Role Of Medial Prefrontal Cortex Research Articles

The role of medial prefrontal cortex in cognition, aging and Parkinson disease

The prefrontal cortex (PFC) is a vital center for executive control, influencing cognition, emotion, memory, and sociability. Specifically, the medial prefrontal cortex (mPFC), a part of the PFC, monitors actions toward goals, aids decision-making, and regulates cognitive control. It assesses outcomes relative to expected rewards, selects appropriate behavior based on continuous performance analysis, and facilitates strategic adaptation in response to adverse results. Unfortunately, these cognitive functions decline with age due to changes in neuroplasticity, especially in neurodegenerative disorders like Parkinson's Disease (PD) and Alzheimer's Disease (AD). Neurodegenerative diseases disrupt normal brain activity, leading to tissue atrophy and cognitive impairment caused by degeneration and neuronal death. PD is the second most common neurodegenerative disease globally, characterized by a decline in neurotransmitters and dopaminergic neuron death in the substantia nigra, along with the presence of Lewy bodies. Recognizing these factors as risk factors for PD development is crucial. This article examines how aging affects cognitive activities regulated by the mPFC, a pivotal region for critical cognitive functions. By applying predetermined criteria, the review selects the most relevant articles to provide a comprehensive understanding of cognitive deficits mediated by the mPFC in both healthy and pathological aging.

MPFC catecholamines modulate attentional capture by appetitive distracters and attention to time in a peak-interval procedure in rats.

The behavioral and neural mechanisms by which distracters delay interval timing behavior are currently unclear. Distracters delay timing in a considerable dynamic range: Some distracters have no effect on timing ("run"), whereas others seem to "stop" timing; some distracters restart ("reset") the entire timing mechanisms at their offset, whereas others seem to capture attentional resources long after their termination ("over-reset"). While the run-reset range of delays is accounted for by the Time-Sharing Hypothesis (Buhusi, 2003, 2012), the behavioral and neural mechanisms of "over-resetting" are currently uncertain. We investigated the role of novelty (novel/familiar) and significance (consequential/inconsequential) in the time-delaying effect of distracters and the role of medial prefrontal cortex (mPFC) catecholamines by local infusion of norepinephrine-dopamine reuptake inhibitor (NDRI) nomifensine in a peak-interval (PI) procedure in rats. Results indicate differences in time delay between groups, suggesting a role for both novelty and significance: inconsequential, familiar distracters "stopped" timing, novel distracters "reset" timing, whereas appetitively conditioned distracters "over-reset" timing. mPFC infusion of nomifensine modulated attentional capture by appetitive distracters in a "U"-shaped fashion, reduced the delay after novel distracters, but had no effects after inconsequential, familiar distracters. These results were not due to nomifensine affecting either timing accuracy, precision, or peak response rate. Results may help elucidate the behavioral and physiological mechanisms underlying interval timing and attention to time and may contribute to developing new treatment strategies for disorders of attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Role of Medial Prefrontal Cortex in Acupuncture Treatment for Functional Dyspepsia.

Acupuncture is an effective therapy for functional dyspepsia (FD). However, the efficacy of acupuncture in the treatment of FD varies among individuals in clinical practice. This study aimed to reveal the brain response patterns in acupuncture higher response/lower response FD patients. Firstly, we performed a within-group comparison of brain function activity before and after acupuncture treatment in 115 FD patients and analyzed the correlation between brain function activity changes and clinical improvements. Secondly, 115 subjects were divided into the acupuncture higher response group or the lower response group based on the median clinical improvement values. The changes in functional brain activity after acupuncture treatment were investigated in these two groups, respectively. Finally, the identified brain regions associated with the clinical improvements were set as regions of interest (ROI), and the ROI-to-voxel functional connectivity comparisons were also performed in both groups, respectively. The results demonstrated that the functional activities of the left cerebellum inferior, right middle temporal gyrus, and right medial prefrontal cortex (mPFC) were increased, and the left Heschl and right middle cingulate cortex were decreased in 115 FD patients after acupuncture treatment. The functional connectivity changes of mPFC were correlated with improving the Nepean Dyspepsia Symptom Index. The significant increase in mPFC functional activity was also found in acupuncture higher response FD patients but not in lower response FD patients. The functional connectivity between the mPFC and default mode network (DMN) was significantly diminished in the higher response group but not in the lower response group. In conclusion, this study suggested that modulating the functional activity of the mPFC and its connectivity to the DMN may be one of the important mechanisms of acupuncture for treating FD with a higher response.

