Orbitofrontal cortex as a cognitive map of task space.

Orbitofrontal cortex (OFC) has long been known to play an important role in decision making. However, the exact nature of that role has remained elusive. Here, we propose a unifying theory of OFC function. We hypothesize that OFC provides an abstraction of currently available information in the form of a labeling of the current task state, which is used for reinforcement learning (RL) elsewhere in the brain. This function is especially critical when task states include unobservable information, for instance, from working memory. We use this framework to explain classic findings in reversal learning, delayed alternation, extinction, and devaluation as well as more recent findings showing the effect of OFC lesions on the firing of dopaminergic neurons in ventral tegmental area (VTA) in rodents performing an RL task. In addition, we generate a number of testable experimental predictions that can distinguish our theory from other accounts of OFC function.

Integrating orbitofrontal cortex into prefrontal theory: common processing themes across species and subdivisions.

Currently, many theories highlight either representational memory or rule representation as the hallmark of prefrontal function. Neurophysiological findings in the primate dorsolateral prefrontal cortex indicate that both features may characterize prefrontal processing. Neurons in the dorsolateral prefrontal cortex encode information in working memory, and this information is represented when relevant to the rules governing performance in a task. In this review, we discuss recent reports of encoding in primate and rat orbitofrontal regions indicating that these features also characterize activity in the orbitofrontal subdivision of the prefrontal cortex. These data indicate that (1) neural activity in the orbitofrontal cortex links the current incentive value of reinforcers to cues, rather than representing the physical features of cues or associated reinforcers; (2) this incentive-based information is represented in the orbitofrontal cortex when it is relevant to the rules guiding performance in a task; and (3) incentive information is also represented in the orbitofrontal cortex in working memory during delays when neither the cues nor reinforcers are present. Therefore, although the orbitofrontal cortex appears to be uniquely specialized to process incentive or motivational information, it may be integrated into a more global framework of prefrontal function characterized by representational encoding of performance-relevant information.

A novel method for detecting licking behavior during recording of electrophysiological signals from the brain.

We have developed a novel method for detecting licking at a fluid well that is compatible with behavioral neurophysiology. This method uses off-the-shelf fiber optic technology to introduce a light beam through the fluid-air interface of a fluid bolus in a well. A self-adjusting optical sensor detects licking as disturbances in the amplified light surface within the interface when the fluid is disturbed. The proper configuration of fluid well and fiber optics will reliably detect licking and introduce no artifacts into simultaneous high-impedance recordings of extracellular neural activity. This method is also compatible with delivery of multiple fluids to the same well. Unlike present methods of detecting licking in neurophysiological experiments, our approach does not involve the passage of current or capacitance changes in which the animal forms part of a circuit, nor does it require movement of the licking apparatus or any other response beyond the actual licking of the fluid. As a result, noise artifacts in the unit recordings do not occur, and the sensor is highly resistant to artifacts caused by exploration or licking at the fluid well in the absence of liquid. We present neural recording data from units in the nucleus accumbens demonstrating these properties of the lick detector.

Changes in functional connectivity in orbitofrontal cortex and basolateral amygdala during learning and reversal training.

Interconnections between orbitofrontal cortex (OFC) and basolateral amygdala (ABL) are critical for encoding and using associative information about the motivational significance of stimuli. Previously, we reported that neurons in OFC and ABL fired selectively to cues during odor discrimination learning and reversal training. Here we conducted an analysis of correlated firing in the cell pairs recorded in the previous study. Correlated firing during the intertrial intervals was compared across task phases during different phases of acquisition and reversal learning. Changes in correlated activity during initial learning and subsequent accurate performance on the discrimination problems closely resembled the changes in odor selectivity in OFC and ABL reported earlier. Increased correlated firing was most pronounced in OFC during accurate go, no-go performance in the postcriterion phase of performance, whereas correlated firing in ABL increased primarily during an earlier phase of learning. In contrast, findings during subsequent reversal training diverged from our earlier report in which odor selectivity diminished in OFC and reversed in ABL. When the reinforcement contingencies of the odors were reversed after the rat had learned the original associations, correlated firing further increased significantly in OFC but remained stable in ABL. This evidence that associative encoding increments with reversal learning in OFC suggests that the original associations, although not expressed as stimulus driven activity, may be maintained within the network as new associations are acquired.

