Prefrontal Cortex Circuits Research Articles

Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions.

Our understanding of depression and its treatment has advanced with the advent of ketamine as a rapid acting antidepressant and the development and refinement of tools capable of selectively altering the activity of populations of neuronal subtypes. This work has resulted in a paradigm shift away from dysregulation of single neurotransmitter systems in depression towards circuit level abnormalities impacting function across multiple brain regions and neurotransmitter systems. Studies on the features of circuit level abnormalities demonstrate structural changes within the prefrontal cortex (PFC) and functional changes in its communication with distal brain structures. Treatments that impact the activity of brain regions, such as transcranial magnetic stimulation or rapid acting antidepressants like ketamine, appear to reverse depression associated circuit abnormalities though the mechanisms underlying the reversal, as well as development of these abnormalities remains unclear. Recently developed optogenetic and chemogenetic tools that allow high fidelity control of neuronal activity in pre-clinical models have begun to elucidate the contributions of the PFC and its circuitry to depression- and anxiety-like behavior. These tools offer unprecedented access to specific circuits and neuronal subpopulations that promise to offer a refined view of the circuit mechanisms surrounding depression and potential mechanistic targets for development and reversal of depression associated circuit abnormalities.

Anxiety and Stress Alter Decision-Making Dynamics and Causal Amygdala-Dorsolateral Prefrontal Cortex Circuits During Emotion Regulation in Children

BackgroundAnxiety and stress reactivity are risk factors for the development of affective disorders. However, the behavioral and neurocircuit mechanisms that potentiate maladaptive emotion regulation are poorly understood. Neuroimaging studies have implicated the amygdala and dorsolateral prefrontal cortex (DLPFC) in emotion regulation, but how anxiety and stress alter their context-specific causal circuit interactions is not known. Here, we use computational modeling to inform affective pathophysiology, etiology, and neurocircuit targets for early intervention. MethodsForty-five children (10–11 years of age; 25 boys) reappraised aversive stimuli during functional magnetic resonance imaging scanning. Clinical measures of anxiety and stress were acquired for each child. Drift-diffusion modeling of behavioral data and causal circuit analysis of functional magnetic resonance imaging data, with a National Institute of Mental Health Research Domain Criteria approach, were used to characterize latent behavioral and neurocircuit decision-making dynamics driving emotion regulation. ResultsChildren successfully reappraised negative responses to aversive stimuli. Drift-diffusion modeling revealed that emotion regulation was characterized by increased initial bias toward positive reactivity during viewing of aversive stimuli and increased drift rate, which captured evidence accumulation during emotion evaluation. Crucially, anxiety and stress reactivity impaired latent behavioral dynamics associated with reappraisal and decision making. Anxiety and stress increased dynamic casual influences from the right amygdala to DLPFC. In contrast, DLPFC, but not amygdala, reactivity was correlated with evidence accumulation and decision making during emotion reappraisal. ConclusionsOur findings provide new insights into how anxiety and stress in children impact decision making and amygdala-DLPFC signaling during emotion regulation, and uncover latent behavioral and neurocircuit mechanisms of early risk for psychopathology.

Parvalbumin Interneuron Dysfunction in a Thalamo-Prefrontal Cortical Circuit in Disc1 Locus Impairment Mice.

Altered cortical excitation-inhibition (E-I) balance resulting from abnormal parvalbumin interneuron (PV IN) function is a proposed pathophysiological mechanism of schizophrenia and other major psychiatric disorders. Preclinical studies have indicated that disrupted-in-schizophrenia-1 (Disc1) is a useful molecular lead to address the biology of prefrontal cortex (PFC)-dependent cognition and PV IN function. To date, PFC inhibitory circuit function has not been investigated in depth in Disc1 locus impairment (LI) mouse models. Therefore, we used a Disc1 LI mouse model to investigate E-I balance in medial PFC (mPFC) circuits. We found that inhibition onto layer 2/3 excitatory pyramidal neurons in the mPFC was significantly reduced in Disc1 LI mice. This reduced inhibition was accompanied by decreased GABA release from local PV, but not somatostatin (SOM) INs, and by impaired feedforward inhibition (FFI) in the mediodorsal thalamus (MD) to mPFC circuit. Our mechanistic findings of abnormal PV IN function in a Disc1 LI model provide insight into biology that may be relevant to neuropsychiatric disorders including schizophrenia.

Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.

Structural and Functional Abnormities of Amygdala and Prefrontal Cortex in Major Depressive Disorder With Suicide Attempts.

Finding neural features of suicide attempts (SA) in major depressive disorder (MDD) may be helpful in preventing suicidal behavior. The ventral and medial prefrontal cortex (PFC), as well as the amygdala form a circuit implicated in emotion regulation and the pathogenesis of MDD. The aim of this study was to identify whether patients with MDD who had a history of SA show structural and functional connectivity abnormalities in the amygdala and PFC relative to MDD patients without a history of SA. We measured gray matter volume in the amygdala and PFC and amygdala-PFC functional connectivity using structural and functional magnetic resonance imaging (MRI) in 158 participants [38 MDD patients with a history of SA, 60 MDD patients without a history of SA, and 60 healthy control (HC)]. MDD patients with a history of SA had decreased gray matter volume in the right and left amygdala (F = 30.270, P = 0.000), ventral/medial/dorsal PFC (F = 15.349, P = 0.000), and diminished functional connectivity between the bilateral amygdala and ventral and medial PFC regions (F = 22.467, P = 0.000), compared with individuals who had MDD without a history of SA, and the HC group. These findings provide evidence that the amygdala and PFC may be closely related to the pathogenesis of suicidal behavior in MDD and implicate the amygdala-ventral/medial PFC circuit as a potential target for suicide intervention.

Effects of ketamine and other rapidly acting antidepressants on hippocampal excitatory and inhibitory transmission.

A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior. Intense research has centered on the effects of ketamine, and the other rapidly acting antidepressants, on excitatory and inhibitory circuits in hippocampus and medial prefrontal cortex to determine common mechanisms, including key modifications in synaptic transmission and the precise location of the NMDARs that mediate the rapid and sustained antidepressant response. We review data comparing the effects of ketamine with other NMDAR receptor modulators and the muscarinic M1 acetylcholine receptor antagonist, scopolamine, together with evidence supporting the disinhibition hypothesis and the direct inhibition hypothesis of ketamine's mechanism of action on synaptic circuits using preclinical models.

Dopamine Gates Visual Signals in Monkey Prefrontal Cortex Neurons

The neurotransmitter dopamine, which acts via the D1-like receptor (D1R) and D2-like receptor (D2R) family, may play an important role in gating sensory information to the prefrontal cortex (PFC). We tested this hypothesis in awake macaques and recorded visual motion-direction tuning functions of single PFC neurons. Using micro-iontophoretic drug application combined with single-unit recordings, we simulated receptor-specific dopaminergic input to the PFC and explored cellular gating mechanisms. We find that stimulating D1Rs, and particularly D2Rs, enhances the single-neuron and populationcoding quality in PFC neurons. D2R stimulation causes aclear increase of the neurons' responses to the preferred motion direction and a decrease to the non-preferred motion direction, thus enhancing neuronal signal-to-noise ratio. Neither D1R nor D2R stimulation had any impact on the neurons' tuning sharpness. These results elucidate the mechanisms of how receptor-specific dopamine effects can act as a gating signal that enables privileged access of sensory information to PFC circuits.

Sign and goal tracker rats process differently the incentive salience of a conditioned stimulus.

Sign and goal tracker animals show different behavioral patterns in response to conditioned stimuli, which may be driven by different neural circuits involved in processing stimuli. Here, we explored whether sign and goal-tracker profiles implicated different brain regions and responses to incentive salience of stimuli. We performed three experiments using male Wistar rats. Experiment 1 showed that lesioning the medial prefrontal cortex increased the prevalence of the goal-tracker phenotype. Experiment 2 assessed the developmental trajectory of the salience incentive attribution to a conditioned stimulus, showing that increased incentive salience of stimuli increased the prevalence of the sign-tracker phenotype in mature, but not preadolescent rats. In experiment 3, the functional impact of the medial prefrontal cortex circuits was analyzed with a latent inhibition procedure. Sign tracker rats showed a reduced latent inhibition to stimuli previously exposed when compared to goal tracker or intermediate rats. The overall results of this study highlight a key role of the medial prefrontal cortex for sign tracking behavior. The expression of sign and goal tracker phenotypes changed after lesion to the medial prefrontal cortex (experiment 1), differed across development (experiment 2), and showed differences in the attentional processes to previously exposed stimuli, as preexposure to CS was ineffective in sign tracker animals (experiment 3). These data indicate that the responses to the incentive salience of stimuli in sign tracker and goal tracker profiles are likely driven by different neural circuitry, with a different role of prefrontal cortical function.

