Barry Setlow

Encoding Predicted Outcome and Acquired Value in Orbitofrontal Cortex during Cue Sampling Depends upon Input from Basolateral Amygdala

Certain goal-directed behaviors depend critically upon interactions between orbitofrontal cortex (OFC) and basolateral amygdala (ABL). Here we describe direct neurophysiological evidence of this cooperative function. We recorded from OFC in intact and ABL-lesioned rats learning odor discrimination problems. As rats learned these problems, we found that lesioned rats exhibited marked changes in the information represented in OFC during odor cue sampling. Lesioned rats had fewer cue-selective neurons in OFC after learning; the cue-selective population in lesioned rats did not include neurons that were also responsive in anticipation of the predicted outcome; and the cue-activated representations that remained in lesioned rats were less associative and more often bound to cue identity. The results provide a neural substrate for representing acquired value and features of the predicted outcome during cue sampling, disruption of which could account for deficits in goal-directed behavior after damage to this system.

Different Roles for Orbitofrontal Cortex and Basolateral Amygdala in a Reinforcer Devaluation Task

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) are critical for using learned representations of outcomes to guide behavior. Neurophysiological findings suggest complementary roles in which the BLA acquires associations between cues and outcomes and the OFC subsequently uses them to guide behavior. Here, we have used a reinforcer devaluation paradigm to test this hypothesis. In this paradigm, rats are first trained to associate a light conditioned stimulus (CS) with a food outcome, and then the food is devalued by pairing it with illness. After this devaluation procedure, responding to the CS is assessed in a single probe session. Previously, we have shown that BLA and OFC lesions made before training do not affect the acquisition of conditioned responding but do impair the sensitivity of that responding to reinforcer devaluation. Rats with such lesions fail to exhibit the spontaneous decrease in conditioned responding to the light cue observed in controls in the probe test. Here, we have extended those findings by showing that performance in the probe test is impaired by OFC lesions made after light-food conditioning but not by BLA lesions made after that training. These findings indicate that the OFC and BLA play different roles in mediating normal goal-directed performance in this, and likely other, settings. The BLA seems critical to forming representations linking cues to the incentive properties of outcomes but not for maintaining these representations in memory, updating them with new information, or for expressing them in behavior. In contrast, the OFC seems essential for one or more of these latter processes.

Neural encoding in ventral striatum during olfactory discrimination learning

A growing body of evidence implicates the ventral striatum in using information acquired through associative learning. The present study examined the activity of ventral striatal neurons in awake, behaving rats during go/no-go odor discrimination learning and reversal. Many neurons fired selectively to odor cues predictive of either appetitive (sucrose) or aversive (quinine) outcomes. Few neurons were selective when first exposed to the odors, but many acquired this differential activity as rats learned the significance of the cues. A substantial proportion of these neurons encoded the cues learned motivational significance, and these neurons tended to reverse their firing selectivity after reversal of odor-outcome contingencies. Other neurons that became selectively activated during learning did not reverse, but instead appeared to encode specific combinations of cues and associated motor responses. The results support a role for ventral striatum in using the learned significance, both appetitive and aversive, of predictive cues to guide behavior.

Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions

Addictive drugs, such as cocaine, cause long‐lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30u2003mg/kg/d, i.p.) or vehicle for 14u2003days and then trained after a 2‐week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine‐treated rats, who demonstrated long‐lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long‐lasting effects on orbitofrontal‐dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine‐induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization.

Disconnection of the basolateral amygdala complex and nucleus accumbens impairs appetitive pavlovian second-order conditioned responses.

There is considerable evidence that the basolateral complex of the amygdala (ABL) is involved in learning about the motivational value of otherwise neutral stimuli. The authors examined the role in this function of the ABL and one of its major efferent structures. the nucleus accumbens. Male Long-Evans rats received either sham, ipsilaterally, or contralaterally placed unilateral lesions of the ABL and accumbens and were trained in an appetitive Pavlovian second-order conditioning task. Sham-lesioned and ipsilaterally lesioned rats acquired the task normally, but contralaterally lesioned rats, in which the ABL and accumbens were functionally disconnected, failed to acquire second-order conditioned responses (although they did acquire second-order conditioned orienting responses). The results suggest that the ABL and accumbens are part of a system critical for processing information about learned motivational value.

Cocaine exposure causes long-term increases in impulsive choice.

In this study, the authors examined the long-term effects of prior exposure to cocaine on a delay-discounting task commonly used to measure impulsive choice. Male Long-Evans rats received daily intraperitoneal injections of 30 mg/kg cocaine HCl or saline for 14 days. Following 3 weeks of withdrawal, rats began training. On each trial, rats were given a choice between 2 levers. A press on 1 lever resulted in immediate delivery of a single 45-mg food pellet, and a press on the other resulted in delivery of 4 pellets after a delay period. Impulsive choice was defined as preference for the small immediate over the large delayed reward. Three months after treatment, cocaine-exposed rats displayed increased impulsive choice behavior. They also showed less anticipatory responding (entries into the food trough) during the delays prior to reward delivery, indicating that the enhanced impulsive choice in these rats may be related to deficits in bridging the delay between response and reward. These data demonstrate that cocaine exposure can cause enduring increases in impulsive choice behavior, consistent with observations in human subjects with drug addictions.

