The Impairment of Deviant Detection in the Auditory Cortex by the Serotonergic Psychedelic DOI

Research Background

Psychedelics are a class of psychoactive substances capable of significantly altering perception, cognition, and mood. They have recently regained attention due to their potential therapeutic value, such as in treating depression and anxiety. Although the visual effects of psychedelics have been extensively studied, their impact on the auditory system remains poorly understood. Previous research suggests that psychedelics may distort time perception and sound perception, but the underlying neural mechanisms are not yet fully elucidated. In particular, how psychedelics alter neural activity in the brain to influence auditory perception remains an open question.

This study aimed to investigate the effects of the serotonin receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on the activity of auditory cortical neurons, focusing on its role in deviance detection. Deviance detection is a key mechanism in the brain for processing expected versus unexpected stimuli, reflecting the balance between top-down and bottom-up neural signaling. By studying the effects of DOI on auditory cortical neurons, the researchers sought to uncover how psychedelics induce perceptual distortions by altering neural activity.

Research Source

This study was conducted by Max Horrocks, Jennifer L. Mohn, and Santiago Jaramillo, all affiliated with the Institute of Neuroscience at the University of Oregon. The research paper was published in the Journal of Neurophysiology in 2025, with the first release on December 27, 2024, and the DOI is 10.1152/jn.00411.2024.

Research Design and Methods

The study adopted a systematic experimental approach to evaluate the effects of DOI on neuronal activity in the auditory cortex of awake mice. The experimental design included the following main steps:

1. Animal and Experimental Preparation

• Animal Selection: The study used six adult C57BL/6J mice, with four for electrophysiological recordings and two for head-twitch response testing.
  
• Auditory Stimuli: Experiments were conducted in a sound-isolation chamber, using pure tones and frequency-modulated (FM) sounds as stimuli. Sounds were delivered via speakers, covering a frequency range from 2 kHz to 40 kHz.
  
• Electrophysiological Recordings: Neuronal activity in the auditory cortex was recorded using Neuropixels probes. Probes were implanted in the auditory cortex, spanning multiple subregions.
  

2. Experimental Procedure

• Experimental Phases: Each mouse underwent three phases during the experiment: pre-saline injection, post-saline injection, and post-DOI injection. Neuronal activity was recorded in each phase during sound presentation.
  
• Drug Administration: DOI was administered subcutaneously at a dose of 10 mg/kg, with saline as the control.
  
• Data Analysis: Single-neuron spike sorting was performed using Kilosort software, followed by data analysis in Python to assess neuronal frequency selectivity, response variability, and deviance detection.
  

3. Highlights of Experimental Methods

• Neuropixels Probe Technology: This technology enabled simultaneous recording of activity from multiple neurons, providing high-precision data acquisition.
  
• Deviance Detection Assessment: Standard-deviant stimulus sequences were designed to quantify differences in neuronal responses to expected (standard) and unexpected (deviant) stimuli.
  

Research Results

1. Effects of DOI on Neuronal Activity

The study found that DOI significantly reduced both spontaneous and sound-evoked firing rates in auditory cortical neurons. Neuronal activity decreased significantly after DOI injection, both in spontaneous activity and in responses to sound stimuli.

2. Increased Response Variability

DOI also increased trial-to-trial variability in neuronal responses, indicating reduced response consistency. This effect was more pronounced during running states.

3. No Significant Changes in Frequency Selectivity

Although DOI affected overall neuronal activity, its impact on frequency selectivity was inconsistent. Most neurons showed no significant changes in frequency tuning curves before and after DOI injection.

4. Impaired Deviance Detection

DOI significantly reduced the difference in neuronal responses to deviant versus standard stimuli. This reduction was primarily driven by weakened responses to deviant stimuli rather than enhanced responses to standard stimuli, suggesting that DOI reduces the auditory cortex’s sensitivity to unexpected events.

Research Conclusions

This study revealed that the psychedelic DOI impairs deviance detection by reducing neuronal activity and response variability in the auditory cortex. This finding provides new insights into how psychedelics induce perceptual distortions by altering neural signal processing. The results suggest that psychedelics may disrupt the balance between top-down and bottom-up signaling, affecting the brain’s sensitivity to and processing of unexpected events.

Research Highlights and Value

• Scientific Value: This study is the first to systematically evaluate the effects of the psychedelic DOI on auditory cortical neuronal activity, particularly its role in deviance detection.
  
• Methodological Innovation: The use of Neuropixels probe technology enabled high-precision recording and analysis of activity from multiple neurons.
  
• Practical Value: The findings provide important clues for understanding the mechanisms of psychedelics and may offer new directions for treating related mental disorders.
  

Additional Valuable Information

The researchers also monitored animal behavior (e.g., locomotor state) during the experiments, finding that the effects of DOI on neuronal activity were not solely due to behavioral changes. Additionally, the study validated DOI’s dose effects to ensure the reliability of the experimental results.

This study provides critical experimental evidence for exploring the effects of psychedelics on perception and neural activity, laying a solid foundation for future related research.