Rat Orbitofrontal Cortex Research Articles

Phase-Amplitude Coupling in Rat Orbitofrontal Cortex Discriminates between Correct and Incorrect Decisions during Associative Learning

Cross-frequency interactions between oscillations in local field potentials (LFPs) are thought to support communication between brain structures by temporally coordinating neural activity. It is unknown, however, whether such interactions differentiate between different levels of performance in decision-making tasks. Here, we investigated theta (4-12 Hz) to gamma (30-100 Hz) phase-amplitude coupling in LFP recordings from rat orbitofrontal cortex. Across subsequent periods of a task in which rats learned to discriminate two odors associated with positive and negative outcomes, theta-to-gamma phase-amplitude coupling (PAC) was highest during the odor-sampling task period that preceded a Go/NoGo decision. This task-dependent modulation could not be explained by changes in oscillatory power and appeared to be time-locked to odor onset, not to the timing of the behavioral response. We found that PAC strength during odor sampling correlated with learning, as indexed by improved performance across trials. Moreover, this increase in PAC magnitude was apparent only on trials with correct Go and NoGo decisions, but not incorrect Go decisions. In addition, we found that PAC preferred coupling phase showed consistency over sessions only for correct, but not incorrect trials. In conclusion, orbitofrontal cortex theta-gamma PAC strength differentiates between different levels of performance in an olfactory decision-making task and may play a role in the generation and utilization of stimulus-based outcome predictions, necessary for adaptive decision-making.

A Novel Role for Brain Interleukin-6: Facilitation of Cognitive Flexibility in Rat Orbitofrontal Cortex

A Novel Role for Brain Interleukin-6: Facilitation of Cognitive Flexibility in Rat Orbitofrontal Cortex

High-resolution spatio-temporal bioactivity of a novel peptide revealed by optical imaging in rat orbitofrontal cortex in vitro: Possible implications for neurodegenerative diseases

Acetylcholinesterase (AChE) is now well known to have a secondary, non-enzymatic function independent of cholinergic transmission. In the last decade, the part of the molecule responsible for this action has been identified, i.e. a 14 amino acid peptide fragment (‘T14’), deriving from the C-terminus of AChE: this peptide has been shown to be bioactive in a range of preparations and to act at an allosteric site on α7 nicotinic acetylcholine receptors (α7-nAChRs). Of particular significance is the finding that AChE-related peptides trigger calcium-induced neurotoxicity that may be pivotal in the process of neurodegenerative diseases, such as Alzheimer's. However to date all studies have been performed on isolated cell preparations. The aim of this study was therefore to characterise the bioactivity of T14 on meso-scale in vitro cortical networks (‘neuronal assemblies’) from rat brain slices containing orbitofrontal cortex. Local field potential (LFP) recordings showed that the T14 peptide has a selective, holistic action on cortical networks in a modulatory biphasic manner i.e. predisposing excitation at concentrations of up to 1 μM, after which the trend is reversed in favour of inhibition at higher doses (>1 μM). By contrast, a scrambled variant of the T14 peptide sequence (S14), showed no significant changes in neuronal activation. Optical imaging using voltage-sensitive dyes (VSDI) corroborated the electrophysiological findings and also provided further insight into the spatial dynamics of the effects of the peptide: T14 application had a facilitatory effect i.e. increased the time-course of activation at sub-micromolar concentrations only (700 nM) without significantly affecting the spread of evoked assemblies. Moreover: co-applying T14 with the α7-nAChR competitive antagonist methyllycaconitine (MLA) produced inhibition in activation synchrony not seen with either agent on their own, suggesting an additive inhibitory effect. In conclusion, the T14 peptide derived from AChE produced a dose-dependent biphasic modulation of cortical networks activity dependent on the α7-nAChR: these findings should thus provide a more comprehensive insight into the immediate actions of a novel bioactive agent of high potential relevance to neurodegenerative disorders such as Alzheimer's disease.

Risk preference was affected by inactivation of rat anterior insular cortex and orbitofrontal cortex in the amount and delay gambling tasks

Risk preference was affected by inactivation of rat anterior insular cortex and orbitofrontal cortex in the amount and delay gambling tasks

Mastering Memory Maintenance

The mechanisms involved in the formation of enduring memories are still largely unknown. Lesburgueres et al. (p. [924][1]; see the Perspective by [Sweatt][2] ) investigated the hippocampal-cortical dialogue during memory consolidation. Neurons in the rat orbitofrontal cortex appeared to be “

Reduced neuronal inhibition and coordination of adolescent prefrontal cortex during motivated behavior.

