Biology subjects

Schoenbaum, G.

Publications and source records attributed to Schoenbaum, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Characterization of nucleus accumbens dopamine dynamics during positive and negative operant reinforcement in rats

We previously reported, using in-vivo fiber photometry, that operant responding reinforced by access to a peer (social self-administration) is associated with phasic dopamine increases in nucleus accumbens (NAc) core following lever insertion (reward-availability cue) and gradual increases preceding lever-pressing. Here, we sought to replicate these findings and determine whether dopamine signals (1) generalize to responding for high-carbohydrate palatable food, (2) show opposite patterns during negative reinforcement (shock avoidance/escape), and (3) depend on whether reinforcers are experienced alone or together. We trained rats (n=11; 6 females) to lever-press for access to a same-sex peer (15 s/trial) and palatable food (45-mg pellet/trial), followed by shock avoidance/escape (0.18-0.26 mA). After training, we expressed the dopamine sensor GRAB-DA2m and implanted optic fibers into NAc core. We measured dopamine activity during sessions with either one- or three-reinforcers. During social self-administration, dopamine activity showed phasic increases following lever insertion and gradual increases preceding lever-pressing; responses were moderately greater during sessions with all three reinforcers. Palatable food self-administration showed a similar pattern, but responses were approximately twofold greater during single-reinforcer sessions. During shock avoidance/escape, dopamine activity showed phasic decreases at warning onset, lever insertion, and shock onset; responses were also greater during single-reinforcer sessions. Results suggest that NAc core dopamine signaling distinguishes positive from negative reinforcement and is modulated by reinforcer availability. Compared with single-reinforcer sessions, dopamine responses during food self-administration and shock avoidance/escape were reduced during sessions with all three reinforcers, whereas responses during social self-administration modestly increased. Significance statementNucleus accumbens (NAc) dopamine is critical for processing the valence of positive reinforcers, whereas its role in negative reinforcement is less well understood. Here, we extended our prior work on operant social self-administration to determine whether these findings generalize to food reinforcement, show the opposite pattern during operant negative reinforcement (shock avoidance/escape), and depend on whether reinforcers are experienced alone or together. Results suggest that NAc core dopamine activity differentiates positive and negative reinforcement and is modulated by the presence of other available reinforcers. Specifically, dopamine responses during food self-administration and shock avoidance/escape were reduced when all three reinforcers were available together compared with when each reinforcer was experienced alone, whereas responses during social self-administration showed the opposite pattern.

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bioRxiv2025

Distinct contributions of anterior and posterior orbitofrontal cortex to outcome-guided behavior

The lateral orbitofrontal cortex (OFC) is critical for flexibly adjusting choices when outcome values change. Anterior and posterior parts of the human lateral OFC differ in cytoarchitecture and connectivity, but whether these subregions make differential contributions to outcome-guided (i.e., goal-directed) behavior remains unclear. Outcome-guided behavior requires (a) representations of stimulus-outcome associations and (b) inferring the current value of options when making decisions. Here, we test whether these two functions are differentially supported by the posterior (pOFC) and anterior (aOFC) parts of the lateral OFC, using transcranial magnetic stimulation (TMS) to selectively disrupt activity in functional networks centered on the pOFC and aOFC during a two-day outcome devaluation task. Participants (n = 48) received pOFC or aOFC network-targeted TMS either on day 1 before learning associations between visual stimuli and sweet or savory food odors, or on day 2 before a meal that selectively devalued one of these outcomes, followed by a choice test. TMS targeting pOFC, but not aOFC, before the meal on day 2 disrupted outcome-guided behavior, as measured by choices of stimuli predicting non-sated rewards in the post-meal choice test. In contrast, TMS targeting aOFC, but not pOFC, before learning on day 1 similarly impaired behavior in the post-meal choice test on day 2. These findings demonstrate that anterior and posterior parts of the lateral OFC make distinct contributions to outcome-guided behavior by supporting learning of stimulus-outcome associations and inferring the current value of options, respectively.

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bioRxiv2025

Generation and characterization of a tamoxifen-inducible, Cre driver rat for transgene expression in microglia

Microglia are the resident immune cells of the central nervous system (CNS) and display diverse functions under both physiological and pathological conditions. The past decade has seen burgeoning interest in microglia function, with a variety of transgenic tools developed for specific genetic manipulation of microglia in various injury, disease, and developmental models. Although the majority of models have been developed in mice, the ability to manipulate microglia in rats provides additional advantages to studying microglial function in the brain especially related to complex behavior. Using BAC transgenesis, our lab has created a transgenic rat (Cx3cr1-CreERT2) that expresses a tamoxifen inducible Cre recombinase (CreERT2) under control of the microglial/macrophage specific fractalkine C-X3-C Motif Chemokine Receptor 1 (Cx3cr1) promoter. In mice, CreERT2 and other transgenes have been expressed in microglia using the Cx3cr1 promoter, however, this is the first demonstration in rats. Importantly, these rats exhibit similar cognitive behaviors compared to their wildtype (WT) controls. Microglial specificity of inducible Cre expression was confirmed by breeding the novel Cx3cr1-CreERT2+/- rat with a previously reported double floxed inverse open reading frame (DIO)-mCherry+/- reporter rat to show tamoxifen inducible mCherry expression that colocalizes with the microglial marker Iba1. In addition, we utilize flow cytometry to demonstrate time and Cre dependent differences in recombination of Cx3cr1+ cells in the spleen, peripheral blood, and brain at two- and eight-weeks post-tamoxifen treatment. Overall, we have created a novel transgenic rat model for researchers to employ in understanding microglial and peripheral immune cell function in rats.

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bioRxiv2025

Prior cocaine use disrupts identification of hidden states by single units and neural ensembles in orbitofrontal cortex

The orbitofrontal cortex (OFC) is critical to identifying task structure and to generalizing appropriately across task states with similar underlying or hidden causes. This capability is at the heart of OFCs proposed role in a network responsible for cognitive mapping, and its loss can explain many deficits associated with OFC damage or inactivation. Substance use disorder is defined by behaviors that share much in common with these deficits, such as an inability to modify learned behaviors in the face of new information about undesired consequences. One explanation for this similarity would be if addictive drugs impacted the ability of OFC to recognize underlying similarities, hidden states, that allow information learned in one setting to be used in another. To explore this possibility, we trained rats to self-administer cocaine and then recorded single unit activity in lateral OFC as these rats performed in an odor sequence task consisting of unique and shared positions. In well-trained controls, we observed chance decoding of sequence at shared positions and near chance decoding even at unique positions, reflecting the irrelevance of distinguishing these positions in the task. By contrast, in cocaine-experienced rats, decoding remained significantly elevated, particularly at the positions that had superficial sensory differences that were collapsed in controls across learning. These neural differences were accompanied by increases in behavioral variability at these positions. A tensor component analysis showed that this effect of reduced generalization after cocaine use also extended across positions in the sequences. These results show that prior cocaine use disrupts the normal identification of hidden states by OFC.

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bioRxiv2025

Neural correlates in basolateral and central amygdala during reward seeking in the face of punishment

The inability to suppress actions despite adverse consequences is a hallmark of compulsive behaviors and is amygdala dependent. To study the amygdalas role in responding despite adverse consequences, we compared single-unit activity in the basolateral (BLA) or central (CeA) amygdala before and after reward-seeking under punishment threat. Rats started each trial by pressing an initial lever, which triggered an outcome-specific 5-s auditory cue (white noise, pure tone, or clicker), signaling one of three reinforcement conditions: 100% sucrose reward, 20% reward/80% omission, or 80% reward/20% footshock punishment. Next, the active and inactive levers were extended, and pressing on the active lever terminated the auditory cue and triggered an outcome-specific 1-s visual cue predicting either reward, reward omission, or shock. After training, we implanted eight tetrodes in the BLA (n=7) or CeA (n=5) and recorded single-unit activity of [~]100 neurons per region during task performance. CeA neurons, and to a lesser extent BLA neurons, responded differently to the distinct auditory cues and outcomes. The discrimination between conditions partially explained the capacity of neuronal activity to predict the latency to lever press to complete the trial. The failure to suppress reward-seeking behavior in the face of punishment coincided with the reactivation of reward-seeking-sensitive and the loss of inhibition of punishment-sensitive neuronal populations. In conclusion, we found that after extended training, opposing populations of activated and inhibited neurons in CeA, and to a lesser extent in BLA, control completion of reward-seeking despite punishment.

