Top-down anticipatory control in prefrontal cortex

Summary The prefrontal cortex has been implicated in a wide variety of executive functions, many involving some form of anticipatory attention. Anticipatory attention involves the pre-selection of specific sensory circuits to allow fast and efficient stimulus processing and a subsequently fast and accurate response. It is generally agreed that the prefrontal cortex plays a critical role in anticipatory attention by exerting a facilitatory “top-down” bias on sensory pathways. In this paper we review recent results indicating that synchronized activity in prefrontal cortex, during anticipation of visual stimulus, can predict features of early visual stimulus processing and behavioral response. Although the mechanisms involved in anticipatory attention are still largely unknown, we argue that the synchronized oscillation in prefrontal cortex is a plausible candidate during sustained visual anticipation. We further propose a learning hypothesis that explains how this top-down anticipatory control in prefrontal cortex is learned based on accumulated prior experience by adopting a Temporal Difference learning algorithm.     

Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex

Dorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding.     

Gene expression changes in the prefrontal cortex, anterior cingulate cortex and nucleus accumbens of mood disorders subjects that committed suicide

Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P ≤ 0.01 and fold change ± 1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain.     

Specific contributions of ventromedial, anterior cingulate, and lateral prefrontal cortex for attentional selection and stimulus valuation

Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. These valuation signals were topographically largely separated from neurons predicting the stimulus location to which attention covertly shifted, and which were evident across the complete medial-to-lateral extent of the PFC, encompassing anterior cingulate cortex (ACC), and lateral PFC (LPFC). LPFC responses showed particularly early-onset selectivity and primarily facilitated attention shifts to contralateral targets. Spatial selectivity within ACC was delayed and heterogeneous, with similar proportions of facilitated and suppressed responses during contralateral attention shifts. The integration of spatial and valuation signals about attentional target stimuli was observed in a confined cluster of neurons at the intersection of vmPFC, ACC, and LPFC. These results suggest that valuation processes reflecting stimulus-specific outcome predictions are recruited during covert attentional control. Value predictions and the spatial identification of attentional targets were conveyed by largely separate neuronal populations, but were integrated locally at the intersection of three major prefrontal areas, which may constitute a functional hub within the larger attentional control network.     

Behavioral shifts and action valuation in the anterior cingulate cortex

Rapid optimization of behavior requires decisions about when to explore and when to exploit discovered resources. The mechanisms that lead to fast adaptations and their interaction with action valuation are a central issue. We show here that the anterior cingulate cortex (ACC) encodes multiple feedbacks devoted to exploration and its immediate termination. In a task that alternates exploration and exploitation periods, the ACC monitored negative and positive outcomes relevant for different adaptations. In particular, it produced signals specific of the first reward, i.e., the end of exploration. Those signals disappeared in exploitation periods but immediately transferred to the initiation of trials-a transfer comparable to learning phenomena observed for dopaminergic neurons. Importantly, these were also observed for high gamma oscillations of local field potentials shown to correlate with brain imaging signal. Thus, mechanisms of action valuation and monitoring of events/actions are combined for rapid behavioral regulation.     

Pathology of the anterior cingulate cortex in obsessive-compulsive disorder

In this article, the characteristics of the functional activity of the anterior cingulate cortex (ACC), a key element of the neuroanatomical error detection system of the brain in drug-resistant forms of obsessive-compulsive disorder (OCD) are discussed on the basis of both original and published data. Available data indicate the presence of a functional deficit zone in the ACC during PCD. This fact suggests that the functions of the ACC in OCD patients are partially redistributed between other brain areas. Thus, in contrast to the previously accepted ideas, the target of stereotactic surgery for OCD is a pathologically altered brain region. Probably, this explains the fact that the operation does not lead to significant changes in the patient’s psyche. The pathological reorganization of the functional activity of the brain in OCD remains unclear and requires further investigation.     

Long-term potentiation in the anterior cingulate cortex and chronic pain

Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli from the periphery ‘teach’ humans and animals to avoid potentially dangerous objects or environments, whereas tissue injury itself causes unnecessary chronic pain that can even last for long periods of time. Conventional pain medicines often fail to control chronic pain. Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain. Injuries trigger long-term potentiation of synaptic transmission in the spinal cord dorsal horn and anterior cingulate cortex, and such persistent potentiation does not require continuous neuronal activity from the periphery. At the synaptic level, potentiation of excitatory transmission caused by injuries may be mediated by the enhancement of glutamate release from presynaptic terminals and potentiated postsynaptic responses of AMPA receptors. Preventing, ‘erasing’ or reducing such potentiation may serve as a new mechanism to inhibit chronic pain in patients in the future.     

