Theta oscillations in anterior cingulate cortex and orbitofrontal cortex differentially modulate accuracy and speed in flexible reward learning.

Flexible reward learning relies on frontal cortex, with substantial evidence indicating that anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) subregions play important roles. Recent studies in both rat and macaque suggest theta oscillations (5-10 Hz) may be a spectral signature that coordinates this learning. However, network-level interactions between ACC and OFC in flexible learning remain unclear. We investigated the learning of stimulus-reward associations using a combination of simultaneous in vivo electrophysiology in dorsal ACC and ventral OFC, partnered with bilateral inhibitory DREADDs in ACC. In freely behaving male and female rats and using a within-subject design, we examined accuracy and speed of response across distinct and precisely defined trial epochs during initial visual discrimination learning and subsequent reversal of stimulus-reward contingencies. Following ACC inhibition, there was a propensity for random responding in early reversal learning, with correct vs. incorrect trials distinguished only from OFC, not ACC, theta power differences in the reversal phase. ACC inhibition also hastened incorrect choices during reversal. This same pattern of change in accuracy and speed was not observed in viral control animals. Thus, characteristics of impaired reversal learning following ACC inhibition are poor deliberation and weak theta signaling of accuracy in this region. The present results also point to OFC theta oscillations as a prominent feature of reversal learning, unperturbed by ACC inhibition.

Sex differences in patch-leaving foraging decisions in rats.

The ubiquity, importance, and sophistication of foraging behavior makes it an ideal platform for studying naturalistic decision making in animals. We developed a spatial patch-foraging task for rats, in which subjects chose how long to remain in one foraging patch as the rate of food earnings steadily decreased. The cost of seeking out a new location was varied across sessions. The behavioral task was designed to mimic the structure of natural foraging problems, where distinct spatial locations are associated with different reward statistics, and decisions require navigation and movement through space. Male and female Long-Evans rats generally followed the predictions of theoretical models of foraging, albeit with a consistent tendency to persist with patches for too long compared to behavioral strategies that maximize food intake rate. The tendency to choose overly-long patch residence times was stronger in male rats. We also observed sex differences in locomotion as rats performed the task, but these differences in movement only partially accounted for the differences in patch residence durations observed between male and female rats. Together, these results suggest a nuanced relationship between movement, sex, and foraging decisions.

Sex differences in patch-leaving foraging decisions in rats.

The ubiquity, importance, and sophistication of foraging behavior makes it an ideal platform for studying naturalistic decision making in animals. We developed a spatial patch-foraging task for rats, in which subjects chose how long to remain in one foraging patch as the rate of food earnings steadily decreased. The cost of seeking out a new location was varied across sessions. The behavioral task was designed to mimic the structure of natural foraging problems, where distinct spatial locations are associated with different reward statistics, and decisions require navigation and movement through space. Male and female Long-Evans rats generally followed the predictions of theoretical models of foraging, albeit with a consistent tendency to persist with patches for too long compared to behavioral strategies that maximize food intake rate. The tendency to choose overly-long patch residence times was stronger in male rats. We also observed sex differences in locomotion as rats performed the task, but these differences in movement only partially accounted for the differences in patch residence durations observed between male and female rats. Together, these results suggest a nuanced relationship between movement, sex, and foraging decisions.

Quitting while you're ahead: Patch foraging and temporal cognition.

Theoretical models of foraging are based on the maximization of food intake rate. Remarkably, foragers often hew close to the predictions of rate maximization, except for a frequently observed bias to remain in patches for too long. By sticking with depleting options beyond the optimal patch residence time-a phenomenon referred to as overharvesting or overstaying-foragers miss out on food they could have earned had they sought a new option elsewhere. Here, we review potential causes of overstaying and consider the role that temporal cognition might play in this phenomenon. We first consider how an explicit, internal sense of time might inform foraging behaviors, and next examine patch-leaving choices from the perspective of intertemporal decision-making. Finally, we identify promising areas for future research that will provide a better understanding of how foraging decisions are made, and what factors drive the tendency to overharvest patches. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Spatial Representations in Rat Orbitofrontal Cortex.