Aversive stimuli bias corticothalamic responses to motivationally significant cues.

Making predictions about future rewards or punishments is fundamental to adaptive behavior. These processes are influenced by prior experience. For example, prior exposure to aversive stimuli or stressors changes behavioral responses to negative- and positive-value predictive cues. Here, we demonstrate a role for medial prefrontal cortex (mPFC) neurons projecting to the paraventricular nucleus of the thalamus (PVT; mPFC→PVT) in this process. We found that a history of aversive stimuli negatively biased behavioral responses to motivationally relevant cues in mice and that this negative bias was associated with hyperactivity in mPFC→PVT neurons during exposure to those cues. Furthermore, artificially mimicking this hyperactive response with selective optogenetic excitation of the same pathway recapitulated the negative behavioral bias induced by aversive stimuli, whereas optogenetic inactivation of mPFC→PVT neurons prevented the development of the negative bias. Together, our results highlight how information flow within the mPFC→PVT circuit is critical for making predictions about motivationally-relevant outcomes as a function of prior experience.

Behavior Decision of Mobile Robot With a Neurophysiologically Motivated Reinforcement Learning Model

Online model-free reinforcement learning (RL) approaches play a crucial role in coping with the real-world applications, such as the behavioral decision making in robotics. How to balance the exploration and exploitation processes is a central problem in RL. A balanced ratio of exploration/exploitation has a great influence on the total learning time and the quality of the learned strategy. Therefore, various action selection policies have been presented to obtain a balance between the exploration and exploitation procedures. However, these approaches are rarely, automatically, and dynamically regulated to the environment variations. One of the most amazing self-adaptation mechanisms in animals is their capacity to dynamically switch between exploration and exploitation strategies. This article proposes a novel neurophysiologically motivated model which simulates the role of medial prefrontal cortex (MPFC) and lateral prefrontal cortex (LPFC) in behavior decision. The sensory input is transmitted to the MPFC, then the ventral tegmental area (VTA) receives a reward and calculates a dopaminergic reinforcement signal, and the feedback categorization neurons in anterior cingulate cortex (ACC) calculate the vigilance according to the dopaminergic reinforcement signal. Then the vigilance is transformed to LPFC to regulate the exploration rate, finally the exploration rate is transmitted to thalamus to calculate the corresponding action probability. This action selection mechanism is introduced to the actor–critic model of the basal ganglia, combining with the cerebellum model based on the developmental network to construct a new hybrid neuromodulatory model to select the action of the agent. Both the simulation comparison with other four traditional action selection policies and the physical experiment results demonstrate the potential of the proposed neuromodulatory model in action selection.

Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways

Serotonin2B receptor (5-HT2BR) antagonists inhibit cocaine-induced hyperlocomotion independently of changes of accumbal dopamine (DA) release. Given the tight relationship between accumbal DA activity and locomotion, and the inhibitory role of medial prefrontal cortex (mPFC) DA on subcortical DA neurotransmission and DA-dependent behaviors, it has been suggested that the suppressive effect of 5-HT2BR antagonists on cocaine-induced hyperlocomotion may result from an activation of mPFC DA outflow which would subsequently inhibit accumbal DA neurotransmission. Here, we tested this hypothesis by means of the two selective 5-HT2BR antagonists, RS 127445 and LY 266097, using a combination of neurochemical, behavioral and cellular approaches in male rats.The intraperitoneal (i.p.) administration of RS 127445 (0.16 mg/kg) or LY 266097 (0.63 mg/kg) potentiated cocaine (10 mg/kg, i.p.)-induced mPFC DA outflow. The suppressant effect of RS 127445 on cocaine-induced hyperlocomotion was no longer observed in rats with local 6-OHDA lesions in the mPFC. Also, RS 127445 blocked cocaine-induced changes of accumbal glycogen synthase kinase (GSK) 3β phosphorylation, a postsynaptic cellular marker of DA neurotransmission. Finally, in keeping with the location of 5-HT2BRs on GABAergic interneurons in the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABAAR antagonist bicuculline (100 μM) prevented the effect of the systemic or local (1 μM, intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow. Likewise, intra-DRN bicuculline injection (0.1 μg/0.2 μl) prevented the effect of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and GSK3β phosphorylation.These results show that DRN 5-HT2BR blockade suppresses cocaine-induced hyperlocomotion by potentiation of cocaine-induced DA outflow in the mPFC and the subsequent inhibition of accumbal DA neurotransmission.

