The Impairment of Deviance Detection in the Auditory Cortex by DOI

Academic Background

Psychedelics are a class of psychoactive substances that can significantly alter perception, cognition, and mood. In recent years, psychedelics have shown potential applications in treating conditions such as depression, anxiety, and trauma-related disorders. However, while the perceptual distortions induced by psychedelics in the visual system have been extensively studied, the neural mechanisms underlying their effects in the auditory system remain poorly understood. Specifically, how psychedelics affect neural activity in the auditory cortex, thereby leading to changes in auditory perception, is still an unresolved question.

This study aims to investigate the effects of the psychedelic compound 2,5-dimethoxy-4-iodoamphetamine (DOI) on the activity of neurons in the auditory cortex of mice. DOI is a serotonin 2A receptor (5-HT2A) agonist that mimics the effects of classic psychedelics such as LSD and psilocybin. By studying the impact of DOI on the frequency tuning, neural response variability, and deviance detection in auditory cortical neurons, the researchers hope to reveal how psychedelics alter the balance between top-down and bottom-up neural signaling, leading to distortions in auditory perception.

Source of the Paper

This paper was co-authored by Max Horrocks, Jennifer L. Mohn, and Santiago Jaramillo, all affiliated with the Institute of Neuroscience at the University of Oregon, USA. The study was first published on December 27, 2024, in the Journal of Neurophysiology, under the title The Serotonergic Psychedelic DOI Impairs Deviance Detection in the Auditory Cortex.

Research Process and Results

1. Experimental Design and Animal Model

The study used four adult C57BL/6J mice (two males and two females), with neural activity in the auditory cortex recorded using Neuropixels probes. The experiment was divided into three phases: before saline injection, after saline injection, and after DOI injection. In each phase, sound stimulation experiments were conducted to evaluate neuronal responses to pure tones and frequency-modulated (FM) sounds.

2. Sound Stimulation and Neural Recording

Three types of sound stimuli were used in the experiments: pure tones, narrowband chords, and frequency-modulated sounds. Pure tones were used to assess the frequency tuning properties of neurons, while chords and FM sounds were used to study the phenomenon of deviance detection. Deviance detection refers to the stronger response of neurons to rare sounds (oddballs) compared to common sounds (standards), reflecting the brain’s ability to process expected and unexpected stimuli.

3. Effects of DOI on Neural Activity

The study found that DOI significantly reduced both spontaneous activity and sound-evoked responses in auditory cortical neurons. Specifically, after DOI injection, the baseline firing rate and sound-evoked firing rate of neurons decreased significantly. Additionally, DOI increased the variability of neural responses, as evidenced by a significant increase in the Fano factor.

4. Frequency Tuning and Deviance Detection

Although DOI did not significantly affect the frequency tuning properties of neurons, it significantly reduced the difference in neuronal responses to oddball and standard sounds. This reduction was primarily due to DOI weakening the response to oddball sounds, indicating that DOI reduces the auditory cortex’s sensitivity to unexpected events.

5. Mechanisms of Deviance Detection

Further analysis suggested that the inhibitory effect of DOI on deviance detection may involve the weakening of prediction error signaling. Prediction error refers to the brain’s encoding of the difference between expected input and actual input. DOI may interfere with this process, leading to a weakened response to oddball sounds and thereby reducing the ability for deviance detection.

Conclusions and Significance

This study demonstrates that DOI reduces spontaneous and sound-evoked activity in auditory cortical neurons, increases neural response variability, and impairs deviance detection. These findings reveal how psychedelics alter the balance between top-down and bottom-up neural signaling, leading to distortions in auditory perception. Additionally, the study suggests that the inhibitory effect of DOI on deviance detection may involve the weakening of prediction error signaling, providing new insights into the neural mechanisms of psychedelics.

Research Highlights

1. First Systematic Study on the Effects of DOI on Deviance Detection in the Auditory Cortex: This study is the first to comprehensively investigate the impact of DOI on the deviance detection capabilities of auditory cortical neurons, filling a gap in the understanding of psychedelic effects in the auditory system.
2. Revealing the Impact of Psychedelics on Prediction Error Signaling: The results indicate that DOI may weaken prediction error signaling, leading to a reduced response to unexpected events, offering new perspectives on the neural mechanisms of psychedelics.
3. Innovative Experimental Design and Data Analysis Methods: The study utilized Neuropixels probes for high-density neural recordings and combined them with advanced signal processing algorithms, ensuring the accuracy and reliability of the data.

Additional Valuable Information

The research data have been made publicly available on the Zenodo platform (DOI: 10.5281/zenodo.14285875) for further analysis and validation by other researchers. Additionally, the study was supported by the National Institutes of Health (NIH) and the Office of the Vice President for Research & Innovation at the University of Oregon.

Through this study, we have not only deepened our understanding of the mechanisms of psychedelics but also provided important theoretical foundations for the future development of psychedelic-based therapeutic approaches.