Functions of the amygdala and related forebrain areas in attention and cognition.

This paper will concentrate on two features of the systems described by Alheid and Heimer that have influenced research in our laboratory in recent years. In the first part, we describe our findings on a representational function of the amygdaloid basolateral complex that appears to depend on its interconnections with the prefrontal cortex. In the second part, we describe progress assessing the function of magnocellular corticopetal neurons within the basal forebrain and the strong input to this system from the central amygdaloid group. These lines of behavioral research have revealed that sub-systems in the basal forebrain and amygdala serve adaptive functions beyond the domains of motivation and emotion to include attention and cognition.

Orbitofrontal cortex and representation of incentive value in associative learning.

Clinical evidence indicates that damage to ventromedial prefrontal cortex disrupts goal-directed actions that are guided by motivational and emotional factors. As a consequence, patients with such damage characteristically engage in maladaptive behaviors. Other research has shown that neurons in the corresponding orbital region of prefrontal cortex in laboratory animals encode information regarding the incentive properties of goals or expected events. The present study investigates the effect of neurotoxic orbitofrontal cortex (OFC) lesions in the rat on responses that are normally influenced by associations between a conditioned stimulus (CS) and the incentive value of reinforcement. Rats were first trained to associate a visual CS with delivery of food pellets to a food cup. As a consequence of learning, rats approached the food cup during the CS in anticipation of reinforcement. In a second training phase, injection of LiCl followed consumption of the food unconditioned stimulus (US) in the home cage, a procedure used to alter the incentive value of the US. Subsequently, rats were returned to the conditioning chamber, and their responding to the CS in the absence of the food US was tested. Lesions of OFC did not affect either the initial acquisition of a conditioned response to the light CS in the first training phase or taste aversion learning in the second training phase. In the test for devaluation, however, OFC rats exhibited no change in conditioned responding to the visual CS. This outcome contrasts with the behavior of control rats; after devaluation of the US a significant decrease occurred in approach to the food cup during presentation of the CS. The results reveal an inability of a cue to access representational information about the incentive value of associated reinforcement after OFC damage.

Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning.

Orbitofrontal cortex (OFC) is part of a network of structures involved in adaptive behavior and decision making. Interconnections between OFC and basolateral amygdala (ABL) may be critical for encoding the motivational significance of stimuli used to guide behavior. Indeed, much research indicates that neurons in OFC and ABL fire selectively to cues based on their associative significance. In the current study recordings were made in each region within a behavioral paradigm that allowed comparison of the development of associative encoding over the course of learning. In each recording session, rats were presented with novel odors that were informative about the outcome of making a response and had to learn to withhold a response after sampling an odor that signaled a negative outcome. In some cases, reversal training was performed in the same session as the initial learning. Ninety-six of the 328 neurons recorded in OFC and 60 of the 229 neurons recorded in ABL exhibited selective activity during evaluation of the odor cues after learning had occurred. A substantial proportion of those neurons in ABL developed selective activity very early in training, and many reversed selectivity rapidly after reversal. In contrast, those neurons in OFC rarely exhibited selective activity during odor evaluation before the rats reached the criterion for learning, and far fewer reversed selectivity after reversal. The findings support a model in which ABL encodes the motivational significance of cues and OFC uses this information in the selection and execution of an appropriate behavioral strategy.

Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning.

Reciprocal connections between the orbitofrontal cortex and the basolateral nucleus of the amygdala may provide a critical circuit for the learning that underlies goal-directed behavior. We examined neural activity in rat orbitofrontal cortex and basolateral amygdala during instrumental learning in an olfactory discrimination task. Neurons in both regions fired selectively during the anticipation of rewarding or aversive outcomes. This selective activity emerged early in training, before the rats had learned reliably to avoid the aversive outcome. The results support the concept that the basolateral amygdala and orbitofrontal cortex cooperate to encode information that may be used to guide goal-directed behavior.

Functional organization of the hippocampal memory system.

