title: Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons.
abstract: Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.
  
  
  CONCLUSIONS
  Dopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the importance of interaction between acetylcholine, dopamine, and adenosine signals via adenylyl-cyclase coupled GPCRs in shaping the dopamine-dependent cAMP/PKA signaling in striatal neurons. Specifically, a dopamine peak and an acetylcholine dip must interact, via D1 and M4 receptor, and a dopamine dip must interact with adenosine tone, via D2 and A2a receptor, in direct and indirect pathway neurons, respectively, to have any significant downstream PKA activation.
authors.affiliation: Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, 11428 Stockholm, Sweden, Manipal University, 576104 Manipal, India.
authors.forename: Anu G
authors.initials: AG
authors.lastname: Nair
authors.affiliation: Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, 11428 Stockholm, Sweden, jeanette@csc.kth.se tardebut@yahoo.es.
authors.forename: Omar
authors.initials: O
authors.lastname: Gutierrez-Arenas
authors.affiliation: Science for Life Laboratory, Department of Numerical Analysis and Computer Science, Stockholm University, 11418 Stockholm, Sweden.
authors.forename: Olivia
authors.initials: O
authors.lastname: Eriksson
authors.affiliation: UMR8256, Centre National de la Recherche Scientifique, 75005 Paris, France, UMR8256, Biological Adaptation and Ageing, Sorbonne Universités UPMC Université Paris 06, 75005 Paris, France, and.
authors.forename: Pierre
authors.identifier: http://orcid.org/0000-0002-8479-1908
authors.initials: P
authors.lastname: Vincent
authors.affiliation: Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, 11428 Stockholm, Sweden, Science for Life Laboratory, Department of Numerical Analysis and Computer Science, Stockholm University, 11418 Stockholm, Sweden, Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden, jeanette@csc.kth.se tardebut@yahoo.es.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Hellgren Kotaleski
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008959:Models, Neurological; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D004298:Dopamine
keywords: D1R/M4R; D2R/A2AR; acetylcholine; dopamine; reward learning; striatal plasticity