Preliminary Evidence of the Role of Medial Prefrontal Cortex in Self-Enhancement: A Transcranial Magnetic Stimulation Study.

Humans employ a number of strategies to improve their position in their given social hierarchy. Overclaiming involves presenting oneself as having more knowledge than one actually possesses, and it is typically invoked to increase one’s social standing. If increased expectations to possess knowledge is a perceived social pressure, such expectations should increase bouts of overclaiming. As the medial prefrontal cortex (MPFC) is sensitive to social pressure and disruption of the MPFC leads to decreases in overclaiming, we predicted that transcranial magnetic stimulation (TMS) applied to the MPFC would reduce overclaiming and the effects would be enhanced in the presence of social pressure. Twelve participants were given a test in which half of the words were real and half were fake, and they were asked how well they knew each word. They were not told that any of the words were fake. Half of the participants were exposed to social pressure while the other half were not. Following TMS delivered to the MPFC, overclaiming rates decreased, specifically under conditions of high social pressure. Medial PFC TMS did not influence real word responses and real words did not interact with the MPFC and social pressure. These preliminary findings support the significant role the MPFC plays in social cognition and the importance of the MPFC in mediating socially meaningful situations. We suggest the role of the MPFC as being highly influenced by the premium placed on social manipulation in human evolution.

Establishing a Causal Role for Medial Prefrontal Cortex in Reality Monitoring.

Reality monitoring is defined as the ability to distinguish internally self-generated information from externally-derived information. Functional imaging studies have consistently found that the medial prefrontal cortex (mPFC) is a key brain region subserving reality monitoring. This study aimed to determine a causal role for mPFC in reality monitoring using navigated repetitive transcranial magnetic stimulation (nrTMS). In a subject-blinded sham-controlled crossover design, healthy individuals received either active or sham nrTMS targeting mPFC. Active modulation of mPFC using nrTMS at a frequency of 10 Hz, significantly improved identification of both self-generated and externally-derived information during reality monitoring, when compared to sham or baseline. Targeted excitatory modulation of mPFC also improved positive mood, reduced negative mood, and increased overall alertness/arousal. These results establish optimal nrTMS dosing parameters that maximized tolerability/comfort and induced significant neuromodulatory effects in the mPFC target. Importantly, this is a proof-of-concept study that establishes the mPFC as a novel brain target that can be stimulated with nrTMS to causally impact both higher-order reality monitoring and mood.

Reconsidering longstanding assumptions about the role of medial prefrontal cortex (MPFC) in social evaluation

The psychological nature of the association between MPFC modulation and social evaluation remains poorly understood. Despite confounds, small samples, and mixed results in existing research, MPFC activation is often interpreted as a reflection of socioemotional association and/or perceived similarity between the self and an evaluation target. The present research addressed issues from the existing literature by examining whether MPFC is modulated by (a) socioemotional associations unconfounded by previous knowledge (memory effects (Study 1, N = 48), repetition suppression (Study 2, N = 43), multi-voxel pattern analysis (Study 1 & 2)) and (b) perceived similarity to self (Study 2). MPFC was modulated by self-reference and trait-relevance, but there was not significant empirical support for the interpretation that MPFC modulation reflects socioemotional association or perceived similarity. These findings highlight the weak basis for prevailing assumptions about the psychological significance of MPFC in social evaluation and the need for studies which test multiple mechanisms.

Dorsomedial prefrontal cortex neurons encode nicotine-cue associations.

