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Sample records for prefrontal cortex inhibition

  1. Anterior prefrontal cortex inhibition impairs control over social emotional actions.

    PubMed

    Volman, Inge; Roelofs, Karin; Koch, Saskia; Verhagen, Lennart; Toni, Ivan

    2011-10-25

    When dealing with emotional situations, we often need to rapidly override automatic stimulus-response mappings and select an alternative course of action [1], for instance, when trying to manage, rather than avoid, another's aggressive behavior. The anterior prefrontal cortex (aPFC) has been linked to the control of these social emotional behaviors [2, 3]. We studied how this control is implemented by inhibiting the left aPFC with continuous theta burst stimulation (cTBS; [4]). The behavioral and cerebral consequences of this intervention were assessed with a task quantifying the control of social emotional actions and with concurrent measurements of brain perfusion. Inhibition of the aPFC led participants to commit more errors when they needed to select rule-driven responses overriding automatic action tendencies evoked by emotional faces. Concurrently, task-related perfusion decreased in bilateral aPFC and posterior parietal cortex and increased in amygdala and left fusiform face area. We infer that the aPFC controls social emotional behavior by upregulating regions involved in rule selection [5] and downregulating regions supporting the automatic evaluation of emotions [6]. These findings illustrate how exerting emotional control during social interactions requires the aPFC to coordinate rapid action selection processes, the detection of emotional conflicts, and the inhibition of emotionally-driven responses. PMID:22000109

  2. Diminished appetitive startle modulation following targeted inhibition of prefrontal cortex.

    PubMed

    Hurlemann, René; Arndt, Stephan; Schlaepfer, Thomas E; Reul, Juergen; Maier, Wolfgang; Scheele, Dirk

    2015-01-01

    From an evolutionary perspective the startle eye-blink response forms an integral part of the human avoidance behavioral repertoire and is typically diminished by pleasant emotional states. In major depressive disorder (MDD) appetitive motivation is impaired, evident in a reduced interference of positive emotion with the startle response. Given the pivotal role of frontostriatal neurocircuitry in orchestrating appetitive motivation, we hypothesized that inhibitory transcranial magnetic stimulation (TMS) would reduce appetitive neuromodulation in a manner similar to MDD. Based on a pre-TMS functional MRI (fMRI) experiment we selected the left dorsolateral and dorsomedial prefrontal cortices as target regions for subsequent sham-controlled inhibitory theta-burst TMS (TBS) in 40 healthy male volunteers. Consistent with our hypothesis, between-group comparisons revealed a TBS-induced inhibition of appetitive neuromodulation, manifest in a diminished startle response suppression by hedonic stimuli. Collectively, our results suggest that functional integrity of left dorsolateral and dorsomedial prefrontal cortex is critical for mediating a pleasure-induced down-regulation of avoidance responses which may protect the brain from a depressogenic preponderance of defensive stress. PMID:25752944

  3. Diminished appetitive startle modulation following targeted inhibition of prefrontal cortex

    PubMed Central

    Hurlemann, René; Arndt, Stephan; Schlaepfer, Thomas E.; Reul, Juergen; Maier, Wolfgang; Scheele, Dirk

    2015-01-01

    From an evolutionary perspective the startle eye-blink response forms an integral part of the human avoidance behavioral repertoire and is typically diminished by pleasant emotional states. In major depressive disorder (MDD) appetitive motivation is impaired, evident in a reduced interference of positive emotion with the startle response. Given the pivotal role of frontostriatal neurocircuitry in orchestrating appetitive motivation, we hypothesized that inhibitory transcranial magnetic stimulation (TMS) would reduce appetitive neuromodulation in a manner similar to MDD. Based on a pre-TMS functional MRI (fMRI) experiment we selected the left dorsolateral and dorsomedial prefrontal cortices as target regions for subsequent sham-controlled inhibitory theta-burst TMS (TBS) in 40 healthy male volunteers. Consistent with our hypothesis, between-group comparisons revealed a TBS-induced inhibition of appetitive neuromodulation, manifest in a diminished startle response suppression by hedonic stimuli. Collectively, our results suggest that functional integrity of left dorsolateral and dorsomedial prefrontal cortex is critical for mediating a pleasure-induced down-regulation of avoidance responses which may protect the brain from a depressogenic preponderance of defensive stress. PMID:25752944

  4. The effects of transcranial direct current stimulation over the dorsolateral prefrontal cortex on cognitive inhibition.

    PubMed

    Metzuyanim-Gorlick, Shlomit; Mashal, Nira

    2016-06-01

    The present study examines the effects of bilateral transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) (anodal over left and cathodal over right DLPFC). This study describes the long-term effects of tDCS on cognitive inhibition, using the Hayling task. Twenty volunteers participated in the study and were assigned to either an active or a sham group. Participants heard sentences with the final word missing. They were asked then to complete the sentence with a word that either is appropriate in the context of the sentence (initiation condition) or is completely unrelated in this specific context (suppression condition). All participants performed a baseline Hayling task followed by six stimulation sessions. Subsequent to completion of these stimulations, we assessed immediately Hayling performance and re-assessed this performance 1 month. The results indicate a significant decrease in the number of errors in the active group, but only in the suppression condition that continued for 1 month after the sixth stimulation. The current findings suggest that tDCS can improve cognitive inhibition for the long-term in healthy adults and that the DLPFC has a special role in selecting the correct response and suppressing irrelevant semantic information. PMID:26821316

  5. Chronic Stress Impairs Prefrontal Cortex-Dependent Response Inhibition and Spatial Working Memory

    PubMed Central

    Mika, Agnieszka; Mazur, Gabriel J.; Hoffman, Ann N.; Talboom, Joshua S.; Bimonte-Nelson, Heather A.; Sanabria, Federico; Conrad, Cheryl D.

    2012-01-01

    Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague Dawley rats were first trained on the RAWM and subsequently trained on FMI. Following acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when food reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing precision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher’s r to z transformation revealed no significant differences between control and stress with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been direct compared within the same animals following chronic stress, using FMI, an appetitive task, and RAWM, a non-appetitive task. PMID:22905921

  6. MRI volumetry of prefrontal cortex

    NASA Astrophysics Data System (ADS)

    Sheline, Yvette I.; Black, Kevin J.; Lin, Daniel Y.; Pimmel, Joseph; Wang, Po; Haller, John W.; Csernansky, John G.; Gado, Mokhtar; Walkup, Ronald K.; Brunsden, Barry S.; Vannier, Michael W.

    1995-05-01

    Prefrontal cortex volumetry by brain magnetic resonance (MR) is required to estimate changes postulated to occur in certain psychiatric and neurologic disorders. A semiautomated method with quantitative characterization of its performance is sought to reliably distinguish small prefrontal cortex volume changes within individuals and between groups. Stereological methods were tested by a blinded comparison of measurements applied to 3D MR scans obtained using an MPRAGE protocol. Fixed grid stereologic methods were used to estimate prefrontal cortex volumes on a graphic workstation, after the images are scaled from 16 to 8 bits using a histogram method. In addition images were resliced into coronal sections perpendicular to the bicommissural plane. Prefrontal cortex volumes were defined as all sections of the frontal lobe anterior to the anterior commissure. Ventricular volumes were excluded. Stereological measurement yielded high repeatability and precision, and was time efficient for the raters. The coefficient of error was prefrontal cortex boundaries on 3D images was critical to obtaining accurate measurements. MR prefrontal cortex volumetry by stereology can yield accurate and repeatable measurements. Small frontal lobe volume reductions in patients with brain disorders such as depression and schizophrenia can be efficiently assessed using this method.

  7. URB597 inhibits oxidative stress induced by alcohol binging in the prefrontal cortex of adolescent rats.

    PubMed

    Pelição, Renan; Santos, Matheus C; Freitas-Lima, Leandro C; Meyrelles, Silvana S; Vasquez, Elisardo C; Nakamura-Palacios, Ester M; Rodrigues, Lívia C M

    2016-06-15

    Heavy episodic drinking (binging), which is highly prevalent among teenagers, results in oxidative damage. Because the prefrontal cortex (PFC) is not completely mature in adolescents, this brain region may be more vulnerable to the effects of alcohol during adolescence. As endocannabinoids may protect the immature PFC from the harmful effects of high doses of alcohol, this study investigated the effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on oxidative stress induced by acute or chronic binge alcohol intake in adolescent rats. At 40min after intraperitoneal pre-treatment with URB597 (0.3mg/kg) or vehicle (Veh), ethanol (EtOH; 3 or 6g/kg, intragastrically) or distilled water (DW) was administered in 3 consecutive sessions (acute binging) or 3 consecutive sessions over 4 weeks (chronic binging). Oxidative stress in PFC slices in situ was measured by dihydroethidium fluorescence staining. At the higher EtOH dose (6g/kg), pre-treatment with URB597 significantly reduced (p<0.01) the production of superoxide anions in the PFC after acute (42.8% decrease) and chronic binge EtOH consumption (44.9% decrease) compared with pre-treatment with Veh. As URB597 decreases anandamide metabolism, this evidence shows an antioxidant effect of endocannabinoids to suppress acute and chronic binge alcohol intake-induced oxidative stress in the PFC of adolescent rats. PMID:27150075

  8. Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.

    PubMed

    Liang, J; Xu, W; Hsu, Y-T; Yee, A X; Chen, L; Südhof, T C

    2015-07-01

    Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs. PMID:25824299

  9. Learning-dependent Changes in the Neuronal Correlates of Response Inhibition in the Prefrontal Cortex and Hippocampus

    PubMed Central

    Byeon, Jung Seop

    2014-01-01

    It has been suggested that the hippocampus and the prefrontal cortex (PFC) play key roles in representing contextual memory and utilizing contextual information for flexible response selection. During response selection, a correct response should be facilitated and an incorrect response should be inhibited flexibly in association with a cueing stimulus. However, it is poorly understood how the hippocampal and PFC networks behave during such flexible control of facilitation and inhibition of behavioral responses. To find neural correlates of context-cued flexible response selection, the current study employed an object-place paired-associate (OPPA) task in which object A is only rewarded in place 1 and object B is associated with reward in place 2 while recording single units simultaneously from the hippocampus and PFC. During the task, response inhibition in front of a contextually wrong object is required for successful performance and such inhibitory responses were observed before the rat learned the task. A significant proportion of neurons that fired differentially depending on the existence of inhibitory behavior in the PFC was observed during the pre-learning stage. By contrast, the proportion of such neurons in the hippocampus was significantly greater than chance during post-learning stage. The results suggest that the development of inhibitory behavior is a critical behavioral marker that foretells an upcoming acquisition of the task and the hippocampus and PFC are involved in learning contextual response selection by learning how to control the inhibition of behavior as learning progresses. PMID:24963284

  10. Dissociating Value Representation and Inhibition of Inappropriate Affective Response during Reversal Learning in the Ventromedial Prefrontal Cortex123

    PubMed Central

    Manson, Kirk F.; Schiller, Daniela

    2015-01-01

    Abstract Decision-making studies have implicated the ventromedial prefrontal cortex (vmPFC) in tracking the value of rewards and punishments. At the same time, fear-learning studies have pointed to a role of the same area in updating previously learned cue–outcome associations. To disentangle these accounts, we used a reward reversal-learning paradigm in a functional magnetic resonance imaging study in 18 human participants. Participants first learned that one of two colored squares (color A) was associated with monetary reward, whereas the other (color B) was not, and then had to learn that these contingencies reversed. Consistent with value representation, activity of a dorsal region of vmPFC was positively correlated with reward magnitude. Conversely, a more ventral region of vmPFC responded more to color A than to color B after contingency reversal, compatible with a role of inhibiting the previously learned response that was no longer appropriate. Moreover, the response strength was correlated with subjects’ behavioral learning strength. Our findings provide direct evidence for the spatial dissociation of value representation and affective response inhibition in the vmPFC. PMID:26730406

  11. Inactivation Or Inhibition Of Neuronal Activity In The Medial Prefrontal Cortex Largely Reduces Pup Retrieval And Grouping in Maternal Rats

    PubMed Central

    Febo, Marcelo; Felix-Ortiz, Ada C.; Johnson, Tehya R.