Distraction of olfactory bulb-medial prefrontal cortex circuit may induce anxiety-like behavior in allergic rhinitis.

Allergic rhinitis is a chronic inflammatory disease of the upper respiratory tract, which is associated with high incidence of anxiety symptom. There is evidence that medial prefrontal cortex modulates anxiety-related behaviors and receives projections from olfactory bulb. Since olfactory dysfunction has been reported in allergic rhinitis, we aimed to evaluate anxiety-like behavior and oscillations of olfactory bulb-medial prefrontal cortex circuit in an animal model of allergic rhinitis. The number of open arm entries in elevated zero maze was significantly reduced in sensitized rats exposed to intranasal ovalbumin compared to the control group, which was indicating the enhancement of anxiety-like behavior in allergic rhinitis animals. Analysis of local field potentials in olfactory bulb and medial prefrontal cortex during immobility and exploration state showed that anxiety-like behavior induced by allergic rhinitis was in association with increased activity of medial prefrontal cortex and enhancement of olfactory bulb-medial prefrontal cortex coupling in delta and theta bands. Moreover, in allergic rhinitis animals, theta strongly coordinates local gamma activity in olfactory bulb and medial prefrontal cortex, which means to have a strong local theta/gamma coupling. We suggested that disruption of olfactory bulb-medial prefrontal cortex circuit due to allergic reactions might have a governing role for inducing anxiety-like behavior in the allergic rhinitis experimental model.

Interleukin 6 Dependent Synaptic Plasticity in a Social Defeat-Susceptible Prefrontal Cortex Circuit

The role of the pro-inflammatory cytokine interleukin-6 (IL-6) in the etiology of stress-induced synaptic plasticity is yet unknown. We took advantage of a genetically modified mouse (TG) in which IL-6 trans-signaling via the soluble IL-6 receptor was blocked, to determine the role of IL-6 trans-signaling in the effects of a Social Defeat protocol (SD) on synaptic function of the medial prefrontal cortex (mPFC). Synaptic function in stress-sensitive (S) and stress-resilient (R) animals was studied in a mPFC slice preparation with whole-cell patch-clamp recording. SD altered numerous synaptic properties of the mPFC: R WT (but not TG) displayed a decreased ratio between N methyl-D-aspartate receptor (NMDAR-) dependent and amino propionic acid receptor (AMPAR-) dependent-current (INMDA/IAMPA), while S WT animals (but not TG) showed a reduced ratio between AMPA and γ-amino-butyric acid receptor type A (GABAAR)-dependent currents (IAMPA/IGABA). Also, SD induced an increase in the frequency but a decrease in the amplitude of excitatory action-potential dependent PSCs (sEPSCs), both in an IL-6 dependent manner, as well as a generalized (S/R-independent) decrease in the frequency of action potential independent (miniature) excitatory (IL-6 dependent) as well as inhibitory (IL-6 independent) postsynaptic current frequency. Interestingly, corner preference (measuring the intensity of social defeat) correlated positively with INMDA/IAMPA and eEPSC frequency and negatively with IAMPA/IGABA. Our results suggest that SD induces behaviorally-relevant synaptic rearrangement in mPFC circuits, part of which is IL-6 dependent. In particular, IL-6 is necessary to produce synaptic plasticity leading to stress resilience in some individuals, but to stress sensitivity in others.

Pubertal development mediates the association between family environment and brain structure and function in childhood.