The role of medial prefrontal cortex (mPFC) in regulating nicotine taking and seeking remains largely unexplored. In this study we took advantage of the high time-resolution of optogenetic intervention by decreasing (Arch3.0) or increasing (ChR2) the activity of neurons in the dorsal and ventral mPFC during 5-s nicotine cue presentations in order to evaluate their contribution to cued nicotine seeking and taking. Wistar rats were trained to self-administer intravenous nicotine in 1 h self-administration sessions twice a day for a minimum of 10 days. Subsequently, dmPFC or vmPFC neuronal activity was modulated during or following presentation of the 5-s nicotine cue, both under extinction and self-administration conditions. We also used in vivo electrophysiology to record the activity of dmPFC neurons during nicotine self-administration and extinction tests. We show that optogenetic inhibition of dmPFC neurons during, but not following, response-contingent presentations of the nicotine cue increased nicotine seeking. We found no effect on nicotine self-administration or on food seeking in an extinction test. We also show that this effect is specific to dmPFC, because optogenetic inhibition of vmPFC had no effect on nicotine seeking and taking. In vivo recordings revealed that dmPFC network neuronal activity was modulated more strongly following nicotine cue presentation in extinction, compared to following nicotine self-administration. Our results strongly suggest that a population of neurons within the dmPFC is involved in encoding the incentive value of nicotine-associated cues.

Inactivation of the Medial-Prefrontal Cortex Impairs Interval Timing Precision, but Not Timing Accuracy or Scalar Timing in a Peak-Interval Procedure in Rats.

Motor sequence learning, planning and execution of goal-directed behaviors, and decision making rely on accurate time estimation and production of durations in the seconds-to-minutes range. The pathways involved in planning and execution of goal-directed behaviors include cortico-striato-thalamo-cortical circuitry modulated by dopaminergic inputs. A critical feature of interval timing is its scalar property, by which the precision of timing is proportional to the timed duration. We examined the role of medial prefrontal cortex (mPFC) in timing by evaluating the effect of its reversible inactivation on timing accuracy, timing precision and scalar timing. Rats were trained to time two durations in a peak-interval (PI) procedure. Reversible mPFC inactivation using GABA agonist muscimol resulted in decreased timing precision, with no effect on timing accuracy and scalar timing. These results are partly at odds with studies suggesting that ramping prefrontal activity is crucial to timing but closely match simulations with the Striatal Beat Frequency (SBF) model proposing that timing is coded by the coincidental activation of striatal neurons by cortical inputs. Computer simulations indicate that in SBF, gradual inactivation of cortical inputs results in a gradual decrease in timing precision with preservation of timing accuracy and scalar timing. Further studies are needed to differentiate between timing models based on coincidence detection and timing models based on ramping mPFC activity, and clarify whether mPFC is specifically involved in timing, or more generally involved in attention, working memory, or response selection/inhibition.

The role of medial prefrontal cortex in processing emotional self-referential information: a combined TMS/fMRI study.

In this study we investigate the neural basis of emotional content in self-referential processing by using a combination of off-line repetitive Transcranial Magnetic Stimulation (rTMS) applied to the medial prefrontal cortex (mPFC) and whole-brain functional Magnetic Resonance Imaging (fMRI).We applied effective or ineffective (sham) 1-Hz rTMS to the mPFC of 14 healthy participants who immediately thereafter underwent fMRI while performing a personality attribution task to self or to others. rTMS produced an increase in the participants' reaction time (≈ 60msec) when processing negative attributes. The neuroimaging findings indicated the involvement of a network of cortical nodes distant from those at the stimulation site; these distant nodes showed task-specific changes in blood oxygen level-dependent (BOLD) activity after effective TMS. The posterior cingulate cortex seemingly encoded the negative dimension of stimuli, but it did not differentiate between self or other. On the contrary the left angular gyrus and the left anterior temporal cortex showed changes indicating encoding of negative self-directed categorization. The mPFC region did not show effects of rTMS along the self-other dimension, but only along the affective dimension. The results indicate that the mPFC is a pivotal node in a cortical network that supports affective referential reasoning. Therefore, a key function of mPFC seems to be related to the processing of negative attributes. In the other nodes of the network the two dimensions of self-other attribution and affective attribution are partially independent, but largely overlapping with different degrees of local specialization.

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.

Representation of actions and outcomes in medial prefrontal cortex during delayed conditional decision-making: Population analyses of single neuron activity.

