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September 2015 - October 2015
Publications
Publications (71)
Cannabinoid receptor-1 (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual-, sex-, and experience-dependent differences in pavlovian behaviors, we predicted a role for dorsomedial striatum (DMS) CB1R signaling in driving rigid...
Cannabinoid-1 receptor (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual, sex, and experience-dependent differences in Pavlovian behaviors, we predicted a role for dorsomedial striatum CB1R signaling in driving sign-tracking...
Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dop...
Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluoresc...
Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate- rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; e...
Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based, instrumental tasks parallel those engaged by Pavlovian based behavioral procedures. Recently, co...
Rationale
Discriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign-tracking (ST) and goal-tracking (GT) differences in Pavlovian approach predict distinct cue-modulated vulnerabilities to cocaine...
Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate-rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; en...
Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluoresc...
Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based, instrumental tasks parallel those engaged by Pavlovian based behavioral procedures. Recently, co...
Goal-tracking rats are sensitive to Pavlovian outcome devaluation while sign-tracking rats are devaluation insensitive. During outcome devaluation, goal-tracking (GT) rats flexibly modify responding to cues based on the current value of the associated outcome. However, sign-tracking (ST) rats rigidly respond to cues regardless of the current outcom...
Rationale
Discriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign tracking (ST) and goal tracking (GT) individual differences in Pavlovian approach to food cues predict distinct vulnerabilities...
[This corrects the article DOI: 10.3389/fnbeh.2020.00153.].
To survive in a complex environment, individuals form associations between environmental stimuli and rewards to organize and optimize reward seeking behaviors. The basolateral amygdala (BLA) uses these learned associations to inform decision-making processes. In this review, we describe functional projections between BLA and its cortical and striat...
Rats rely on communication between the basolateral amygdala (BLA) and nucleus accumbens (NAc) to express lever directed approach in a Pavlovian lever autoshaping (PLA) task that distinguishes sign- and goal-tracking rats. During PLA, sign-tracking rats preferentially approach an insertable lever cue, while goal-tracking rats approach a foodcup wher...
The time-dependent increase in cue-triggered opioid seeking, termed “incubation of opioid craving,” is modeled in rodents by examining responding for opioid-associated cues after a period of forced abstinence. With opioid drugs, withdrawal symptoms may heighten cue reactivity by recruiting brain systems involved in both reward seeking and stress re...
Rats rely on communication between basolateral amygdala (BLA) and nucleus accumbens (NAc) to express lever directed approach in a Pavlovian lever autoshaping (PLA) task that distinguishes sign- and goal-tracking rats. Sign-tracking rats inflexibly respond to cues even after the associated outcome is devalued, whereas goal-tracking rats adaptively s...
The relative value of and motivation for abused drugs often increases with drug experience and differs based on drug availability. Here, we determined how different intake patterns of fentanyl, a μ‐opioid agonist, alter economic demand for fentanyl and how 5‐HT2A receptor stimulation affects economic demand for fentanyl. We used a within‐session de...
Individual differences in Pavlovian approach predict differences in devaluation sensitivity. Recent studies indicate goal-tracking (GT) rats are sensitive to outcome devaluation while sign-tracking (ST) rats are not. With extended training in Pavlovian lever autoshaping (PLA), GT rats display more lever-directed behavior, typical of ST rats, sugges...
Outbred rats display variable preferences for bittersweet solutions, expressed as preference or avoidance of high concentrations of artificial sweeteners over water. This may reflect individual differences in appetitive/aversive conflict processing that may have predictive validity for disorders of motivation. Here we use a homecage two-bottle choi...
Rationale
Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking.
Objectives
Here, we determine whether systemic injectio...
Recent computational models of sign tracking (ST) and goal tracking (GT) have accounted for observations that dopamine (DA) is not necessary for all forms of learning and have provided a set of predictions to further their validity. Among these, a central prediction is that manipulating the intertrial interval (ITI) during autoshaping should change...
Development of sign tracking and DA signals over training averaged across rats.
(A-B) Average beam break (solid) and lever press (dashed) rate for 120-s (A) and 60-s (B) ITI groups. (C-D) Average lever press rate for 120-s (C) and 60-s (D) ITI groups. Data are the same as in A and B but with a smaller scale so that differences and timing can be bet...
Underlying data for S3 Fig.
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Underlying data for S4 Fig.
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Task and electrode placement.
(A) DA release was recorded during a standard Pavlovian conditioned approach behavior task for 10 d. Each behavioral session consisted of 25 trials presented at a random time interval of either 60 s (± 30; n = 7 rats) or 120 s (± 30; n = 12 rats). (B-C) Placement of chronic recording electrodes within the NAc core [39]...
Underlying data for Fig 2.
(XLSX)
Underlying data for Fig 3.
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Underlying data for S2 Fig.
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Sign tracking is more prominent in rats that performed sessions with 120-s ITIs.
(A) Average beam break (solid) and lever press (dashed) rate for 120-s (red) and 60-s (blue) ITI groups. (B) Average lever press rate for 120-s (red) and 60-s (blue) ITI groups. Data are the same as in “A” but with a smaller scale so that differences and timing can be...
Food cup entries and lever pressing over time for each training session.
Lever pressing (B,D) and food cup entries (A,C) over the trial time for each of the 10 sessions for 120-s ITI (A,B) and 60-s ITI (C,D) sessions. For the 120-s ITI group, lever pressing was high during the first session and already near maximum levels for that group by the seco...
