Abstract
Glutamatergic transmission in the nucleus accumbens shell (NAcSh) is a substrate for reward learning and motivation. Metabotropic glutamate (mGlu) receptors regulate NAcSh synaptic strength by inducing long-term depression (LTD). Inputs from prefrontal cortex (PFC) and medio-dorsal thalamus (MDT) drive opposing motivated behaviors yet mGlu receptor regulation of these synapses is unexplored. We examined Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific populations of NAc medium spiny neurons (MSNs) using D1tdTom BAC transgenic mice and optogenetics. Synaptically evoked long-term depression (LTD) at MDT-NAcSh synapses required mGlu5 but not mGlu1 and was specific for D1(+) MSNs, whereas PFC LTD was expressed at both D1(+) and D1(−) MSNs and required mGlu1 but not mGlu5. Two weeks after five daily non-contingent cocaine exposures (15 mg/kg), LTD was attenuated at MDT-D1(+) synapses but was rescued by the mGlu5-positive allosteric modulator (PAM) VU0409551. These results highlight unique plasticity mechanisms regulating specific NAcSh synapses.
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Acknowledgements
We would like to thank Kevin Manz and Drs Max Joffe and Carrie Grueter for their comments and critiques of this manuscript.
Funding
This was supported by NIDA R00 DA031699 (for BAG). CWL is an inventor on multiple composition of matter patents protecting allosteric modulators of GPCRs. JMR’s work has been funded by NIH, Alzheimer’s Drug Discovery Foundation, Harrington Discovery Institute, Thome Alzheimer’s Disease Drug Discovery Foundation, and Brain & Behavior Research Foundation. She is an inventor on patents that protect different classes of muscarinic receptor allosteric modulators. PJC has been funded by NIH, Michael J. Fox Foundation, Dystonia Medical Research Foundation, CHDI Foundation and others.
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Over the past 3 years PJC has served on the Scientific Advisory Boards for Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development, Clinical Mechanism (POCM) and Proof of Concept (POC) Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. The remaining authors declare that they have no conflict of interest.
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Turner, B.D., Rook, J.M., Lindsley, C.W. et al. mGlu1 and mGlu5 modulate distinct excitatory inputs to the nucleus accumbens shell. Neuropsychopharmacol 43, 2075–2082 (2018). https://doi.org/10.1038/s41386-018-0049-1
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DOI: https://doi.org/10.1038/s41386-018-0049-1
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