Spatial reference and working memory across the lifespan of male Fischer 344 rats.

Loss of mnemonic function is among the earliest and most disconcerting consequences of the aging process. This study was designed to provide a comprehensive profile of spatial mnemonic abilities in male Fischer 344 (F344) rats across the lifespan. Young, middle-aged, and aged F344 rats were trained in spatial reference and working memory versions of the water maze task. There was a progressive age-related decline in spatial reference memory across the lifespan. Reliable individual differences were observed among aged rats, with some aged rats performing as well as young cohorts and others performing outside this range. An age-related delay-dependent decline was observed on a working memory version of the water maze task although no relationship between performance on reference and working memory tasks was present. Notably, middle-aged rats were impaired relative to young on both tasks. Together these data demonstrate that individual differences in spatial reference memory exist among aged F344 rats and provide novel data demonstrating an unrelated decline in working memory across the lifespan, suggesting that age-related mnemonic dysfunction may occur across multiple brain systems.

The basolateral complex of the amygdala is necessary for acquisition but not expression of CS motivational value in appetitive Pavlovian second-order conditioning

The basolateral complex of the amygdala (ABL) is involved in processing information about stimulus motivational value. However, it is not clear whether the ABL is critical for acquisition, maintenance, or expression of this information. Our previous work has shown that ABL lesions made prior to training, block acquisition of an appetitive Pavlovian second‐order conditioning task, in which performance is thought to depend on the acquisition of motivational (conditioned reinforcement) value by the first‐order conditioned stimulus (CS). The present experiments examined the effects of ABL lesions made after first‐order conditioning, when the CS acquires motivational value, but before second‐order conditioning, the test for acquired value of that CS. Rats received pairings of a visual CS with a food reinforcer. They then received bilateral sham or excitotoxic lesions of the ABL. After recovery, they received pairings of a second‐order auditory CS with the previously conditioned visual CS. In two experiments, both sham and lesioned rats acquired normal second‐order conditioned behaviours. Some of the same rats were then given another round of second‐order conditioning with novel CSs. In this case, when first‐order training occurred after surgery, some second‐order conditioned behaviours were impaired in lesioned rats. Tests of the associative underpinnings of second‐order conditioned behaviours showed that those behaviours impaired by ABL lesions were based on stimulus–response associations. The results show that although the ABL is critical for second‐order conditioning, this role is limited to acquisition of information about the motivational value of the first‐order CS, and it is not critical for maintenance of this information or for its use in forming second‐order associations.

Self-Administered Cocaine Causes Long-Lasting Increases in Impulsive Choice in a Delay Discounting Task

Cocaine use is associated with high levels of impulsive choice (preference for immediate over delayed rewards), but it is not clear whether cocaine use causes elevated impulsive choice, or whether elevated impulsive choice is solely a predisposing factor for cocaine use. This study examined the effects of prior cocaine self-administration on rats performing a delay discounting task commonly used to measure impulsive choice. Male Long-Evans rats were implanted with intravenous catheters, and following recovery, were trained to self-administer 30 mg/kg/day cocaine HCl (approx. 0.5 mg/kg/infusion) for 14 consecutive days (a control group received yoked intravenous saline infusions). Following three weeks of withdrawal, all rats were food-restricted and began training on the delay discounting task in standard operant chambers. On each trial, rats were given a choice between two levers. A press on one lever delivered a small food reward immediately, and a press on the other delivered a large food reward after a variable delay period. Rats that self-administered cocaine displayed greater impulsive choice (enhanced preference for the small immediate over the large delayed reward, as reflected by shorter indifference points) compared to controls, but were no different from controls on a probabilistic discounting task in which they chose between small certain and large uncertain rewards. These data suggest that self-administered cocaine can cause lasting elevations in impulsive choice, and that the high levels of impulsive choice observed in human cocaine users may be due in part to long-term effects of cocaine on brain function.

A systems approach to orbitofrontal cortex function: recordings in rat orbitofrontal cortex reveal interactions with different learning systems.

The recognition that certain aspects of prefrontal function can be effectively modeled in rats has led to a slow expansion of interest in rat prefrontal cortex over the past decade. One of the most promising of these model systems is the orbitofrontal cortex of the rat. Rat orbitofrontal cortex is anatomically similar to the orbital prefrontal region in primates, and this similarity is borne out by behavioral and neurophysiological findings. Here we will present data on orbitofrontal cortex function from a number of parallel studies from our laboratories that employed single unit recording techniques to probe neural encoding in rat orbitofrontal cortex and related parts of the amygdala and the hippocampal memory systems. Together, these reports and associated behavioral studies suggest that the orbitofrontal region, in both rats and primates, is specialized to integrate concrete and abstract sensory constructs with information regarding the incentive value of associated outcomes to guide or modulate behavior. To the extent that monkey prefrontal function can model certain aspects of human prefrontal function, we argue that this model can now be extended to the rat orbitofrontal cortex. In addition, we argue that the function of orbitofrontal cortex needs to be considered in terms of its interactions with other brain systems.