    2010-01-01

    Previous research suggests that the maternal medial prefrontal cortex (mPFC) may play a role in maternal care and that cocaine sensitization before pregnancy can affect neuronal activity within this region. The present work was carried out to test whether the mPFC does actually play a role in the expression of maternal behaviors in the rats and to understand what specific behaviors this cortical area may modulate. In the first experiment, tetrodotoxin (TTX) was used to chemically inactivate the mPFC during tests for maternal behavior latencies. Lactating rats were tested on postpartum day 7–9. The results of this first experiment indicate that there is a large effect of TTX-induced inactivation on retrieval behavior latencies. TTX nearly abolished the expression of maternal retrieval of pups without significantly impairing locomotor activity. In the second experiment, GABA-mediated inhibition was used to test maternal behavior latencies and durations of maternal and other behaviors in postpartum dams. In agreement with experiment 1, it was observed that dams capable of retrieving are rendered incapable by inhibition in the mPFC. GABA-mediated inhibition in the mPFC largely reduced retrieval without altering other indices of maternal care and non-specific behavior such as ambulation time, self-grooming, and inactivity. Moreover, in both experiments dams were able to establish contact with pups within seconds. The overall results indicate that the mPFC may play an active role in modulating maternal care, particularly retrieval behavior. External factors that affect the function of the frontal cortical site may result in significant impairments in maternal goal-directed behavior as reported in our earlier work. PMID:20156425

  12. Layer II/III of the prefrontal cortex: inhibition by the serotonin 5-HT1A receptor in development and stress

    PubMed Central

    Goodfellow, Nathalie M.; Benekareddy, Madhurima; Vaidya, Vidita A.; Lambe, Evelyn K.

    2009-01-01

    The modulation of the prefrontal cortex by the neurotransmitter serotonin (5-HT) is thought to play a key role in determining adult anxiety levels. Layer II/III of the prefrontal cortex, which mediates communication across cortical regions, displays a of high level 5-HT1A receptor binding in normal individuals and a significantly lower level in patients with mood and anxiety disorders. Here, we examine how serotonin modulates pyramidal neurons in layer II/III of the rat prefrontal cortex throughout postnatal development and in adulthood. Using whole cell recordings in brain slices of the rat medial prefrontal cortex, we observed that serotonin directly inhibits layer II/III pyramidal neurons through 5-HT1A receptors across postnatal development (P6 to P96). In adulthood, a sex difference in these currents emerges, consistent with human imaging studies of 5-HT1A receptor binding. We examined the effects of early life stress on the 5-HT1A receptor currents in layer II/III. Surprisingly, animals subjected to early life stress displayed significantly larger 5-HT1A-mediated outward currents throughout the third and fourth postnatal weeks following elevated 5-HT1A expression during the second postnatal week. Subsequent exposure to social isolation in adulthood resulted in the almost-complete elimination of 5-HT1A currents in layer II/III neurons suggesting an interaction between early life events and adult experiences. These data represent the first examination of functional 5-HT1A receptors in layer II/III of the prefrontal cortex during normal development as well as after stress. PMID:19675243

  13. Evidence for inhibitory deficits in the prefrontal cortex in schizophrenia

    PubMed Central

    Radhu, Natasha; Garcia Dominguez, Luis; Farzan, Faranak; Richter, Margaret A.; Semeralul, Mawahib O.; Chen, Robert; Fitzgerald, Paul B.

    2015-01-01

    Abnormal gamma-aminobutyric acid inhibitory neurotransmission is a key pathophysiological mechanism underlying schizophrenia. Transcranial magnetic stimulation can be combined with electroencephalography to index long-interval cortical inhibition, a measure of GABAergic receptor-mediated inhibitory neurotransmission from the frontal and motor cortex. In previous studies we have reported that schizophrenia is associated with inhibitory deficits in the dorsolateral prefrontal cortex compared to healthy subjects and patients with bipolar disorder. The main objective of the current study was to replicate and extend these initial findings by evaluating long-interval cortical inhibition from the dorsolateral prefrontal cortex in patients with schizophrenia compared to patients with obsessive-compulsive disorder. A total of 111 participants were assessed: 38 patients with schizophrenia (average age: 35.71 years, 25 males, 13 females), 27 patients with obsessive-compulsive disorder (average age: 36.15 years, 11 males, 16 females) and 46 healthy subjects (average age: 33.63 years, 23 females, 23 males). Long-interval cortical inhibition was measured from the dorsolateral prefrontal cortex and motor cortex through combined transcranial magnetic stimulation and electroencephalography. In the dorsolateral prefrontal cortex, long-interval cortical inhibition was significantly reduced in patients with schizophrenia compared to healthy subjects (P = 0.004) and not significantly different between patients with obsessive-compulsive disorder and healthy subjects (P = 0.5445). Long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex were also significantly greater in patients with schizophrenia compared to patients with obsessive-compulsive disorder (P = 0.0465). There were no significant differences in long-interval cortical inhibition across all three groups in the motor cortex. These results demonstrate that long-interval cortical inhibition deficits in the

  14. Mapping Prefrontal Cortex Functions in Human Infancy

    ERIC Educational Resources Information Center

    Grossmann, Tobias

    2013-01-01

    It has long been thought that the prefrontal cortex, as the seat of most higher brain functions, is functionally silent during most of infancy. This review highlights recent work concerned with the precise mapping (localization) of brain activation in human infants, providing evidence that prefrontal cortex exhibits functional activation much…

  15. Response Inhibition in Adults and Teenagers: Spatiotemporal Differences in the Prefrontal Cortex

    ERIC Educational Resources Information Center

    Vidal, Julie; Mills, Travis; Pang, Elizabeth W.; Taylor, Margot J.

    2012-01-01

    Inhibition is a core executive function reliant on the frontal lobes that shows protracted maturation through to adulthood. We investigated the spatiotemporal characteristics of response inhibition during a visual go/no-go task in 14 teenagers and 14 adults using magnetoencephalography (MEG) and a contrast between two no-go experimental conditions…

  16. Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement.

    PubMed

    Halladay, Lindsay R; Blair, Hugh T

    2015-08-01

    Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were "strategy-selective" cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors. PMID:25972588

  17. Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement

    PubMed Central

    Blair, Hugh T.

    2015-01-01

    Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were “strategy-selective” cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors. PMID:25972588

  18. Pilot Study of Response Inhibition and Error Processing in the Posterior Medial Prefrontal Cortex in Healthy Youth

    ERIC Educational Resources Information Center

    Fitzgerald, Kate Dimond; Zbrozek, Christopher D.; Welsh, Robert C.; Britton, Jennifer C.; Liberzon, Israel; Taylor, Stephan F.

    2008-01-01

    Background: Recent neuroimaging work suggests that inhibitory and error processing in healthy adults share overlapping, but functionally distinct neural circuitries within the posterior medial frontal cortex (pMFC); however, it remains unknown whether the pMFC is differentially engaged by response inhibition compared to error commission in the…

  19. Auditory connections and functions of prefrontal cortex

    PubMed Central

    Plakke, Bethany; Romanski, Lizabeth M.

    2014-01-01

    The functional auditory system extends from the ears to the frontal lobes with successively more complex functions occurring as one ascends the hierarchy of the nervous system. Several areas of the frontal lobe receive afferents from both early and late auditory processing regions within the temporal lobe. Afferents from the early part of the cortical auditory system, the auditory belt cortex, which are presumed to carry information regarding auditory features of sounds, project to only a few prefrontal regions and are most dense in the ventrolateral prefrontal cortex (VLPFC). In contrast, projections from the parabelt and the rostral superior temporal gyrus (STG) most likely convey more complex information and target a larger, widespread region of the prefrontal cortex. Neuronal responses reflect these anatomical projections as some prefrontal neurons exhibit responses to features in acoustic stimuli, while other neurons display task-related responses. For example, recording studies in non-human primates indicate that VLPFC is responsive to complex sounds including vocalizations and that VLPFC neurons in area 12/47 respond to sounds with similar acoustic morphology. In contrast, neuronal responses during auditory working memory involve a wider region of the prefrontal cortex. In humans, the frontal lobe is involved in auditory detection, discrimination, and working memory. Past research suggests that dorsal and ventral subregions of the prefrontal cortex process different types of information with dorsal cortex processing spatial/visual information and ventral cortex processing non-spatial/auditory information. While this is apparent in the non-human primate and in some neuroimaging studies, most research in humans indicates that specific task conditions, stimuli or previous experience may bias the recruitment of specific prefrontal regions, suggesting a more flexible role for the frontal lobe during auditory cognition. PMID:25100931

  20. Finding prefrontal cortex in the rat.

    PubMed

    Leonard, Christiana M

    2016-08-15

    The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent connections The cortical projection field of the mediodorsal nucleus of the thalamus (MD) was identified in the rat using the Fink-Heimer silver technique for tracing degenerating fibers. Small stereotaxic lesions confined to MD were followed by terminal degeneration in the dorsal bank of the rhinal sulcus (sulcal cortex) and the medial wall of the hemisphere anterior and dorsal to the genu of the corpus callosum (medial cortex). No degenerating fibers were traced to the convexity of the hemisphere. The cortical formation receiving a projection from MD is of a relatively undifferentiated type which had been previously classified as juxtallocortex. A study of the efferent fiber connections of the rat׳s MD-projection cortex demonstrated some similarities to those of monkey prefrontal cortex. A substantial projection to the pretectal area and deep layers of the superior colliculus originates in medial cortex, a connection previously reported for caudal prefrontal (area 8) cortex in the monkey. Sulcal cortex projects to basal olfactory structures and lateral hypothalamus, as does orbital frontal cortex in the monkey. The rat׳s MD-projection cortex differs from that in the monkey in that it lacks a granular layer and appears to have no prominent direct associations with temporal and juxtahippocampal areas. Furthermore, retrograde degeneration does not appear in the rat thalamus after damage to MD-projection areas, suggesting that the striatum or thalamus receives a proportionally larger share of the MD-projection in this animal than it does in the monkey. Comparative behavioral investigations are in progress to investigate functional differences between granular prefrontal cortex in the primate and the relatively primitive MD-projection cortex in the rat. © 1969. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26867704

  1. A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

    PubMed Central

    Humby, Trevor; Eddy, Jessica B; Good, Mark A; Reichelt, Amy C; Wilkinson, Lawrence S

    2013-01-01

    Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory ‘stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control. PMID:23657439

  2. Developmental Outcomes after Early Prefrontal Cortex Damage

    ERIC Educational Resources Information Center

    Eslinger, Paul J.; Flaherty-Craig, Claire V.; Benton, Arthur L.

