Nucleus accumbens dopamine and learned fear revisited: a review and some new findings (original) (raw)
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Neuroscience Letters, 2008
The involvement of dopamine (DA) mechanisms in the nucleus accumbens (NAC) in fear conditioning has been proposed by many studies that have challenged the view that the NAC is solely involved in the modulation of appetitive processes. However, the role of the core and shell subregions of the NAC in aversive conditioning remains unclear. The present study examined DA release in these NAC subregions using microdialysis during the expression of fear memory. Guide cannulae were implanted in rats in the NAC core and shell. Five days later, the animals received 10 footshocks (0.6 mA, 1 s duration) in a distinctive cage A (same context). On the next day, dialysis probes were inserted through the guide cannulae into the NAC core and shell subregions, and the animals were behaviorally tested for fear behavior either in the same context (cage A) or in a novel context (cage B). Dialysates were collected every 5 min for 90 min and analyzed by high-performance liquid chromatography. The rats exhibited a significant fear response in cage A but not in cage B. Moreover, increased DA levels in both NAC subregions were observed 5-25 min after the beginning of the test when the animals were tested in the same context compared with accumbal DA levels from rats tested in the different context. These findings suggest that DA mechanisms in both the NAC core and shell may play an important role in the expression of contextual fear memory.
PLoS ONE, 2010
The neurotransmitter dopamine (DA) is essential for learning in a Pavlovian fear conditioning paradigm known as fear-potentiated startle (FPS). Mice lacking the ability to synthesize DA fail to learn the association between the conditioned stimulus and the fearinducing footshock. Previously, we demonstrated that restoration of DA synthesis to neurons of the ventral tegmental area (VTA) was sufficient to restore FPS. Here, we used a target-selective viral restoration approach to determine which mesocorticolimbic brain regions receiving DA signaling from the VTA require DA for FPS. We demonstrate that restoration of DA synthesis to both the basolateral amygdala (BLA) and nucleus accumbens (NAc) is required for long-term memory of FPS. These data provide crucial insight into the dopamine-dependent circuitry involved in the formation of fear-related memory.
Behavioral neuroscience, 2014
The prediction-error model of dopamine (DA) signaling has largely been confirmed with various appetitive Pavlovian conditioning procedures and has been supported in tests of Pavlovian extinction. Studies have repeatedly shown, however, that extinction does not erase the original memory of conditioning as the prediction-error model presumes, putting the model at odds with contemporary views that treat extinction as an episode of learning rather than unlearning of conditioning. Here, we combined fast-scan cyclic voltammetry (FSCV) with appetitive Pavlovian conditioning to assess DA release directly during extinction and reinstatement. DA was monitored in the nucleus accumbens core, which plays a key role in reward processing. Following at least 4 daily sessions of 16 tone-food pairings, fast-scan cyclic voltammetry was performed while rats received additional tone-food pairings followed by tone alone presentations (i.e., extinction). Acquisition memory was reinstated with noncontingen...
Learning & Memory, 2010
We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.
Learning from punishment is a powerful means for behavioral adaptation with high relevance for various mechanisms of self-protection. Several studies have explored the contribution of released dopamine (DA) or responses of DA neurons on reward seeking using rewards such as food, water, and sex. Phasic DA signals evoked by rewards or conditioned reward predictors are well documented, as are modulations of these signals by such parameters as reward magnitude, probability, and deviation of actually occurring from expected rewards. Less attention has been paid to DA neuron firing and DA release in response to aversive stimuli, and the prediction and avoidance of punishment. In this review, we first focus on DA changes in response to aversive stimuli as measured by microdialysis and voltammetry followed by the change in electrophysiological signatures by aversive stimuli and fearful events. We subsequently focus on the role of DA and effect of DA manipulations on signaled avoidance learning, which consists of learning the significance of a warning cue through Pavlovian associations and the execution of an instrumental avoidance response. We present a coherent framework utilizing the data on microdialysis, voltammetry, elec-trophysiological recording, electrical brain stimulation, and behavioral analysis. We end by outlining current gaps in the literature and proposing future directions aimed at incorporating technical and conceptual progress to understand the involvement of reward circuit on punishment based decisions.
