Rat Orbitofrontal Cortex Research Articles

A neuronal population code for resemblance between drug and nondrug reward outcomes in the orbitofrontal cortex.

The orbitofrontal cortex (OFC) is implicated in choice and decision-making in both human and non-human animals. We previously identified in the rat OFC a mechanism that influences individual drug choices and preferences between a drug and a nondrug (i.e., sweet) outcome that is common across different types of drugs (cocaine and heroin). Importantly, this research also revealed some intriguing drug-specific differences. Notably, the size of non-selective OFC neurons that indiscriminately encode both the drug and the sweet outcomes varies as a function of the drug outcome available (cocaine or heroin). Here we tested the hypothesis that the relative size of the non-selective OFC population somehow represents the degree of resemblance between the drug and nondrug reward outcomes. We recorded OFC neuronal activity in vivo in the same individual rats while they were choosing between two outcomes with varying degrees of resemblance: high (two concentrations of sweet), intermediate (sweet versus heroin) and low (sweet versus cocaine). We found that the percentage of non-selective OFC neurons dramatically increased with the degree of resemblance between choice outcomes, from 26 to 62%. Overall, these findings reveal the existence of a neuronal population code for resemblance between different kinds of choice outcomes in the OFC.

Neurons in rat orbitofrontal cortex and medial prefrontal cortex exhibit distinct responses in reward and strategy-update in a risk-based decision-making task.

The orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC) are known to participate in risk-based decision-making. However, whether neuronal activities of these two brain regions play similar or differential roles during different stages of risk-based decision-making process remains unknown. Here we conducted multi-channel in vivo recordings in the OFC and mPFC simultaneously when rats were performing a gambling task. Rats were trained to update strategy as the task was shifted in two stages. Behavioral testing suggests that rats exhibited different risk preferences and response latencies to food rewards during stage-1 and stage-2. Indeed, the firing patterns and numbers of non-specific neurons and nosepoking-predicting neurons were similar in OFC and mPFC. However, there were no reward-expecting neurons and significantly more reward-excitatory neurons (fired as rats received rewards) in the mPFC. Further analyses suggested that nosepoking-predicting neurons may encode the overall value of reward and strategy, whereas reward-expecting neurons show more intensive firing to a big food reward in the OFC. Nosepoking-predicting neurons in mPFC showed no correlation with decision-making strategy updating, whereas the response of reward-excitatory neurons in mPFC, which were barely observed in OFC, were inhibited during nosepoking, but were enhanced in the post-nosepoking period. These findings indicate that neurons in the OFC and mPFC exhibit distinct responses in decision-making process during reward consumption and strategy updating. Specifically, OFC encodes the overall value of a choice and is thus important for learning and strategy updating, whereas mPFC plays a key role in monitoring and execution of a strategy.

Medial orbitofrontal inactivation does not affect economic choice.

How are decisions made between different goods? One theory spanning several fields of neuroscience proposes that their values are distilled to a single common neural currency, the calculation of which allows for rational decisions. The orbitofrontal cortex (OFC) is thought to play a critical role in this process, based on the presence of neural correlates of economic value in lateral OFC in monkeys and medial OFC in humans. We previously inactivated lateral OFC in rats without affecting economic choice behavior. Here we inactivated medial OFC in the same task, again without effect. Behavior in the same rats was disrupted by inactivation during progressive ratio responding previously shown to depend on medial OFC, demonstrating the efficacy of the inactivation. These results indicate that medial OFC is not necessary for economic choice, bolstering the proposal that classic economic choice is likely mediated by multiple, overlapping neural circuits.

Lateral Orbitofrontal Inactivation Dissociates Devaluation-Sensitive Behavior and Economic Choice

How do we choose between goods that have different subjective values, like apples and oranges? Neuroeconomics proposes that this is done by reducing complex goods to a single unitary value to allow comparison. This value is computed "on the fly" from the underlying model of the goods space, allowing decisions to meet current needs. This is termed "model-based" behavior to distinguish it from pre-determined, habitual, or "model-free" behavior. The lateral orbitofrontal cortex (OFC) supports model-based behavior in rats and primates, but whether the OFC is necessary for economic choice is less clear. Here we tested this question by optogenetically inactivating the lateral OFC in rats in a classic model-based task and during economic choice. Contrary to predictions, inactivation disrupted model-based behavior without affecting economic choice.

Functional Heterogeneity within Rat Orbitofrontal Cortex in Reward Learning and Decision Making.