    2004-01-01

    The neuropsychological bases of cognitive, social, and moral development are minimally understood, with a seemingly wide chasm between developmental theories and brain maturation models. As one approach to bridging ideas in these areas, we review 10 cases of early prefrontal cortex damage from the clinical literature, highlighting overall clinical…

  3. Optogenetic Inhibition of Dorsal Medial Prefrontal Cortex Attenuates Stress-Induced Reinstatement of Palatable Food Seeking in Female Rats

    PubMed Central

    Calu, Donna J.; Kawa, Alex B.; Marchant, Nathan J.; Navarre, Brittany M.; Henderson, Mark J.; Chen, Billy; Yau, Hau-Jie; Bossert, Jennifer M.; Schoenbaum, Geoffrey; Deisseroth, Karl; Harvey, Brandon K.; Hope, Bruce T.; Shaham, Yavin

    2013-01-01

    Relapse to maladaptive eating habits during dieting is often provoked by stress. Recently, we identified a role of dorsal medial prefrontal cortex (mPFC) neurons in stress-induced reinstatement of palatable food seeking in male rats. It is unknown whether endogenous neural activity in dorsal mPFC drives stress-induced reinstatement in female rats. Here, we used an optogenetic approach, in which female rats received bilateral dorsal mPFC microinjections of viral constructs coding light-sensitive eNpHR3.0 – eYFP or control eYFP protein and intracranial fiber optic implants. Rats were food restricted and trained to lever press for palatable food pellets. Subsequently, pellets were removed, and lever pressing was extinguished; then the effect of bilateral dorsal mPFC light delivery on reinstatement of food seeking was assessed after injections of the pharmacological stressor yohimbine (an α-2 andrenoceptor antagonist) or pellet priming, a manipulation known to provoke food seeking in hungry rats. Dorsal mPFC light delivery attenuated yohimbine-induced reinstatement of food seeking in eNpHR3.0-injected but not eYFP-injected rats. This optical manipulation had no effect on pellet-priming-induced reinstatement or ongoing food-reinforced responding. Dorsal mPFC light delivery attenuated yohimbine-induced Fos immuno-reactivity and disrupted neural activity during in vivo electrophysiological recording in awake rats. Optical stimulation caused significant outward currents and blocked electrically evoked action potentials in eNpHR3.0-injected but not eYFP-injected mPFC hemispheres. Light delivery alone caused no significant inflammatory response in mPFC. These findings indicate that intracranial light delivery in eNpHR3.0 rats disrupts endogenous dorsal mPFC neural activity that plays a role in stress-induced relapse to food seeking in female rats. PMID:23283335

  4. The role of prefrontal cortex in psychopathy

    PubMed Central

    Koenigs, Michael

    2014-01-01

    Psychopathy is a personality disorder characterized by remorseless and impulsive antisocial behavior. Given the significant societal costs of the recidivistic criminal activity associated with the disorder, there is a pressing need for more effective treatment strategies, and hence, a better understanding of the psychobiological mechanisms underlying the disorder. The prefrontal cortex (PFC) is likely to play an important role in psychopathy. In particular, the ventromedial and anterior cingulate sectors of PFC are theorized to mediate a number of social and affective decision-making functions that appear to be disrupted in psychopathy. This article provides a critical summary of human neuroimaging data implicating prefrontal dysfunction in psychopathy. A growing body of evidence associates psychopathy with structural and functional abnormalities in ventromedial PFC and anterior cingulate cortex. Although this burgeoning field still faces a number of methodological challenges and outstanding questions that will need to be resolved by future studies, the research to date has established a link between psychopathy and PFC. PMID:22752782

  5. Prefrontal Cortex and Social Cognition in Mouse and Man

    PubMed Central

    Bicks, Lucy K.; Koike, Hiroyuki; Akbarian, Schahram; Morishita, Hirofumi

    2015-01-01

    Social cognition is a complex process that requires the integration of a wide variety of behaviors, including salience, reward-seeking, motivation, knowledge of self and others, and flexibly adjusting behavior in social groups. Not surprisingly, social cognition represents a sensitive domain commonly disrupted in the pathology of a variety of psychiatric disorders including Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). Here, we discuss convergent research from animal models to human disease that implicates the prefrontal cortex (PFC) as a key regulator in social cognition, suggesting that disruptions in prefrontal microcircuitry play an essential role in the pathophysiology of psychiatric disorders with shared social deficits. We take a translational perspective of social cognition, and review three key behaviors that are essential to normal social processing in rodents and humans, including social motivation, social recognition, and dominance hierarchy. A shared prefrontal circuitry may underlie these behaviors. Social cognition deficits in animal models of neurodevelopmental disorders like ASD and SCZ have been linked to an altered balance of excitation and inhibition (E/I ratio) within the cortex generally, and PFC specifically. A clear picture of the mechanisms by which altered E/I ratio in the PFC might lead to disruptions of social cognition across a variety of behaviors is not well understood. Future studies should explore how disrupted developmental trajectory of prefrontal microcircuitry could lead to altered E/I balance and subsequent deficits in the social domain. PMID:26635701

  6. Prefrontal Cortex and Social Cognition in Mouse and Man.

    PubMed

    Bicks, Lucy K; Koike, Hiroyuki; Akbarian, Schahram; Morishita, Hirofumi

    2015-01-01

    Social cognition is a complex process that requires the integration of a wide variety of behaviors, including salience, reward-seeking, motivation, knowledge of self and others, and flexibly adjusting behavior in social groups. Not surprisingly, social cognition represents a sensitive domain commonly disrupted in the pathology of a variety of psychiatric disorders including Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). Here, we discuss convergent research from animal models to human disease that implicates the prefrontal cortex (PFC) as a key regulator in social cognition, suggesting that disruptions in prefrontal microcircuitry play an essential role in the pathophysiology of psychiatric disorders with shared social deficits. We take a translational perspective of social cognition, and review three key behaviors that are essential to normal social processing in rodents and humans, including social motivation, social recognition, and dominance hierarchy. A shared prefrontal circuitry may underlie these behaviors. Social cognition deficits in animal models of neurodevelopmental disorders like ASD and SCZ have been linked to an altered balance of excitation and inhibition (E/I ratio) within the cortex generally, and PFC specifically. A clear picture of the mechanisms by which altered E/I ratio in the PFC might lead to disruptions of social cognition across a variety of behaviors is not well understood. Future studies should explore how disrupted developmental trajectory of prefrontal microcircuitry could lead to altered E/I balance and subsequent deficits in the social domain. PMID:26635701

  7. CaMKII inhibition in the prefrontal cortex specifically increases the positive reinforcing effects of sweetened alcohol in C57BL/6J mice.

    PubMed

    Faccidomo, Sara; Reid, Grant T; Agoglia, Abigail E; Ademola, Sherifat A; Hodge, Clyde W

    2016-02-01

    Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is required for synaptic plasticity and has been proposed to be a primary molecular component of the etiology of alcohol addiction. Chronic alcohol intake upregulates CaMKIIα protein expression in reward-related brain regions including the amygdala and nucleus accumbens, and CaMKIIα activity in the amygdala is required for the positive reinforcing effects of alcohol, suggesting this system promotes consumption in the early stages of alcohol addiction. Alternatively, the medial prefrontal cortex (mPFC) is known to inhibit limbic activity via CaMKII-dependent excitatory projections and may, therefore, enable top-down regulation of motivation. Here we sought to remove that regulatory control by site-specifically inhibiting CaMKII activity in the mPFC, and measured effects on the positive reinforcing effects of sweetened alcohol in C57BL/6J mice. Infusion of the CAMKII inhibitor KN-93 (0-10.0 μg) in the mPFC primarily increased alcohol+sucrose reinforced response rate in a dose- and time-dependent manner. KN-93 infusion reduced response rate in behavior-matched sucrose-only controls. Importantly, potentiation of operant responding for sweetened alcohol occurred immediately after infusion, at a time during which effects on sucrose responding were not observed, and persisted through the session. These results suggest that endogenous CaMKII activity in the mPFC exerts inhibitory control over the positive reinforcing effects of alcohol. Downregulation of CaMKII signaling in the mPFC might contribute to escalated alcohol use. PMID:26608538

  8. Discourse Production Following Injury to the Dorsolateral Prefrontal Cortex

    ERIC Educational Resources Information Center

    Coelho, Carl; Le, Karen; Mozeiko, Jennifer; Krueger, Frank; Grafman, Jordan

    2012-01-01

    Individuals with damage to the prefrontal cortex, and the dorsolateral prefrontal cortex (DLPFC) in particular, often demonstrate difficulties with the formulation of complex language not attributable to aphasia. The present study employed a discourse analysis procedure to characterize the language of individuals with left (L) or right (R) DLPFC…

  9. Medial Prefrontal Cortex Lesions Abolish Contextual Control of Competing Responses

    ERIC Educational Resources Information Center

    Haddon, J. E.; Killcross, A. S.

    2005-01-01

    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…

  10. Ventromedial prefrontal cortex mediates visual attention during facial emotion recognition.

    PubMed

    Wolf, Richard C; Philippi, Carissa L; Motzkin, Julian C; Baskaya, Mustafa K; Koenigs, Michael

    2014-06-01

    The ventromedial prefrontal cortex is known to play a crucial role in regulating human social and emotional behaviour, yet the precise mechanisms by which it subserves this broad function remain unclear. Whereas previous neuropsychological studies have largely focused on the role of the ventromedial prefrontal cortex in higher-order deliberative processes related to valuation and decision-making, here we test whether ventromedial prefrontal cortex may also be critical for more basic aspects of orienting attention to socially and emotionally meaningful stimuli. Using eye tracking during a test of facial emotion recognition in a sample of lesion patients, we show that bilateral ventromedial prefrontal cortex damage impairs visual attention to the eye regions of faces, particularly for fearful faces. This finding demonstrates a heretofore unrecognized function of the ventromedial prefrontal cortex-the basic attentional process of controlling eye movements to faces expressing emotion. PMID:24691392

  11. Glycogen synthase kinase-3β inhibition in the medial prefrontal cortex mediates paradoxical amphetamine action in a mouse model of ADHD

    PubMed Central

    Yen, Yi-Chun; Gassen, Nils C.; Zellner, Andreas; Rein, Theo; Landgraf, Rainer; Wotjak, Carsten T.; Anderzhanova, Elmira

    2015-01-01

    Psychostimulants show therapeutic efficacy in the treatment of attention-deficit hyperactivity disorder (ADHD). It is generally assumed that they ameliorate ADHD symptoms via interfering with monoaminergic signaling. We combined behavioral pharmacology, neurochemistry and molecular analyses to identify mechanisms underlying the paradoxical calming effect of amphetamine in low trait anxiety behavior (LAB) mice, a novel multigenetic animal model of ADHD. Amphetamine (1 mg/kg) and methylphenidate (10 mg/kg) elicited similar dopamine and norepinephrine release in the medial prefrontal cortex (mPFC) and in the striatum of LAB mice. In contrast, amphetamine decreased, while methylphenidate increased locomotor activity. This argues against changes in dopamine and/or norepinephrine release as mediators of amphetamine paradoxical effects. Instead, the calming activity of amphetamine corresponded to the inhibition of glycogen synthase kinase 3β (GSK3β) activity, specifically in the mPFC. Accordingly, not only systemic administration of the GSK3β inhibitor TDZD-8 (20 mg/kg), but also local microinjections of TDZD-8 and amphetamine into the mPFC, but not into the striatum, decreased locomotor activity in LAB mice. Amphetamine effects seem to depend on NMDA receptor signaling, since pre- or co-treatment with MK-801 (0.3 mg/kg) abolished the effects of amphetamine (1 mg/kg) on the locomotion and on the phosphorylation of GSK3β at the level of the mPFC. Taken together, the paradoxical calming effect of amphetamine in hyperactive LAB mice concurs with a decreased GSK3β activity in the mPFC. This effect appears to be independent of dopamine or norepinephrine release, but contingent on NMDA receptor signaling. PMID:25852508

  12. Ventromedial prefrontal cortex mediates visual attention during facial emotion recognition

    PubMed Central

    Wolf, Richard C.; Philippi, Carissa L.; Motzkin, Julian C.; Baskaya, Mustafa K.

