Subregions Of Medial Prefrontal Cortex Research Articles

Distinctive Roles of Medial Prefrontal Cortex Subregions in Strategic Conformity to Social Hierarchy.

People often align their behaviors and decisions with others' expectations, especially those of higher social positions, when they are being observed. However, little attention has been paid to the neural mechanisms underlying increased conformity to the social hierarchy under social observation. Using a preference rating task, we investigated whether and how individual preferences for novel stimuli were influenced by others' preferences by manipulating others' social hierarchy and observational context. The behavioral results showed that human participants of both sexes were more likely to change their preferences to match those of a superior partner in a public than in a private context. fMRI data revealed distinct contributions of the subregions of the medial prefrontal cortex (mPFC) to increased conformity to social hierarchy under observation. Specifically, the ventral mPFC showed increased activity when participants' preferences aligned with those of superior partners, regardless of behavioral manifestation. The rostral mPFC showed increased activity when conforming to a superior partner and nonconforming to an inferior one, indicating goal-dependent valuation. The dorsal mPFC showed increased activity in private conditions with a superior partner but only in those with a higher tendency to conform. These findings support the hierarchical allostatic regulation model of the mPFC function for social valuation and suggest strategic conformity as a way to minimize metabolic costs.SIGNIFICANCE STATEMENT This study revealed distinct roles of subregions of the mPFC in increased conformity to individuals of different social ranks under observation. Specifically, the ventral mPFC showed increased activity when participants' preferences aligned with those of higher-ranking partners, whereas the rostral mPFC showed increased activity when conforming to a superior partner and nonconforming to an inferior partner, indicating goal-dependent valuation. The dorsal mPFC was more active in private conditions with a superior partner but only in those with a higher tendency to conform. These findings support the hierarchical allostatic regulation model of the mPFC function for social valuation and suggest strategic conformity as a way to minimize metabolic costs.

Inactivation of the infralimbic cortex decreases discriminative stimulus-controlled relapse to cocaine seeking in rats.

Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS-) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days. The behavioral and neural mechanisms underlying trial-based DS-control of drug seeking have rarely been investigated. Here we show that following discrimination training in our trial-based procedure, the DS+ and DS- independently control the expression and suppression of cocaine seeking during abstinence. Using microinjections of GABAA + GABAB receptor agonists (muscimol + baclofen) in medial prefrontal cortex, we report that infralimbic, but not prelimbic, subregion of medial prefrontal cortex is critical to persistent DS-controlled relapse to cocaine seeking after prolonged abstinence, but not DS-guided discriminated cocaine seeking or DS-controlled cocaine self-admininstration. Finally, using ex vivo whole-cell recordings from pyramidal neurons in the medial prefrontal cortex, we demonstrate that the disruption of DS-controlled cocaine seeking following infralimbic cortexmicroinjections of muscimol+baclofen is likely a result of suppression of synaptic transmission in the region via a presynaptic mechanism of action.

Prefrontal corticotropin-releasing factor neurons impair sustained attention via distal transmitter release.

The prefrontal cortex (PFC) supports cognitive processes critical for goal-directed behavior. Although the PFC contains a high density of corticotropin-releasing factor (CRF) neurons, their role in cognition has been largely unexplored. We recently demonstrated that CRF neurons in the caudal dorsomedial PFC (dmPFC) of rats act to impair working memory via activation of local CRF receptors. However, there is heterogeneity in the neural mechanisms that support the diversity of PFC-dependent cognitive processes. Currently, the degree to which PFC CRF neurons impact other forms of PFC-dependent cognition is unknown. To address this issue, the current studies examined the effects of chemogenetic manipulations of PFC CRF neurons on sustained attention in male rats. Similar to working memory, activation of caudal dmPFC CRF neurons impaired, while inhibition of these neurons or global CRF receptor antagonism improved, sustained attention. However, unlike working memory, the sustained attention-impairing effect of PFC CRF neurons was not dependent on local CRF receptors. Moreover, CRF infusion into the caudal dmPFC or other medial PFC subregions had no effect on task performance. Together, these observations demonstrate that while caudal dmPFC CRF neurons impair both working memory and sustained attention, these actions involve distinct neural circuits (local CRF release for working memory and extra-PFC release for sustained attention). Nonetheless, the procognitive actions of systemically administered CRF antagonists across both tasks are similar to those seen with attention deficit hyperactivity disorder-related treatments. Thus, CRF antagonists may have potential for use in the treatment of PFC cognitive dysfunction.

Prevention of the return of extinguished fear by disrupting the interaction of neuronal nitric oxide synthase with its carboxy-terminal PDZ ligand.