Background:To respond adaptively in a dynamic environment, it is important for organisms to utilise information about recent events to decide between response options.Methods:To examine the role of medial prefrontal cortex in adaptive decision-making, we recorded single neuron activity in rats performing a dynamic delayed non-matching to position task.Results:We recorded activity from 1335 isolated neurons, 458 (34%) with criterion event-related activity, of which 431 (94%) exhibited 1 of 10 distinct excitatory response types: five at different times relative to delivery (or lack) of reinforcement following sample and choice responses and five correlated with movements or lever press actions that occurred multiple times in each trial. Normalised population averages revealed a precisely timed cascade of population responses representing the temporal organisation behavioural events that constitute delayed non-matching to position trials. Firing field analyses identified a subset of neurons with restricted spatial fields: responding to the conjunction of a behavioural event with a specific location. Anatomical analyses showed considerable overlap in the distribution of different response types in medial prefrontal cortex with a significant trend for dorsal areas to contain more neurons with action-related activity and ventral areas more responses related to action outcomes.Conclusion:These results indicate that medial prefrontal cortex contains discrete populations of neurons that represent the temporal organisation of actions and outcomes during delayed non-matching to position trials. They support the hypothesis that medial prefrontal cortex promotes flexible control of complex behaviours by action–outcome contingencies.

Transcranial direct current stimulation of the medial prefrontal cortex dampens mind-wandering in men

Mind-wandering, the mind’s capacity to stray from external events and generate task-unrelated thought, has been associated with activity in the brain default network. To date, little is understood about the contribution of individual nodes of this network to mind-wandering. Here, we investigated the role of medial prefrontal cortex (mPFC) in mind-wandering, by perturbing this region with transcranial direct current stimulation (tDCS). Young healthy participants performed a choice reaction time task both before and after receiving cathodal tDCS over mPFC, and had their thoughts periodically sampled. We found that tDCS over mPFC - but not occipital or sham tDCS - decreased the propensity to mind-wander. The tDCS-induced reduction in mind-wandering occurred in men, but not in women, and was accompanied by a change in the content of task-unrelated though, which became more related to other people (as opposed to the self) following tDCS. These findings indicate that mPFC is crucial for mind-wandering, possibly by helping construction of self-relevant scenarios capable to divert attention inward, away from perceptual reality. Gender-related differences in tDCS-induced changes suggest that mPFC controls mind-wandering differently in men and women, which may depend on differences in the structural and functional organization of distributed brain networks governing mind-wandering, including mPFC.

Prelimbic cortex extracellular signal-regulated kinase 1/2 activation is required for memory retrieval of long-term inhibitory avoidance

Neural mechanism underlying memory retrieval has been extensively studied in the hippocampus and amygdala. However, little is known about the role of medial prefrontal cortex in long-term memory retrieval. We evaluate this issue in one-trial step-through inhibitory avoidance (IA) paradigm. Our results showed that, 1) inactivation of mPFC by local infusion of GABAA-receptor agonist muscimol caused severe deficits in retrieval of 1-day and 7-day but had no effects on 2-h inhibitory avoidance memory; 2) the protein level of phosphorylated-ERK1/2 in mPFC were significantly increased following retrieval of 1-day and 7-day IA memory, so did the numbers of phosphorylated-ERK (pERK) and phosphorylated-CREB (pCREB) labeled neurons; 3) intra-mPFC infusion of ERK kinase inhibitor PD98095 significantly reduced phosphorylated ERK1/2 levels and phosphorylated-ERK1/2 and phosphorylated-CREB labeled cells, and severely impaired retrieval of 7-day IA memory when the drugs were administrated 30min prior to test. The present study provides evidence that retrieval of long-lasting memory for inhibitory avoidance requires mPFC and involves the ERK-CREB signaling cascade.