    2014-01-01

    The ventromedial prefrontal cortex is known to play a crucial role in regulating human social and emotional behaviour, yet the precise mechanisms by which it subserves this broad function remain unclear. Whereas previous neuropsychological studies have largely focused on the role of the ventromedial prefrontal cortex in higher-order deliberative processes related to valuation and decision-making, here we test whether ventromedial prefrontal cortex may also be critical for more basic aspects of orienting attention to socially and emotionally meaningful stimuli. Using eye tracking during a test of facial emotion recognition in a sample of lesion patients, we show that bilateral ventromedial prefrontal cortex damage impairs visual attention to the eye regions of faces, particularly for fearful faces. This finding demonstrates a heretofore unrecognized function of the ventromedial prefrontal cortex—the basic attentional process of controlling eye movements to faces expressing emotion. PMID:24691392

  13. Cytotoxic lesion of the medial prefrontal cortex abolishes the partial reinforcement extinction effect, attenuates prepulse inhibition of the acoustic startle reflex and induces transient hyperlocomotion, while sparing spontaneous object recognition memory in the rat.

    PubMed

    Yee, B K

    2000-01-01

    The partial reinforcement extinction effect refers to the increase in resistance to extinction of an operant response acquired under partial reinforcement relative to that acquired under continuous reinforcement. Prepulse inhibition of the acoustic startle response refers to the reduction in startle reactivity towards an intense acoustic pulse stimulus when it is shortly preceded by a weak prepulse stimulus. These two behavioural phenomena appear to be related to different forms of attentional processes. While the prepulse inhibition effect reflects an inherent early attentional gating mechanism, the partial reinforcement extinction effect is believed to involve the development of acquired inattention, i.e. the latter requires the animals to learn about what to and what not to attend. Impairments in prepulse inhibition and the partial reinforcement extinction effect have been independently linked to the neuropsychology of attentional dysfunctions seen in schizophrenia. The proposed neural substrates underlying these behaviourial phenomena also appear to overlap considerably: both focus on the nucleus accumbens and emphasize the functional importance of its limbic afferents, including that originating from the medial prefrontal cortex, on accumbal output/activity. The present study demonstrated that cytotoxic medial prefrontal cortex lesions which typically damaged the prelimbic, the infralimbic and the dorsal anterior cingulate areas could lead to the abolition of the partial reinforcement extinction effect and the attenuation of prepulse inhibition. The lesions also resulted in a transient elevation of spontaneous locomotor activity. In contrast, the same lesions spared performance in a spontaneous object recognition memory test, in which the lesioned animals displayed normal preference for a novel object when the novel object was presented in conjunction with a familiar object seen 10 min earlier within an open field arena. The present results lend support to the

  14. Divergent Plasticity of Prefrontal Cortex Networks

    PubMed Central

    Moghaddam, Bita; Homayoun, Houman

    2010-01-01

    The ‘executive’ regions of the prefrontal cortex (PFC) such as the dorsolateral PFC (dlPFC) and its rodent equivalent medial PFC (mPFC) are thought to respond in concert with the ‘limbic’ regions of the PFC such as the orbitofrontal (OFC) cortex to orchestrate behavior that is consistent with context and expected outcome. Both groups of regions have been implicated in behavioral abnormalities associated with addiction and psychiatric disorders, in particular, schizophrenia and mood disorders. Theories about the pathophysiology of these disorders, however, incorporate abnormalities in discrete PFC regions independently of each other or assume they are one and the same and, thus, bunch them under umbrella of ‘PFC dysfunction.’ Emerging data from animal studies suggest that mPFC and OFC neurons display opposing patterns of plasticity during associative learning and in response to repeated exposure to psychostimulants. These data corroborate clinical studies reporting different patterns of activation in OFC versus dlPFC in individuals with schizophrenia or addictive disorders. These suggest that concomitant but divergent engagement of discrete PFC regions is critical for learning stimulus-outcome associations, and the execution of goal-directed behavior that is based on these associations. An atypical interplay between these regions may lead to abnormally high or low salience assigned to stimuli, resulting in symptoms that are fundamental to many psychiatric and addictive disorders, including attentional deficits, improper affective response to stimuli, and inflexible or impulsive behavior. PMID:17912252

  15. Distinct Roles of the Prefrontal and Posterior Parietal Cortices in Response Inhibition.

    PubMed

    Zhou, Xin; Qi, Xue-Lian; Constantinidis, Christos

    2016-03-29

    The dorsolateral prefrontal cortex and posterior parietal cortex have been implicated in the planning of movements and inhibition of inappropriate responses, though their precise roles in these functions are not known. To address this question, we trained monkeys to perform memory-guided saccade and anti-saccade tasks and compared neural responses in the same animals. A population of neurons with no motor responses was also activated by a stimulus appearing out of the receptive field and could therefore mediate vector inversion. These neurons were found almost exclusively in the prefrontal cortex. Prefrontal cortical activity better predicted the level of performance in the task. Representation of the saccade goal also peaked in the prefrontal cortex at a time that was predictive of reaction time. These results suggest that the prefrontal cortex is the primary site of vector inversion in the cerebral cortex and explain the importance of this area in response inhibition. PMID:26997283

  16. Optogenetic dissection of medial prefrontal cortex circuitry

    PubMed Central

    Riga, Danai; Matos, Mariana R.; Glas, Annet; Smit, August B.; Spijker, Sabine; Van den Oever, Michel C.

    2014-01-01

    The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders. PMID:25538574

  17. The medial prefrontal cortex exhibits money illusion

    PubMed Central

    Weber, Bernd; Rangel, Antonio; Wibral, Matthias; Falk, Armin

    2009-01-01

    Behavioral economists have proposed that money illusion, which is a deviation from rationality in which individuals engage in nominal evaluation, can explain a wide range of important economic and social phenomena. This proposition stands in sharp contrast to the standard economic assumption of rationality that requires individuals to judge the value of money only on the basis of the bundle of goods that it can buy—its real value—and not on the basis of the actual amount of currency—its nominal value. We used fMRI to investigate whether the brain's reward circuitry exhibits money illusion. Subjects received prizes in 2 different experimental conditions that were identical in real economic terms, but differed in nominal terms. Thus, in the absence of money illusion there should be no differences in activation in reward-related brain areas. In contrast, we found that areas of the ventromedial prefrontal cortex (vmPFC), which have been previously associated with the processing of anticipatory and experienced rewards, and the valuation of goods, exhibited money illusion. We also found that the amount of money illusion exhibited by the vmPFC was correlated with the amount of money illusion exhibited in the evaluation of economic transactions. PMID:19307555

  18. Distinct Roles of the Prefrontal and Posterior Parietal Cortices in Response Inhibition

    PubMed Central

    Zhou, Xin; Qi, Xue-Lian; Constantinidis, Christos

    2016-01-01

    SUMMARY The dorsolateral prefrontal and posterior parietal cortex have been implicated in planning of movements and inhibition of inappropriate responses, though their precise roles in these functions are not known. To address this question we trained monkeys to perform memory guided saccade and anti-saccade tasks and compared neural responses in the same animals. A population of neurons with no motor responses was also activated by a stimulus appearing out of the receptive field and could therefore mediate vector inversion. These neurons were found almost exclusively in the prefrontal cortex. Prefrontal cortical activity better predicted the level of performance in the task. Representation of the saccade goal also peaked in the prefrontal cortex at a time that was predictive of reaction time. These results suggest that prefrontal cortex is the primary site of vector inversion in the cerebral cortex and explain the importance of this area in response inhibition. PMID:26997283

  19. Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia.

    PubMed

    Zuo, Daiying; Bzdega, Tomasz; Olszewski, Rafal T; Moffett, John R; Neale, Joseph H

    2012-06-22

    The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3. PMID:22570482

  20. Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia*

    PubMed Central

    Zuo, Daiying; Bzdega, Tomasz; Olszewski, Rafal T.; Moffett, John R.; Neale, Joseph H.

    2012-01-01

    The “glutamate” theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3. PMID:22570482

  1. Neurodynamics of the prefrontal cortex during conditional visuomotor associations.

    PubMed

    Loh, Marco; Pasupathy, Anitha; Miller, Earl K; Deco, Gustavo

    2008-03-01

    The prefrontal cortex is believed to be important for cognitive control, working memory, and learning. It is known to play an important role in the learning and execution of conditional visuomotor associations, a cognitive task in which stimuli have to be associated with actions by trial-and-error learning. In our modeling study, we sought to integrate several hypotheses on the function of the prefrontal cortex using a computational model, and compare the results to experimental data. We constructed a module of prefrontal cortex neurons exposed to two different inputs, which we envision to originate from the inferotemporal cortex and the basal ganglia. We found that working memory properties do not describe the dominant dynamics in the prefrontal cortex, but the activation seems to be transient, probably progressing along a pathway from sensory to motor areas. During the presentation of the cue, the dynamics of the prefrontal cortex is bistable, yielding a distinct activation for correct and error trails. We find that a linear change in network parameters relates to the changes in neural activity in consecutive correct trials during learning, which is important evidence for the underlying learning mechanisms. PMID:18004947

  2. Dissociation in prefrontal cortex of affective and attentional shifts.

    PubMed

    Dias, R; Robbins, T W; Roberts, A C

    1996-03-01

    The prefrontal cortex is implicated in such human characteristics as volition, planning, abstract reasoning and affect. Frontal-lobe damage can cause disinhibition such that the behaviour of a subject is guided by previously acquired responses that are inappropriate to the current situation. Here we demonstrate that disinhibition, or a loss of inhibitory control, can be selective for particular cognitive functions and that different regions of the prefrontal cortex provide inhibitory control in different aspects of cognitive processing. Thus, whereas damage to the lateral prefrontal cortex (Brodmann's area 9) in monkeys causes a loss of inhibitory control in attentional selection, damage to the orbito-frontal cortex in monkeys causes a loss of inhibitory control in 'affective' processing, thereby impairing the ability to alter behaviour in response to fluctuations in the emotional significance of stimuli. These findings not only support the view that the prefrontal cortex has multiple functions, but also provide evidence for the distribution of different cognitive functions within specific regions of prefrontal cortex. PMID:8598908

  3. Deficits in prospective memory following damage to the prefrontal cortex.

    PubMed

    Umeda, Satoshi; Kurosaki, Yoshiko; Terasawa, Yuri; Kato, Motoichiro; Miyahara, Yasuyuki

    2011-07-01

    Neuropsychological investigations of prospective memory (PM), representing memory of future intentions or plans, have evolved over the past two decades. The broadly accepted divisions involved in PM consist of a prospective memory component (PMC), a process for remembering to remember, and a retrospective memory component, a process for remembering the content of the intended action. Previous functional neuroimaging studies have provided some evidence that the rostral prefrontal cortex (BA10) is one of areas that is critical for prospective remembering. However, the question of whether damage to part of the prefrontal cortex affects attenuated performance for PMC remains unresolved. In this study, 74 participants with traumatic brain injury (TBI) including focal damage to frontal or temporal lobe areas were administered thirteen standard neuropsychological tests and the PM task. To identify influential areas contributing to PM performance, discriminant function analysis was conducted. The results indicated that the following three areas are highly contributory to PM performance: the right dorsolateral prefrontal cortex; the right ventromedial prefrontal cortex; and the left dorsomedial prefrontal cortex. Comparing differences in neuropsychological test scores showed that orientation scores were significantly higher in the greater PM performance group, suggesting that PMC represents an integrated memory function associated with awareness of current status. These data contribute to our understanding of the neural substrates and functional characteristics of the PMC. PMID:21477605

  4. The Medial Prefrontal Cortex Is Critical for Memory Retrieval and Resolving Interference

    ERIC Educational Resources Information Center

    Peters, Gregory J.; David, Christopher N.; Marcus, Madison D.; Smith, David M.