Pavlovian fear memory induced by activation in the anterior cingulate cortex

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA_A receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception.     

GABAergic disinhibition facilitates polysynaptic excitatory transmission in rat anterior cingulate cortex

Various studies implicate the anterior cingulate cortex (ACC) in processing pain. Combining whole-cell patch clamp recordings in rat ACC slices and a formalin-induced conditioned place avoidance (F-CPA) behavioral model, the present study was to address the effect of GABA(A) receptors on excitatory transmission to ACC layer V neurons and its possible functional significance related to pain. Removal of GABA(A) inhibition by bicuculline (10 microM) induced a novel long-lasting response in layer V neurons, which could be blocked by high divalent extracellular solution and was sensitive to relatively higher rate stimuli. Co-application of NMDA receptor antagonist APV (50 microM) and non-NMDA receptor antagonist DNQX (10 microM) completely blocked the responses. Enhancement of inhibition by intra-ACC microinjection of muscimol abolished the acquisition of F-CPA without affecting formalin-induced acute nociceptive responses. These results suggest that GABA(A) inhibition may be involved in pain-related aversion by modulating glutamate-mediated excitatory transmission in the ACC.     

Shift in the intrinsic excitability of medial prefrontal cortex neurons following training in impulse control and cued-responding tasks

Impulse control is an executive process that allows animals to inhibit their actions until an appropriate time. Previously, we reported that learning a simple response inhibition task increases AMPA currents at excitatory synapses in the prelimbic region of the medial prefrontal cortex (mPFC). Here, we examined whether modifications to intrinsic excitability occurred alongside the synaptic changes. To that end, we trained rats to obtain a food reward in a response inhibition task by withhold responding on a lever until they were signaled to respond. We then measured excitability, using whole-cell patch clamp recordings in brain slices, by quantifying action potentials generated by the injection of depolarizing current steps. Training in this task depressed the excitability of layer V pyramidal neurons of the prelimbic, but not infralimbic, region of the mPFC relative to behavioral controls. This decrease in maximum spiking frequency was significantly correlated with performance on the final session of the task. This change in intrinsic excitability may represent a homeostatic mechanism counterbalancing increased excitatory synaptic inputs onto those neurons in trained rats. Interestingly, subjects trained with a cue that predicted imminent reward availability had increased excitability in infralimbic, but not the prelimbic, pyramidal neurons. This dissociation suggests that both prelimbic and infralimbic neurons are involved in directing action, but specialized for different types of information, inhibitory or anticipatory, respectively.     

Cellular localization of cannabinoid receptors and activated G-proteins in rat anterior cingulate cortex

Cannabinoid receptors are found in moderate density throughout the cerebral cortex. The anterior cingulate cortex (ACC) is of particular interest due its high level of cannabinoid receptors and role in behaviors known to be modulated by cannabinoids. These studies were conducted to determine the cellular localization of cannabinoid receptors and to compare the level of cannabinoid receptor binding with receptor-mediated G-protein activity in the rat ACC. Either ibotenic acid or undercut lesions were made in ACC, and brains were processed for [3H]WIN 55,212-2 and WIN 55,212-2-stimulated [35S]GTPgammaS autoradiography. Both cannabinoid receptors and receptor-activated G-proteins were highest in laminae I and VI of ACC in control tissue. Although similar levels of receptor binding were found in these laminae, significantly higher levels of receptor-activated G-proteins were found in lamina VI. Ibotenic acid lesions that destroyed ACC neurons decreased [3H]WIN 55,212-2 binding by 60-70% and eliminated WIN 55,212-2-stimulated [35S]GTPgammaS binding. In contrast, deafferentation of the ACC with undercut lesions had no significant effect on cannabinoid receptor binding or G-protein activation. These results indicate that cannabinoid receptors in laminae I and VI of the ACC are located on somatodendritic elements or axons intrinsic to the ACC. In addition, differences in the relative levels of cannabinoid binding sites and activated G-proteins between cortical laminae indicate that the efficiency of cannabinoid receptors for G-protein activation may vary within a specific brain region.     

Anterior medial prefrontal cortex exhibits activation during task preparation but deactivation during task execution

Background

The anterior prefrontal cortex (PFC) exhibits activation during some cognitive tasks, including episodic memory, reasoning, attention, multitasking, task sets, decision making, mentalizing, and processing of self-referenced information. However, the medial part of anterior PFC is part of the default mode network (DMN), which shows deactivation during various goal-directed cognitive tasks compared to a resting baseline. One possible factor for this pattern is that activity in the anterior medial PFC (MPFC) is affected by dynamic allocation of attentional resources depending on task demands. We investigated this possibility using an event related fMRI with a face working memory task.