Psychosocial acceleration theory suggests that pubertal maturation is accelerated in response to adversity. In addition, suboptimal caregiving accelerates development of the amygdala-medial prefrontal cortex circuit. These findings may be related. Here, we assess whether associations between family environment and measures of the amygdala-medial prefrontal cortex circuit are mediated by pubertal development in more than 2000 9- and 10-year-old children from the Adolescent Brain Cognitive Development Study (http://dx.doi.org/10.15154/1412097). Using structural equation modeling, demographic, child-reported, and parent-reported data on family dynamics were compiled into a higher level family environment latent variable. Magnetic resonance imaging preprocessing and compilations were performed by the Adolescent Brain Cognitive Development Study's data analysis core. Anterior cingulate cortex (ACC) thickness, area, white matter fractional anisotropy, amygdala volume, and cingulo-opercular network-amygdala resting-state functional connectivity were assessed. For ACC cortical thickness and ACC fractional anisotropy, significant indirect effects indicated that a stressful family environment relates to more advanced pubertal stage and more mature brain structure. For cingulo-opercular network-amygdala functional connectivity, results indicated a trend in the expected direction. For ACC area, evidence for quadratic mediation by pubertal stage was found. Sex-stratified analyses suggest stronger results for girls. Despite small effect sizes, structural measures of circuits important for emotional behavior are associated with family environment and show initial evidence of accelerated pubertal development.

The nucleus reuniens of the thalamus sits at the nexus of a hippocampus and medial prefrontal cortex circuit enabling memory and behavior.

The nucleus reuniens of the thalamus (RE) is a key component of an extensive network of hippocampal and cortical structures and is a fundamental substrate for cognition. A common misconception is that RE is a simple relay structure. Instead, a better conceptualization is that RE is a critical component of a canonical higher-order cortico-thalamo-cortical circuit that supports communication between the medial prefrontal cortex (mPFC) and the hippocampus (HC). RE dysfunction is implicated in several clinical disorders including, but not limited to Alzheimer's disease, schizophrenia, and epilepsy. Here, we review key anatomical and physiological features of the RE based primarily on studies in rodents. We present a conceptual model of RE circuitry within the mPFC–RE–HC system and speculate on the computations RE enables. We review the rapidly growing literature demonstrating that RE is critical to, and its neurons represent, aspects of behavioral tasks that place demands on memory focusing on its role in navigation, spatial working memory, the temporal organization of memory, and executive functions.

Does emotion regulation engage the same neural circuit as working memory? A meta-analytical comparison between cognitive reappraisal of negative emotion and 2-back working memory task

Research into cognitive emotion regulation (ER) extends our understanding of human cognition, which is capable of processing objective information and is crucial in maintaining subjective/internal homeostasis. Among various ER strategies, the alleviation of negative emotion via reappraisal is of particular importance for adaptation and psychological well-being. Although still debated, previous neuroimaging studies tend to infer that the reappraisal ER is mediated by the capability of working memory (WM), which has not been examined empirically. This meta-analytical study of published neuroimaging literature used activation likelihood estimation (ALE) to compare the neural circuits that regulate negative emotion (reappraisal tasks; 46 studies/1254 subjects) and execute WM (2-back tasks; 50 studies/1312 subjects), with special emphasis on the prefrontal cortex (PFC). Taking the canonical WM network as a reference, ALE results revealed that the dorsal midline PFC was partly shared by both ER and WM, whereas ER-specific PFC structures were delineated in the inferior, middle, and superior frontal cortices, as well as in the posterior brain regions. The peak coordinates of ER in the middle frontal cortex were dorsal to those of WM by 15.1 mm (left) and 21.6 mm (right). The results support specialized emotion-related neural substrates in the PFC, negating the assumption that reappraisal ER and WM rely on the same neural resources. The holistic picture of "emotional brain" may need to incorporate the emotion-related PFC circuit, together with subcortical and limbic emotion centers.

Valence processing differs across stimulus modalities

Although it is often assumed that valence processing in the prefrontal cortex (PFC) is similar for stimuli originating from different sensory modalities, evidence supporting this view is lacking. To address this, we recruited 20 male participants and used a delayed-response fMRI design to test whether perceived pleasantness of flavors and images is similarly processed in the PFC. As predicted, significant correlations were observed between image and flavor pleasantness ratings, and PFC response to these stimuli; however, these responses were spatially different, with flavor pleasantness reflected in more ventrally located PFC regions than image pleasantness. These results indicate that, contrary to the general assumption of a singular circuit representing pleasantness, distinct PFC circuits are recruited depending upon stimulus modality. We argue that the ventral-dorsal distinction may be attributed to a difference in proximal versus distal stimulus representations.