Adolescence is a time of both cognitive maturation and vulnerability to several major psychiatric illnesses and drug dependence. There is increasing awareness that behavioral or pharmacological intervention during this period may be critical for disease prevention in susceptible individuals. Therefore, we must attain a deeper understanding of how the adolescent brain processes salient events relevant to motivated behavior. To do this, we recorded single-unit and local field potential activity in the orbitofrontal cortex of rats as they performed a simple reward-driven operant task. Adolescents encoded basic elements of the task differently than adults, indicating that neuronal processing of salient events differs in the two age groups. Entrainment of local field potential oscillations, variance in spike timing, and relative proportions of inhibitory and excitatory responses differed in an event-specific manner. Overall adolescent phasic neural activity was less inhibited and more variable through much of the task. Cortical inhibition is essential for efficient communication between neuronal groups, and reduced inhibitory control of cortical activity has been implicated in schizophrenia and other disorders. Thus, these results suggest that reduced inhibitory responses of adolescent cortical neurons to salient events could be a critical mechanism for some of the increased vulnerabilities of this period.

Beyond Reversal: A Critical Role for Human Orbitofrontal Cortex in Flexible Learning from Probabilistic Feedback

Damage to the orbitofrontal cortex (OFC) has been linked to impaired reinforcement processing and maladaptive behavior in changing environments across species. Flexible stimulus-outcome learning, canonically captured by reversal learning tasks, has been shown to rely critically on OFC in rats, monkeys, and humans. However, the precise role of OFC in this learning remains unclear. Furthermore, whether other frontal regions also contribute has not been definitively established, particularly in humans. In the present study, a reversal learning task with probabilistic feedback was administered to 39 patients with focal lesions affecting various sectors of the frontal lobes and to 51 healthy, demographically matched control subjects. Standard groupwise comparisons were supplemented with voxel-based lesion-symptom mapping to identify regions within the frontal lobes critical for task performance. Learning in this dynamic stimulus-reinforcement environment was considered both in terms of overall performance and at the trial-by-trial level. In this challenging, probabilistic context, OFC damage disrupted both initial and reversal learning. Trial-by-trial performance patterns suggest that OFC plays a critical role in interpreting feedback from a particular trial within the broader context of the outcome history across trials rather than in simply suppressing preexisting stimulus-outcome associations. The findings show that OFC, and not other prefrontal regions, plays a necessary role in flexible stimulus-reinforcement learning in humans.

Contributions of the orbitofrontal cortex to impulsive choice: interactions with basal levels of impulsivity, dopamine signalling, and reward-related cues

Individual differences in impulsive decision-making may be critical determinants of vulnerability to impulse control disorders and substance abuse, yet little is known of their biological or behavioural basis. The orbitofrontal cortex (OFC) has been heavily implicated in the regulation of impulsive decision-making. However, lesions of the OFC in rats have both increased and decreased impulsivity in delay-discounting paradigms, where impulsive choice is defined as the selection of small immediate over larger delayed rewards. Reviewing the different methods used, we hypothesized that the effects of OFC inactivation on delay discounting may be critically affected by both subjects' baseline level of impulsive choice and the presence or absence of a cue to bridge the delay between selection and delivery of the large reward. Here, we show that OFC inactivation increased impulsive choice in less impulsive rats when the delay was cued, but decreased impulsive choice in highly impulsive rats in an uncued condition. Providing explicit environmental cues to signal the delay-to-reinforcement appears to change the way in which the OFC is recruited in the decision-making process in a baseline-dependent fashion. This change may reflect activation of the dopamine system, as intra-OFC infusions of dopamine receptor antagonists increased impulsive choice but only when the delay was cued.

The pairwise phase consistency: A bias-free measure of rhythmic neuronal synchronization

Oscillatory activity is a widespread phenomenon in nervous systems and has been implicated in numerous functions. Signals that are generated by two separate neuronal sources often demonstrate a consistent phase-relationship in a particular frequency-band, i.e., they demonstrate rhythmic neuronal synchronization. This consistency is conventionally measured by the PLV (phase-locking value) or the spectral coherence measure. Both statistical measures suffer from significant bias, in that their sample estimates overestimate the population statistics for finite sample sizes. This is a significant problem in the neurosciences where statistical comparisons are often made between conditions with a different number of trials or between neurons with a different number of spikes. We introduce a new circular statistic, the PPC (pairwise phase consistency). We demonstrate that the sample estimate of the PPC is a bias-free and consistent estimator of its corresponding population parameter. We show, both analytically and by means of numerical simulations, that the population statistic of the PPC is equivalent to the population statistic of the squared PLV. The variance and mean squared error of the PPC and PLV are compared. Finally, we demonstrate the practical relevance of the method in actual neuronal data recorded from the orbitofrontal cortex of rats that engage in a two-odour discrimination task. We find a strong increase in rhythmic synchronization of spikes relative to the local field potential (as measured by the PPC) for a wide range of low frequencies (including the theta-band) during the anticipation of sucrose delivery in comparison to the anticipation of quinine delivery.