    2013-01-01

    The prefrontal cortex (PFC) is known to be critically involved in strategy switching, attentional set shifting, and inhibition of prepotent responses. A central feature of this kind of behavioral flexibility is the ability to resolve conflicting response tendencies, suggesting a general role of the PFC in resolving interference. If so, the PFC…

  5. A parametric relief signal in human ventrolateral prefrontal cortex.

    PubMed

    Fujiwara, Juri; Tobler, Philippe N; Taira, Masato; Iijima, Toshio; Tsutsui, Ken-Ichiro

    2009-02-01

    People experience relief whenever outcomes are better than they would have been, had an alternative course of action been chosen. Here we investigated the neuronal basis of relief with functional resonance imaging in a choice task in which the outcome of the chosen option and that of the unchosen option were revealed sequentially. We found parametric activation increases in anterior ventrolateral prefrontal cortex with increasing relief (chosen outcomes better than unchosen outcomes). Conversely, anterior ventrolateral prefrontal activation was unrelated to the opposite of relief, increasing regret (chosen outcomes worse than unchosen outcomes). Furthermore, the anterior ventrolateral prefrontal activation was unrelated to primary gains and increased with relief irrespective of whether the chosen outcome was a loss or a gain. These results suggest that the anterior ventrolateral prefrontal cortex encodes a higher-order reward signal that lies at the core of current theories of emotion. PMID:18992349

  6. Interplay of hippocampus and prefrontal cortex in memory

    PubMed Central

    Preston, Alison R.; Eichenbaum, Howard

    2013-01-01

    Recent studies on the hippocampus and the prefrontal cortex have considerably advanced our understanding of the distinct roles of these brain areas in the encoding and retrieval of memories, and of how they interact in the prolonged process by which new memories are consolidated into our permanent storehouse of knowledge. These studies have led to a new model of how the hippocampus forms and replays memories and how the prefrontal cortex engages representations of the meaningful contexts in which related memories occur, as well as how these areas interact during memory retrieval. Furthermore, they have provided new insights into how interactions between the hippocampus and prefrontal cortex support the assimilation of new memories into pre-existing networks of knowledge, called schemas, and how schemas are modified in this process as the foundation of memory consolidation. PMID:24028960

  7. Polysialic Acid Acute Depletion Induces Structural Plasticity in Interneurons and Impairs the Excitation/Inhibition Balance in Medial Prefrontal Cortex Organotypic Cultures

    PubMed Central

    Castillo-Gómez, Esther; Pérez-Rando, Marta; Vidueira, Sandra; Nacher, Juan

    2016-01-01

    The structure and function of the medial prefrontal cortex (mPFC) is affected in several neuropsychiatric disorders, including schizophrenia and major depression. Recent studies suggest that imbalances between excitatory and inhibitory activity (E/I) may be responsible for this cortical dysfunction and therefore, may underlie the core symptoms of these diseases. This E/I imbalance seems to be correlated with alterations in the plasticity of interneurons but there is still scarce information on the mechanisms that may link these phenomena. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is a good candidate, because it modulates the neuronal plasticity of interneurons and its expression is altered in schizophrenia and major depression. To address this question, we have developed an in vitro model using mPFC organotypic cultures of transgenic mice displaying fluorescent spiny interneurons. After enzymatic depletion of PSA, the spine density of interneurons, the number of synaptic puncta surrounding pyramidal neuron somata and the E/I ratio were strongly affected. These results point to the polysialylation of NCAM as an important factor in the maintenance of E/I balance and the structural plasticity of interneurons. This may be particularly relevant for better understanding the etiology of schizophrenia and major depression. PMID:27445697

  8. Prefrontal Cortex Activity Related to Abstract Response Strategies

    PubMed Central

    Genovesio, Aldo; Brasted, Peter J.; Mitz, Andrew R.; Wise, Steven P.

    2005-01-01

    Overview In monkeys, foraging strategies depend not only on a context established by spatial or symbolic cues, but also on the relations among cues. Genovesio et al. recorded the activity of prefrontal cortex neurons while monkeys chose a strategy based on the relation between consecutive symbolic cues. For the same cues and actions, the monkeys also learned fixed responses to the same symbols. Many neurons had activity selective for a given strategy, others for whether the monkeys’ response choice depended on a symbol or the relation between symbols. These findings indicate that the primate prefrontal cortex contributes to implementing abstract strategies. PMID:16039571

  9. D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence.

    PubMed

    Kang, S; Paul, K; Hankosky, E R; Cox, C L; Gulley, J M

    2016-06-01

    Amphetamine (AMPH) exposure leads to changes in behavior and dopamine receptor function in the prefrontal cortex (PFC). Since dopamine plays an important role in regulating GABAergic transmission in the PFC, we investigated if AMPH exposure induces long-lasting changes in dopamine's ability to modulate inhibitory transmission in the PFC as well as whether the effects of AMPH differed depending on the age of exposure. Male Sprague-Dawley rats were given saline or 3 mg/kg AMPH (i.p.) repeatedly during adolescence or adulthood and following a withdrawal period of up to 5 weeks (Experiment 1) or up to 14 weeks (Experiment 2), they were sacrificed for in vitro whole-cell recordings in layer V/VI of the medial PFC. We found that in brain slices from either adolescent- or adult-exposed rats, there was an attenuation of dopamine-induced increases in inhibitory synaptic currents in pyramidal cells. These effects did not depend on age of exposure, were mediated at least partially by a reduced sensitivity of D1 receptors in AMPH-treated rats, and were associated with an enhanced behavioral response to the drug in a separate group of rats given an AMPH challenge following the longest withdrawal period. Together, these data reveal a prolonged effect of AMPH exposure on medial PFC function that persisted for up to 14 weeks in adolescent-exposed animals. These long-lasting neurophysiological changes may be a contributing mechanism to the behavioral consequences that have been observed in those with a history of amphetamine abuse. PMID:26946269

  10. Development of Rostral Prefrontal Cortex and Cognitive and Behavioural Disorders

    ERIC Educational Resources Information Center

    Dumontheil, Iroise; Burgess, Paul W.; Blakemore, Sarah-Jayne

    2008-01-01

    Information on the development and functions of rostral prefrontal cortex (PFC), or Brodmann area 10, has been gathered from different fields, from anatomical development to functional neuroimaging in adults, and put forward in relation to three particular cognitive and behavioural disorders. Rostral PFC is larger and has a lower cell density in…

  11. Extinction Circuits for Fear and Addiction Overlap in Prefrontal Cortex

    ERIC Educational Resources Information Center

    Peters, Jamie; Kalivas, Peter W.; Quirk, Gregory J.

    2009-01-01

    Extinction is a form of inhibitory learning that suppresses a previously conditioned response. Both fear and drug seeking are conditioned responses that can lead to maladaptive behavior when expressed inappropriately, manifesting as anxiety disorders and addiction, respectively. Recent evidence indicates that the medial prefrontal cortex (mPFC) is…

  12. Prefrontal Cortex Contributions to Episodic Retrieval Monitoring and Evaluation

    ERIC Educational Resources Information Center

    Cruse, Damian; Wilding, Edward L.

    2009-01-01

    Although the prefrontal cortex (PFC) plays roles in episodic memory judgments, the specific processes it supports are not understood fully. Event-related potential (ERP) studies of episodic retrieval have revealed an electrophysiological modulation--the right-frontal ERP old/new effect--which is thought to reflect activity in PFC. The functional…

  13. Prefrontal cortex and executive function in young children: a review of NIRS studies

    PubMed Central

    Moriguchi, Yusuke; Hiraki, Kazuo

    2013-01-01

    Executive function (EF) refers to the higher-order cognitive control process for the attainment of a specific goal. There are several subcomponents of EF, such as inhibition, cognitive shifting, and working memory. Extensive neuroimaging research in adults has revealed that the lateral prefrontal cortex plays an important role in EF. Developmental studies have reported behavioral evidence showing that EF changes significantly during preschool years. However, the neural mechanism of EF in young children is still unclear. This article reviews recent near-infrared spectroscopy (NIRS) research that examined the relationship between the development of EF and the lateral prefrontal cortex. Specifically, this review focuses on inhibitory control, cognitive shifting, and working memory in young children. Research has consistently shown significant prefrontal activation during tasks in typically developed children, but this activation may be abnormal in children with developmental disorders. Finally, methodological issues and future directions are discussed. PMID:24381551

  14. Social cognition in patients following surgery to the prefrontal cortex.

    PubMed

    Jenkins, Lisanne Michelle; Andrewes, David Gordon; Nicholas, Christian Luke; Drummond, Katharine Jann; Moffat, Bradford Armstrong; Phal, Pramit; Desmond, Patricia; Kessels, Roy Peter Caspar

    2014-12-30

    Impaired social cognition, including emotion recognition, may explain dysfunctional emotional and social behaviour in patients with lesions to the ventromedial prefrontal cortex (VMPFC). However, the VMPFC is a large, poorly defined area that can be sub-divided into orbital and medial sectors. We sought to investigate social cognition in patients with discrete, surgically circumscribed prefrontal lesions. Twenty-seven patients between 1 and 12 months post-neurosurgery were divided into groups based on Brodmann areas resected, determined by post-surgical magnetic resonance imaging. We hypothesised that patients with lesions to the VMPFC (n=5), anterior cingulate cortex (n=4), orbitofrontal cortex (n=7) and dorsolateral prefrontal cortex (DLPFC, n=11) would perform worse than a control group of 26 extra-cerebral neurosurgery patients on measures of dynamic facial emotion recognition, theory of mind (ToM) and empathy. Results indicated the VMPFC-lesioned group performed significantly worse than the control group on the facial emotion recognition task overall, and for fear specifically, and performed worse on the ToM measure. The DLPFC group also performed worse on the ToM and empathy measures, but DLPFC lesion location was not a predictor of performance in hierarchical multiple regressions that accounted for other variables, including the reduced estimated verbal IQ in this group. It was concluded that isolated orbital or medial prefrontal lesions are not sufficient to produce impairments in social cognition. This is the first study to demonstrate that it is the combination of lesions to both areas that affect social cognition, irrespective of lesion volume. While group sizes were similar to other comparable studies that included patients with discrete, surgically circumscribed lesions to the prefrontal cortex, future large, multi-site studies are needed to collect larger samples and confirm these results. PMID:25284626

  15. Thalamic control of layer 1 circuits in prefrontal cortex

    PubMed Central

    Cruikshank, Scott J.; Ahmed, Omar J.; Stevens, Tanya R.; Patrick, Saundra L.; Gonzalez, Amalia N.; Elmaleh, Margot; Connors, Barry W.

