bioRxiv Science⌕ Search

Biology subjects

O'Neal, T. J.

Publications and source records attributed to O'Neal, T. J..

2 recordsLinked to original sources

Valence ambiguity dynamically shapes striatal dopamine heterogeneity

Adaptive decision making relies on dynamic updating of learned associations where environmental cues come to predict positive and negatively valenced stimuli, such as food or threat. Flexible cue-guided behaviors depend on a network of brain systems, including dopamine signaling in the striatum, which is critical for learning and maintenance of conditioned behaviors. Critically, it remains unclear how dopamine signaling encodes multi-valent, dynamic learning contexts, where positive and negative associations must be rapidly disambiguated. To understand this, we employed a Pavlovian discrimination paradigm, where cues predicting positive and negative outcomes were intermingled during conditioning sessions, and their meaning was serially reversed across training. We found that rats readily distinguished these cues, and updated their behavior rapidly upon valence reversal. Using fiber photometry, we recorded dopamine signaling in three major striatal subregions -,the dorsolateral striatum (DLS), the nucleus accumbens core, and the nucleus accumbens medial shell - and found heterogeneous responses to positive and negative conditioned cues and their predicted outcomes. Valence ambiguity introduced by cue reversal reshaped striatal dopamine on different timelines: nucleus accumbens core and shell signals updated more readily than those in the DLS. Together, these results suggest that striatal dopamine flexibly encodes multi-valent learning contexts, and these signals are dynamically modulated by changing contingencies to resolve ambiguity about the meaning of environmental cues.

neuroscience↗

A conditioned place preference for heroin is signaled by increased dopamine and direct pathway activity and decreased indirect pathway activity in the nucleus accumbens

Initial drug use promotes the development of conditioned reinforcement, whereby the reinforcing properties of a drug become attributed to drug-associated stimuli, such as cues and contexts. A principal role for the nucleus accumbens (NAc) in the response to drug-associated stimuli has been well-documented. In particular, direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity towards the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement remains unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to address these outstanding questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and activation of the NAc post-conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of addiction. SIGNIFICANCE STATEMENTThe attribution of the reinforcing effects of drugs to neutral stimuli (e.g., cues and contexts) contributes to the maintenance of addiction, as re-exposure to drug-associated stimuli can reinstate drug seeking and taking even after long periods of abstinence. The nucleus accumbens (NAc) has an established role in encoding the value of drug-associated stimuli, and dopamine release into the NAc is known to modulate the reinforcing effects of drugs, including heroin. Using fiber photometry, we show that entering a heroin-paired context is driven by dopamine signaling and NAc direct pathway activation, whereas exiting a heroin-paired context is driven by NAc indirect pathway activation. This study provides further insight into the role of NAc microcircuitry in encoding the reinforcing properties of heroin.

neuroscience↗