NF1-cAMP signaling dissociates cell type-specific contributions of striatal medium spiny neurons to reward valuation and motor control

PLoS Biol. 2019 Oct 10;17(10):e3000477. doi: 10.1371/journal.pbio.3000477. eCollection 2019 Oct.


The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- and D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways are parsed out to regulate distinct behavioral outcomes in a neuron-specific manner is poorly understood. Here, we reveal that distinct contributions of D1R-MSNs and D2R-MSNs towards reward and motor behaviors are delineated by the multifaceted signaling protein neurofibromin 1 (NF1). Using genetic mouse models, we show that NF1 in D1R-MSN modulates opioid reward, whereas loss of NF1 in D2R-MSNs delays motor learning by impeding the formation and consolidation of repetitive motor sequences. We found that motor learning deficits upon NF1 loss were associated with the disruption in dopamine signaling to cAMP in D2R-MSN. Restoration of cAMP levels pharmacologically or chemogenetically rescued the motor learning deficits seen upon NF1 loss in D2R-MSN. Our findings illustrate that multiplex signaling capabilities of MSNs are deployed at the level of intracellular pathways to achieve cell-specific control over behavioral outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Corpus Striatum / physiology*
  • Cyclic AMP / metabolism
  • Dopamine / metabolism
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Motor Activity / physiology
  • Neurofibromin 1 / metabolism*
  • Neurons / metabolism
  • Neurons / physiology*
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Reward
  • Signal Transduction


  • DRD2 protein, mouse
  • Drd1 protein, mouse
  • Neurofibromin 1
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Cyclic AMP
  • Dopamine