In humans declarative or explicit memory is supported by the hippocampus and related structures of the medial temporal lobe working in concert with the cerebral cortex. This paper reviews our progress in developing an animal model for studies of cortical-hippocampal interactions in memory processing. Our findings support the view that the cortex maintains various forms of memory representation and that hippocampal structures extend the persistence and mediate the organization of these codings. Specifically, the parahippocampal region, through direct and reciprocal interconnections with the cortex, is sufficient to support the convergence and extended persistence of cortical codings. The hippocampus itself is critical to the organization cortical representations in terms of relationships among items in memory and in the flexible memory expression that is the hallmark of declarative memory.

Information coding in the rodent prefrontal cortex. I. Single-neuron activity in orbitofrontal cortex compared with that in pyriform cortex.

1. Extracellular spike activity was recorded from 1,942 single neurons in orbitofrontal cortex (OF) and 591 single neurons in pyriform cortex (PIR) over multiple sessions in rats performing an eight-odor discrimination task in which the stimulus sequence contained predictable associations between particular odor pairs. Neural firing patterns were examined in relation to task events in the current trial and variables associated with current sensory processing, events of recent past trials, and long-term associations involving the odor cues. 2. Overall, 34% of single neurons in OF and 30% of single neurons in PIR fired selectively during one or more salient trial events including trial initiation, odor sampling, performance of the discriminative response, and water consumption. The activity of other cells recorded in OF (13%) and PIR (10%) was suppressed for the duration of each trial. Although the proportion of some cell types differed between the two areas, the firing patterns of OF and PIR neurons were qualitatively indistinguishable. 3. Firing during odor sampling and the discriminative response was influenced by the identity of the current odor. Some cells fired selectively to a single odor, but most cells were coarsely tuned such that they fired to several of the eight odors to differing degrees consistent with previous reports. Considerable odor coding was observed in both OF and PIR. 4. Firing during trial initiation and odor sampling was also influenced by the identity and reward association of the odor presented in the immediately preceding trial. The influence of past odor identity and valence was observed in both OF and PIR. 5. Firing during trial events was also influenced by the acquired associations between odors and their assigned reward contingencies and between pairs of odors involved in predictive relationships. The reward valence of the current odor significantly influenced firing during odor sampling and the discriminative response; some cells responded preferentially to rewarded odors and others to nonrewarded odors. Firing during trial initiation and odor sampling reflected whether or not the odor in the current trial had been predicted by the odor in the preceding trial. In addition, firing during odor sampling reflected the expectation of reward in the following trial that could be inferred from the predictable associations between odors. Each of these properties was observed in both OF and PIR. 6. The findings in OF were consistent with the view that prefrontal subdivisions mediate the temporal organization of complex behaviors within specific informational domains. OF appears to be concerned with the specific domain of olfaction.(ABSTRACT TRUNCATED AT 400 WORDS)

Information coding in the rodent prefrontal cortex. II. Ensemble activity in orbitofrontal cortex.

1. Neural activity was recorded from the orbitofrontal cortex (OF) of rats performing an eight-odor discrimination task that included predictable associations between particular odor pairs. A modified linear discriminant analysis was employed to characterize the population response in each trial of the task as a point in an N-dimensional activity space with the firing rate of each cell in the population represented on one of the N dimensions. The ability of the ensemble to discriminate among conditions of a variable was reflected in the tendency of population responses to cluster together in this activity space for repetitions of a given condition. We assessed coding of several variables describing the period of odor sampling, focusing on aspects of current, past, and future events reflected in single-neuron firing patterns, in ensembles composed of 22-138 cells active during the period when the rats sampled the discriminative stimulus in each trial. 2. OF ensembles performed well at discriminating variables with relevance to task demands represented in single-neuron firing patterns, specifically the physical attributes and assigned reward contingency of the current odor as well as the expectation of reward in the following trial that could be inferred from the predictable associations between particular pairs of odors. OF ensembles were able to correctly identify the identity and assigned reward contingency of the current odor in up to 52% (chance = 12.5%) and 99% (chance = 50%) of all trials, respectively, such that the observed behavioral performance required a population of 5,364 odor-responsive cells in the case of odor identity and only 40 cells in the case of valence. Expectations regarding upcoming rewards based on both assigned response contingency and associations between particular pairs of odors were correctly classified in up to 67% (chance = 20%) of all trials such that the observed level of behavioral performance required a population of 3,169 cells. 3. Other information represented in the single-neuron firing patterns, such as the identity and reward contingency of the preceding odor and specific odor-odor associations, was poorly encoded by OF ensembles. Thus neural ensembles in OF may represent only some of the information reflected in single-neuron activity. Stable coding of only the most useful and relevant information by the ensemble might emerge from the tuning properties of single neurons under the influence of the task at hand, producing in the well-trained animal the observed pattern of broad and diverse coding by single neurons and selective, task-relevant coding by neural ensembles in OF.