Exposure therapy based on the extinction of fear memory is first-line treatment for post-traumatic stress disorder (PTSD). However, fear extinction is relatively easy to learn but difficult to remember, extinguished fear often relapses under a number of circumstances. Here, we report that extinction learning-induced association of neuronal nitric oxide synthase (nNOS) with its carboxy-terminal PDZ ligand (CAPON) in the infralimbic (IL) subregion of medial prefrontal cortex negatively regulates extinction memory and dissociating nNOS-CAPON can prevent the return of extinguished fear in mice. Extinction training significantly increases nNOS-CAPON association in the IL. Disruptors of nNOS-CAPON increase extracellular signal-regulated kinase (ERK) phosphorylation and facilitate the retention of extinction memory in an ERK2-dependent manner. More importantly, dissociating nNOS-CAPON after extinction training enhances long-term potentiation and excitatory synaptic transmission, increases spine density in the IL, and prevents spontaneous recovery, renewal and reinstatement of remote fear of mice. Moreover, nNOS-CAPON disruptors do not affect other types of learning. Thus, nNOS-CAPON can serve as a new target for treating PTSD.

The role of medial prefrontal cortex in the working memory maintenance of one\u2019s own emotional responses

The role of medial prefrontal cortex (MPFC) in maintaining emotional information within working memory (WM) remains insufficiently investigated – with some studies suggesting this process activates MPFC and others suggesting its activity is suppressed. To reconcile these different results, we asked 26 healthy participants to complete a WM task involving the maintenance of emotional content (EWM), visual content (VWM), or no content (“rest”) after exposure to emotion-provoking images. We also assessed individual differences in emotional awareness (EA). We observed that dorsal MPFC was more active during EWM than VWM; further, relative to the rest condition, both of these WM conditions involved suppression of ventral MPFC. We also observed that the dorsal anterior cingulate subregion of dorsal MPFC was positively associated with EA. We discuss how these results may be able to reconcile the findings of previous EWM studies, and extend understanding of the relationship between MPFC, EA, and WM.

The phosphodiesterase 10A selective inhibitor, TAK-063, induces c-Fos expression in both direct and indirect pathway medium spiny neurons and sub-regions of the medial prefrontal cortex in rats

TAK-063, a selective phosphodiesterase 10A (PDE10A) inhibitor, produces potent antipsychotic-like and pro-cognitive effects in rodents via balanced activation of striatal direct and indirect pathway medium spiny neurons (MSNs). Brain activity modulation by TAK-063 has been characterized using pharmacological magnetic resonance imaging and electroencephalography in animals, revealing modulation of activity in the prefrontal cortex (PFC) where there is little or no PDE10A expression. To understand the specific brain regions and cells affected by TAK-063 in rats, we assessed neural activation in the striatal complex and PFC using immunofluorescence staining to measure c-Fos expression. TAK-063 at 0.3 and 3mg/kg induced a dose-dependent increase in the number of c-Fos immunoreactive cells in the striatal complex. Furthermore, TAK-063 increased the number of MSNs expressing c-fos mRNA in both the D1 receptor-expressing direct pathway and D2 receptor-expressing indirect pathway of the striatal complex. TAK-063 (0.3 and 3mg/kg) induced c-Fos expression in the anterior cingulate cortex (ACC) and prelimbic cortex (PrL), but not the infralimbic, dorsal peduncular, primary motor or anterior insular cortices. These findings suggest that administration of TAK-063 activates similar numbers of direct and indirect pathway MSNs, resulting in activation predominantly in medial PFC sub-regions, such as the ACC and PrL.

Disconnection Between Amygdala and Medial Prefrontal Cortex in Psychotic Disorders.

Distracting emotional information impairs attention more in schizophrenia (SCZ) than in never-psychotic individuals. However, it is unclear whether this impairment and its neural circuitry is indicative generally of psychosis, or specifically of SCZ, and whether it is even more specific to certain SCZ symptoms (eg, deficit syndrome). It is also unclear if this abnormality contributes to impaired behavioral performance and real-world functioning. Functional imaging data were recorded while individuals with SCZ, bipolar disorder with psychosis (BDP) and no history of psychotic disorders (CON) attended to identity of faces while ignoring their emotional expressions. We examined group differences in functional connectivity between amygdala, involved in emotional evaluation, and sub-regions of medial prefrontal cortex (MPFC), involved in emotion regulation and cognitive control. Additionally, we examined correlation of this connectivity with deficit syndrome and real-world functioning. Behaviorally, SCZ showed the worst accuracy when matching the identity of emotional vs neutral faces. Neurally, SCZ showed lower amygdala-MPFC connectivity than BDP and CON. BPD did not differ from CON, neurally or behaviorally. In patients, reduced amygdala-MPFC connectivity during emotional distractors was related to worse emotional vs neutral accuracy, greater deficit syndrome severity, and unemployment. Thus, reduced amygdala-MPFC functional connectivity during emotional distractors reflects a deficit that is specific to SCZ. This reduction in connectivity is associated with worse clinical and real-world functioning. Overall, these findings provide support for the specificity and clinical utility of amygdala-MPFC functional connectivity as a potential neural marker of SCZ.

Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats.

Background:Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment.Methods:Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray’s Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats’ depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests.Results:The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats.Conclusion:These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats’ depressive behaviors, suggesting a therapeutic target for further exploration.

A common neural code for perceived and inferred emotion.

Although the emotions of other people can often be perceived from overt reactions (e.g., facial or vocal expressions), they can also be inferred from situational information in the absence of observable expressions. How does the human brain make use of these diverse forms of evidence to generate a common representation of a target's emotional state? In the present research, we identify neural patterns that correspond to emotions inferred from contextual information and find that these patterns generalize across different cues from which an emotion can be attributed. Specifically, we use functional neuroimaging to measure neural responses to dynamic facial expressions with positive and negative valence and to short animations in which the valence of a character's emotion could be identified only from the situation. Using multivoxel pattern analysis, we test for regions that contain information about the target's emotional state, identifying representations specific to a single stimulus type and representations that generalize across stimulus types. In regions of medial prefrontal cortex (MPFC), a classifier trained to discriminate emotional valence for one stimulus (e.g., animated situations) could successfully discriminate valence for the remaining stimulus (e.g., facial expressions), indicating a representation of valence that abstracts away from perceptual features and generalizes across different forms of evidence. Moreover, in a subregion of MPFC, this neural representation generalized to trials involving subjectively experienced emotional events, suggesting partial overlap in neural responses to attributed and experienced emotions. These data provide a step toward understanding how the brain transforms stimulus-bound inputs into abstract representations of emotion.

Neural activity during health messaging predicts reductions in smoking above and beyond self-report.

The current study tested whether neural activity in response to messages designed to help smokers quit could predict smoking reduction, above and beyond self-report. Using neural activity in an a priori region of interest (a subregion of medial prefrontal cortex [MPFC]), in response to ads designed to help smokers quit smoking, we prospectively predicted reductions in smoking in a community sample of smokers (N = 28) who were attempting to quit smoking. Smoking was assessed via expired carbon monoxide (CO; a biological measure of recent smoking) at baseline and 1 month following exposure to professionally developed quitting ads. A positive relationship was observed between activity in the MPFC region of interest and successful quitting (increased activity in MPFC was associated with a greater decrease in expired CO). The addition of neural activity to a model predicting changes in CO from self-reported intentions, self-efficacy, and ability to relate to the messages significantly improved model fit, doubling the variance explained (R²self-report = .15, R²self-report + neural activity = .35, R²change = .20). Neural activity is a useful complement to existing self-report measures. In this investigation, we extend prior work predicting behavior change based on neural activity in response to persuasive media to an important health domain and discuss potential psychological interpretations of the brain-behavior link. Our results support a novel use of neuroimaging technology for understanding the psychology of behavior change and facilitating health promotion.

Frontocerebellar connectivity: climbing through the inferior olive

Frontocerebellar connectivity: climbing through the inferior olive

Activity in prelimbic cortex is required for adjusting the anxiety response level during the elevated plus-maze retest

The prelimbic (PL) subregion of medial prefrontal cortex has been implicated in anxiety regulation. It is unknown, however, whether PL cortex also serves to fine-tuning the level of anxiety-related behavior exhibited on the next exposure to the same potentially threatening situation. To address this, we infused cobalt (1.0 mM) to temporarily inactivate the PL cortex during testing, post-testing or retesting in the elevated plus-maze (EPM). This protocol was chosen because it allowed us to concurrently investigate anxiety and the process of aversive learning and memory. PL cortex inactivation during the EPM testing increased the exploration of open-arms, substantiating its role in anxiety. PL cortex inactivation during the EPM retesting counteracted the further avoidance to open-arms exhibited by rats. Interestingly, as evidenced by min-by-min analysis, the cobalt-treated group behaved on EPM retesting as did the vehicle-treated group on EPM testing. This result may imply that activity in PL cortex is necessary for retrieving previously learned information that adjusts the anxiety response level on EPM retesting. Alternatively, a simple reduction in anxiety could explain the cobalt-induced increase in retest open-arms exploration. Neither test nor post-test PL cortex inactivation affected the further avoidance to open-arms observed on EPM retesting. To extend the investigation of PL cortex role in the regulation of open-arms avoidance, we infused other drugs prior to testing or retesting in the EPM. Antagonism of PL cortex adrenergic beta-1 receptors with atenolol (10 nmol), cholinergic muscarinic receptors with scopolamine (20 nmol) or glutamatergic N-methyl-d-aspartic acid (NMDA) receptors with AP5 (6.0 nmol) interfered with the level of open-arms exploration on testing, but not on retesting.