Rat orbitofrontal cortex (OFC) is located in the dorsal bank of the rhinal sulcus, and is divided into the medial orbital area, ventral orbital area, ventrolateral orbital area, lateral orbital area, dorsolateral orbital area, and agranular insular areas. Over the past 20 years, there has been a marked increase in the number of publications focused on the functions of rat OFC. While collectively this extensive body of work has provided great insight into the functions of OFC, leading to theoretical and computational models of its functions, one issue that has emerged relates to what is defined as OFC because targeting of this region can be quite variable between studies of appetitive behavior, even within the same species. Also apparent is that there is an oversampling and undersampling of certain subregions of rat OFC for study, and this will be demonstrated here. The intent of the Viewpoint is to summarize studies in rat OFC, given the diversity of what groups refer to as "OFC," and to integrate these with the findings of recent anatomical studies. The primary aim is to help discern functions in reward learning and decision-making, clearing the course for future empirical work.

Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula.

Hedonic hotspots are brain sites where particular neurochemical stimulations causally amplify the hedonic impact of sensory rewards, such as "liking" for sweetness. Here, we report the mapping of two hedonic hotspots in cortex, where mu opioid or orexin stimulations enhance the hedonic impact of sucrose taste. One hedonic hotspot was found in anterior orbitofrontal cortex (OFC), and another was found in posterior insula. A suppressive hedonic coldspot was also found in the form of an intervening strip stretching from the posterior OFC through the anterior and middle insula, bracketed by the two cortical hotspots. Opioid/orexin stimulations in either cortical hotspot activated Fos throughout a distributed "hedonic circuit" involving cortical and subcortical structures. Conversely, cortical coldspot stimulation activated circuitry for "hedonic suppression." Finally, food intake was increased by stimulations at several prefrontal cortical sites, indicating that the anatomical substrates in cortex for enhancing the motivation to eat are discriminable from those for hedonic impact.

Dorsal and ventral parts of thalamic nucleus submedius project to different areas of rat orbitofrontal cortex: A single neuron-tracing study using virus vectors.

The rodent orbitofrontal cortex is involved in a variety of cognitive and behavioral functions that require thalamic input to be successfully expressed. Although the thalamic nucleus submedius (Sm) is a major source of afferents to the orbitofrontal cortex, thalamocortical projection from the Sm has not been fully elucidated. In the present study, we first divided the rat Sm into dorsal and ventral parts according to the distribution of vesicular glutamate transporter 2-immunoreactive varicosities, which were somatosensory afferents from the brain stem. Subsequently we investigated dendritic and axonal arborizations of individual dorsal and ventral Sm neurons by visualizing the processes with Sindbis virus vectors expressing membrane-targeted fluorescent proteins. The number of dendritic processes of ventral Sm neurons was greater than that of dorsal Sm neurons. In the cerebral cortex, all the reconstructed Sm neurons sent axons primarily to layers 2-5. Interestingly, dorsal Sm neurons formed a single axon arbor exclusively within the ventrolateral orbital area, whereas ventral Sm neurons made two axon arbors in the lateral orbital and ventral orbital areas simultaneously. The spread of each axon arbor was 500-1000 µm in diameter in the direction tangential to the cortical surface. These results indicate that the dorsal and ventral Sm comprise two distinct thalamocortical pathways. The dorsal Sm pathway relay somatosensory information to the ventrolateral orbital area and may be involved in emotional and aversive aspects of nociceptive information processing, whereas the ventral Sm pathway seems to co-activate distant orbitofrontal cortical areas, and may link their functions under certain circumstances.

Neuronal representation of individual heroin choices in the orbitofrontal cortex.

Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action-which was the non-drug action in the large majority of individuals-progressively fired more than non-preferred action-coding neurons 1second after the onset of choice trials and around 1second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice.

Ensembles in medial and lateral orbitofrontal cortex construct cognitive maps emphasizing different features of the behavioral landscape.

The orbitofrontal cortex (OFC) has long been implicated in the ability to use the current value of expected outcomes to guide behavior. More recently, this specific role has been conceptualized as a special case of a more general function that OFC plays in constructing a "cognitive map" of the behavioral task space by labeling the current task state and learning relationships among task states. Here, we have used single unit recording data from 2 prior studies to examine whether and how information relating different states within and across trials is represented in medial versus lateral OFC in rats. Using a hierarchical clustering analysis, we examined how neurons from each area represented information about differently valued trial types, defined by the cue-outcome pairings, versus how those same neurons represented information about similar epochs between these different trial types, such as the stimulus sample, delay, and reward consumption epochs. This analysis revealed that ensembles in the lateral OFC (lOFC) group states according to trial epoch, whereas those in the medial OFC (mOFC) organize the same states by trial type. These results suggest that the lOFC and mOFC construct cognitive maps that emphasize different features of the behavioral landscape, with lOFC tracking events based on local similarities, irrespective of their values and mOFC tracking more distal or higher order relationships relevant to value. (PsycINFO Database Record

