Controlling one’s world: Identification of sub-regions of primate PFC underlying goal-directed behavior

Impaired detection of causal relationships between actions and their outcomes can lead to maladaptive behavior. However, causal roles of specific prefrontal cortex (PFC) sub-regions and the caudate nucleus in mediating such relationships in primates are unclear. We inactivated and over-activated five PFC sub-regions, reversibly and pharmacologically: areas 24 (perigenual anterior cingulate cortex), 32 (medial PFC), 11 (anterior orbitofrontal cortex, OFC), 14 (rostral ventromedial PFC/medial OFC) and 14-25 (caudal ventromedial PFC), and the anteromedial caudate, to examine their role in expressing learned action-outcome contingencies using a contingency degradation paradigm in marmosets. Area 24 or caudate inactivation impaired the response to contingency change, while area 11 inactivation enhanced it, and inactivation of areas 14, 32 or 14-25 had no effect. Over-activation of areas 11 and 24 impaired this response. These findings demonstrate distinct roles of PFC sub-regions in goal-directed behavior and illuminate the candidate neurobehavioral substrates of psychiatric disorders including obsessive-compulsive disorder.

[1]  HighWire Press Philosophical Transactions of the Royal Society of London , 1781, The London Medical Journal.

[2]  R. Rescorla Predictability and number of pairings in Pavlovian fear conditioning , 1966 .

[3]  L. J. Hammond The effect of contingency upon the appetitive conditioning of free-operant behavior. , 1980, Journal of the experimental analysis of behavior.

[4]  HighWire Press The journal of neuroscience : the official journal of the Society for Neuroscience. , 1981 .

[5]  A. Dickinson Actions and habits: the development of behavioural autonomy , 1985 .

[6]  D. Amaral,et al.  The amygdalostriatal projections in the monkey. An anterograde tracing study , 1985, Brain Research.

[7]  J. Lerma,et al.  Effects of dihydrokainic acid of extracellular amino acids and neuronal excitability in the in vivo rat hippocampus , 1987, Neuropharmacology.

[8]  J. Mazziotta,et al.  Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. , 1988, The American journal of psychiatry.

[9]  A. Dickinson,et al.  The Intentionality of Animal Action , 1990 .

[10]  J. Wadiche,et al.  Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  N. Alpert,et al.  Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. , 1994, Archives of general psychiatry.

[12]  B. Balleine,et al.  Goal-directed instrumental action: contingency and incentive learning and their cortical substrates , 1998, Neuropharmacology.

[13]  R. Swanson,et al.  Astrocyte glutamate transport: Review of properties, regulation, and physiological functions , 2000, Glia.

[14]  Clay B. Holroyd,et al.  The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity. , 2002, Psychological review.

[15]  B. Balleine,et al.  The role of prelimbic cortex in instrumental conditioning , 2003, Behavioural Brain Research.

[16]  S. Haber The primate basal ganglia: parallel and integrative networks , 2003, Journal of Chemical Neuroanatomy.

[17]  M. Walton,et al.  Action sets and decisions in the medial frontal cortex , 2004, Trends in Cognitive Sciences.

[18]  S. Whiteside,et al.  A meta–analysis of functional neuroimaging in obsessive–compulsive disorder , 2004, Psychiatry Research: Neuroimaging.

[19]  E. Rolls The functions of the orbitofrontal cortex , 1999, Brain and Cognition.

[20]  M. Delgado,et al.  Modulation of Caudate Activity by Action Contingency , 2004, Neuron.

[21]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[22]  B. Balleine,et al.  Lesions of Medial Prefrontal Cortex Disrupt the Acquisition But Not the Expression of Goal-Directed Learning , 2005, The Journal of Neuroscience.

[23]  B. Balleine,et al.  The role of the dorsomedial striatum in instrumental conditioning , 2005, The European journal of neuroscience.

[24]  T. Yoshiura,et al.  Brain activation of patients with obsessive-compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: A functional magnetic resonance imaging study , 2005, Biological Psychiatry.

[25]  R. Paulsen,et al.  A microdialysis study in rat brain of dihydrokainate, a glutamate uptake inhibitor , 2006, Neurochemical Research.

[26]  Timothy E. J. Behrens,et al.  Optimal decision making and the anterior cingulate cortex , 2006, Nature Neuroscience.

[27]  C. Padoa-Schioppa,et al.  Neurons in the orbitofrontal cortex encode economic value , 2006, Nature.

[28]  E. Procyk,et al.  Reward encoding in the monkey anterior cingulate cortex. , 2006, Cerebral cortex.

