Psychosis linked to the omission of chemical rewards in brain: Mouse study

Summary: Researchers investigate the role the dopamine 2 receptor plays in psychosis.

Source: University of Tokyo

A recent study in mice led a team of researchers in Japan to believe that psychosis may be caused by problems with specialized nerve cells deep within the brain, as well as a certain kind of learning behavior. The researchers hope this could provide insight into the emergence of delusions in patients with psychosis or schizophrenia with the aim of finding ways to help them.

Psychosis is a debilitating psychological condition with a long history. Described in the medical writings of Hippocrates as early as the 4th century B.C., the psychotic state of hallucinations, delusions and disordered thought represent an existential threat to an afflicted human mind. Now, a team of researchers from the International Research Center for Neurointelligence (IRCN) and the Graduate School of Medicine at the University of Tokyo, and the Graduate School of Informatics at Kyoto University, proposes that psychosis involves defective neural signaling in a deep brain area called the ventral striatum during a behavior called discrimination learning.

Led by Lecturer Sho Yagishita and Professor Haruo Kasai, the researchers studied the way mice predict future rewards in their environment, a behavior known as reward learning, which is shared by us humans and other mammals, too. Reward learning involves the release of a chemical messenger dopamine to a receptor protein in the brain called dopamine D1 receptor (D1R) to signal the anticipation of a reward. Specifically, the team searched for a second dopamine signal that occurs only when the anticipated reward fails to materialize — reward omission.

The researchers suspected this signal for reward omission existed in neurons of the ventral striatum area of the brain that contain a counterpart to D1R, dopamine D2 receptor (D2R). Coincidentally, D2R is the major brain receptor for nearly every antipsychotic medication used to date. The team showed that reward omission triggers a signal in these neurons called the dopamine dip, a drop in dopamine levels, which lasts less than a second.

These dips seem to contribute to the process of discrimination learning, which includes how all animals, including humans, judge previously learned rewards and punishments. To explore the connection between dips and discrimination learning, the researchers used sophisticated optogenetic technologies to artificially increase or decrease the dips for the first time and measured their effects on how the mice estimated rewards. Optogenetics is a way to activate artificial light-sensitive proteins with finely controlled laser light to turn neuronal activity on or off.

“We initially observed that dips caused certain synaptic structures called spines to expand and send signals within D2R neurons,” said Yagishita. “We searched for several years before we discovered that discrimination learning was the cognitive process that refines reward learning following dopamine dips.”

To establish a link to psychosis, the authors administered a well-known psychosis-inducing drug, methamphetamine, and showed that both discrimination learning and dopamine dips were impaired. As a result, mice showed exaggerated behavioral and dopamine responses even when no reward was presented, as is the case in human psychosis. These deficits could be prevented with an antipsychotic compound that blocks D2R activity.

“If D2R signaling and discrimination learning is impaired, subjects may be unable to assign an appropriate significance to objects or people in their environment, and their fears or insecurities may fill in the gap,” said Yagishita. “For example, persecutory delusions arise from mistakenly assigning malevolent intent to strangers who pose no threat.”

The authors propose that these findings open a previously unknown window into psychosis. Their data show that an antipsychotic D2R drug can reverse effects of a psychosis-inducing one by specifically restoring the dopamine dips and discrimination learning to normal levels. Their hypothesis is that an impairment in discrimination learning can result in an inability to predict the environment accurately, leading to overt symptoms of psychosis or schizophrenia.

This shows the D2R
Microscopic image of a neuron that expresses D2R. The image is credited to Yagishita et al.

“The brain seems to have an intrinsic capacity for fantasy or delusional thinking, but there are built-in controls like D2R discrimination learning that help us to correct our misjudgments,” commented Kasai. “Our study raises the possibility that when these corrective controls break down, we can risk losing contact with reality and may enter a downward spiral of pathology.”

Looking ahead, Kasai concluded, “We hope to build a general learning model to accommodate clinical disorders of cognition that can also lead to new principles for next-generation AI (artificial intelligence).”

This research is a peer-reviewed experimental study in mice.

Funding: This work was supported by CREST (JPMJCR1652 to H.K.) from JST, SRPBS (JP19dm0107120 to H.K.), Brain/MINDS (19dm0207069h0001 to S.Y.) from AMED, Grants-in-Aid (No. 26221001 to H.K.; 19K16249, 16H06395, 16H06396 and 16K21720 to S.Y.) from JSPS, the World Premier International Research Center Initiative (WPI) from MEXT, Takeda Science Foundation (to S.Y.), and The Naito Foundation (to Y.I.). M.T. and T.S. are the Research Fellows for Young Scientists of JSPS.

About this neuroscience research article

University of Tokyo
Media Contacts:
Sho Yagishita – University of Tokyo
Image Source:
The image is credited to Yagishita et al.

Original Research: Closed access
“Dopamine D2 receptors in discrimination learning and spine enlargement”. Iino, Y., Sawada, T., Yamaguchi, K., Tajiri, M., Ishii, S., Kasai, H., Yagishita, S.
Nature doi:10.1038/s41586-020-2115-1.


Dopamine D2 receptors in discrimination learning and spine enlargement

Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3,4,5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.

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