Defining the Role of Interneuron N-Methyl-D-Aspartate Receptors in Prefrontal Cortex Inhibition

SEE CORRESPONDING ARTICLE ON PAGE 460 Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell–Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal CortexBiological PsychiatryVol. 84Issue 6PreviewTesting hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive and thus are unlikely to participate in NMDAR antagonist–mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses. Full-Text PDF

Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D1 - and D2 -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A2A receptors (A2A R) also control PFC-related responses and A2A R antagonists are potential anti-psychotic drugs. As tight antagonistic A2A R-D2 R and synergistic A2A R-D1 R interactions occur in other brain regions, we now investigated the crosstalk between A2A R and D1 /D2 R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D2 R-like antagonist sulpiride but not by the D1 R antagonist SCH23390 and was mimicked by the D2 R agonist sumanirole, but not by the agonists of either D4 R (A-412997) or D3 R (PD128907). Dopamine inhibition was prevented by the A2A R antagonist, SCH58261, and attenuated in A2A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A2A R and D2 R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A2A R-D2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A2A R antagonists.

Genetic advances in post-traumatic stress disorder

Post-traumatic stress disorder, or PTSD, is a condition that affects a subgroup of individuals that have suffered a previous traumatic event capable of generating changes at a psychological and behavioural level. These changes affect the personal, family, and social environment of those who suffer from this condition. Different genes have been identified as risk markers for development of this disorder. The population heterogeneity and individual differences (genetic and environmental) of each subject have made it difficult to identify valid markers in previous studies. For this reason, studies of Gene×Environment (G×E) have gathered importance in the last two decades, with the aim of identifying of the phenotypes of a particular disease. These studies have included genes such as SLC64A, FKBP5, and ADCYAP1R1, among others. Little is known about the interaction between the genes, pathways, and the molecular and neural circuitry that underlie PTSD. However their identification and association with stimuli and specific environments that stimulate the development of PTSD makes it focus of interest for identify genomic variations in this disorder. In turn, the epigenetic modifications that regulate the expression of genes involved in the hypothalamic–pituitary–adrenal (HPA) axis and the amygdala–hippocampal–medial prefrontal cortex circuits play a role in the identification of biomarkers and endophenotypes in PTSD. In this review, the advances in genetic and epigenetic that have occurred in the genomic era in PTSD are presented.

Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell–Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex

BackgroundTesting hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive and thus are unlikely to participate in NMDAR antagonist–mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses. Thus, if presynaptic NMDARs enhance gamma-aminobutyric acid release at PVBC-to-PC synapses, they could participate in NMDAR-dependent PC disinhibition. Here, we examined whether presynaptic NMDAR effects could modulate gamma-aminobutyric acid release at PVBC-to-PC synapses in mouse PFC. MethodsUsing whole-cell recordings from synaptically connected pairs in mouse PFC, we determined whether NMDA or NMDAR antagonist application affects PVBC-to-PC inhibition in a manner consistent with a presynaptic mechanism. ResultsNMDAR activation enhanced by ∼40% the synaptic current at PVBC-to-PC pairs. This effect was consistent with a presynaptic mechanism given that it was 1) observed with postsynaptic NMDARs blocked by intracellular MK801, 2) associated with a lower rate of transmission failures and a higher transmitter release probability, and 3) blocked by intracellular MK801 in the PVBC. NMDAR antagonist application did not affect the synaptic currents in PVBC-to-PC pairs, but it reduced the inhibitory currents elicited in PCs with simultaneous glutamate release by extracellular stimulation. ConclusionsWe demonstrate that NMDAR activation enhances PVBC-to-PC inhibition in a manner consistent with presynaptic mechanisms, and we suggest that the functional impact of this presynaptic effect depends on the activity state of the PFC network.

Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control.

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease.

Working Memory and Decision-Making in a Frontoparietal Circuit Model.

Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models.SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental "building blocks" of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks.