Different prefrontal areas contribute in distinctly different ways to rule-guided behaviour in the context of a Wisconsin Card Sorting Test (WCST) analog for macaques. For example, causal evidence from circumscribed lesions in NHPs reveals that dorsolateral prefrontal cortex (dlPFC) is necessary to maintain a reinforced abstract rule in working memory, orbitofrontal cortex (OFC) is needed to rapidly update representations of rule value, and the anterior cingulate cortex (ACC) plays a key role in cognitive control and integrating information for correct and incorrect trials over recent outcomes. Moreover, recent lesion studies of frontopolar cortex (FPC) suggest it contributes to representing the relative value of unchosen alternatives, including rules. Yet we do not understand how these functional specializations relate to intrinsic neuronal activities nor the extent to which these neuronal activities differ between different prefrontal regions. After reviewing the aforementioned causal evidence I will present our new data from studies using multi-area multi-electrode recording techniques in NHPs to simultaneously record from four different prefrontal regions implicated in rule-guided behaviour. Multi-electrode micro-arrays (‘Utah arrays’) were chronically implanted in dlPFC, vlPFC, OFC, and FPC of two macaques, allowing us to simultaneously record single and multiunit activity, and local field potential (LFP), from all regions while the monkey performs the WCST analog. Rule-related neuronal activity was widespread in all areas recorded but it differed in degree and in timing between different areas. I will also present preliminary results from decoding analyses applied to rule-related neuronal activities both from individual clusters and also from population measures. These results confirm and help quantify dynamic task-related activities that differ between prefrontal regions. We also found task-related modulation of LFPs within beta and gamma bands in FPC. By combining this correlational recording methods with trial-specific causal interventions (electrical microstimulation) to FPC we could significantly enhance and impair animals performance in distinct task epochs in functionally relevant ways, further consistent with an emerging picture of regional functional specialization within a distributed framework of interacting and interconnected cortical regions.

The project of functional neuroanatomy typically considers single brain areas as the core functional unit of the brain. Functional neuroanatomists typically use specialized tasks that are designed to isolate hypothesized functions from other cognitive processes. Our lab takes a broader view; specifically, we consider brain regions as parts of larger circuits and we take cognitive processes as part of more complex behavioral repertoires. In my talk, I will discuss the ramifications of this perspective for thinking about the role of the orbitofrontal cortex. I will discuss results of recent experiments from my lab that tackle the question of OFC function within the context of larger brain networks and in freely moving foraging tasks. I will argue that this perspective challenges conventional accounts of the role of OFC and invites new ones. I will conclude by speculating on implications for the practice of functional neuroanatomy.

Goal-directed navigation requires precise estimates of spatial relationships between current position and future goal, as well as planning of an associated route or action. While neurons in the hippocampal formation can represent the animal’s position and nearby trajectories, their role in determining the animal’s destination or action has been questioned. We thus hypothesize that brain regions outside the hippocampal formation may play complementary roles in navigation, particularly for guiding goal-directed behaviours based on the brain’s internal cognitive map. In this seminar, I will first describe a subpopulation of neurons in the retrosplenial cortex (RSC) that increase their firing when the animal approaches environmental boundaries, such as walls or edges. This boundary coding is independent of direct visual or tactile sensation but instead depends on inputs from the medial entorhinal cortex (MEC) that contains spatial tuning cells, such as grid cells or border cells. However, unlike MEC border cells, we found that RSC border cells encode environmental boundaries in a self-centred egocentric coordinate frame, which may allow an animal for efficient avoidance from approaching walls or edges during navigation. I will then discuss whether the brain can possess a precise estimate of remote target location during active environmental exploration. Such a spatial code has not been described in the hippocampal formation. However, we found that neurons in the rat orbitofrontal cortex (OFC) form spatial representations that persistently point to the animal’s subsequent goal destination throughout navigation. This destination coding emerges before navigation onset without direct sensory access to a distal goal, and are maintained via destination-specific neural ensemble dynamics. These findings together suggest key roles for extra-hippocampal regions in spatial navigation, enabling animals to choose appropriate actions toward a desired destination by avoiding possible dangers.

Classic economists proposed that economic choices rely on the computation and comparison of subjective values. This hypothesis continues to inform economic theory and experimental research, but behavioral measures are ultimately not sufficient to prove the proposal. Consistent with the hypothesis, when agents make choices, neurons in the orbitofrontal cortex (OFC) encode the subjective value of offered and chosen goods. Moreover, neuronal activity in this area suggests the formation of a decision. However, it is unclear whether these neural processes are causally related to choices. More generally, the evidence linking choices to value signals in the brain remains correlational. In my talk, I will present recent results showing that neuronal activity in OFC are causal to economic choices.

Human neuroimaging research has consistently shown that drug addiction is associated with structural and functional changes within the orbitofrontal cortex (OFC). In view of the important role of the OFC in value-based decision-making, these changes have been hypothesised to bias choice towards drug use despite and at the expense of other competing pursuits, thereby explaining drug addiction. Here I will present in vivo recording data in the OFC supporting this hypothesis in a choice-based model of addiction where rats could choose between two actions, one rewarded by a drug (cocaine or heroin), the other by a nondrug alternative (saccharin).

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, I will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, our multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk I will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising neuroimaging studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging for empirically guiding the development of effective neurorehabilitation strategies (encompassing cognitive reappraisal and transcranial direct current stimulation) in drug addiction.

Learning the consequences our choices have as we interact with our world is critical for flexible behavior. Relational knowledge of one’s environment gives structure to otherwise-individual one-to-one stimulus-outcome mappings, providing a substrate to globally update behavioral contingencies in the face of changes in the landscape of reward. In the brain, this relational knowledge is thought to be encoded in the hippocampus (HPC) in the form of a cognitive map, while prefrontal regions, such as orbitofrontal cortex (OFC), are thought to instantiate subjective estimates of location on the map, though direct neurophysiological evidence is lacking. In this talk, I will present recent work demonstrating the causal relationship between HPC and OFC as nonhuman primates perform a reward learning task requiring them to learn and maintain knowledge of changing stimulus-outcome associations. I will then provide direct evidence that single primate hippocampal neurons represent an abstract map of the value space defined by the task. Finally, I use behavioral modeling to highlight one possible strategy by which knowledge of value space is exploited by animals to detect changes in choice-outcome mappings and proactively update their behavior in response.

Animals are motivated to acquire knowledge. A particularly striking example is information seeking behavior: animals often seek out sensory cues that will inform them about the properties of uncertain future rewards, even when there is no way for them to use this information to influence the reward outcome, and even when this information comes at a considerable cost. Evidence from monkey electrophysiology and human fMRI studies suggests that orbitofrontal cortex and midbrain dopamine neurons represent the subjective value of knowledge during information seeking behavior. However, it remains unclear how the brain assigns value to information and how it integrates this with other incentives to drive behavior. We have therefore developed a task to test if information preferences are present in mice and study how informational value is imparted on stimuli. Mice are trained to enter a center port and receive an initial odor that instructs them to either go to an informative side port, go to an uninformative side port, or choose freely between them. The chosen side port then yields a second odor cue followed by a delayed probabilistic water reward. The informative port’s odor cue indicates whether the upcoming reward will be big or small. The uninformative port’s odor cue is uncorrelated with the trial outcome. Crucially, the two ports only differ in their odor cues, not in their water value since both offer identical probabilities of big and small rewards. We find that mice prefer the informative port. This preference is evident as a higher percentage choice of the informative port when given a free choice (67% +/- 1.7%, n = 14, p < 0.03), as well as by faster reaction times when instructed to go to the informative port (544ms +/- 21ms vs 795ms +/- 21ms, n = 14, p < 0.001). The preference for information is robust to within-animal reversals of informative and uninformative port locations, and, moreover, mice are willing to pay for information by choosing the informative port even if its reward amount is reduced to be substantially lower than the uninformative port. These behavioral observations suggest that odor stimuli are imparted with informational value as mice learn the information seeking task. We are currently imaging neural activity in orbitofrontal cortex with microendoscopes to identify changes in neural activity that may reflect value associated with the acquisition of knowledge.

Inhibitory microcircuits play an important role regulating cortical responses to sensory stimuli. Interneurons that inhibit dendritic or somatic integration are gatekeepers for neural activity, synaptic plasticity and the formation of sensory representations. We have been investigating the synaptic plasticity mechanisms underlying the formation of ensembles in olfactory and orbitofrontal cortex. We have been focusing on the roles of three inhibitory neuron classes in gating excitatory synaptic plasticity in olfactory cortex- somatostatin (SST-INs), parvalbumin (PV-INs), and vasoactive intestinal polypeptide (VIP-INs) interneurons. Further, we are investigating the rules for inhibitory plasticity and a potential role in stabilizing ensembles in associative cortices. I will present new findings to support distinct roles for different interneuron classes in the gating and stabilization of ensemble representations of olfactory responses.