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bioRxiv2025

Persistent representation of a prior schema in the orbitofrontal cortex facilitates learning of a conflicting schema

Schemas allow efficient behavior in new situations, but reliance on them can impair flexibility when new demands conflict, culminating in psychopathology. Evidence implicates the orbitofrontal cortex (OFC) in deploying schemas in new situations congruent with previously acquired knowledge. But how does this role affect learning of a conflicting behavioral schema? Here we addressed this question by recording single-unit activity in the OFC of rats learning odor problems with identical external information but orthogonal rules governing reward. Consistent with schema formation, OFC representations adapted to track the underlying rules, and both performance and encoding was faster on subsequent than initial problems. Surprisingly however, when the rule governing reward changed, persistent representation of the prior schema was correlated with acquisition of the new. Thus, OFC was not a source of interference and instead supported new learning by accurately and independently representing the old schema as the new was acquired.

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bioRxiv2025

Distinct prelimbic cortex ensembles encode response execution and inhibition

Learning when to initiate or withhold actions is essential for survival and requires integration of past experiences with new information to adapt to changing environments. While stable prelimbic cortex (PL) ensembles have been identified during reward learning, it remains unclear how they adapt when contingencies shift. Does the same ensemble adjust its activity to support behavioral suppression upon reward omission, or is a distinct ensemble recruited for this new learning? We used single-cell calcium imaging to longitudinally track PL neurons in rats across operant food reward Training, Extinction and Reinstatement, trained rat-specific decoders to predict trial-wise behavior, and implemented an in-silico deletion approach to characterize ensemble contributions to behavior. We show that operant training and extinction recruit distinct PL ensembles that encode response execution and inhibition, and that both ensembles are re-engaged and maintain their roles during Reinstatement. These findings highlight ensemble-based encoding of multiple learned associations within a region, with selective ensemble recruitment supporting behavioral flexibility under changing contingencies.

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bioRxiv2025

Accumbal acetylcholine signals associative salience

Learning is driven by prediction errors, which determine what is learned, and salience, which controls the learning rate. Dopamine in the nucleus accumbens correlates with prediction errors, but salience mechanisms are less clear. We hypothesized that acetylcholine acts as a salience signal, as it regulates dopamine-induced plasticity. To test this, we recorded acetylcholine and dopamine dynamics in rats across three learning tasks. Our findings reveal a characteristic pattern of evolving neuromodulator responses during learning. First, indiscriminate cholinergic dips appeared, then dopamine responses differentiated based on predicted value, followed by the cholinergic dips also varying by value. Stable performance required this full pattern, and acetylcholine dips could be decoupled from value by changing reward contingencies. The observed acetylcholine dynamics fit an associative salience term predicted by hybrid attentional associative learning models, suggesting that dopamine and acetylcholine act complementarily to determine the content and rate of learning. TeaserAcetylcholine shapes learning rate by signaling the salience of predictive cues.

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bioRxiv2024

Dopaminergic responses to identity prediction errors depend differently on the orbitofrontal cortex and hippocampus

Adaptive behavior depends on the ability to predict specific events, particularly those related to rewards. Armed with such associative information, we can infer the current value of predicted rewards based on changing circumstances and desires. To support this ability, neural systems must represent both the value and identity of predicted rewards, and these representations must be updated when they change. Here we tested whether prediction error signaling of dopamine neurons depends on two areas known to represent the specifics of rewarding events, the HC and OFC. We monitored the spiking activity of dopamine neurons in rat VTA during changes in the number or flavor of expected rewards designed to induce errors in the prediction of reward value or reward identity, respectively. In control animals, dopamine neurons registered both error types, transiently increasing firing to additional drops of reward or changes in reward flavor. These canonical firing signatures of value and identity prediction errors were significantly disrupted in rats with ipsilateral neurotoxic lesions of either HC or OFC. Specifically, HC lesions caused a failure to register either type of prediction error, whereas OFC lesions caused persistent signaling of identity prediction errors and much more subtle effects on signaling of value errors. These results demonstrate that HC and OFC contribute distinct types of information to the computation of prediction errors signaled by dopaminergic neurons.

