these findings. This work was supported by the São Paulo Research Foundation (FAPESP, Brazil—2017/22473-9); OneMind Institute; MnDRIVE Brain Conditions Initiative; and UMN Medical Discovery Team on Addictions.

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© 2021, The Author(s).

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title = "Lost in translation: no effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats",

abstract = "The orbitofrontal cortex–ventromedial striatum (OFC–VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. Male Long-Evans rats implanted with optical fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC–VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after, and 1 h after each stimulation, 1 and 2 weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC–VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional set-shifting. OFC–VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the stimulation protocol altered OFC–VMS synaptic weighting. In sum, although we induced physiological changes in the OFC–VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. This suggests possible limitations to translation of mouse findings to species higher on the phylogenetic chain.",

author = "{de Oliveira}, {Amanda R.} and Reimer, {Adriano E.} and Simandl, {Gregory J.} and Nagrale, {Sumedh S.} and Widge, {Alik S.}",

note = "Funding Information: We would like to thank the University Imaging Centers, University of Minnesota (https://med.umn.edu/uic) for performing the tissue clearing, microscopy, and image processing for the PEGASOS protocol. We thank Dr. Sarah Heilbronner for assistance with the PEGASOS image processing. We thank Dr. Susanne Ahmari for several rounds of helpful discussion in both design and interpretation of these findings. This work was supported by the S{\~a}o Paulo Research Foundation (FAPESP, Brazil—2017/22473-9); OneMind Institute; MnDRIVE Brain Conditions Initiative; and UMN Medical Discovery Team on Addictions. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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Lost in translation: no effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

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