Cognitive representations of intracranial self-stimulation of midbrain dopamine neurons depend on stimulation frequency

This paper reports a study on the cognitive representation of intracranial self-stimulation (ICSS) of midbrain dopamine neurons. The authors aimed to answer why rats work to obtain ICSS, i.e., how the pulsatile activation of dopamine neurons is represented in the brain.

Research Background: The pulsatile activation of dopamine neurons is typically considered a reward prediction error signal, serving as a teaching signal in the learning process. However, if this signal itself does not carry a value representation, why would rats work to obtain it? Previous studies have not explored the cognitive representation basis of ICSS in depth.

Author Affiliation: This study was a collaboration between the University of California, Los Angeles (UCLA) and Rutgers University. The first author is from the Department of Psychology at UCLA, and the co-authors are from Rutgers University. The research was published in the journal Nature Neuroscience.

Research Procedure: 1) Introduced the channelrhodopsin-2 (ChR2) gene into dopamine neurons, making them light-responsive. 2) Trained rats to associate two different auditory cues with either sucrose reward or 20Hz/50Hz optogenetic stimulation of dopamine neurons. 3) Trained rats to press a lever to obtain sucrose reward or dopamine neuron stimulation, with increasing difficulty. 4) Conducted a Pavlovian-to-Instrumental Transfer (PIT) test to observe whether auditory cues would promote the corresponding lever-pressing behavior.

Key Findings: a) 20Hz optogenetic stimulation of dopamine neurons (mimicking physiological prediction error signals) could not support rats’ continued lever-pressing in more challenging situations, and the corresponding auditory cues failed to elicit specific PIT effects. b) 50Hz non-physiological high-frequency stimulation promoted sustained lever-pressing and elicited specific PIT effects, suggesting it was encoded as a concrete reward event. c) 20Hz and 50Hz stimulations evoked similar numbers of action potentials in dopamine neurons, but 50Hz produced more dense, phasic bursts, leading to greater dopamine release in the striatum.

Research Significance: 1) Physiological prediction error-level dopamine neuron activity alone is insufficient to support reward-seeking behavior and is not encoded as a reward event. 2) Non-physiological high-frequency stimulation is encoded as a concrete reward event, potentially reflecting the essence of drug-seeking behavior in addiction. 3) The pattern of dopamine release (peak and duration) may determine whether it serves as a teaching signal or a reward representation.

This study elucidates the cognitive representation mechanism of ICSS, the association between dopamine neuron activity patterns and their functional roles, and has significant implications for understanding pathological conditions such as addiction.