A novel delta opioid agonist, BW373U86, in squirrel monkeys responding under a schedule of shock titration.

The squirrel monkey titration procedure was used to assess the antinociceptive effects of the novel delta opioid agonist (+/-)-4-(a-R*)-a(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxyb enzyl)- N,N-diethylbenzamide (BW373U86). Under this procedure shock increased every 15 sec from 0.01 to 2.0 mA in 30 steps. Five responses terminated the shock for 15 sec, after which the shock resumed at a lower intensity. The intensity at which the monkeys maintained the shock 50% of the time (median shock level, MSL) was determined. BW373U86 (1.0-30.0 mg/kg i.m.) increased MSL, but these increases were not dose-dependent and lasted only 15 min or less. Doses of BW373U86 that increased MSL often produced tremors and/or convulsions immediately after administration. When 1.0 mg/kg of naltrindole, a delta opioid antagonist, was given in combination with BW373U86, doses of BW373U86 up to 30 mg/kg no longer increased MSL nor did tremors and/or convulsions occur. Doses of BW373U86 (0.01-0.3 mg/kg i.m.) that did not increase MSL when administered alone shifted the dose-effect curve for the mu agonist l-methadone to the left. These shifts were antagonized dose-dependently by naltrindole. In monkeys that were tolerant to morphine, BW373U86 (0.03-0.1 mg/kg i.m.) shifted the morphine dose-effect curve leftward. In addition, BW373U86 altered the effects of the partial opioid agonists, buprenorphine, nalbuphine, butorphanol and levallorphan such that doses of these drugs that did not increase MSL when administered alone, often did so in the presence of BW373U86. Taken together, these findings indicate that BW373U86 has a delta agonist profile in the squirrel monkey; however, its antinociceptive effects in the shock titration procedure may be due to its toxic effects.

Discontinuation of sustained sucrose-feeding aggravates morphine withdrawal.

Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet to investigate the relationship between the prolonged consumption of a high carbohydrate diet and opioid function as evidenced by opioid dependence and withdrawal. Morphine dependence, assayed by tailflick, was induced, followed by naloxone-precipitated withdrawal, gauged by weight loss. Sucrose-fed animals developed lowered pain thresholds prior to dependence induction relative to those of control animals, but failed to exhibit any differences from controls in the development of dependence. Weight loss during withdrawal was increased by the discontinuation of sustained sucrose-feeding. In addition, the induction of dependence first decreased, then increased the animals' preference for sucrose. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia, but do aggravate the symptoms of precipitated withdrawal when access to sucrose is denied prior to the injection of naloxone.

Relationships between sustained sucrose-feeding and opioid tolerance and withdrawal.

This study examines the effect of sustained sucrose consumption on the development of tolerance to morphine analgesia (20 mg/kg IP injections) and subsequent, naloxone-precipitated withdrawal (2 mg/kg IP). Food intakes are also measured. Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet. Pain thresholds and intakes were monitored for two weeks, then morphine tolerance was induced, followed by precipitated withdrawal. Tolerance was assayed by the tailflick method, and withdrawal was gauged by weight loss. The animals given access to sucrose developed lowered pain thresholds prior to tolerance induction relative to those of control animals, but they failed to exhibit any differences from controls in tolerance development of severity of withdrawal. The induction of tolerance first decreased, then increased sucrose consumption and steadily decreased chow consumption. Naloxone-precipitated withdrawal decreased chow consumption, but failed to affect the ingestion of the sucrose solution. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia; however, tolerance induction biphasically alters sucrose consumption.