Enhanced Selectivity for Aversive Cues in Dopamine Axons Projecting to the Medial Prefrontal Cortex During Classical Conditioning

Core Concepts

Mesocortical dopamine axons show diverse preferences for rewarding and aversive stimuli, with a strong bias toward aversive processing. During classical conditioning, the selectivity for aversive cues is enhanced in aversive-preferring dopamine axons, but not in reward-preferring axons.

Abstract

The study used two-photon calcium imaging to investigate the activity of individual dopamine axons projecting to the medial prefrontal cortex (mPFC) in mice. The authors found that dopamine axons exhibited diverse preferences for rewarding and aversive stimuli, with a population bias toward aversive processing.
During classical conditioning, where rewarding and aversive stimuli were paired with preceding auditory cues, the authors observed the following:

Aversive-preferring dopamine axons maintained their preference for aversive stimuli throughout the conditioning, while reward-preferring axons maintained their preference for rewarding stimuli.

As the mice learned to discriminate the reward and aversive cues, the selectivity for the aversive cue was enhanced in aversive-preferring axons, but not in reward-preferring axons.

This enhanced selectivity for the aversive cue in aversive-preferring axons was observed specifically in trials where the mice correctly discriminated the cues, based on either anticipatory licking or facial expressions.

These findings suggest that a subpopulation of mesocortical dopamine axons preferentially encodes aversive-related signals, and this aversive processing is modulated by both classical conditioning across days and trial-by-trial cue discrimination within a day.

Stats

"Licking latency: 0.538 ± 0.065 s, n = 8 animals"
"Percentage of error trials in discrimination based on anticipatory licking: 25.3% ± 6.1% (n = 6 animals)"
"Percentage of error trials in discrimination based on facial expressions: 16.0% ± 1.4% (n = 6 animals)"

Quotes

"Consistently, dysregulation of dopamine signaling in the PFC has been suggested to underlie a wide array of neuropsychiatric disorders, including schizophrenia, depression, attention-deficit/hyperactivity disorder, and post-traumatic stress disorder."
"Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day."

Key Insights Distilled From

Functional Diversity of Dopamine Axons in Prefrontal Cortex During Classical Conditioning

by Abe,K., Kamb... at www.biorxiv.org 08-24-2023

https://www.biorxiv.org/content/10.1101/2023.08.23.554475v2

Deeper Inquiries

How do the molecular and genetic profiles of aversive-preferring and reward-preferring dopamine axons in the mPFC differ, and how might this relate to their functional diversity

The molecular and genetic profiles of aversive-preferring and reward-preferring dopamine axons in the medial prefrontal cortex (mPFC) exhibit differences that may contribute to their functional diversity. Studies have shown that dopamine neurons projecting to the mPFC can be categorized based on their genetic profiles, with some expressing vesicular glutamate transporter 2 (Vglut2) and others lacking this marker. Vglut2-expressing dopamine neurons have been associated with a stronger response to aversive stimuli, while Vglut2-negative dopamine neurons may show a preference for rewarding stimuli. This distinction in genetic expression could underlie the observed diversity in the response of dopamine axons to rewarding and aversive stimuli in the mPFC. The presence or absence of Vglut2 may influence the neurotransmitter release profile of these axons, impacting their signaling properties and functional roles in processing different types of stimuli. Additionally, other molecular markers and genetic features specific to aversive-preferring and reward-preferring dopamine axons could further contribute to their distinct functional characteristics, such as response to classical conditioning and cue discrimination.

What are the potential implications of the enhanced aversive cue processing in mesocortical dopamine axons for understanding the role of dopamine in prefrontal cortex-related psychiatric disorders

The enhanced aversive cue processing in mesocortical dopamine axons has significant implications for understanding the role of dopamine in prefrontal cortex-related psychiatric disorders. Dysfunction in dopamine signaling in the prefrontal cortex has been implicated in various neuropsychiatric conditions, including schizophrenia, depression, attention-deficit/hyperactivity disorder, and post-traumatic stress disorder. The findings of enhanced aversive cue processing in dopamine axons suggest that these neurons play a crucial role in encoding and processing aversive stimuli, which are essential for adaptive behavioral responses to threatening or stressful situations. Dysregulation of aversive processing in the prefrontal cortex, mediated by dopamine axons, could contribute to the development and maintenance of psychiatric disorders characterized by altered responses to aversive stimuli. Understanding the neural mechanisms underlying aversive cue processing in mesocortical dopamine axons may provide insights into the pathophysiology of these disorders and guide the development of targeted interventions aimed at restoring normal dopamine signaling in the prefrontal cortex.

Could the trial-by-trial modulation of aversive cue selectivity in aversive-preferring dopamine axons be leveraged to develop novel interventions for disorders involving dysfunctional aversive processing, such as post-traumatic stress disorder

The trial-by-trial modulation of aversive cue selectivity in aversive-preferring dopamine axons could offer a promising avenue for developing novel interventions for disorders involving dysfunctional aversive processing, such as post-traumatic stress disorder (PTSD). By leveraging the ability of these dopamine axons to adjust their response to aversive cues based on behavioral discrimination, therapeutic strategies could be designed to target and modulate this neural circuitry. For individuals with PTSD, who often exhibit heightened sensitivity to aversive stimuli and maladaptive responses to trauma-related cues, interventions that specifically target the aversive processing pathways in the prefrontal cortex could help regulate emotional responses and improve coping mechanisms. Techniques such as optogenetic modulation or pharmacological interventions aimed at enhancing the selectivity of aversive cue processing in aversive-preferring dopamine axons could potentially be explored as novel treatment approaches for PTSD and other disorders characterized by aversive processing abnormalities.