The orbitofrontal cortex (OFC) and hippocampus share striking cognitive and functional similarities. As a result, both structures have been proposed to encode "cognitive maps" that provide useful scaffolds for planning complex behaviors. However, while this function has been exemplified by spatial coding in neurons of hippocampal regions-particularly place and grid cells-spatial representations in the OFC have been investigated far less. Here we sought to address this by recording OFC neurons from male rats engaged in an open-field foraging task like that originally developed to characterize place fields in rodent hippocampal neurons. Single-unit activity was recorded as rats searched for food pellets scattered randomly throughout a large enclosure. In some sessions, particular flavors of food occurred more frequently in particular parts of the enclosure; in others, only a single flavor was used. OFC neurons showed spatially localized firing fields in both conditions, and representations changed between flavored and unflavored foraging periods in a manner reminiscent of remapping in the hippocampus. Compared with hippocampal recordings taken under similar behavioral conditions, OFC spatial representations were less temporally reliable, and there was no significant evidence of grid tuning in OFC neurons. These data confirm that OFC neurons show spatial firing fields in a large, two-dimensional environment in a manner similar to hippocampus. Consistent with the focus of the OFC on biological meaning and goals, spatial coding was weaker than in hippocampus and influenced by outcome identity.SIGNIFICANCE STATEMENT The orbitofrontal cortex (OFC) and hippocampus have both been proposed to encode "cognitive maps" that provide useful scaffolds for planning complex behaviors. This function is exemplified by place and grid cells identified in hippocampus, the activity of which maps spatial environments. The current study directly demonstrates very similar, though not identical, spatial representatives in OFC neurons, confirming that OFC-like hippocampus-can represent a spatial map under the appropriate experimental conditions.

A bidirectional corticoamygdala circuit for the encoding and retrieval of detailed reward memories.

Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the rewards they predict. Here, we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and the outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition we performed a serial circuit disconnection and found that the lOFC→BLA and BLA→lOFC pathways form a functional circuit regulating the encoding (lOFC→BLA) and subsequent use (BLA→lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.

Prior Cocaine Use Alters the Normal Evolution of Information Coding in Striatal Ensembles during Value-Guided Decision-Making.

Substance use disorders (SUDs) are characterized by maladaptive behavior. The ability to properly adjust behavior according to changes in environmental contingencies necessitates the interlacing of existing memories with updated information. This can be achieved by assigning learning in different contexts to compartmentalized "states." Though not often framed this way, the maladaptive behavior observed in individuals with SUDs may result from a failure to properly encode states because of drug-induced neural alterations. Previous studies found that the dorsomedial striatum (DMS) is important for behavioral flexibility and state encoding, suggesting the DMS may be an important substrate for these effects. Here, we recorded DMS neural activity in cocaine-experienced male rats during a decision-making task where blocks of trials represented distinct states to probe whether the encoding of state and state-related information is affected by prior drug exposure. We found that DMS medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) encoded such information and that prior cocaine experience disrupted the evolution of representations both within trials and across recording sessions. Specifically, DMS MSNs and FSIs from cocaine-experienced rats demonstrated higher classification accuracy of trial-specific rules, defined by response direction and value, compared with those drawn from sucrose-experienced rats, and these overly strengthened trial-type representations were related to slower switching behavior and reaction times. These data show that prior cocaine experience paradoxically increases the encoding of state-specific information and rules in the DMS and suggest a model in which abnormally specific and persistent representation of rules throughout trials in DMS slows value-based decision-making in well trained subjects.SIGNIFICANCE STATEMENT Substance use disorders (SUDs) may result from a failure to properly encode rules guiding situationally appropriate behavior. The dorsomedial striatum (DMS) is thought to be important for such behavioral flexibility and encoding that defines the situation or "state." This suggests that the DMS may be an important substrate for the maladaptive behavior observed in SUDs. In the current study, we show that prior cocaine experience results in over-encoding of state-specific information and rules in the DMS, which may impair normal adaptive decision-making in the task, akin to what is observed in SUDs.

Processing in Lateral Orbitofrontal Cortex Is Required to Estimate Subjective Preference during Initial, but Not Established, Economic Choice.

The orbitofrontal cortex (OFC) is proposed to be critical to economic decision making. Yet one can inactivate OFC without affecting well-practiced choices. One possible explanation of this lack of effect is that well-practiced decisions are codified into habits or configural-based policies not normally thought to require OFC. Here, we tested this idea by training rats to choose between different pellet pairs across a set of standard offers and then inactivating OFC subregions during choices between novel offers of previously experienced pairs or between novel pairs of previously experienced pellets. Contrary to expectations, controls performed as well on novel as experienced offers yet had difficulty initially estimating their subjective preference on novel pairs, difficulty exacerbated by lateral OFC inactivation. This pattern of results indicates that established economic choice reflects the use of an underlying model or goods space and that lateral OFC is only required for normal behavior when the established framework must incorporate new information.

Can the VTA Come Out to Play? Only When the mPFC's Predictions Go Astray!

Confidence in perceptual decisions scales neural responses to violations in reward expectation. In this issue of Neuron, Lak et al. (2020) show that the medial prefrontal cortex in mice computes a confidence-dependent expectation signal that influences how dopamine neurons convey reward prediction errors to guide learning.

