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Dichotomous regulation of striatal plasticity by dynorphin

Molecular Psychiatry volume 28, pages 434–447 (2023)Cite this article

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Abstract

Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) is regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bi-directionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) signaling in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin in D1 neurons show comparable motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bi-directionally modulate synaptic plasticity and behavior in the direct pathway.

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Fig. 1: Pathway-specific modulation of striatal STDP-LTP by KOR.
Fig. 2: Direct pathway-specific deletion of pDyn.
Fig. 3: D1-pDyn cKO enhanced LTP in dSPNs, but not iSPNs.
Fig. 4: D1R signaling modulated the effect of dyn/KOR on dSPN LTP.
Fig. 5: Behavioral assessment of pDyn WT and cKO mice.
Fig. 6: Enhanced reversal learning in pDyn cKO mice in 4-choice odor discrimination task.

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Acknowledgements

We thank Dr. Eddy Albarran, Dr. Richard Roth for advice on the paper, Drs. Yu Liu and Xiaobai Ren for technical assistance, and the members of Ding lab for valuable discussions. This work was funded by NINDS/NIH NS091144 (to JBD), NS107315, DK108797, DK046200 (to DK) the GG gift fund (to JBD), the Stanford Bio-X Bowes Graduate Student Fellowship (to RY), and Stanford Neuroscience Institute Interdisciplinary Scholar Awards (to R.R.L.)

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  1. These authors contributed equally: Renzhi Yang, Rupa R. Lalchandani Tuan.

Authors and Affiliations

  1. Biology Graduate Program, Stanford University, Stanford, CA, USA

    Renzhi Yang

  2. Department of Neurosurgery, Stanford University, Stanford, CA, USA

    Rupa R. Lalchandani Tuan, Fuu-Jiun Hwang, Daniel W. Bloodgood & Jun B. Ding

  3. Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA, USA

    Rupa R. Lalchandani Tuan

  4. Division of Endocrinology, Department of Pediatrics, F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Dong Kong

  5. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

    Jun B. Ding

  6. Stanford Bio-X, Stanford University, Stanford, CA, USA

    Jun B. Ding

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Contributions

RY, RRL, and JBD conceived this project. RY performed electrophysiology recording and operant chamber behavior experiments. RRL characterized lox-pDyn mice, and performed immunostaining and behavioral experiments. FJH performed the spine imaging. DK and JBD designed and generated lox-pDyn mice. RY and RRL analyzed the data. RY, RRL, DWB and JBD wrote the paper with input from all authors.

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Correspondence to Jun B. Ding.

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Yang, R., Tuan, R.R.L., Hwang, FJ. et al. Dichotomous regulation of striatal plasticity by dynorphin. Mol Psychiatry 28, 434–447 (2023). https://doi.org/10.1038/s41380-022-01885-0

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