The role of the striatum in compulsive behavior in intact and orbitofrontal-cortex-lesioned rats: possible involvement of the serotonergic system.

In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

“Doing more and getting more” task performance: The importance of the orbitofrontal cortex in rats

“Doing more and getting more” task performance: The importance of the orbitofrontal cortex in rats

Single-cell and population coding of expected reward probability in the orbitofrontal cortex of the rat.

The orbitofrontal cortex (OFC) has been implicated in decision-making under uncertainty, but it is unknown how information about the probability or uncertainty of future reward is coded by single orbitofrontal neurons and ensembles. We recorded neuronal ensembles in rat OFC during an olfactory discrimination task in which different odor stimuli predicted different reward probabilities. Single-unit firing patterns correlated to the expected reward probability primarily within an immobile waiting period before reward delivery but also when the rat executed movements toward the reward site. During these pre-reward periods, a subset of OFC neurons was sensitive to differences in probability but only very rarely discriminated on the basis of reward uncertainty. In the reward period, neurons responded during presentation or omission of reward or during both types of outcome. At the population level, neurons were characterized by a wide divergence in firing-rate variability attributable to expected probability. A population analysis using template matching as reconstruction method indicated that OFC generates a distributed representation of reward probability with a weak dependence on neuronal group size. The analysis furthermore confirmed that predictive information coded by OFC populations was quantitatively related to reward probability, but not to uncertainty.

A defined network of fast-spiking interneurons in orbitofrontal cortex: responses to behavioral contingencies and ketamine administration

Orbitofrontal cortex (OFC) is a region of prefrontal cortex implicated in the motivational control of behavior and in related abnormalities seen in psychosis and depression. It has been hypothesized that a critical mechanism in these disorders is the dysfunction of GABAergic interneurons that normally regulate prefrontal information processing. Here, we studied a subclass of interneurons isolated in rat OFC using extracellular waveform and spike train analysis. During performance of a goal-directed behavioral task, the firing of this class of putative fast-spiking (FS) interneurons showed robust temporal correlations indicative of a functionally coherent network. FS cell activity also co-varied with behavioral response latency, a key indicator of motivational state. Systemic administration of ketamine, a drug that can mimic psychosis, preferentially inhibited this cell class. Together, these results support the idea that OFC–FS interneurons form a critical link in the regulation of motivation by prefrontal circuits during normal and abnormal brain and behavioral states.

Developmental changes of signaling molecules that regulate neurite outgrowth and myelination in the rat orbitofrontal and visual cortex

Developmental changes of signaling molecules that regulate neurite outgrowth and myelination in the rat orbitofrontal and visual cortex

Delta EEG Activity in Left Orbitofrontal Cortex in Rats Related to Food Reward and Craving

The orbitofrontal cortex (OFC) is particularly important for the neural representation of reward value. Previous studies indicated that electroencephalogram (EEG) activity in the OFC was involved in drug administration and withdrawal. The present study investigated EEG activity in the OFC in rats during the development of food reward and craving. Two environments were used separately for control and food-related EEG recordings. In the food-related environment rats were first trained to eat chocolate peanuts; then they either had no access to this food, but could see and smell it (craving trials), or had free access to this food (reward trials). The EEG in the left OFC was recorded during these trials. We showed that, in the food-related environment the EEG activity peaking in the delta band (2-4 Hz) was significantly correlated with the stimulus, increasing during food reward and decreasing during food craving when compared with that in the control environment. Our data suggests that EEG activity in the OFC can be altered by food reward; moreover, delta rhythm in this region could be used as an index monitoring changed signal underlying this reward.

Population coding of reward magnitude in the orbitofrontal cortex of the rat.

Although single-cell coding of reward-related information in the orbitofrontal cortex (OFC) has been characterized to some extent, much less is known about the coding properties of orbitofrontal ensembles. We examined population coding of reward magnitude by performing ensemble recordings in rat OFC while animals learned an olfactory discrimination task in which various reinforcers were associated with predictive odor stimuli. Ensemble activity was found to represent information about reward magnitude during several trial phases, namely when animals moved to the reward site, anticipated reward during an immobile period, and received it. During the anticipation phase, Bayesian and template-matching reconstruction algorithms decoded reward size correctly from the population activity significantly above chance level (highest value of 43 and 48%, respectively; chance level, 33.3%), whereas decoding performance for the reward delivery phase was 76 and 79%, respectively. In the anticipation phase, the decoding score was only weakly dependent on the size of the neuronal group participating in reconstruction, consistent with a redundant, distributed representation of reward information. In contrast, decoding was specific for temporal segments within the structure of a trial. Decoding performance steeply increased across the first few trials for every rewarded odor, an effect that could not be explained by a nonspecific drift in response strength across trials. Finally, when population responses to a negative reinforcer (quinine) were compared with sucrose reinforcement, coding in the delivery phase appeared to be related to reward quality, and thus was not based on ingested liquid volume.