    2012-01-01

    Knowledge of thalamocortical (TC) processing comes mainly from studying core thalamic systems that project to middle layers of primary sensory cortices. However, most thalamic relay neurons comprise a matrix of cells that are densest in the “nonspecific” thalamic nuclei and usually target layer 1 of multiple cortical areas. A longstanding hypothesis is that matrix TC systems are crucial for regulating neocortical excitability during changing behavioral states, yet we know almost nothing about the mechanisms of such regulation. It is also unclear whether synaptic and circuit mechanisms that are well established for core sensory TC systems apply to matrix TC systems. Here we describe studies of thalamic matrix influences on mouse prefrontal cortex using optogenetic and in vitro electrophysiology techniques. Channelrhodopsin-2 was expressed in midline and paralaminar (matrix) thalamic neurons, and their layer 1-projecting TC axons were activated optically. Contrary to conventional views, we found that matrix TC projections to layer 1 could transmit relatively strong, fast, high-fidelity synaptic signals. Layer 1 TC projections preferentially drove inhibitory interneurons of layer 1, especially those of the late-spiking subtype, and often triggered feedforward inhibition in both layer 1 interneurons and pyramidal cells of layers 2/3. Responses during repetitive stimulation were far more sustained for matrix than for core sensory TC pathways. Thus, matrix TC circuits appear to be specialized for robust transmission over relatively extended periods, consistent with the sort of persistent activation observed during working memory and potentially applicable to state-dependent regulation of excitability. PMID:23223300

  16. Right dorsolateral prefrontal cortical activity and behavioral inhibition.

    PubMed

    Shackman, Alexander J; McMenamin, Brenton W; Maxwell, Jeffrey S; Greischar, Lawrence L; Davidson, Richard J

    2009-12-01

    Individuals show marked variation in their responses to threat. Such individual differences in behavioral inhibition play a profound role in mental and physical well-being. Behavioral inhibition is thought to reflect variation in the sensitivity of a distributed neural system responsible for generating anxiety and organizing defensive responses to threat and punishment. Although progress has been made in identifying the key constituents of this behavioral inhibition system in humans, the involvement of dorsolateral prefrontal cortex (DLPFC) remains unclear. Here, we acquired self-reported Behavioral Inhibition System Sensitivity scores and high-resolution electroencephalography from a large sample (n= 51). Using the enhanced spatial resolution afforded by source modeling techniques, we show that individuals with greater tonic (resting) activity in right-posterior DLPFC rate themselves as more behaviorally inhibited. This observation provides novel support for recent conceptualizations of behavioral inhibition and clues to the mechanisms that might underlie variation in threat-induced negative affect. PMID:19906125

  17. A dorsolateral prefrontal cortex semi-automatic segmenter

    NASA Astrophysics Data System (ADS)

    Al-Hakim, Ramsey; Fallon, James; Nain, Delphine; Melonakos, John; Tannenbaum, Allen

    2006-03-01

    Structural, functional, and clinical studies in schizophrenia have, for several decades, consistently implicated dysfunction of the prefrontal cortex in the etiology of the disease. Functional and structural imaging studies, combined with clinical, psychometric, and genetic analyses in schizophrenia have confirmed the key roles played by the prefrontal cortex and closely linked "prefrontal system" structures such as the striatum, amygdala, mediodorsal thalamus, substantia nigra-ventral tegmental area, and anterior cingulate cortices. The nodal structure of the prefrontal system circuit is the dorsal lateral prefrontal cortex (DLPFC), or Brodmann area 46, which also appears to be the most commonly studied and cited brain area with respect to schizophrenia. 1, 2, 3, 4 In 1986, Weinberger et. al. tied cerebral blood flow in the DLPFC to schizophrenia.1 In 2001, Perlstein et. al. demonstrated that DLPFC activation is essential for working memory tasks commonly deficient in schizophrenia. 2 More recently, groups have linked morphological changes due to gene deletion and increased DLPFC glutamate concentration to schizophrenia. 3, 4 Despite the experimental and clinical focus on the DLPFC in structural and functional imaging, the variability of the location of this area, differences in opinion on exactly what constitutes DLPFC, and inherent difficulties in segmenting this highly convoluted cortical region have contributed to a lack of widely used standards for manual or semi-automated segmentation programs. Given these implications, we developed a semi-automatic tool to segment the DLPFC from brain MRI scans in a reproducible way to conduct further morphological and statistical studies. The segmenter is based on expert neuroanatomist rules (Fallon-Kindermann rules), inspired by cytoarchitectonic data and reconstructions presented by Rajkowska and Goldman-Rakic. 5 It is semi-automated to provide essential user interactivity. We present our results and provide details on

  18. Distinct Contributions of the Basolateral Amygdala and the Medial Prefrontal Cortex to Learning and Relearning Extinction of Context Conditioned Fear

    ERIC Educational Resources Information Center

    Laurent, Vincent; Westbrook, R. Frederick

    2008-01-01

    We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but…

  19. The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor Pathway Connectivity

    PubMed Central

    Hughes, Laura E.; Anderson, Michael C.; Rowe, James B.

    2015-01-01

    Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants' stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control. PMID:25589771

  20. Molecular influences on working memory circuits in dorsolateral prefrontal cortex.

    PubMed

    Arnsten, Amy F T; Jin, Lu E

    2014-01-01

    The working memory circuits of the primate dorsolateral prefrontal cortex (dlPFC) are modulated in a unique manner, often opposite to the molecular mechanisms needed for long-term memory consolidation. Working memory, our "mental sketch pad" is an ephemeral process, whereby transient, mental representations form the foundation for abstract thought. The microcircuits that generate mental representations are found in deep layer III of the dlPFC, where pyramidal cells excite each other to keep information "in mind" through NMDA receptor synapses on spines. The catecholaminergic and cholinergic arousal systems have rapid and flexible influences on the strength of these connections, thus allowing coordination between arousal and cognitive states. These modulators can rapidly weaken connectivity, for example, as occurs during uncontrollable stress, via feedforward calcium-cAMP signaling opening potassium (K(+)) channels near synapses on spines. Lower levels of calcium-cAMP-K(+) channel signaling provide negative feedback within recurrent excitatory circuits, and help to gate inputs to shape the contents of working memory. There are also explicit mechanisms to inhibit calcium-cAMP signaling and strengthen connectivity, for example, postsynaptic α2A-adrenoceptors on spines. This work has led to the development of the α2A agonist, guanfacine, for the treatment of a variety of dlPFC disorders. In mental illness, there are a variety of genetic insults to the molecules that normally serve to inhibit calcium-cAMP signaling in spines, thus explaining why so many genetic insults can lead to the same phenotype of impaired dlPFC cognitive function. Thus, the molecular mechanisms that provide mental flexibility may also confer vulnerability when dysregulated in cognitive disorders. PMID:24484703

  1. Capturing the temporal evolution of choice across prefrontal cortex.

    PubMed

    Hunt, Laurence T; Behrens, Timothy E J; Hosokawa, Takayuki; Wallis, Jonathan D; Kennerley, Steven W

    2015-01-01

    Activity in prefrontal cortex (PFC) has been richly described using economic models of choice. Yet such descriptions fail to capture the dynamics of decision formation. Describing dynamic neural processes has proven challenging due to the problem of indexing the internal state of PFC and its trial-by-trial variation. Using primate neurophysiology and human magnetoencephalography, we here recover a single-trial index of PFC internal states from multiple simultaneously recorded PFC subregions. This index can explain the origins of neural representations of economic variables in PFC. It describes the relationship between neural dynamics and behaviour in both human and monkey PFC, directly bridging between human neuroimaging data and underlying neuronal activity. Moreover, it reveals a functionally dissociable interaction between orbitofrontal cortex, anterior cingulate cortex and dorsolateral PFC in guiding cost-benefit decisions. We cast our observations in terms of a recurrent neural network model of choice, providing formal links to mechanistic dynamical accounts of decision-making. PMID:26653139

  2. Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats.

    PubMed

    Rao, Raghavendra; Ennis, Kathleen; Mitchell, Eugena P; Tran, Phu V; Gewirtz, Jonathan C

    2016-01-01

    Recurrent hypoglycemia is common in infants and children. In developing rat models, recurrent moderate hypoglycemia leads to neuronal injury in the medial prefrontal cortex. To understand the effects beyond neuronal injury, 3-week-old male rats were subjected to 5 episodes of moderate hypoglycemia (blood glucose concentration, approx. 30 mg/dl for 90 min) once daily from postnatal day 24 to 28. Neuronal injury was determined using Fluoro-Jade B histochemistry on postnatal day 29. The effects on brain-derived neurotrophic factor (BDNF) and its cognate receptor, tyrosine kinase receptor B (TrkB) expression, which is critical for prefrontal cortex development, were determined on postnatal day 29 and at adulthood. The effects on prefrontal cortex-mediated function were determined by assessing the prepulse inhibition of the acoustic startle reflex on postnatal day 29 and 2 weeks later, and by testing for fear-potentiated startle at adulthood. Recurrent hypoglycemia led to neuronal injury confined primarily to the medial prefrontal cortex. BDNF/TrkB expression in the prefrontal cortex was suppressed on postnatal day 29 and was accompanied by lower prepulse inhibition, suggesting impaired sensorimotor gating. Following the cessation of recurrent hypoglycemia, the prepulse inhibition had recovered at 2 weeks. BDNF/TrkB expression in the prefrontal cortex had normalized and fear-potentiated startle was intact at adulthood. Recurrent moderate hypoglycemia during development has significant adverse effects on the prefrontal cortex in the posthypoglycemic period. PMID:26820887

  3. Morphometric Correlation of Impulsivity in Medial Prefrontal Cortex

    PubMed Central

    Cho, Sang Soo; Pellecchia, Giovanna; Aminian, Kelly; Ray, Nicola; Segura, Barbara; Obeso, Ignacio

    2014-01-01

    Impulsivity is a complex behaviour composed of different domains encompassing behavioural disinhibition, risky decision-making and delay discounting abnormalities. To investigate regional brain correlates between levels of individual impulsivity and grey matter volume, we performed voxel-based morphometric correlation analysis in 34 young, healthy subjects using impulsivity scores measured with Barratt Impulsivity Scale-11 and computerized Kirby’s delay discounting task. The VBM analysis showed that impulsivity appears to be reliant on a network of cortical (medial prefrontal cortex and dorsolateral prefrontal cortex) and subcortical (ventral striatum) structures emphasizing the importance of brain networks associated with reward related decision-making in daily life as morphological biomarkers for impulsivity in a normal healthy population. While our results in healthy volunteers may not directly extend to pathological conditions, they provide an insight into the mechanisms of impulsive behaviour in patients with abnormalities in prefrontal/frontal-striatal connections, such as in drug abuse, pathological gambling, ADHD and Parkinson’s disease. PMID:23274773

  4. I find you more attractive … after (prefrontal cortex) stimulation.

    PubMed

    Ferrari, Chiara; Lega, Carlotta; Tamietto, Marco; Nadal, Marcos; Cattaneo, Zaira

    2015-06-01

    Facial attractiveness seems to be perceived immediately. Neuroimaging evidence suggests that the appraisal of facial attractiveness is mediated by a network of cortical and subcortical regions, mainly encompassing the reward circuit, but also including prefrontal cortices. The prefrontal cortex is involved in high-level processes, so how does its activity relate to beauty appreciation? To shed light on this, we asked male and female participants to evaluate the attractiveness of faces of the same and other sex prior and after transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC). We found that increasing excitability via anodal tDCS in the right but not in the left DLPFC increased perceived attractiveness of the faces, irrespective of the sex of the faces or the sex of the viewers. Identical stimulation over the same site did not affect estimation of other facial characteristics, such as age, thereby suggesting that the effects of anodal tDCS over the right DLPFC might be selective for facial attractiveness, and might not generalize to decisions concerning other facial attributes. Overall, our data suggest that the right DLPFC plays a causal role in explicit judgment of facial attractiveness. The mechanisms mediating such effect are discussed. PMID:25912761

  5. Lesion mapping of cognitive control and value-based decision making in the prefrontal cortex

    PubMed Central

    Gläscher, Jan; Adolphs, Ralph; Damasio, Hanna; Bechara, Antoine; Rudrauf, David; Calamia, Matthew; Paul, Lynn K.; Tranel, Daniel

    2012-01-01

    A considerable body of previous research on the prefrontal cortex (PFC) has helped characterize the regional specificity of various cognitive functions, such as cognitive control and decision making. Here we provide definitive findings on this topic, using a neuropsychological approach that takes advantage of a unique dataset accrued over several decades. We applied voxel-based lesion-symptom mapping in 344 individuals with focal lesions (165 involving the PFC) who had been tested on a comprehensive battery of neuropsychological tasks. Two distinct functional-anatomical networks were revealed within the PFC: one associated with cognitive control (response inhibition, conflict monitoring, and switching), which included the dorsolateral prefrontal cortex and anterior cingulate cortex and a second associated with value-based decision-making, which included the orbitofrontal, ventromedial, and frontopolar cortex. Furthermore, cognitive control tasks shared a common performance factor related to set shifting that was linked to the rostral anterior cingulate cortex. By contrast, regions in the ventral PFC were required for decision-making. These findings provide detailed causal evidence for a remarkable functional-anatomical specificity in the human PFC. PMID:22908286

  6. Prefrontal Cortex and Drug Abuse Vulnerability: Translation to Prevention and Treatment Interventions

    PubMed Central

    Perry, Jennifer L.; Joseph, Jane E.; Jiang, Yang; Zimmerman, Rick S.; Kelly, Thomas H.; Darna, Mahesh; Huettl, Peter; Dwoskin, Linda P.; Bardo, Michael T.