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bioRxiv2024

Generalized cue reactivity in dopamine neurons after opioids

Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. The leading hypothesis is that dopamine release by addictive drugs represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation compared to non-drug reward alternatives. However, this hypothesis has not been directly tested. Here we developed Pavlovian and operant procedures to measure firing responses, within the same dopamine neurons, to drug versus natural reward cues, which we found to be similarly enhanced compared to cues predicting natural rewards in drug-naive controls. This enhancement was associated with increased behavioral reactivity to the drug cue, suggesting that dopamine release is still critical to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting new models of dopaminergic function in drug addiction, and provide critical insights into the neurobiology of cue reactivity with potential implications for relapse prevention.

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bioRxiv2024

Dopamine and acetylcholine correlations in the nucleus accumbens depend on behavioral task states

Dopamine in the nucleus accumbens ramps up as animals approach desired goals. These ramps have received intense scrutiny because they seem to violate long-held hypotheses on dopamine function. Furthermore, it has been proposed that they are driven by local acetylcholine release, i.e., that they are mechanistically separate from dopamine signals related to reward prediction errors. Here, we tested this hypothesis by simultaneously recording accumbal dopamine and acetylcholine signals in rats executing a task involving motivated approach. Contrary to recent reports, we found that dopamine ramps were not coincidental with changes in acetylcholine. Instead, we found that acetylcholine could be positively, negatively, or uncorrelated with dopamine depending on whether the task phase was determined by a salient cue, reward prediction error, or active approach, respectively. Our results suggest that accumbal dopamine and acetylcholine are largely independent but may combine to engage different postsynaptic mechanisms depending on the behavioral task states.

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bioRxiv2024

Prior cocaine use diminishes encoding of latent information by orbitofrontal, but not medial, prefrontal ensembles

Maladaptive decision-making is a hallmark of substance use disorders, though how drugs of abuse alter neural representations supporting adaptive behavior remains poorly understood. Past studies show the orbitofrontal (OFC) and prelimbic (PL) cortices are important for decision making, tracking both task-relevant and latent information. However, previous studies have focused on how drugs of abuse impact the firing rates of individual units. More work at the ensemble level is necessary to accurately characterize potential drug-induced changes. Using single-unit recordings in rats during a multidimensional decision-making task and then applying population and ensemble level analyses, we show that prior use of cocaine altered the strength and structure of task-relevant and latent representations in the OFC, changes relatable to suboptimal decision making in this and perhaps other settings. These data expand our understanding of the neuropathological underpinnings of maladaptive decision-making in SUDs, potentially enabling enhanced future treatment strategies.

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bioRxiv2023

The selective D3-Receptor antagonist VK4-116 effectively treats behavioral inflexibility in rats caused by self-administration and withdrawal from cocaine

Chronic psychostimulant use can cause long lasting changes to neural and cognitive function that persist even after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism, and striatal D2/D3 receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3 receptor (D3R) antagonists and partial agonists, has shown significant promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been focused on treating inflexible and potentially maladaptive non-drug behaviors following chronic psychostimulant use. Here we tested the selective D3R antagonist VK4-116 as a treatment for the long-term behavioral inflexibility in abstinent male and female rats with a prior history of chronic cocaine use. Rats were first trained to self-administer cocaine (0.75 mg/kg/reinforcer) or a sucrose liquid (10%, .04 mL/reinforcer) for 2 weeks (FR1 schedule, max 60 reinforcers in 3 hrs/ day), followed by 4 weeks of abstinence. Cognitive and behavioral flexibilities were then assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given an VK4-116 (15 mg/kg, i.p.) or vehicle 30 mins prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) demonstrated significant evidence of flexible SPC behavior, whereas cocaine use (cocaine-vehicle) disrupted SPC behavior. Remarkably, the D3R antagonist VK4-116 mitigated this cocaine deficit in the cocaine-VK4-116 group, demonstrating flexible SPC to levels comparable to the control groups. These preclinical findings demonstrate that highly selective dopamine D3R antagonists, particularly VK4-116, show significant promise as a pharmacological treatment for the long-term negative behavioral consequences of cocaine use disorder.

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bioRxiv2023

Striatal dopamine release reflects a multi-factorial prediction error

Dopamine is classically thought to drive learning based on errors in the prediction of rewards and punishments 1. However, animals also learn to predict cues with no intrinsic value 2, and it is unclear if such latent learning also relies on dopaminergic prediction errors. Here, we tested this by recording dopamine release in the nucleus accumbens and dorsomedial striatum while rats executed a sensory preconditioning task that incorporates both types of learning 3. We found that dopamine release in both regions correlated with errors in predicting value-neutral cues during latent learning and with errors in predicting reward during reward-based conditioning. Moreover, dopamine in the nucleus accumbens reflected inferred value in the probe test, supported by orbitofrontal cortex activity. Our findings suggest that dopamine signals a domain- general, multi-factorial prediction error, capable of supporting model-based learning.

