New findings from a research collaboration between Kyoto University, the National Institute for Physiological Sciences (NIPS) and the International Research Center for Neurointelligence (IRCN) at The University of Tokyo reveal that healthy reward learning and memory in the brain is realized by a delicate intracellular balance between dopamine D2 receptor (D2R) and regulators of G protein signaling (RGS), which can be disrupted in brain disorders like schizophrenia and DYT1 dystonia.
In the mammalian brain, reward learning and memory depend on dopamine (DA) signaling. One type of signal, defined by a short absence of DA (0.5–2 s) called the “DA dip”, triggers long-term memory formation. To understand the underlying mechanism of the DA dip the researchers previously developed a computational model of DA signaling (Urakubo et al., 2020; PLoS Comput Biol 16(7): e1008078). In the current study, Urakubo et al. examined how DA dips are processed through a biochemical signaling network to generate long-term memory. Computer simulations and theoretical analyses showed that the DA dip signal is processed only if there is a balance in the levels of two key molecules, D2R and RGS (Fig 1A,1B). This balance is achieved during healthy development, whereas an imbalance between D2R and RGS levels is evident in patients with schizophrenia and DYT1 dystonia (Fig 1B), and could manifest in abnormal long-term memory. In computational analyses, the D2R–RGS imbalance hampered DA dip detectability, disturbed long-term memory formation, and resulted in selective symptoms of schizophrenia and dystonia. Thus, the balance between D2R and RGS appears to be a key biochemical control point for normal learning and memory in the brain.
Fig 1: Molecular balance requirement for learning and memory. (A) In a brain region known as the striatum, learning and memory are inhibited by D2R, and facilitated by RGS. (B) Normal learning and memory are realized only if the concentrations of D2R and RGS are balanced in a certain level (blue shaded area), and the concentration of RGS is over a certain level (red shaded area). The concentrations of D2R and RGS are balanced in healthy development (green and gray points), but disrupted in schizophrenia and DYT1 dystonia (blue and red points, respectively).
The article, “Weakly correlated activity of pallidal neurons in behaving monkeys” was published in PLoS Computational Biology at DOI [10.1371/journal.pcbi. 1009364].
Primary keyword: Biology
Additional keywords: Computational model, Intracellular signaling, Phasic decrease in dopamine, Schizophrenia, DYT1 dystonia