    2010-01-01

    Vulnerability to drug abuse is related to both reward seeking and impulsivity, two constructs thought to have a biological basis in the prefrontal cortex (PFC). This review addresses similarities and differences in neuroanatomy, neurochemistry and behavior associated with PFC function in rodents and primates. Emphasis is placed on monoamine and amino acid neurotransmitter systems located in anatomically distinct subregions: medial prefrontal cortex (mPFC); lateral prefrontal cortex (lPFC); anterior cingulate cortex (ACC); and orbitofrontal cortex (OFC). While there are complex interconnections and overlapping functions among these regions, each is thought to be involved in various functions related to health-related risk behaviors and drug abuse vulnerability. Among the various functions implicated, evidence suggests that mPFC is involved in reward processing, attention and drug reinstatement; lPFC is involved in decision-making, behavioral inhibition and attentional gating; ACC is involved in attention, emotional processing and self-monitoring; and OFC is involved in behavioral inhibition, signaling of expected outcomes and reward/punishment sensitivity. Individual differences factors (e.g., age and sex) influence functioning of these regions, which, in turn, impacts drug abuse vulnerability. Implications for the development of drug abuse prevention and treatment strategies aimed at engaging PFC inhibitory processes that may reduce risk-related behaviors are discussed, including the design of effective public service announcements, cognitive exercises, physical activity, direct current stimulation, feedback control training and pharmacotherapies. A major challenge in drug abuse prevention and treatment rests with improving intervention strategies aimed at strengthening PFC inhibitory systems among at-risk individuals. PMID:20837060

  7. Complementary Patterns of Direct Amygdala and Hippocampal Projections to the Macaque Prefrontal Cortex

    PubMed Central

    Aggleton, John P.; Wright, Nicholas F.; Rosene, Douglas L.; Saunders, Richard C.

    2015-01-01

    The projections from the amygdala and hippocampus (including subiculum and presubiculum) to prefrontal cortex were compared using anterograde tracers injected into macaque monkeys (Macaca fascicularis, Macaca mulatta). Almost all prefrontal areas were found to receive some amygdala inputs. These connections, which predominantly arose from the intermediate and magnocellular basal nucleus, were particularly dense in parts of the medial and orbital prefrontal cortex. Contralateral inputs were not, however, observed. The hippocampal projections to prefrontal areas were far more restricted, being confined to the ipsilateral medial and orbital prefrontal cortex (within areas 11, 13, 14, 24a, 32, and 25). These hippocampal projections principally arose from the subiculum, with the fornix providing the sole route. Thus, while the lateral prefrontal cortex essentially receives only amygdala inputs, the orbital prefrontal cortex receives both amygdala and hippocampal inputs, though these typically target different areas. Only in medial prefrontal cortex do direct inputs from both structures terminate in common sites. But, even when convergence occurs within an area, the projections predominantly terminate in different lamina (hippocampal inputs to layer III and amygdala inputs to layers I, II, and VI). The resulting segregation of prefrontal inputs could enable the parallel processing of different information types in prefrontal cortex. PMID:25715284

  8. Maturational alterations in constitutive activity of medial prefrontal cortex kappa-opioid receptors in Wistar rats.

    PubMed

    Sirohi, Sunil; Walker, Brendan M

    2015-11-01

    Opioid receptors can display spontaneous agonist-independent G-protein signaling (basal signaling/constitutive activity). While constitutive κ-opioid receptor (KOR) activity has been documented in vitro, it remains unknown if KORs are constitutively active in native systems. Using [(35) S] guanosine 5'-O-[gamma-thio] triphosphate coupling assay that measures receptor functional state, we identified the presence of medial prefrontal cortex KOR constitutive activity in young rats that declined with age. Furthermore, basal signaling showed an age-related decline and was insensitive to neutral opioid antagonist challenge. Collectively, the present data are first to demonstrate age-dependent alterations in the medial prefrontal cortex KOR constitutive activity in rats and changes in the constitutive activity of KORs can differentially impact KOR ligand efficacy. These data provide novel insights into the functional properties of the KOR system and warrant further consideration of KOR constitutive activity in normal and pathophysiological behavior. Opioid receptors exhibit agonist-independent constitutive activity; however, kappa-opioid receptor (KOR) constitutive activity has not been demonstrated in native systems. Our results confirm KOR constitutive activity in the medial prefrontal cortex (mPFC) that declines with age. With the ability to presynaptically inhibit multiple neurotransmitter systems in the mPFC, maturational or patho-logical alterations in constitutive activity could disrupt corticofugal glutamatergic pyramidal projection neurons mediating executive function. Regulation of KOR constitutive activity could serve as a therapeutic target to treat compromised executive function. PMID:26257334

  9. The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear

    PubMed Central

    Giustino, Thomas F.; Maren, Stephen

    2015-01-01

    Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here, we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression. PMID:26617500

  10. The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear.

    PubMed

    Giustino, Thomas F; Maren, Stephen

    2015-01-01

    Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here, we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression. PMID:26617500

  11. Synaptic Cytoskeletal Plasticity in the Prefrontal Cortex Following Psychostimulant Exposure.

    PubMed

    DePoy, Lauren M; Gourley, Shannon L

    2015-09-01

    Addiction is characterized by maladaptive decision-making, a loss of control over drug consumption and habit-like drug seeking despite adverse consequences. These cognitive changes may reflect the effects of drugs of abuse on prefrontal cortical neurobiology. Here, we review evidence that amphetamine and cocaine fundamentally remodel the structure of excitatory neurons in the prefrontal cortex. We summarize evidence in particular that these psychostimulants have opposing effects in the medial and orbital prefrontal cortices ('mPFC' and 'oPFC', respectively). For example, amphetamine and cocaine increase dendrite length and spine density in the mPFC, while dendrites are impoverished and dendritic spines are eliminated in the oPFC. We will discuss evidence that certain cytoskeletal regulatory proteins expressed in the oPFC and implicated in postnatal (adolescent) neural development also regulate behavioral sensitivity to cocaine. These findings potentially open a window of opportunity for the identification of novel pharmacotherapeutic targets in the treatment of drug abuse disorders in adults, as well as in drug-vulnerable adolescent populations. Finally, we will discuss the behavioral implications of drug-related dendritic spine elimination in the oPFC, with regard to reversal learning tasks and tasks that assess the development of reward-seeking habits, both used to model aspects of addiction in rodents. PMID:25951902

  12. Higher Order Spike Synchrony in Prefrontal Cortex during Visual Memory

    PubMed Central

    Pipa, Gordon; Munk, Matthias H. J.

    2009-01-01

    Precise temporal synchrony of spike firing has been postulated as an important neuronal mechanism for signal integration and the induction of plasticity in neocortex. As prefrontal cortex plays an important role in organizing memory and executive functions, the convergence of multiple visual pathways onto PFC predicts that neurons should preferentially synchronize their spiking when stimulus information is processed. Furthermore, synchronous spike firing should intensify if memory processes require the induction of neuronal plasticity, even if this is only for short-term. Here we show with multiple simultaneously recorded units in ventral prefrontal cortex that neurons participate in 3 ms precise synchronous discharges distributed across multiple sites separated by at least 500 μm. The frequency of synchronous firing is modulated by behavioral performance and is specific for the memorized visual stimuli. In particular, during the memory period in which activity is not stimulus driven, larger groups of up to seven sites exhibit performance dependent modulation of their spike synchronization. PMID:21713065

  13. Medial prefrontal cortex role in recognition memory in rodents.

    PubMed

    Morici, Juan Facundo; Bekinschtein, Pedro; Weisstaub, Noelia V

    2015-10-01

    The study of the neurobiology of recognition memory, defined by the integration of the different components of experiences that support recollection of past experiences have been a challenge for memory researches for many years. In the last twenty years, with the development of the spontaneous novel object recognition task and all its variants this has started to change. The features of recognition memory include a particular object or person ("what"), the context in which the experience took place, which can be the arena itself or the location within a particular arena ("where") and the particular time at which the event occurred ("when"). This definition instead of the historical anthropocentric one allows the study of this type of episodic memory in animal models. Some forms of recognition memory that require integration of different features recruit the medial prefrontal cortex. Focusing on findings from spontaneous recognition memory tasks performed by rodents, this review concentrates on the description of previous works that have examined the role that the medial prefrontal cortex has on the different steps of recognition memory. We conclude that this structure, independently of the task used, is required at different memory stages when the task cannot be solved by a single item strategy. PMID:26115848

  14. Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression.

    PubMed

    Andersen, Anders H; Smith, Charles D; Slevin, John T; Kryscio, Richard J; Martin, Catherine A; Schmitt, Frederick A; Blonder, Lee X

    2015-01-01

    Parkinson's disease (PD) is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD) patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD) patients. Participants included 18 ndPD patients (11 men, 7 women) and 10 dPD patients (7 men, 3 women). Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC) on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN). DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients. PMID:26793404

  15. Ventromedial prefrontal cortex, adding value to autobiographical memories.

    PubMed

    Lin, Wen-Jing; Horner, Aidan J; Burgess, Neil

    2016-01-01

    The medial prefrontal cortex (mPFC) has been consistently implicated in autobiographical memory recall and decision making. Its function in decision making tasks is believed to relate to value representation, but its function in autobiographical memory recall is not yet clear. We hypothesised that the mPFC represents the subjective value of elements during autobiographical memory retrieval. Using functional magnetic resonance imaging during an autobiographical memory recall task, we found that the blood oxygen level dependent (BOLD) signal in ventromedial prefrontal cortex (vmPFC) was parametrically modulated by the affective values of items in participants' memories when they were recalling and evaluating these items. An unrelated modulation by the participant's familiarity with the items was also observed. During retrieval of the event, the BOLD signal in the same region was modulated by the personal significance and emotional intensity of the memory, which was correlated with the values of the items within them. These results support the idea that vmPFC processes self-relevant information, and suggest that it is involved in representing the personal emotional values of the elements comprising autobiographical memories. PMID:27338616

  16. Analysis of oxysterols and cholesterol in prefrontal cortex of suicides.

    PubMed

    Freemantle, Erika; Chen, Gary Gang; Cruceanu, Cristiana; Mechawar, Naguib; Turecki, Gustavo

    2013-07-01

    Brain oxysterol levels, which are enzymatic oxidation products of cholesterol (Chl), have been proposed to reflect the dynamic process of physiological synapse maintenance and repair of nerve terminals within the central nervous system (CNS), due to the turnover of membrane Chl. Modifications of oxysterols have important implications in neurological conditions, especially in neurodegenerative and psychiatric disorders in which alterations of synaptic plasticity or cell signalling are implicated, such as depression. Oxysterols can diffuse across the blood-brain barrier and have been hypothesized to provide a mechanism by which the brain can eliminate excess Chl to maintain a steady state. Relations of 24-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27OH) specifically may provide a depiction of CNS Chl homeostasis. Thus, the objective of this study was to integrate oxysterol measures and gene expression measures in an effort to identify how they may relate to depression and suicide. Using post-mortem human prefrontal cortex tissue, quantification of metabolites by GC-MS and gene expression by qRT-PCR were performed with the aim to provide a characterization of enzymatic oxidative Chl homeostasis. Results show a significant increase in 24OH, which suggests a higher turnover of Chl to 24OH in the prefrontal cortex of suicide cases. An increase in 24OH may, in combination with liver-X receptor activation, explain the observed reduction of low central and peripheral Chl in suicide and would have implications for synapse maintenance and loss in the neuropathology of depression and suicide. PMID:23369504