[29]  Timothy Edward John Behrens,et al.  Contrasting roles for cingulate and orbitofrontal cortex in decisions and social behaviour , 2007, Trends in Cognitive Sciences.

[30]  Keiji Tanaka,et al.  Medial prefrontal cell activity signaling prediction errors of action values , 2007, Nature Neuroscience.

[31]  B. Balleine,et al.  Orbitofrontal Cortex Mediates Outcome Encoding in Pavlovian But Not Instrumental Conditioning , 2007, The Journal of Neuroscience.

[32]  Vivian V. Valentin,et al.  Determining the Neural Substrates of Goal-Directed Learning in the Human Brain , 2007, The Journal of Neuroscience.

[33]  Trevor W Robbins,et al.  Forebrain connectivity of the prefrontal cortex in the marmoset monkey (Callithrix jacchus): An anterograde and retrograde tract‐tracing study , 2007, The Journal of comparative neurology.

[34]  H. Seo,et al.  Temporal Filtering of Reward Signals in the Dorsal Anterior Cingulate Cortex during a Mixed-Strategy Game , 2007, The Journal of Neuroscience.

[35]  J. Price Definition of the Orbital Cortex in Relation to Specific Connections with Limbic and Visceral Structures and Other Cortical Regions , 2007, Annals of the New York Academy of Sciences.

[36]  J. O'Doherty,et al.  What We Know and Do Not Know about the Functions of the Orbitofrontal Cortex after 20 Years of Cross-Species Studies , 2007, The Journal of Neuroscience.

[37]  Bruce Fischl,et al.  A Role for the Human Dorsal Anterior Cingulate Cortex in Fear Expression , 2007, Biological Psychiatry.

[38]  E. Bullmore,et al.  Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: The orbitofronto-striatal model revisited , 2008, Neuroscience & Biobehavioral Reviews.

[39]  B. Peterson,et al.  The neural bases of obsessive–compulsive disorder in children and adults , 2008, Development and Psychopathology.

[40]  Richard S. J. Frackowiak,et al.  Evidence for Segregated and Integrative Connectivity Patterns in the Human Basal Ganglia , 2008, The Journal of Neuroscience.

[41]  Timothy E. J. Behrens,et al.  Frontal Cortex Subregions Play Distinct Roles in Choices between Actions and Stimuli , 2008, The Journal of Neuroscience.

[42]  Timothy E. J. Behrens,et al.  Choice, uncertainty and value in prefrontal and cingulate cortex , 2008, Nature Neuroscience.

[43]  B. Balleine,et al.  Calculating Consequences: Brain Systems That Encode the Causal Effects of Actions , 2008, The Journal of Neuroscience.

[44]  John M. Pearson,et al.  Fictive Reward Signals in the Anterior Cingulate Cortex , 2009, Science.

[45]  E. Coutureau,et al.  Transient role of the rat prelimbic cortex in goal‐directed behaviour , 2009, The European journal of neuroscience.

[46]  A. Dickinson,et al.  Associative theories of goal-directed behaviour: a case for animal–human translational models , 2009, Psychological research.

[47]  Kathleen J. Burman,et al.  Architectural subdivisions of medial and orbital frontal cortices in the marmoset monkey (Callithrix jacchus) , 2009, The Journal of comparative neurology.

[48]  D. Barch,et al.  Goal representations and motivational drive in schizophrenia: the role of prefrontal-striatal interactions. , 2010, Schizophrenia bulletin.

[49]  Timothy Edward John Behrens,et al.  Separate value comparison and learning mechanisms in macaque medial and lateral orbitofrontal cortex , 2010, Proceedings of the National Academy of Sciences.

[50]  B. Hayden,et al.  Neurons in Anterior Cingulate Cortex Multiplex Information about Reward and Action , 2010, The Journal of Neuroscience.

[51]  B. Cohen,et al.  Blockade of Astrocytic Glutamate Uptake in Rats Induces Signs of Anhedonia and Impaired Spatial Memory , 2010, Neuropsychopharmacology.

[52]  P. Janak,et al.  Posterior dorsomedial striatum is critical for both selective instrumental and Pavlovian reward learning , 2010, The European journal of neuroscience.

[53]  Rudolf N Cardinal,et al.  Whisker: A client—server high-performance multimedia research control system , 2010, Behavior research methods.

[54]  M. Petrides,et al.  Quantitative demonstration of comparable architectonic areas within the ventromedial and lateral orbital frontal cortex in the human and the macaque monkey brains , 2010, The European journal of neuroscience.