Real-time dopamine efflux in the nucleus accumbens core during Pavlovian conditioning
Behavioral Neuroscience, 2008
To assess the role of dopamine input to the nucleus accumbens core in anticipatory learning, fastscan cyclic voltammetry was combined with appetitive Pavlovian conditioning. One group of rats (Paired) received 16 tone-food pairings for at least four daily sessions while the control group (Unpaired) received the same number of unpaired tone and food presentations. Both groups showed transient dopamine responses during food presentation throughout training, confirming dopamine involvement in reward processing. Only the Paired Group, however, showed consistently timed dopamine transients during the 10-s tone presentation. Transients first appeared near the end of the tone period as each animal acquired the tone-food association and then occurred progressively sooner on subsequent sessions. Later sessions also revealed a consistently timed dopamine response soon after food delivery in Paired animals. Collectively, these results implicate phasic dopamine release in the acquisition of Pavlovian learning and also suggest an early dopamine response to the unconditioned stimulus as training continues. Keywords dopamine transients; nucleus accumbens core; Pavlovian conditioning; voltammetry Traditionally, dopamine (DA) has been implicated in the unconditional reinforcing effects of food, sex, and drugs (Wise, 1978, 1982). In recent years, however, this view of DA has been challenged (Horvitz, 2000; Ikemoto & Panksepp, 1999; Salamone, Cousins, & Snyder, 1997). Most evidence now suggests that rather than mediate the unconditional effects of reward (e.g., the hedonia hypothesis), DA is involved in anticipation of reward and/or behavioral activation (Ikemoto & Panksepp, 1999) and/or the selection of appropriate action-outcome routines (Redgrave & Gurney, 2006). Evidence for DA involvement in reward anticipation comes primarily from electrophysiological studies. Recording the activity of presumed DA neurons in the ventral tegmental area (VTA), the main source of mesolimbic DA, has revealed that, although these cells are responsive to delivery of the unconditioned stimulus (US) and not the conditioned stimulus (CS) at the outset of learning, they increase firing to the CS and inhibit firing to the US over the course of training (Mirenowicz & Schultz, 1994, 1996). Thus, DA neurons appear to shift their firing to the cue, which presumably enables the anticipation of the US. The temporal convergence of reward prediction with cue presentation is consistent with several temporal difference (TD) models of learning. According to these models, prediction errors are propagated back to the earliest relevant cue or time point (Schultz, Dayan & Montague,
Behavioural Brain Research, 1999
Recent research has suggested that the mesencephalic dopaminergic (DA) system is activated by stress. For example, alterations in DA metabolites have been found in the ventral tegmental area (VTA) following footshock and immobilization in the rat . Furthermore, this activation appears selective to DA neurons within the VTA since no changes were observed within the substantia nigra . While this research suggests that DA neurons in the VTA are activated by aversive events, there has been a paucity of electrophysiological research designed to examine the sensory response characteristics of these DA neurons, and in particular their response to stimuli which predict aversive events. The present study was conducted to investigate the response characteristics of DA neurons within the VTA of the awake rabbit to acoustic stimuli which, via Pavlovian aversive conditioning procedures, came to predict the occurrence of a mild shock to the pinna. 45% of the neurons meeting pre-established criteria for DA neurons demonstrated either significant excitation or inhibition to conditioned aversive stimuli. These neurons responded differentially to CS + and CS − presentations. Some of these neurons (65%) demonstrated a greater increase in activity during the CS+ compared to the CS−, some (22%) demonstrated a greater decrease in activity during the CS + compared to the CS− and some (13%) demonstrated a greater increase in activity during the CS − compared to the CS + . Further, conditioned heart rate responses in the rabbits occurred during the recording of a majority of these neurons. These overall results suggest that conditioned aversive stimuli can affect the firing of VTA DA neurons and that these neurons comprise a heterogenous population with respect to their response profiles.
The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses
European Journal of Neuroscience
The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus-reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value (“incentive salience”) to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of Pavlovian conditioned approach behavior - one in which the cue acquires powerful motivational properties (sign-tracking) and another closely related one in which it does not (goal-tracking). After acquisition of these conditioned responses (CRs), intra-accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign-tracking CR, but not a goal-tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction-like decline in behavior, but maximally impaired expression of a sign-tracking CR on the very first trial, indicating the effect was not due to new learning (i.e., it occurred in the absence of new prediction-error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus-reward associations, but in attributing incentive salience to reward cues, transforming predictive CSs into incentive stimuli with powerful motivational properties.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2019
Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associating conditioned stimuli with aversive events. Hebbian plasticity within these networks requires additional reinforcement to store particularly salient experiences into long-term memory. Here, we have identified a circuit reciprocally connecting the ventral periaqueductal grey (vPAG)/ dorsal raphe (DR) region and the central amygdala (CE) that gates fear learning. We found that vPAG/DR dopaminergic (vPdRD) neurons encode a positive prediction error in response to unpredicted shocks, and may reshape intra-amygdala connectivity via a dopamine-dependent form of long-term potentiation (LTP). Negative feedback from the CE to vPdRD neurons might limit reinforcement to events that have not been predicted. These findings add a new module to the midbrain DA circuit architecture underlying associative reinforcement learning and identify vPdRD neurons as critical component of Pavlovian fear conditioning. We propose that dysregulation of vPdRD neuronal activity may contribute to fear-related psychiatric disorders. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial\_policies/license.html#terms * To whom correspondence should be addressed. Author Contributions: F.G. conceived, designed, performed and analyzed most of the experiments and wrote the manuscript. T.M. and S.M. performed whole-cell patch clamp and LFP recordings for LTP experiments. J.K. and P.P. performed and analyzed Ca 2+ imaging experiments. J.G. performed mouse surgeries. D.K performed anatomical tracings and designed and tested AAVs for optogenetics, DREADDs and GCaMP6m.A.R. designed, performed and analyzed microdialysis experiments. S.B. and K.K. performed and analyzed SCH injections, fear conditioning, acute anxiety assays and pain tests. J. Z. designed RNAi viral vectors and supervised knock down experiments. V.L. co-supervised experiments and wrote the manuscript. W.H. initiated and conceived the project, designed, analyzed and supervised experiments and wrote the manuscript. All authors contributed to the experimental design and interpretation and commented on the manuscript.