Preference for Cocaine is Represented in the Orbitofrontal Cortex by an Increased Proportion of Cocaine Use-Coding Neurons

Cocaine addiction is a harmful preference for drug use over and at the expense of other nondrug-related activities. Here we identify in the rat orbitofrontal cortex (OFC) a mechanism that explains individual preferences between cocaine use and an alternative, nondrug action. OFC neuronal activity was recorded while rats performed each of these 2 actions separately or while they chose between them. First, we found that these actions are encoded by 2 nonoverlapping neuronal populations and that the relative size of the cocaine population represented individual preferences. A larger relative size was only observed in cocaine-preferring individuals. Second, OFC neurons encoding a given individual's preferred action progressively fired more than other action-coding neurons few seconds before the preferred action was actually chosen, suggesting a prechoice neuronal competition for action selection. In cocaine-preferring rats, this manifested by a prechoice ramping-up activity in favor of the cocaine population. Finally, pharmacological manipulation of prechoice activity in favor of the cocaine population caused nondrug-preferring rats to shift their choice to cocaine. Overall, this study suggests that an individual preference for cocaine is represented in the OFC by a population size bias that systematically advantages cocaine use-coding neurons during prechoice competition for action selection.

Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents.

We previously reported that the kinase AKT is activated in the nucleus accumbens (NAc) of rodents in response to excessive consumption of alcohol. One of the important downstream targets of AKT is the mammalian Target Of Rapamycin in Complex 1 (mTORC1), which was also activated by alcohol intake. mTORC1 controls dendritic protein translation, and we showed that the mTORC1-dependent translational machinery is activated in the NAc in response to alcohol intake. Importantly, systemic or intra-NAc inhibition of the AKT/mTORC1 pathway attenuated alcohol-drinking behaviors. Here, we mapped the activation patterns of AKT and mTORC1 in corticostriatal regions of rodents consuming large amounts of alcohol. We found that the activation of AKT and mTORC1 in response to cycles of binge drinking of 20 percent alcohol was centered in the NAc shell. Both kinases were not activated in the dorsolateral striatum (DLS); however, AKT, but not mTORC1, was activated in the dorsomedial striatum (DMS) of mice but not rats. Interestingly, excessive intake of alcohol produced a selective activation of the AKT/mTORC1 pathway in the orbitofrontal cortex (OFC), which was not observed in medial prefrontal cortex (mPFC). Furthermore, this signaling pathway was not activated in the NAc shell or OFC of rats consuming moderate amounts of alcohol nor was it activated in rats consuming sucrose. Together, our results suggest that excessive alcohol intake produces a brain region selective activation of the AKT/mTORC1 pathway, which is likely to contribute to NAc shell and OFC-dependent mechanisms that underlie the development and maintenance of alcohol drinking behavior.

Extended exposure to sugar and/or caffeine produces distinct behavioral and neurochemical profiles in the orbitofrontal cortex of rats: Implications for neural function.

Caffeine is a psychostimulant commonly consumed with high levels of sugar. The increased availability of highly caffeinated, high sugar energy drinks could put some consumers at risk of being exposed to high doses of caffeine and sugar. Notably, research that has examined the consequences of this combination is limited. Here, we explored the effect of chronic exposure to caffeine and/or sugar on behavior and protein levels in the orbitofrontal cortex (OFC) of rats. The OFC brain region has been implicated in neuropsychiatric conditions, including obesity and addiction behaviors. Adult male Sprague-Dawley rats were treated for 26 days with control, caffeine (0.6 g/L), 10% sugar, or combination of both. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label-free quantitative shotgun analysis revealed that 21, 12, and 23% of proteins identified in the OFC were differentially expressed by sugar and/or caffeine. The results demonstrate that the intake of high levels of sugar and/or low to moderate levels of caffeine has different behavioral consequences. Moreover, each treatment results in a unique proteomic profile with different implications for neural health.