Methodology/Principal Findings

Sixteen students participated in a single fMRI session. They were asked to form a task set to remember the faces (Face memory condition) or to ignore them (No face memory condition), then they were given 6 seconds of preparation period before the onset of the face stimuli. During this 6-second period, four single digits were presented one at a time at the center of the display, and participants were asked to add them and to remember the final answer. When participants formed a task set to remember faces, the anterior MPFC exhibited activation during a task preparation period but deactivation during a task execution period within a single trial.

Conclusions/Significance

The results suggest that the anterior MPFC plays a role in task set formation but is not involved in execution of the face working memory task. Therefore, when attentional resources are allocated to other brain regions during task execution, the anterior MPFC shows deactivation. The results suggest that activation and deactivation in the anterior MPFC are affected by dynamic allocation of processing resources across different phases of processing.     

A synaptic model for pain: long-term potentiation in the anterior cingulate cortex

Investigation of molecular and cellular mechanisms of synaptic plasticity is the major focus of many neuroscientists. There are two major reasons for searching new genes and molecules contributing to central plasticity: first, it provides basic neural mechanism for learning and memory, a key function of the brain; second, it provides new targets for treating brain-related disease. Long-term potentiation (LTP), mostly intensely studies in the hippocampus and amygdala, is proposed to be a cellular model for learning and memory. Although it remains difficult to understand the roles of LTP in hippocampus-related memory, a role of LTP in fear, a simplified form of memory, has been established. Here, I will review recent cellular studies of LTP in the anterior cingulate cortex (ACC) and then compare studies in vivo and in vitro LTP by genetic/ pharmacological approaches. I propose that ACC LTP may serve as a cellular model for studying central sensitization that related to chronic pain, as well as pain-related cognitive emotional disorders. Understanding signaling pathways related to ACC LTP may help us to identify novel drug target for various mental disorders.     

NMDA受体参与小鼠的前额扣带回的神经突触传递

谷氨酸性突触是哺乳动物神经系统的主要兴奋性突触。在正常条件下,大多数的突触反应是由谷氨酸的AMPA受体传递的。NMDA受体在静息电位下为镁离子抑制。在被激活时,NMDA受体主要参与突触的可塑性变化。但是,许多NMDA受体拮抗剂在全身或局部注射时能产生行为效应,提示NMDA受体可能参与静息状态的生理功能。此文中,我们在离体的前额扣带回脑片上进行电生理记录,发现NMDA受体参与前额扣带回的突触传递。在重复刺激或近于生理性温度时,NMDA受体传递的反应更为明显。本文直接显示了NMDA受体参与前额扣带回的突触传递,并提示NMDA受体在前额扣带回中起着调节神经元兴奋的重要作用。     

Dopamine receptors regulate NMDA receptor surface expression in prefrontal cortex neurons

Interactions between dopamine (DA) and glutamate systems in the prefrontal cortex (PFC) are important in addiction and other psychiatric disorders. Here, we examined DA receptor regulation of NMDA receptor surface expression in postnatal rat PFC neuronal cultures. Immunocytochemical analysis demonstrated that surface expression (synaptic and non-synaptic) of NR1 and NR2B on PFC pyramidal neurons was increased by the D1 receptor agonist SKF 81297 (1 microM, 5 min). Activation of protein kinase A (PKA) did not alter NR1 distribution, indicating that PKA does not mediate the effect of D1 receptor stimulation. However, the tyrosine kinase inhibitor genistein (50 microM, 30 min) completely blocked the effect of SKF 81297 on NR1 and NR2B surface expression. Protein cross-linking studies confirmed that SKF 81297 (1 microM, 5 min) increased NR1 and NR2B surface expression, and further showed that NR2A surface expression was not affected. Genistein blocked the effect of SKF 81297 on NR1 and NR2B. Surface-expressed immunoreactivity detected with a phospho-specific antibody to tyrosine 1472 of NR2B also increased after D1 agonist treatment. Our results show that tyrosine phosphorylation plays an important role in the trafficking of NR2B-containing NMDA receptors in PFC neurons and the regulation of their trafficking by DA receptors.     

Primate anterior cingulate cortex: where motor control, drive and cognition interface

Controversy surrounds the function of the anterior cingulate cortex. Recent discussions about its role in behavioural control have centred on three main issues: its involvement in motor control, its proposed role in cognition and its relationship with the arousal/drive state of the organism. I argue that the overlap of these three domains is key to distinguishing the anterior cingulate cortex from other frontal regions, placing it in a unique position to translate intentions to actions.