Brain mediators of cardiovascular responses to social threat: Part I: Reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity

Social threat is a key component of mental “stress” and a potent generator of negative emotions and physiological responses in the body. How the human brain processes social context and drives peripheral physiology, however, is relatively poorly understood. Human neuroimaging and animal studies implicate the dorsal medial prefrontal cortex (MPFC), though this heterogeneous region is likely to contain multiple sub-regions with diverse relationships with physiological reactivity and regulation. We used fMRI combined with a novel multi-level path analysis approach to identify brain mediators of the effects of a public speech preparation task (social evaluative threat, SET) on heart rate (HR). This model provides tests of functional pathways linking experimentally manipulated threat, regional fMRI activity, and physiological output, both across time (within person) and across individuals (between persons). It thus integrates time series connectivity and individual difference analyses in the same path model. The results provide evidence for two dissociable, inversely coupled sub-regions of MPFC that independently mediated HR responses. SET caused activity increases in a more dorsal pregenual cingulate region, whose activity was coupled with HR increases. Conversely, SET caused activity decreases in a right ventromedial/medial orbital region, which were coupled with HR increases. Individual differences in coupling strength in each pathway independently predicted individual differences in HR reactivity. These results underscore both the importance and heterogeneity of MPFC in generating physiological responses to threat.

Emotion regulation in spider phobia: role of the medial prefrontal cortex

Phobic responses are strong emotional reactions towards phobic objects, which can be described as a deficit in the automatic regulation of emotions. Difficulties in the voluntary cognitive control of these emotions suggest a further phobia-specific deficit in effortful emotion regulation mechanisms. The actual study is based on this emotion regulation conceptualization of specific phobias. The aim is to investigate the neural correlates of these two emotion regulation deficits in spider phobics. Sixteen spider phobic females participated in a functional magnetic resonance imaging (fMRI) study in which they were asked to voluntarily up- and down-regulate their emotions elicited by spider and generally aversive pictures with a reappraisal strategy. In line with the hypothesis concerning an automatic emotion regulation deficit, increased activity in the insula and reduced activity in the ventromedial prefrontal cortex was observed. Furthermore, phobia-specific effortful regulation within phobics was associated with altered activity in medial prefrontal cortex areas. Altogether, these results suggest that spider phobic subjects are indeed characterized by a deficit in the automatic as well as the effortful regulation of emotions elicited by phobic compared with aversive stimuli. These two forms of phobic emotion regulation deficits are associated with altered activity in different medial prefrontal cortex subregions.

Event Frequency Modulates the Processing of Daily Life Activities in Human Medial Prefrontal Cortex

Event sequence knowledge is necessary to learn, plan, and perform activities of daily life. Clinical observations suggest that the prefrontal cortex (PFC) is crucial for goal-directed behavior such as carrying out plans, controlling a course of actions, or organizing everyday life routines. Functional neuroimaging studies provide further evidence that the PFC is involved in processing event sequence knowledge, with the medial PFC (Brodmann area 10) primarily engaged in mediating predictable event sequences. However, the exact role of the medial PFC in processing event sequence knowledge depending on the frequency of corresponding daily life activities remains obscure. We used event-related functional magnetic resonance imaging while healthy volunteers judged whether event sequences from high- (HF), moderate- (MF), and low-frequency (LF) daily life activities were correctly ordered. The results demonstrated that different medial PFC subregions were activated depending on frequency. The anterior medial Area 10 was differentially activated for LF and the posterior medial Area 10 for HF activities. We conclude that subregions of the medial PFC are differentially engaged in processing event sequence knowledge depending on how often the activity was reportedly performed in daily life.

Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear

Recent studies using lesion, infusion, and unit-recording techniques suggest that the infralimbic (IL) subregion of medial prefrontal cortex (mPFC) is necessary for the inhibition of conditioned fear following extinction. Brief microstimulation of IL paired with conditioned tones, designed to mimic neuronal tone responses, reduces the expression of conditioned fear to the tone. In the present study we used microstimulation to investigate the role of additional mPFC subregions: the prelimbic (PL), dorsal anterior cingulate (ACd), and medial precentral (PrCm) cortices in the expression and extinction of conditioned fear. These are tone-responsive areas that have been implicated in both acquisition and extinction of conditioned fear. In contrast to IL, microstimulation of PL increased the expression of conditioned fear and prevented extinction. Microstimulation of ACd and PrCm had no effect. Under low-footshock conditions (to avoid ceiling levels of freezing), microstimulation of PL and IL had opposite effects, respectively increasing and decreasing freezing to the conditioned tone. We suggest that PL excites amygdala output and IL inhibits amygdala output, providing a mechanism for bidirectional modulation of fear expression.

Potential contributions of efferents from medial prefrontal cortex to neural activation following sexual behavior in the male rat

The limbic system plays an important role in the regulation of sexual motivation and reward. At the core of this system is an interconnected mesocorticolimbic circuit, comprised of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. Previously, our laboratory showed that sexual behavior causes neural activation in the ventral tegmental area of male rats. The main goal of this study is to identify afferent inputs to ventral tegmental area neurons that may contribute to their activation during sexual behavior. Hence, the anterograde tracer biotinylated dextran amine was injected into subregions of the rat medial prefrontal cortex, which is known to project to the ventral tegmental area. Visualization of biotinylated dextran amine-labeled axons was combined with immunostaining for sex-induced Fos expression. Quantitative analysis showed that the majority of sex-activated ventral tegmental area neurons receive putative contacts from the infralimbic and prelimbic—but not the anterior cingulate—subregions of the medial prefrontal cortex. Thus, inputs from infralimbic area and prelimbic are in an anatomical position to provide a major source of input during sexual behavior. A second goal of this study was to determine if the medial prefrontal cortex projects to sex-activated neurons in other brain regions important for sexual behavior and motivation. Infralimbic area and prelimbic area sent projections to nucleus accumbens, medial preoptic area, principal nucleus of the bed nucleus of the stria terminalis, basolateral amygdala, and parvocellular subparafasicular thalamic nucleus. Thus, the infralimbic and prelimbic subregions of the medial prefrontal cortex may also influence sexual behavior and motivation via brain regions other than the ventral tegmental area.

MEDIAL PREFRONTAL CORTEX LESIONS ABOLISH CONTEXTUAL CONTROL OF COMPETING RESPONSES

There is much debate as to the extent and nature of functional specialization within the different subregions of the prefrontal cortex. The current study was undertaken to investigate the effect of damage to medial prefrontal cortex subregions in the rat. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two different contexts. At test, they received presentations of audiovisual compounds of these training stimuli in extinction. These compounds had dictated either the same (congruent trials) or different (incongruent trials) responses during training. In sham-operated controls, contextual cues came to control responding to conflicting information provided by incongruent stimulus compounds. Experiment 1 demonstrated that this contextual control of responding was not evident in individual rats with large amounts of damage that included the prelimbic and cingulate subregions of the prefrontal cortex. Experiment 2 further dissociated the result of Experiment 1, demonstrating that lesions specific to the anterior cingulate cortex were sufficient to produce a deficit early on during presentation of an incongruent stimulus compound but that performance was unimpaired as presentation progressed. This early deficit suggests a role for the anterior cingulate cortex in the detection of response conflict, and for the medial prefrontal cortex in the contextual control of competing responses, providing evidence for functional specialization within the rat prefrontal cortex.

Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat

Altered dopamine regulation in the medial prefrontal cortex has been linked to drug abuse and disorders such as schizophrenia. Heterogeneous expression of the dopamine transporter, as well as the ability of the norepinephrine transporter to clear dopamine in the prefrontal cortex, delineates two potential sites for the regulation of synaptic dopamine within the cortex. The present study used in vivo microdialysis to compare the effects of local infusions of dopamine and norepinephrine uptake blockers in the caudate putamen and two subregions of the prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices. Results revealed that all dopamine uptake blockers produced greater increases in dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In addition, amphetamine administration increased dopamine efflux to a greater degree in the prelimbic, relative to the anterior cingulate, cortex. In contrast, the increase in dopamine efflux was similar in both subregions in the presence of nomifensine and desmethylimipramine. Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion. These data indicate a more prominent role for the dopamine transporter in the clearance of extracellular dopamine in the caudate-putamen relative to the prefrontal cortex and an important role for NET in the clearance of dopamine in both the prelimbic and anterior cingulate subregions of the rat medial prefrontal cortex.