Chronic stress affects the number of GABAergic neurons in the orbitofrontal cortex of rats

Cortical GABAergic dysfunctions have been documented by clinical studies in major depression. We used here an animal model for depression and investigated whether long-term stress exposure can affect the number of GABAergic neurons in the orbitofrontal cortex (OFC). Adult male rats were subjected to 7-weeks of daily stress exposure and behaviorally phenotyped as anhedonic or stress-resilient animals. GABAergic interneurons were identified by immunohistochemistry and systematically quantified. We analyzed calbindin-(CB), calretinin-(CR), cholecystokinin-(CCK), parvalbumin-(PV), neuropeptide Y-(NPY) and somatostatin-positive (SST+) neurons in the following specific subareas of the OFC: medial orbital (MO), ventral orbital (VO), lateral orbital (LO) and dorsolateral orbital (DLO) cortex. For comparison, we also analyzed the primary motor cortex (M1) as a non-limbic cortical area. Stress had a pronounced effect on CB+ neurons and reduced their densities by 40–50% in the MO, VO and DLO. Stress had no effect on CCK+, CR+, PV+, NPY+ and SST+ neurons in any cortical areas. None of the investigated GABAergic neurons were affected by stress in the primary motor cortex. Interestingly, in the stress-resilient animals, we observed a significantly increased density of CCK+ neurons in the VO. NPY+ neuron densities were also significantly different between the anhedonic and stress-resilient rats, but only in the LO. Our present data demonstrate that chronic stress can specifically reduce the density of calbindin-positive GABAergic neurons in the orbitofrontal cortex and suggest that NPY and CCK expression in the OFC may relate to the stress resilience of the animals.

Neural Representation of Odor-Guided Behavior in the Rat Olfactory Thalamus.

The mediodorsal thalamus (MDT) is a higher-order corticocortical thalamic nucleus involved in cognition and memory. However, anatomically, the MDT is also the primary site of olfactory representation in the thalamus, receiving strong inputs from olfactory cortex and having reciprocal connections with orbitofrontal cortex (OFC). Nonetheless, its role in olfaction remains unclear. Here, we recorded single units in the MDT, as well as local field potentials in the MDT, piriform cortex (PCX), and OFC in rats performing a two-alternative odor discrimination task. We show that subsets of MDT units display odorant selectivity during sampling, as well as encoding of spatio-motor aspects of the task. Furthermore, the olfactory trans-thalamic network rapidly switches functional connectivity between MDT and cortical areas depending on current task demands, with, for example, MDT-PCX coupling enhanced during odor sampling and MDT-OFC coupling enhanced during the decision/goal approach compared with baseline and presampling. These results demonstrate MDT representation of diverse sensorimotor components of an olfactory task. The mediodorsal thalamus (MDT) is the major olfactory thalamic nucleus and links the olfactory archicortex with the prefrontal neocortex. The MDT is well known to be involved in higher-order cognitive and memory functions, but its role in olfaction is poorly understood. Here, using single-unit and local field potential analyses, we explored MDT function during an odor-guided decision task in rats. We describe MDT odor and multisensory coding and demonstrate behavior-dependent functional connectivity within the MDT/sensory cortex/prefrontal cortex network. Our results suggest a rich representation of olfactory and other information within MDT required to perform this odor-guided task. Our work opens a new model system for understanding MDT function and exploring the important role of MDT in cortical-cortical communication.

Multifaceted Contributions by Different Regions of the Orbitofrontal and Medial Prefrontal Cortex to Probabilistic Reversal Learning.

The ability to adjust behavior in response to changes involving uncertain or probabilistic reward contingencies is an essential survival skill that is impaired in a variety of psychiatric disorders. It is well established that different forms of cognitive flexibility are mediated by anatomically distinct regions of the frontal lobes when reinforcement contingencies are assured, however, less is known about the contribution of these regions to probabilistic reinforcement learning. Here we show that different regions of the orbitofrontal and medial prefrontal cortex make distinct contributions to probabilistic reversal learning. These findings provide novel information about the complex interplay between frontal lobe regions in mediating these processes and accordingly provide insight into possible pathophysiology that underlies impairments in cognitive flexibility observed in mental illnesses.

Quantitative shotgun proteomics reveals extensive changes to the proteome of the orbitofrontal cortex in rats that are hyperactive following withdrawal from a high sugar diet.

In most Westernized societies, there has been an alarming increase in the consumption of sugar-sweetened drinks. For many adults these drinks represent a substantial proportion of their total daily caloric intake. Here we investigated whether extended exposure to sugar changes behavior and protein expression in the orbitofrontal cortex (OFC). Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 10% sucrose solution. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Following the 1-week period free from treatment, sucrose treated rats were significantly more active than the control. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free quantitative shotgun proteomic analyses of three rats from each group found 290 proteins were differentially expressed in the sucrose treated group when compared to the control group. Major changes in the proteome were seen in proteins related to energy metabolism, mitochondrial function and the cellular response to stress. This research does not seek to suggest that sugar will cause specific neurological disorders, however similar changes in proteins have been seen in neurological disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia.

Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex

Impulsivity, which can be subdivided into impulsive action and impulsive choice, is implicated as a factor underlying drug abuse vulnerability. Although previous research has shown that dopamine (DA) systems in prefrontal cortex are involved in impulsivity and substance abuse, it is not known if inherent variation in DA transporter (DAT) function contributes to impulsivity. The current study determined if individual differences in either impulsive action or impulsive choice are related to DAT function in orbitofrontal (OFC) and/or medial prefrontal cortex (mPFC). Rats were first tested both for impulsive action in a cued go/no-go task and for impulsive choice in a delay-discounting task. Following behavioral evaluation, in vitro [3H]DA uptake assays were performed in OFC and mPFC isolated from individual rats. Vmax in OFC, but not mPFC, was correlated with performance in the cued go/no-go task, with decreased OFC DAT function being associated with high impulsive action. In contrast, Vmax in OFC and mPFC was not correlated with performance in the delay-discounting task. The current results demonstrate that impulsive behavior in cued go/no-go performance is associated with decreased DAT function in OFC, suggesting that hyperdopaminergic tone in this prefrontal subregion mediates, at least in part, increased impulsive action.

Role of serotonin transporter function in rat orbitofrontal cortex in impulsive choice

Impulsivity is a multi-faceted personality construct that plays a prominent role in drug abuse vulnerability. Dysregulation of 5-hydroxytryptamine (serotonin, 5-HT) systems in subregions of the prefrontal cortex has been implicated in impulsivity. Extracellular 5-HT concentrations are regulated by 5-HT transporters (SERTs), indicating that these transporters may be important molecular targets underlying individual differences in impulsivity and drug abuse vulnerability. The present study evaluated the role of SERT in mediating individual differences in impulsivity. Rats were tested for both impulsive action using the cued go/no-go task and for impulsive choice using a delay discounting task in a counterbalanced design. Following behavioral evaluation, Km and Vmax were obtained from kinetic analysis of [3H]5-HT uptake by SERT using synaptosomes prepared from both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) obtained from each individual rat. Vmax for SERT in OFC, but not mPFC, was negatively correlated with mean adjusted delay scores in the delay discounting task. In contrast, Vmax for SERT in OFC and mPFC was not correlated with performance in the cued go/no-go task. To further evaluate the relationship between SERT function and impulsive choice, a selective SERT inhibitor, fluoxetine (0, 15, 50 and 150pmol/side) was microinjected bilaterally into OFC and effects on the delay discounting task determined. Following stabilization of behavior, fluoxetine increased mean adjusted delay scores (decreased impulsivity) in high impulsive rats compared to saline microinjection, but had no effect in low impulsive rats. These ex vivo and in vivo results suggest that enhanced SERT function in OFC underlies high impulsive choice behavior.

Orbitofrontal neurons infer the value and identity of predicted outcomes.

The best way to respond flexibly to changes in the environment is to anticipate them. Such anticipation often benefits us if we can infer that a change has occurred, before we have actually experienced the effects of that change. Here we test for neural correlates of this process by recording single-unit activity in the orbitofrontal cortex in rats performing a choice task in which the available rewards changed across blocks of trials. Consistent with the proposal that orbitofrontal cortex signals inferred information, firing changes at the start of each new block as if predicting the not-yet-experienced reward. This change occurs whether the new reward is different in number of drops, requiring signaling of a new value, or in flavor, requiring signaling of a new sensory feature. These results show that orbitofrontal neurons provide a behaviorally relevant signal that reflects inferences about both value-relevant and value-neutral information about impending outcomes.

A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex.

Cytokines, small proteins released by the immune system to combat infection, are typically studied under inflammatory conditions. However, these molecules are also expressed in the brain in basal, nonpathological states, where they can regulate neuronal processes, such as learning and memory. However, little is known about how cytokine signaling in the brain may influence higher-order cognitive functions. Cognitive flexibility is one such executive process, mediated by the prefrontal cortex, which requires an adaptive modification of learned behaviors in response to environmental change. We explored the role of basal IL-6 signaling in the orbitofrontal cortex (OFC) in reversal learning, a form of cognitive flexibility that can be measured in the rat using the attentional set-shifting test. We found that inhibiting IL-6 or its downstream JAK/STAT signaling pathway in the OFC impaired reversal learning, suggesting that basal IL-6 and JAK/STAT signaling facilitate cognitive flexibility. Further, we demonstrated that elevating IL-6 in the OFC by adeno-associated virus-mediated gene delivery reversed a cognitive deficit induced by chronic stress, thus identifying IL-6 and the downstream JAK/STAT signaling pathway as potentially novel therapeutic targets for the treatment of stress-related psychiatric diseases associated with cognitive dysfunction.