Science | Striatal dopamine mediates hallucinations

Interpretation | Edited by Wenqiang Chen (Postdoctoral Fellow, Harvard Medical School) | The brain can produce fast and accurate internal sensory representation to external stimuli.

The rich and colorful life experience profoundly affects our perception of the external world.

There are also times when errors occur in this process, such as hallucinations, which are sensory experiences that occur when external stimuli are absent.

A common example is auditory hallucinations, that is, when there is no sound stimulation, the auditory center of the brain produces incorrect processing of signals.

Hallucinations are prone to occur in many psychopathological conditions, such as schizophrenia, which bring a heavy burden to society and the economy.

Therefore, it is of great significance to understand the neurobiological basis of hallucinations.

Many studies have shown that the abnormal secretion of dopamine in the striatum is one of the causes of hallucinations.

An important piece of evidence is that dopamine receptor antagonists can significantly reduce the symptoms of psychosis, and dopamine agonists can induce these symptoms [1-2].

However, so far, we are still unclear about how dopamine disorders produce hallucinations.
An important reason is that we lack an effective animal model that can simulate the hallucinations of the human brain.To solve this problem, researchers from the Cold Spring Harbor Laboratory in the United States and the University of Washington recently published a research paper titled Striatal dopamine mediates hallucination-like perception in mice online in the Science Journal.
Through cross-species computational psychology, The hallucination-like perception behaviors of humans and mice are compared to establish a mouse model that can simulate human hallucinations.
On this basis, a variety of advanced technologies such as optogenetics, in vivo calcium imaging, dopamine probes, etc.
are used to reveal Striatal dopamine mediates the neurobiological mechanism of hallucinations in mice, so as to better help us understand the relationship between the nervous system and complex mental diseases and help develop therapeutic strategies.

First, the researchers developed a set of psychological audiometry tasks on mice to obtain postdecision confidence.

Hallucinations are essentially false percepts with the same subjective certainty as correct cognition.
Therefore, the researchers cleverly designed a sensory decision task to generate "false percepts" with a high degree of certainty.
(false alarm).

Researchers trained mice to listen to audio signals under white noise and adjust the volume in different experiments to artificially create perceptual ambiguity.

After reward training, mice can "report" their auditory perception through different ports in the nose touch test box (Figure 1).

If the right choice (hit or correct reject) is made, the mouse will receive a water drop reward after different time intervals.

The key to this behavioral paradigm is to use the time investment of mice as a quantitative indicator of their decision-making confidence.

The researchers then used a series of statistical methods to confirm that this indicator can be used to accurately report hallucination-like perceptions in mice (Hallucination-like perception, HALIPs, see the original text Figure 1D-G).

Figure 1.
Mice can "report" hallucinations.
Researchers verify the reliability of the mouse model by using two manipulation methods related to the appearance of human hallucinations.

One of the manipulation methods is ketamine, which is a kind of drug that humans will experience distortion of perception and other mental symptoms after use.

Ketamine can significantly increase the false alarm rate (FA rate) and the confidence of time input when the false alarm occurs (original figure 2I-P).

In order to verify whether this psychological audiometry task is related to the sensory experience when the hallucinations appear, the researchers correlated objective and quantitative HALIPs with human self-reported hallucination tendencies, and established an online version of the audiometry task to recruit subjects .

The audiometry tasks that human subjects participate in are similar to those performed in mice.
They also provide signals of different volumes in the background noise.
Subjects need to press a button to report whether they hear the signal, and use the slider to report in detail.
The confidence of hearing the signal.

The results showed that the performance of human subjects was very similar to that observed in mice.

After multi-dimensional psychological verification, the researchers determined that HALIPs are the strongest and most specific indicators of hallucinations.

Now that it is known that HALIPs can be used as a characteristic indicator of hallucinations, how to use this indicator to study the abnormal secretion of dopamine and psychotic symptoms related to hallucinations? The researchers returned to the mouse model animal and focused on the striatal tail (TS), a brain structure related to sensory processing.

The researchers used fiber-optic recording combined with dopamine probes to study the release of dopamine there, and found that during the experimental phase when no signal was generated, dopamine was released in large amounts before false alarms occurred.

Using optogenetic technology to stimulate the axon ends of dopaminergic neurons in the tail of the striatum can promote the appearance of HALIPs, which further proves the causal relationship between dopamine release and HALIPs in the striatum.

Interestingly, the researchers used the antipsychotic drug haloperidol (a dopamine D2 receptor antagonist) to successfully prevent the increase in false alarms caused by optogenetic stimulation.

In this issue of Science magazine, a review article entitled How dopamine leads to hallucinations written by Professor Miriam Matamales from the School of Psychology at the University of New South Wales in Australia [3] was published in the same issue of Science magazine.
He believed that this article was a well-designed behavioral neuroscience experiment.
Mice were trained to distinguish between different stimuli (audio stimulation or no stimulation) to make different responses (Figure 2), and found that the increase in dopamine levels in the tail of the striatum is a necessary condition for the cortex to produce an auditory response when there is no real auditory stimulus.
A good simulation of the characteristics of human hallucinations, this behavioral paradigm will help fill the generation gap between complex mental system diseases and the nervous system.

Figure 2.
Designing a new behavioral paradigm to study hallucinations in mice.

In general, this article uses a cross-species computational psychology approach to compare the behavioral characteristics of hallucination-like perception in humans and mice.
On this basis, it further verifies the effectiveness of mice as a model animal to study hallucinations and uses optical fibers.
Records, optogenetic techniques and pharmacological methods (Figure 3) have jointly verified that the release of striatal dopamine mediates hallucinations.

This well-designed behavioral paradigm will help us uncover the mystery of a variety of neuropsychiatric diseases.

Figure 3.
Using a cross-species approach to study the neurobiological mechanism of hallucinations in mice. Original link: https://science.
sciencemag.
org/content/372/6537/eabf4740 Platemaker: Eleven References [1] A.
Carlsson, M.
Lindqvist, Effect of Chlorpromazine or Haloperidol on Formation of 3-Methoxytyramine and Normetanephrine in Mouse Brain.
Acta Pharmacol.
Toxicol.
20, 140–144 (1963).
doi: 10.
1111/j.
1600-0773.
1963.
tb01730.
x;[2] B.
Angrist, G.
Sathananthan, S.
Wilk, S.
Gershon, Amphetamine psychosis: Behavioral and biochemical aspects.
J.
Psychiatr.
Res.
11, 13–23 (1974).
doi: 10.
1016/0022-3956(74)90064-8;[3] 10.
1126/science.
abh1310 Reprint Instructions【 Original Articles: BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt.

BioArt reserves all statutory rights and offenders must be investigated.