[55]  B. Balleine,et al.  Human and Rodent Homologies in Action Control: Corticostriatal Determinants of Goal-Directed and Habitual Action , 2010, Neuropsychopharmacology.

[56]  E. Coutureau,et al.  Pavlovian to instrumental transfer: A neurobehavioural perspective , 2010, Neuroscience & Biobehavioral Reviews.

[57]  Timothy Edward John Behrens,et al.  Separable Learning Systems in the Macaque Brain and the Role of Orbitofrontal Cortex in Contingent Learning , 2010, Neuron.

[58]  B. Balleine,et al.  Annals of the New York Academy of Sciences the Orbitofrontal Cortex, Predicted Value, and Choice , 2022 .

[59]  E. Murray,et al.  Dissociable Effects of Subtotal Lesions within the Macaque Orbital Prefrontal Cortex on Reward-Guided Behavior , 2011, The Journal of Neuroscience.

[60]  Timothy E. J. Behrens,et al.  Review Frontal Cortex and Reward-guided Learning and Decision-making Figure 1. Frontal Brain Regions in the Macaque Involved in Reward-guided Learning and Decision-making Finer Grained Anatomical Divisions with Frontal Cortical Systems for Reward-guided Behavior , 2022 .

[61]  Mimi Liljeholm,et al.  Neural Correlates of Instrumental Contingency Learning: Differential Effects of Action–Reward Conjunction and Disjunction , 2011, The Journal of Neuroscience.

[62]  John M. Pearson,et al.  Surprise Signals in Anterior Cingulate Cortex: Neuronal Encoding of Unsigned Reward Prediction Errors Driving Adjustment in Behavior , 2011, The Journal of Neuroscience.

[63]  Kate Dimond Fitzgerald,et al.  Developmental alterations of frontal-striatal-thalamic connectivity in obsessive-compulsive disorder. , 2011, Journal of the American Academy of Child and Adolescent Psychiatry.

[64]  S. Kennerley,et al.  Contrasting reward signals in the orbitofrontal cortex and anterior cingulate cortex , 2011, Annals of the New York Academy of Sciences.

[65]  Clay B. Holroyd,et al.  Motivation of extended behaviors by anterior cingulate cortex , 2012, Trends in Cognitive Sciences.

[66]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[67]  E. Murray,et al.  The role of the anterior cingulate cortex in choices based on reward value and reward contingency. , 2013, Cerebral cortex.

[68]  R. Costa,et al.  Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions , 2013, Nature Communications.

[69]  Philippe Mailly,et al.  The Rat Prefrontostriatal System Analyzed in 3D: Evidence for Multiple Interacting Functional Units , 2013, The Journal of Neuroscience.

[70]  P. Dayan,et al.  Goals and Habits in the Brain , 2013, Neuron.

[71]  K. Zilles,et al.  Cingulate area 32 homologies in mouse, rat, macaque and human: Cytoarchitecture and receptor architecture , 2013, The Journal of comparative neurology.

[72]  T. Robbins,et al.  Counterfactual Processing of Economic Action-Outcome Alternatives in Obsessive-Compulsive Disorder: Further Evidence of Impaired Goal-Directed Behavior , 2014, Biological Psychiatry.

[73]  T. Robbins,et al.  Goal-directed learning and obsessive–compulsive disorder , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[74]  S. Haber,et al.  Estimates of Projection Overlap and Zones of Convergence within Frontal-Striatal Circuits , 2014, The Journal of Neuroscience.

[75]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[76]  D. Bates,et al.  Fitting Linear Mixed-Effects Models Using lme4 , 2014, 1406.5823.

[77]  Scott L. Rauch,et al.  Obsessive–compulsive Disorder (ocd) , 2022 .

[78]  Melissa J. Green,et al.  Corticostriatal Control of Goal-Directed Action Is Impaired in Schizophrenia , 2015, Biological Psychiatry.

[79]  Laura A. Bradfield,et al.  Medial Orbitofrontal Cortex Mediates Outcome Retrieval in Partially Observable Task Situations , 2015, Neuron.

[80]  G. Schoenbaum,et al.  What the orbitofrontal cortex does not do , 2015, Nature Neuroscience.

[81]  Guy B. Williams,et al.  Carrots and sticks fail to change behavior in cocaine addiction , 2016, Science.

[82]  Suzanne N. Haber,et al.  Circuit-Based Corticostriatal Homologies Between Rat and Primate , 2016, Biological Psychiatry.

[83]  T. Robbins,et al.  Role of the Perigenual Anterior Cingulate and Orbitofrontal Cortex in Contingency Learning in the Marmoset , 2016, Cerebral cortex.

