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Dopamine neurons are proposed to signal the reward prediction error in model-free reinforcement learning algorithms. This term represents the unpredicted or ‘excess’ value of the rewarding event, value that is then added to the intrinsic value of any antecedent cues, contexts or events. To support this proposal, proponents cite evidence that artificially-induced dopamine transients cause lasting changes in behavior. Yet these studies do not generally assess learning under conditions where an endogenous prediction error would occur. Here, to address this, we conducted three experiments where we optogenetically activated dopamine neurons while rats were learning associative relationships, both with and without reward. In each experiment, the antecedent cues failed to acquire value and instead entered into associations with the later events, whether valueless cues or valued rewards. These results show that in learning situations appropriate for the appearance of a prediction error, dopamine transients support associative, rather than model-free, learning. Dopamine neurons are proposed to signal the reward prediction error in model-free reinforcement learning algorithms. Here, the authors show that when given during an associative learning task, optogenetic activation of dopamine neurons causes associative, rather than value, learning.

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency. BLA CaMKIIα neuron activity followed reward retrieval and moved to the reward-predictive cue after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers led to a quicker acquisition of the cue-reward contingency. These results indicate BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli.

Sensory preconditioning has been used to implicate midbrain dopamine in model-based learning, contradicting the view that dopamine transients reflect model-free value. However, it has been suggested that model-free value might accrue directly to the preconditioned cue through mediated learning. Here, building on previous work (Sadacca et al., 2016), we address this question by testing whether a preconditioned cue will support conditioned reinforcement in rats. We found that while both directly conditioned and second-order conditioned cues supported robust conditioned reinforcement, a preconditioned cue did not. These data show that the preconditioned cue in our procedure does not directly accrue model-free value and further suggest that the cue may not necessarily access value even indirectly in a model-based manner. If so, then phasic response of dopamine neurons to cues in this setting cannot be described as signaling errors in predicting value.

Learning to predict reward is thought to be driven by dopaminergic prediction errors, which reflect discrepancies between actual and expected value. Here the authors show that learning to predict neutral events is also driven by prediction errors and that such value-neutral associative learning is also likely mediated by dopaminergic error signals. Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus–stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus–stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have drawn for learning of particular types of information from work in naïve subjects. Sharpe et al. find that prior reward-learning experience can prime reward circuits to encode fear memories. This suggests prior experience can shape the way we learn, opening the neural boundaries for learning about particular types of information.

Societal disruption from the COVID-19 pandemic has accelerated the opioid overdose epidemic. Given the drastic increase in opioid overdose deaths during the pandemic, particularly within Black communities,1 it is important to reflect on the state of opioid addiction treatment in the United States. When COVID-19 was declared a public health emergency, more than 400 000 individuals were receiving methadone maintenance treatment (MMT) for opioid use disorder (OUD) across the 50 states, the District of Columbia, and US territories including Puerto Rico.2 Individuals receiving MMT, a gold standard for OUD treatment, have lower rates of death and nonprescribed opioid use than those not receiving treatment and exhibit better treatment retention.3Despite these benefits, many structural barriers exist in accessing MMT, in large part because of decades of racist policies and political scapegoating (e.g., criminalizing those with substance use disorders and being \"tough on crime\" through harsh drug policies for political gain).4 Methadone dispensing is tightly regulated, and the medication can be dispensed only at opioid treatment programs (OTPs) overseen by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Drug Enforcement Administration, and state governments. When used in the treatment of OUD, no other prescription medication is as tightly regulated as methadone.

Methadone is an effective medication to treat opioid use disorder.1 Access to methadone take-home doses (THDs) is restricted by federal and state guidelines. Before the COVID-19 pandemic, patients were obligated to attend opioid treatment programs (OTPs) daily because of concerns about the safety ofTHDs. Eligibility for 14- or28-dayTHDs required daily visits over one or two years, respectively. Federal regulations for THDs changed during the COVID-19 pandemic, allowing OTPs to initiate or extend THDs.2 Emerging data suggest increasing access to THDs does not increase adverse events.3-5In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) enacted exemptions allowing increased THDs to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk by decongregating OTP settings. Patients were allowed 14- or 28-day THDs, on provider discretion, regardless of treatment length. However, implementation varied across OTPs. We conducted three independent studies on the expanded THD exemptions to assess implementation and impact on patients and providers in three geographically diverse OTP settings. We report on lessons learned from the implementation ofthe THD exemptions in three vulnerable population groups in Tennessee, California, and Puerto Rico exposed to differing sociostructural factors that influence treatment access: OTP financial structure, housing status, and incarceration.

In the version of this article initially published, the laser activation at the start of cue X in experiment 1 was described in the first paragraph of the Results and in the third paragraph of the Experiment 1 section of the Methods as lasting 2 s; in fact, it lasted only 1 s. The error has been corrected in the HTML and PDF versions of the article.

Nat. Neurosci. 20, 735–742 (2017); published online 3 April 2017; corrected online 10 April 2017; corrected after print 5 May 2017 In the version of this article initially published, the histogram in Figure 2c, center top graph, was duplicated from the panel below, and the remaining histograms accompanying the scatter plots in Figures 2c and 5c were slightly mis-scaled and misaligned relative to the scatterplots.