Underlying data for Fig 1.
(XLSX)
Previously established individual differences in appetitive approach and devaluation sensitivity observed in goal- and sign-trackers may be attributed to differences in the acquisition, modification, or use of associative information in BLA pathways. Here, we sought to determine the extent to which communication of associative information between B...
Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto’s (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. Thi...
Sign-tracking rats show heightened sensitivity to food- and drug-associated cues, which serve as strong incentives for driving reward seeking. We hypothesized that this enhanced incentive drive is accompanied by an inflexibility when incentive value changes. To examine this we tested rats in Pavlovian outcome devaluation or second-order conditionin...
Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability fa...
Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seek...
Background
Relapse to unhealthy eating habits is a major problem in human dietary treatment. The individuals most commonly seeking dietary treatment are overweight or obese women, yet the commonly used rat reinstatement model to study relapse to palatable food seeking during dieting primarily uses normal-weight male rats. To increase the clinical r...
A study finds that the loss of phasic dopamine signal in ventral, but not dorsal, striatum predicts escalation of cocaine self-administration. We discuss the study's implications for addiction theory and treatment.
Background and rationale:
Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reins...
Relapse to maladaptive eating habits during dieting is often provoked by stress. Recently, we identified a role of dorsal medial prefrontal cortex (mPFC) neurons in stress-induced reinstatement of palatable food seeking in male rats. It is unknown whether endogenous neural activity in dorsal mPFC drives stress-induced reinstatement in female rats....
Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which...
Relapse to old unhealthy eating habits while dieting is often provoked by stress or acute exposure to palatable foods. We adapted a rat reinstatement model, which is used to study drug relapse, to study mechanisms of relapse to palatable food seeking induced by food-pellet priming (non-contingent exposure to a small amount of food pellets) or injec...
The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, c...
In 1985, [Dackis and Gold (1985)][1] suggested that cocaine addiction stems from the depletion of synaptic dopamine in the mesolimbic dopamine reward system, leading to a dysphoric withdrawal state that drives cocaine seeking to restore dopamine to normal, drug-naive levels. They further speculated
Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which...
Attention or variations in event processing help drive learning. Lesion studies have implicated the central nucleus of the amygdala (CeA) in this process, particularly when expected rewards are omitted. However, lesion studies cannot specify how information processing in CeA supports such learning. To address these questions, we recorded CeA neuron...
Initially reported in dopamine neurons, neural correlates of prediction errors have now been shown in a variety of areas, including orbitofrontal cortex, ventral striatum, and amygdala. Yet changes in neural activity to an outcome or cues that precede it can reflect other processes. We review the recent literature and show that although activity in...
The discovery that dopamine neurons signal errors in reward prediction has demonstrated that concepts empirically derived from the study of animal behavior can be used to understand the neural implementation of reward learning. Yet the learning theory models linked to phasic dopamine activity treat attention to events such as cues and rewards as st...
The amygdala is critical for associating predictive cues with primary rewarding and aversive outcomes. This is particularly evident in tasks in which information about expected outcomes is required for normal responding. Here we used a pavlovian overexpectation task to test whether outcome signaling by amygdala might also be necessary for changing...
Humans and other animals change their behavior in response to unexpected outcomes. The orbitofrontal cortex (OFC) is implicated in such adaptive responding, based on evidence from reversal tasks. Yet these tasks confound using information about expected outcomes with learning when those expectations are violated. OFC is critical for the former func...
Aversive states are proposed to drive addiction. Here, Wheeler and colleagues show that drug-associated cues come to activate neural representations of aversive information in nucleus accumbens and that this activation predicts subsequent drug use. These remarkable data identify a potential neural substrate through which aversive affective represen...
The dopamine system is thought to be involved in making decisions about reward. Here we recorded from the ventral tegmental area in rats learning to choose between differently delayed and sized rewards. As expected, the activity of many putative dopamine neurons reflected reward prediction errors, changing when the value of the reward increased or...
Addiction is characterized by compulsive or inflexible behavior, observed both in the context of drug-seeking and in contexts unrelated to drugs. One possible contributor to these inflexible behaviors may be drug-induced dysfunction within circuits that support behavioral flexibility, including the basolateral amygdala (ABL) and the orbitofrontal c...
Addicts and drug-experienced animals have decision-making deficits in reversal-learning tasks and more complex 'gambling' variants. Here we show evidence that these deficits are mediated by persistent encoding of outdated associative information in the basolateral amygdala. Cue-selective neurons in the basolateral amygdala, recorded in cocaine-trea...
Recent proposals have conceptualized piriform cortex as an association cortex, capable of integrating incoming olfactory information with descending input from higher order associative regions such as orbitofrontal cortex and basolateral amygdala (ABL). If true, encoding in piriform cortex should reflect associative features prominent in these area...
Drug addicts make poor decisions. These decision-making deficits have been modeled in addicts and laboratory animals using reversal-learning tasks. However, persistent reversal-learning impairments have been shown in rats and monkeys only after noncontingent cocaine injections. Current thinking holds that to represent the human condition effectivel...
Animals prefer a small, immediate reward over a larger delayed reward (time discounting). Lesions of the orbitofrontal cortex (OFC) can either increase or decrease the breakpoint at which animals abandon the large delayed reward for the more immediate reward as the delay becomes longer. Here we argue that the varied effects of OFC lesions on delaye...