Alterations in neuronal morphology in infralimbic cortex predict resistance to fear extinction following acute stress

Dysfunction in corticolimbic circuits that mediate the extinction of learned fear responses is thought to underlie the perseveration of fear in stress-related psychopathologies, including post-traumatic stress disorder. Chronic stress produces dendritic hypertrophy in basolateral amygdala (BLA) and dendritic hypotrophy in medial prefrontal cortex, whereas acute stress leads to hypotrophy in both BLA and prelimbic cortex. Additionally, both chronic and acute stress impair extinction retrieval. Here, we examined the effects of a single elevated platform stress on extinction learning and dendritic morphology in infralimbic cortex, a region considered to be critical for extinction. Acute stress produced resistance to extinction, as well as dendritic retraction in infralimbic cortex. Spine density on apical and basilar terminal branches was unaffected by stress. However, animals that underwent conditioning and extinction had decreased spine density on apical terminal branches. Thus, whereas dendritic morphology in infralimbic cortex appears to be particularly sensitive to stress, changes in spines may more sensitively reflect learning. Further, in stressed rats that underwent conditioning and extinction, the level of extinction learning was correlated with spine densities, in that rats with poorer extinction retrieval had more immature spines and fewer thin spines than rats with better extinction retrieval, suggesting that stress may have impaired learning-related spine plasticity. These results may have implications for understanding the role of medial prefrontal cortex in learning deficits associated with stress-related pathologies.

Infralimbic prefrontal cortex interacts with nucleus accumbens shell to unmask expression of outcome-selective Pavlovian-to-instrumental transfer.

Although several studies have examined the subcortical circuitry underlying Pavlovian-to-instrumental transfer (PIT), the role of medial prefrontal cortex in this behavior is largely unknown. Elucidating the cortical contributions to PIT will be key for understanding how reward-paired cues control behavior in both adaptive and maladaptive context (i.e., addiction). Here we use bilateral lesions in a rat model to show that infralimbic prefrontal cortex (ilPFC) is necessary for appropriate expression of PIT. Further, we show that ilPFC mediates this effect via functional connectivity with nucleus accumbens shell (NAcS). Together, these data provide the first demonstration that a specific cortico-striatal circuit is necessary for cue-invigorated reward seeking during specific PIT.

Event-related brain potential signaling unexpected timing of feedback: A source localization analysis.

Mediofrontal event-related potential (ERP) components have been extensively reported following performance error or unexpected feedback, and could reflect dopaminergic phasic changes conveyed to medial prefrontal cortex. Recent studies suggest a role for medial prefrontal cortex not only in signaling unexpected feedback but also unexpected timing of expected feedback. However, analyses of this aspect are still scarce. In this study, a task creating a condition of unexpected (anticipated) timing of a predicted feedback was designed and the associated ERP analyzed. Both an aversive and a neutral feedback were considered. ERP analysis evidenced frontocentral component elicited by unexpected, relative to expected, timing of feedback, more significant for aversive than neutral feedback. Cortical generators of this ERP component were estimated using sLORETA source localization method: we found that some regions in the frontal and prefrontal cortex may be responsive to unexpected timing of feedback, to a larger extent in case of aversive than neutral feedback. Results are discussed with respect to findings of previous works. This study can contribute to inform current theories of performance monitoring in frontal/prefrontal cortex and to drive future investigations.

Functional Underpinnings of Emotional Processing

Major depression is associated with abnormal self-processing (i.e self criticism, rumination) characterized by increased activity in cortical midline structures. Among these structures the Medial Prefrontal Cortex (MPFC) has focused research attention. Connected with several cortical and sub-cortical structures, the MPFC activity may predict clinical outcome of depressed patients treated with antidepressant. We have recently showed that the level of activity of MPFC before treatment predict clinical remission at 24 weeks in patients receiving antidepressant. Moreover the level of MPFC activity was not affected by antidepressant, suggesting that this region may constitute a trait marker of major depression. Recent data emphasize that impaired self processing and MPFC may be observed in subjects with genetic vulnerability for affective disorders. Thus we will present data showing that subjects with the short allele S of the 5-HTTLPR promoter gene have increased activity of MPFC during self processing. Consistent with gene x environment interaction hypothesis, the degree of Amygdala activity in S careers was modulated by exposure to life stress events and self processing. Moreover we will discuss the relationships between self-esteem, social stress and the changes in MPFC activity related to exposure to social threat. Overall our talk will emphasize the role of MPFC in the pathophysiology of depression and the multiple determinants (genetic, environmental exposure, social context) of its impairment in affective disorders.