Complementary Task Structure Representations in Hippocampus and Orbitofrontal Cortex during an Odor Sequence Task.

Both hippocampus (HPC) and orbitofrontal cortex (OFC) have been shown to be critical for behavioral tasks that require use of an internal model or cognitive map, composed of the states and the relationships between them, which define the current environment or task at hand. One general idea is that the HPC provides the cognitive map, which is then transformed by OFC to emphasize information of relevance to current goals. Our previous analysis of ensemble activity in OFC in rats performing an odor sequence task revealed a rich representation of behaviorally relevant task structure, consistent with this proposal. Here, we compared those data to recordings from single units in area CA1 of the HPC of rats performing the same task. Contrary to expectations that HPC ensembles would represent detailed, even incidental, information defining the full task space, we found that HPC ensembles-like those in OFC-failed to distinguish states when it was not behaviorally necessary. However, hippocampal ensembles were better than those in OFC at distinguishing task states in which prospective memory was necessary for future performance. These results suggest that, in familiar environments, the HPC and OFC may play complementary roles, with the OFC maintaining the subjects' current position on the cognitive map or state space, supported by HPC when memory demands are high.

Rat Orbitofrontal Ensemble Activity Contains Multiplexed but Dissociable Representations of Value and Task Structure in an Odor Sequence Task.

The orbitofrontal cortex (OFC) has long been implicated in signaling information about expected outcomes to facilitate adaptive or flexible behavior. Current proposals focus on signaling of expected value versus the representation of a value-agnostic cognitive map of the task. While often suggested as mutually exclusive, these alternatives may represent extreme ends of a continuum determined by task complexity and experience. As learning proceeds, an initial, detailed cognitive map might be acquired, based largely on external information. With more experience, this hypothesized map can then be tailored to include relevant abstract hidden cognitive constructs. The map would default to an expected value in situations where other attributes are largely irrelevant, but, in richer tasks, a more detailed structure might continue to be represented, at least where relevant to behavior. Here, we examined this by recording single-unit activity from the OFC in rats navigating an odor sequence task analogous to a spatial maze. The odor sequences provided a mappable state space, with 24 unique "positions" defined by sensory information, likelihood of reward, or both. Consistent with the hypothesis that the OFC represents a cognitive map tailored to the subjects' intentions or plans, we found a close correspondence between how subjects were using the sequences and the neural representations of the sequences in OFC ensembles. Multiplexed with this value-invariant representation of the task, we also found a representation of the expected value at each location. Thus, the value and task structure co-existed as dissociable components of the neural code in OFC.

Suppression of Ventral Hippocampal Output Impairs Integrated Orbitofrontal Encoding of Task Structure.

The hippocampus and orbitofrontal cortex (OFC) both make important contributions to decision making and other cognitive processes. However, despite anatomical links between the two, few studies have tested the importance of hippocampal-OFC interactions. Here, we recorded OFC neurons in rats performing a decision making task while suppressing activity in a key hippocampal output region, the ventral subiculum. OFC neurons encoded information about expected outcomes and rats' responses. With hippocampal output suppressed, rats were slower to adapt to changes in reward contingency, and OFC encoding of response information was strongly attenuated. In addition, ventral subiculum inactivation prevented OFC neurons from integrating information about features of outcomes to form holistic representations of the outcomes available in specific trial blocks. These data suggest that the hippocampus contributes to OFC encoding of both concrete, low-level features of expected outcomes, and abstract, inferred properties of the structure of the world, such as task state.

Rat mPFC and M2 Play a Waiting Game (at Different Timescales).

In this issue of Neuron, Murakami et al. (2017) relate neural activity in frontal cortex to stochastic and deterministic components of waiting behavior in rats; they find that mPFC biases waiting time, while M2 is ultimately responsible for trial-to-trial variability in decisions about how long to wait.

Toward a theoretical role for tonic norepinephrine in the orbitofrontal cortex in facilitating flexible learning.

To adaptively respond in a complex, changing world, animals need to flexibly update their understanding of the world when their expectations are violated. Though several brain regions in rodents and primates have been implicated in aspects of this updating, current models of orbitofrontal cortex (OFC) and norepinephrine neurons of the locus coeruleus (LC-NE) suggest that each plays a role in responding to environmental change, where the OFC allows updating of prior learning to occur without overwriting or unlearning one's previous understanding of the world that changed, while elevated tonic NE allows for increased flexibility in behavior that tracks an animal's uncertainty. In light of recent studies highlighting a specific LC-NE projection to the OFC, in this review we discuss current models of OFC and NE function, and their potential synergy in the updating of associations following environmental change.