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bioRxiv2023

Expectancy-related changes in firing of dopamine neurons depend on hippocampus

The orbitofrontal cortex (OFC) and hippocampus (HC) are both implicated in forming the cognitive or task maps that support flexible behavior. Previously, we used the dopamine neurons as a sensor or tool to measure the functional effects of OFC lesions (Takahashi et al., 2011). We recorded midbrain dopamine neurons as rats performed an odor-based choice task, in which errors in the prediction of reward were induced by manipulating the number or timing of the expected rewards across blocks of trials. We found that OFC lesions ipsilateral to the recording electrodes caused prediction errors to be degraded consistent with a loss in the resolution of the task states, particularly under conditions where hidden information was critical to sharpening the predictions. Here we have repeated this experiment, along with computational modeling of the results, in rats with ipsilateral HC lesions. The results show HC also shapes the map of our task, however unlike OFC, which provides information local to the trial, the HC appears to be necessary for estimating the upper-level hidden states based on the information that is discontinuous or separated by longer timescales. The results contrast the respective roles of the OFC and HC in cognitive mapping and add to evidence that the dopamine neurons access a rich information set from distributed regions regarding the predictive structure of the environment, potentially enabling this powerful teaching signal to support complex learning and behavior.

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bioRxiv2023

Schema cell formation in orbitofrontal cortex is suppressed by hippocampal output

Both orbitofrontal cortex (OFC) and hippocampus (HC) are implicated in the formation of cognitive maps and their generalization into schemas. However how these areas interact in supporting this function remains an open question, with some proposals supporting a serial model in which OFC draws upon task representations created by HC to extract key behavioral features and others proposing a parallel model in which both regions construct representations that highlight different types of information. Here we tested between these two models by asking how schema correlates in OFC would be affected by inactivation of HC output, after learning and during transfer across problems. We found the prevalence and content of schema correlates were unaffected by inactivation after learning, while inactivation during learning accelerated their formation. These results contradict a serial model and favor the proposal that OFC and HC operate in parallel to extract different features defining cognitive maps and schemas.

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bioRxiv2022

Rewarding Value or Prediction Error: Settling the debate over the role of dopamine in reward learning

The discovery that DA transients can be mapped onto the reward prediction errors in temporal difference models is a pinnacle achievement of neuroscience. Yet, there is abundant evidence that DA activity reinforces actions, suggesting it serves as an intrinsically rewarding event. These two possibilities are so conceptually intertwined that it is not surprising that they have been so far experimentally conflated. Here, using computational modeling, behavioural blocking and optogenetics, we show that stimulating VTA DA neurons promotes learning even when a natural reward and DA stimulation are held constant across the learning phases of blocking. These findings provide strong evidence in favour of the prediction error hypothesis rather than encoding the rewarding value of appetitive events.

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bioRxiv2022

The role of the orbitofrontal cortex in creating cognitive maps

We use internal models of the external world to guide behavior, but little is known about how these cognitive maps are created. The orbitofrontal cortex (OFC) is typically thought to access these maps to support model-based decision-making, but it has recently been proposed that its critical contribution may be instead to integrate information into existing and new models. We tested between these alternatives using an outcome-specific devaluation task and a high-potency chemogenetic approach. We found that selectively inactivating OFC principal neurons when rats learned distinct cue-outcome associations, but prior to outcome devaluation, disrupted subsequent model-based inference, confirming that the OFC is critical for creating new cognitive maps. However, OFC inactivation surprisingly led to generalized devaluation. Using a novel reinforcement learning framework, we demonstrate that this effect is best explained not by a switch to a model-free system, as would be traditionally assumed, but rather by a circumscribed deficit in defining credit assignment precision during model construction. We conclude that the critical contribution of the OFC to learning is regulating the specificity of associations that comprise cognitive maps. One Sentence SummaryOFC inactivation impairs learning of new specific cue-outcome associations without disrupting model-based learning in general.

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