[84]  B. Balleine,et al.  Appetitive Pavlovian-instrumental Transfer: A review , 2016, Neuroscience & Biobehavioral Reviews.

[85]  H. Clarke,et al.  Opposing roles of primate areas 25 and 32 and their putative rodent homologs in the regulation of negative emotion , 2017, Proceedings of the National Academy of Sciences.

[86]  Justin S. Feinstein,et al.  Selective impairment of goal-directed decision-making following lesions to the human ventromedial prefrontal cortex , 2017, Brain : a journal of neurology.

[87]  Donald G. Rainnie,et al.  Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor , 2017, Biological Psychiatry.

[88]  R. Costa,et al.  Habits , 2014 .

[89]  Suzanne N. Haber,et al.  Convergence of prefrontal and parietal anatomical projections in a connectional hub in the striatum , 2017, NeuroImage.

[90]  H. H. Hulshoff Pol,et al.  GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies , 2017, Front. Psychiatry.

[91]  Wolfgang M. Pauli,et al.  Learning, Reward, and Decision Making , 2017, Annual review of psychology.

[92]  Michael Koenigs,et al.  Human lesion studies of ventromedial prefrontal cortex , 2017, Neuropsychologia.

[93]  S. Haber,et al.  A connectional hub in the rostral anterior cingulate cortex links areas of emotion and cognitive control , 2018, bioRxiv.

[94]  M. Laubach,et al.  What, If Anything, Is Rodent Prefrontal Cortex? , 2018, eNeuro.

[95]  M. Koenigs,et al.  The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition, and Psychopathology , 2017, Biological Psychiatry.

[96]  Laura A. Bradfield,et al.  Prefrontal Corticostriatal Disconnection Blocks the Acquisition of Goal-Directed Action , 2018, The Journal of Neuroscience.

[97]  Shauna L. Parkes,et al.  Insular and Ventrolateral Orbitofrontal Cortices Differentially Contribute to Goal-Directed Behavior in Rodents , 2018, Cerebral cortex.

[98]  Sarah L. Knot,et al.  Shifting the Balance Between Goals and Habits: Five Failures in Experimental Habit Induction , 2018, Journal of experimental psychology. General.

[99]  Berit Brummerloh,et al.  Impaired awareness of action-outcome contingency and causality during healthy ageing and following ventromedial prefrontal cortex lesions , 2018, Neuropsychologia.

[100]  Bernard W. Balleine,et al.  The Bilateral Prefronto-striatal Pathway Is Necessary for Learning New Goal-Directed Actions , 2018, Current Biology.

[101]  S. Killcross,et al.  Functional heterogeneity within the rodent lateral orbitofrontal cortex dissociates outcome devaluation and reversal learning deficits , 2018, eLife.

[102]  Laura A. Bradfield,et al.  Inferring action-dependent outcome representations depends on anterior but not posterior medial orbitofrontal cortex , 2018, Neurobiology of Learning and Memory.

[103]  Melissa J. Green,et al.  Impairments in action–outcome learning in schizophrenia , 2018, Translational Psychiatry.

[104]  Young T. Hong,et al.  Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex , 2019, Neuron.

[105]  Fred A. Hamprecht,et al.  ilastik: interactive machine learning for (bio)image analysis , 2019, Nature Methods.

[106]  T. Robbins,et al.  Obsessive-Compulsive Disorder: Puzzles and Prospects , 2019, Neuron.

[107]  A. Roberts Prefrontal Regulation of Threat-Elicited Behaviors: A Pathway to Translation. , 2020, Annual review of psychology.

[108]  Bernard W. Balleine,et al.  The Meaning of Behavior: Discriminating Reflex and Volition in the Brain , 2019, Neuron.

[109]  M. Bouton,et al.  Chemogenetic Silencing of Prelimbic Cortex to Anterior Dorsomedial Striatum Projection Attenuates Operant Responding , 2019, eNeuro.

[110]  T. Robbins,et al.  Action-Outcome Knowledge Dissociates From Behavior in Obsessive-Compulsive Disorder Following Contingency Degradation , 2018, bioRxiv.

[111]  H. Clarke,et al.  Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- and reward-elicited responses , 2019, Proceedings of the National Academy of Sciences.

[112]  A. Roberts,et al.  Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset , 2020, Proceedings of the National Academy of Sciences.

[113]  Partha P. Mitra,et al.  Open access resource for cellular-resolution analyses of corticocortical connectivity in the marmoset monkey , 2020, Nature Communications.