Over the river, through the woods: cognitive maps in the hippocampus and orbitofrontal cortex.

The hippocampus and the orbitofrontal cortex (OFC) both have important roles in cognitive processes such as learning, memory and decision making. Nevertheless, research on the OFC and hippocampus has proceeded largely independently, and little consideration has been given to the importance of interactions between these structures. Here, evidence is reviewed that the hippocampus and OFC encode parallel, but interactive, cognitive 'maps' that capture complex relationships between cues, actions, outcomes and other features of the environment. A better understanding of the interactions between the OFC and hippocampus is important for understanding the neural bases of flexible, goal-directed decision making.

The State of the Orbitofrontal Cortex.

State representation is fundamental to behavior. However, identifying the true state of the world is challenging when explicit cues are ambiguous. Here, Bradfield and colleagues show that the medial OFC is critical for using associative information to discriminate ambiguous states.

Hippocampal theta sequences reflect current goals.

Hippocampal information processing is discretized by oscillations, and the ensemble activity of place cells is organized into temporal sequences bounded by theta cycles. Theta sequences represent time-compressed trajectories through space. Their forward-directed nature makes them an intuitive candidate mechanism for planning future trajectories, but their connection to goal-directed behavior remains unclear. As rats performed a value-guided decision-making task, the extent to which theta sequences projected ahead of the animal's current location varied on a moment-by-moment basis depending on the rat's goals. Look-ahead extended farther on journeys to distant goals than on journeys to more proximal goals and was predictive of the animal's destination. On arrival at goals, however, look-ahead was similar regardless of where the animal began its journey from. Together, these results provide evidence that hippocampal theta sequences contain information related to goals or intentions, pointing toward a potential spatial basis for planning.

Decoding the cognitive map: ensemble hippocampal sequences and decision making.

Tolman proposed that complex animal behavior is mediated by the cognitive map, an integrative learning system that allows animals to reconfigure previous experience in order to compute predictions about the future. The discovery of place cells in the rodent hippocampus immediately suggested a plausible neural mechanism to fulfill the 'map' component of Tolman's theory. Recent work examining hippocampal representations occurring at fast time scales suggests that these sequences might be important for supporting the inferential mental operations associated with the cognitive map function. New findings that hippocampal sequences play an important causal role in mediating adaptive behavior on a moment-by-moment basis suggest specific neural processes that may underlie Tolman's cognitive map framework.

Subjective costs drive overly patient foraging strategies in rats on an intertemporal foraging task.

Laboratory studies of decision making often take the form of two-alternative, forced-choice paradigms. In natural settings, however, many decision problems arise as stay/go choices. We designed a foraging task to test intertemporal decision making in rats via stay/go decisions. Subjects did not follow the rate-maximizing strategy of choosing only food items associated with short delays. Instead, rats were often willing to wait for surprisingly long periods, and consequently earned a lower rate of food intake than they might have by ignoring long-delay options. We tested whether foraging theory or delay discounting models predicted the behavior we observed but found that these models could not account for the strategies subjects selected. Subjects' behavior was well accounted for by a model that incorporated a cost for rejecting potential food items. Interestingly, subjects' cost sensitivity was proportional to environmental richness. These findings are at odds with traditional normative accounts of decision making but are consistent with retrospective considerations having a deleterious influence on decisions (as in the "sunk-cost" effect). More broadly, these findings highlight the utility of complementing existing assays of decision making with tasks that mimic more natural decision topologies.

The balance of forward and backward hippocampal sequences shifts across behavioral states.

Place cell firing patterns in the rat hippocampus are often organized as sequences. Sequences falling within cycles of the theta (6-10 Hz) local field potential (LFP) oscillation represent segments of ongoing behavioral trajectories. Sequences expressed during sharp wave ripple (SWR) complexes represent spatial trajectories through the environment, in both the same direction as actual trajectories (forward sequences) and in an ordering opposite that of behavior (backward sequences). Although hippocampal sequences could fulfill unique functional roles depending on the direction of the sequence and the animal's state when the sequence occurs, quantitative comparisons of sequence direction across behavioral and physiological states within the same experiment, employing consistent methodology, are lacking. Here, we used cross-correlation and Bayesian decoding to measure the direction of hippocampal sequences in rats during active behavior, awake rest and slow-wave sleep. During pretask sleep, few sequences were detected in either direction. Sequences within theta cycles during active behavior were overwhelmingly forward. Sequences during quiescent moments of behavior were both forward and backward, in equal proportion. During postbehavior sleep, sequences were again expressed in both directions, but significantly more forward than backward sequences were detected. The shift in the balance of sequence direction could reflect changing functional demands on the hippocampal network across behavioral and physiological states.