Biology subjects

Costa, K. M.

Publications and source records attributed to Costa, K. M..

9 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

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

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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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

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

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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bioRxiv2019

In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

The functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and synaptic connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and juxtacellular labelling in mouse brain to create the first single cell-resolved in vivo functional topography of the midbrain DA system. We identified surprising differences in burst firing among those DA neurons projecting to dorsolateral striatum, which were organized along the medio-lateral substantia nigra (SN) axis. Furthermore, burst properties also differentiated DA neurons in the medial SN that projected either to dorsal or ventral striatum. In contrast, DA neurons projecting to lateral shell of nucleus accumbens displayed identical firing properties, irrespective of whether they were located in the SN or ventral tegmental area (VTA), thus breaching classical anatomical boundaries. Finally, we found robust differences in mean firing rates and pause durations among VTA DA neurons projecting to either lateral or medial shell of nucleus accumbens. Together, our data set establishes a high-resolution functional landscape of midbrain DA neurons, which will facilitate the identification of selective functions and pathophysiological changes within the midbrain DA system.

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bioRxiv2018

Deletion of the alternative splice variant KChIP4a in midbrain dopamine neurons selectively enhances extinction learning

Midbrain dopamine neurons are essential for flexible control of adaptive behaviors. DA neurons that project to different target regions have unique biophysical properties, and it is thought that this diversity reflects functional specialization. This assumption implies the presence of specific genetic determinants with precise impacts on behavior. We tested this general hypothesis by homing in on one particular biophysical mechanism, Kv4 channel inactivation, using a combination of molecular, proteomic, electrophysiological, computational, and behavioral approaches. We demonstrate that KChIP4a, a singular Kv4 {beta}-subunit splice variant, prolongs hyperpolarization-rebound delays selectively in dopamine neurons projecting to the nucleus accumbens core, shifts the integration of inhibitory inputs and, in turn, selectively regulates learning from negative prediction-errors. Our results reveal a highly specialized, gene-to-behavior mechanistic chain that is only operative in a particular dopaminergic subsystem, illuminating how molecularly defined biophysical switches are employed for neuron subtype-specific information processing in the brain. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/344499v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@167984borg.highwire.dtl.DTLVardef@3f8fbborg.highwire.dtl.DTLVardef@f5402aorg.highwire.dtl.DTLVardef@147bb3b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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