Rat orbitofrontal cortex separately encodes response and outcome information during performance of goal-directed behavior.

Orbitofrontal cortex (OFC) neurons encode rewards and the cues that predict them, providing a neural substrate for outcome expectancy, an important component of goal-directed behavior in animals and humans. Here, we recorded and analyzed single units from rat lateral OFC during performance of a task in which the encoding of an expected rewarding outcome could be isolated from the response made in obtaining it. We found concurrent encoding of the expected outcome and the behavioral response in mostly separate populations of OFC units, in each phase of task performance: odor sampling, behavioral response, and waiting during the delay before reward delivery. Population analyses showed that outcome encoding broadly spanned across each behavioral phase, whereas response-selective firings were time-locked to the behavioral events, especially the completion of the behavioral response. A significant subset of outcome-selective units maintained selective firings from either odor sampling or response initiation until reward delivery. In contrast, response-selective units typically showed transient activation time locked to the behavioral events and were less likely to maintain selective firings across behavioral phases than outcome-selective units. These data demonstrate a broader role of OFC information processing in goal-directed behavior, beyond its widely recognized role in outcome expectancy.

Role of Orbitofrontal Cortex Connections in Emotion

The orbitofrontal cortex is extensively connected with diverse neural areas that underlie its participation in emotional function. It receives extensive sensory input and sends output to areas important for emotional processing and expression, including medial temporal cortical areas, hypothalamic and brain stem autonomic areas, and the amygdala. In the rat, the functional relationship between the orbitofrontal cortex and amygdala has been investigated in numerous recent studies. Clearer understanding of the complex connections between the rat orbitofrontal cortex and the amygdala is fundamental to elucidating the functional contributions of these pathways. Recent work shows that, as in the primate, the subdivisions of the rat orbitofrontal cortex issue different patterns of projections to the amygdala, with intriguing variations in the relative distribution of projections to the sensory-related basal areas compared with output areas, such as the central nucleus. Notably, as has been observed in the monkey, the rat orbitofrontal cortex targets the intercalated nuclei, which contain GABAergic interneurons and provide local inhibitory influences within the amygdala. The complex connections between the orbitofrontal cortex and the amygdala, as well as other areas involved in emotion, suggest important implications for the role of the orbitofrontal cortex in anxiety disorders, in which emotional expression is not appropriate to the situation.

Neural Encoding in the Orbitofrontal Cortex Related to Goal‐Directed Behavior

Research using laboratory animals, alongside clinical studies of human patients, support a role for the orbitofrontal cortex (OFC) in adaptive decision-making and goal-directed behavior. The functions of OFC neurons within this domain have been studied extensively in both rats and primates. Electrophysiological recordings during performance of relevant behavioral tasks provide a coherent portrait of OFC encoding that is reward related. OFC neurons represent associative relationships between events, encoding information that is predictive of outcome value. That encoding can be understood as a neural basis for deficits seen after OFC damage in the use of outcome expectancy to guide performance. There is less agreement, however, on whether OFC itself plays a role in translating information on outcome expectancy into the actual guidance of overt behavioral responding. New findings indicate that rat OFC neurons prominently encode additional task-related information and events related to goal-directed action. This encoding can occur in populations of OFC neurons that are independent of the OFC neurons representing reward value. The significance of this emerging evidence may require studies that address the larger scale network through which OFC integrates expected outcome information with behavioral control.

Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments

Humans with drug addiction exhibit compulsive drug-seeking associated with impairment of prefrontal cortex cognitive function. Whether prefrontal cortex dysfunction is a consequence of chronic drug exposure, or mediates the transition from drug use to drug dependence, is unknown. The current study investigates whether a history of escalated vs controlled cocaine intake is associated with specific working memory impairments, and long-lasting alterations of the dorsomedial prefrontal cortex and orbitofrontal cortex in rats. Working memory was assessed in rats with a history of extended (6 h per session) or limited (1 h per session) access to cocaine (0.5 mg/kg per injection), 3-17 days after the last self-administration session, using a delayed nonmatching-to-sample task. The density of neurons, oligodendrocytes, and astrocytes was quantified in the dorsomedial prefrontal cortex and orbitofrontal prefrontal cortex 2 months after the last self-administration session. Working memory impairments were observed after a history of chronic and escalated cocaine intake, but not after repeated limited access to cocaine. Moreover, working memory impairments were correlated with a decreased density of neurons and oligodendrocytes but not astrocytes in the dorsomedial prefrontal cortex, and with a decreased density of oligodendrocytes in the orbitofrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, the prefrontal cortex dysfunctions observed here may exacerbate the loss of control associated with increased drug use and facilitate the progression to drug addiction.