  17. Is the Medial Prefrontal Cortex Necessary for Theory of Mind?

    PubMed Central

    Otti, Alexander; Wohlschlaeger, Afra M.; Noll-Hussong, Michael

    2015-01-01

    Background Successful social interaction relies on the ability to attribute mental states to other people. Previous functional neuroimaging studies have shown that this process, described as Theory of Mind (ToM) or mentalization, is reliably associated with activation of the medial prefrontal cortex (mPFC). However, this study presents a novel and surprising finding that provides new insight into the role of the mPFC in mentalization tasks. Methodology/Principal Findings Twenty healthy individuals were recruited from a wide range of ages and social backgrounds. Participants underwent functional magnetic resonance imaging (fMRI) while viewing a well-established ToM visual paradigm involving moving triangles. Functional MRI data were analyzed using a classical general linear model. No activation was detected in the medial prefrontal cortex (mPFC) during movement patterns that typically elicit ToM. However, increased activity was observed in the right middle occipital gyrus, right temporoparietal junction (TPJ), left middle occipital gyrus and right inferior frontal gyrus. No correlation was found between participants’ age and BOLD response. Conclusions/Significance In contrast with previous neuroimaging research, our findings support the notion that mPFC function is not critical for reasoning about the mental states of others; furthermore, our data indicate that the right TPJ and right inferior frontal gyrus are able to perform mentalization without any contributions from the mPFC. PMID:26301900

  18. Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression

    PubMed Central

    Andersen, Anders H.; Smith, Charles D.; Slevin, John T.; Kryscio, Richard J.; Martin, Catherine A.; Schmitt, Frederick A.; Blonder, Lee X.

    2015-01-01

    Parkinson's disease (PD) is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD) patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD) patients. Participants included 18 ndPD patients (11 men, 7 women) and 10 dPD patients (7 men, 3 women). Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC) on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN). DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients. PMID:26793404

  19. Ventromedial prefrontal cortex, adding value to autobiographical memories

    PubMed Central

    Lin, Wen-Jing; Horner, Aidan J.; Burgess, Neil

    2016-01-01

    The medial prefrontal cortex (mPFC) has been consistently implicated in autobiographical memory recall and decision making. Its function in decision making tasks is believed to relate to value representation, but its function in autobiographical memory recall is not yet clear. We hypothesised that the mPFC represents the subjective value of elements during autobiographical memory retrieval. Using functional magnetic resonance imaging during an autobiographical memory recall task, we found that the blood oxygen level dependent (BOLD) signal in ventromedial prefrontal cortex (vmPFC) was parametrically modulated by the affective values of items in participants’ memories when they were recalling and evaluating these items. An unrelated modulation by the participant’s familiarity with the items was also observed. During retrieval of the event, the BOLD signal in the same region was modulated by the personal significance and emotional intensity of the memory, which was correlated with the values of the items within them. These results support the idea that vmPFC processes self-relevant information, and suggest that it is involved in representing the personal emotional values of the elements comprising autobiographical memories. PMID:27338616

  20. Going and stopping: dichotomies in behavioral control by the prefrontal cortex.

    PubMed

    Gourley, Shannon L; Taylor, Jane R

    2016-04-26

    The rodent dorsal medial prefrontal cortex (PFC), specifically the prelimbic cortex (PL), regulates the expression of conditioned fear and behaviors interpreted as reward seeking. Meanwhile, the ventral medial PFC, namely the infralimbic cortex (IL), is essential to extinction conditioning in both appetitive and aversive domains. Here we review evidence that supports, or refutes, this "PL-go/IL-stop" dichotomy. We focus on the extinction of conditioned fear and the extinction and reinstatement of cocaine- or heroin-reinforced responding following abstinence. We then synthesize evidence that the PL is essential for developing goal-directed response strategies, while the IL supports habit behavior. Finally, we propose that some functions of the orbital PFC parallel those of the medial PFC in the regulation of response selection. Integration of these discoveries may provide points of intervention for inhibiting untethered drug seeking in drug use disorders, extinction failures in post-traumatic stress disorder, or co-morbidities between the two. PMID:27116390

  1. Altered functional connectivity of the insular cortex across prefrontal networks in cocaine addiction.

    PubMed

    Cisler, Josh M; Elton, Amanda; Kennedy, Ashley P; Young, Jonathan; Smitherman, Sonet; Andrew James, George; Kilts, Clinton D

    2013-07-30

    Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. Participants comprised 41 patients with cocaine dependence and 19 controls who underwent a resting-state 3-T functional magnetic resonance imaging scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial prefrontal cortex, inferior frontal gyrus, and bilateral dorsolateral prefrontal cortex. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision-making processes presumably mediated by prefrontal networks in the cocaine dependence process. PMID:23684980

  2. Revisiting the Role of the Prefrontal Cortex in the Pathophysiology of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Halperin, Jeffrey M.; Schulz, Kurt P.

    2006-01-01

    Most neural models for the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) have centered on the prefrontal cortex and its interconnections with the striatum and other subcortical structures. However, research only partially supports these models, and they do not correspond with the development of the prefrontal cortex and its…

  3. Williams Syndrome Hypersociability: A Neuropsychological Study of the Amygdala and Prefrontal Cortex Hypotheses

    ERIC Educational Resources Information Center

    Capitao, Liliana; Sampaio, Adriana; Fernandez, Montse; Sousa, Nuno; Pinheiro, Ana; Goncalves, Oscar F.

    2011-01-01

    Individuals with Williams syndrome display indiscriminate approach towards strangers. Neuroimaging studies conducted so far have linked this social profile to structural and/or functional abnormalities in WS amygdala and prefrontal cortex. In this study, the neuropsychological hypotheses of amygdala and prefrontal cortex involvement in WS…

  4. Dyspnea-Related Cues Engage the Prefrontal Cortex

    PubMed Central

    Herigstad, Mari; Hayen, Anja; Evans, Eleanor; Hardinge, Frances M.; Davies, Robert J.; Wiech, Katja

    2015-01-01

    BACKGROUND: Dyspnea is the major source of disability in COPD. In COPD, environmental cues (eg, the prospect of having to climb stairs) become associated with dyspnea and may trigger dyspnea even before physical activity commences. We hypothesized that brain activation relating to such cues would be different between patients with COPD and healthy control subjects, reflecting greater engagement of emotional mechanisms in patients. METHODS: Using functional MRI (FMRI), we investigated brain responses to dyspnea-related word cues in 41 patients with COPD and 40 healthy age-matched control subjects. We combined these findings with scores on self-report questionnaires, thus linking the FMRI task with clinically relevant measures. This approach was adapted from studies in pain that enabled identification of brain networks responsible for pain processing despite absence of a physical challenge. RESULTS: Patients with COPD demonstrated activation in the medial prefrontal cortex and anterior cingulate cortex, which correlated with the visual analog scale (VAS) response to word cues. This activity independently correlated with patient responses on questionnaires of depression, fatigue, and dyspnea vigilance. Activation in the anterior insula, lateral prefrontal cortex, and precuneus correlated with the VAS dyspnea scale but not with the questionnaires. CONCLUSIONS: The findings suggest that engagement of the emotional circuitry of the brain is important for interpretation of dyspnea-related cues in COPD and is influenced by depression, fatigue, and vigilance. A heightened response to salient cues is associated with increased symptom perception in chronic pain and asthma, and the findings suggest that such mechanisms may be relevant in COPD. PMID:26134891

  5. Dysregulation of cell death machinery in the prefrontal cortex of human alcoholics

    PubMed Central

    Johansson, Sofia; Ekström, Tomas J.; Marinova, Zoya; Ökvist, Anna; Sheedy, Donna; Garrick, Therese; Harper, Clive; Kuzmin, Alexander; Yakovleva, Tatjana; Bakalkin, Georgy

    2012-01-01

    In human alcoholics, the cell density is decreased in the prefrontal cortex (PFC) and other brain areas. This may be due to persistent activation of cell death pathways. To address this hypothesis, we examined the status of cell death machinery in the dorsolateral PFC in alcoholics. Protein and mRNA expression levels of several key pro- and anti-apoptotic genes were compared in post-mortem samples of 14 male human alcoholics and 14 male controls. The findings do not support the hypothesis. On the contrary, they show that several components of intrinsic apoptotic pathway are decreased in alcoholics. No differences were evident in the motor cortex, which is less damaged in alcoholics and was analysed for comparison. Thus, cell death mechanisms may be dysregulated by inhibition of intrinsic apoptotic pathway in the PFC in human alcoholics. This inhibition may reflect molecular adaptations that counteract alcohol neurotoxicity in cells that survive after many years of alcohol exposure and withdrawal. PMID:18937880

  6. Capturing the temporal evolution of choice across prefrontal cortex

    PubMed Central

    Hunt, Laurence T; Behrens, Timothy EJ; Hosokawa, Takayuki; Wallis, Jonathan D; Kennerley, Steven W

    2015-01-01

    Activity in prefrontal cortex (PFC) has been richly described using economic models of choice. Yet such descriptions fail to capture the dynamics of decision formation. Describing dynamic neural processes has proven challenging due to the problem of indexing the internal state of PFC and its trial-by-trial variation. Using primate neurophysiology and human magnetoencephalography, we here recover a single-trial index of PFC internal states from multiple simultaneously recorded PFC subregions. This index can explain the origins of neural representations of economic variables in PFC. It describes the relationship between neural dynamics and behaviour in both human and monkey PFC, directly bridging between human neuroimaging data and underlying neuronal activity. Moreover, it reveals a functionally dissociable interaction between orbitofrontal cortex, anterior cingulate cortex and dorsolateral PFC in guiding cost-benefit decisions. We cast our observations in terms of a recurrent neural network model of choice, providing formal links to mechanistic dynamical accounts of decision-making. DOI: http://dx.doi.org/10.7554/eLife.11945.001 PMID:26653139

  7. The relationship between brain cortical activity and brain oxygenation in the prefrontal cortex during hypergravity exposure.

    PubMed

    Smith, Craig; Goswami, Nandu; Robinson, Ryan; von der Wiesche, Melanie; Schneider, Stefan

    2013-04-01

    Artificial gravity has been proposed as a method to counteract the physiological deconditioning of long-duration spaceflight; however, the effects of hypergravity on the central nervous system has had little study. The study aims to investigate whether there is a relationship between prefrontal cortex brain activity and prefrontal cortex oxygenation during exposure to hypergravity. Twelve healthy participants were selected to undergo hypergravity exposure aboard a short-arm human centrifuge. Participants were exposed to hypergravity in the +Gz axis, starting from 0.6 +Gz for women, and 0.8 +Gz for men, and gradually increasing by 0.1 +Gz until the participant showed signs of syncope. Brain cortical activity was measured using electroencephalography (EEG) and localized to the prefrontal cortex using standard low-resolution brain electromagnetic tomography (LORETA). Prefrontal cortex oxygenation was measured using near-infrared spectroscopy (NIRS). A significant increase in prefrontal cortex activity (P < 0.05) was observed during hypergravity exposure compared with baseline. Prefrontal cortex oxygenation was significantly decreased during hypergravity exposure, with a decrease in oxyhemoglobin levels (P < 0.05) compared with baseline and an increase in deoxyhemoglobin levels (P < 0.05) with increasing +Gz level. No significant correlation was found between prefrontal cortex activity and oxy-/deoxyhemoglobin. It is concluded that the increase in prefrontal cortex activity observed during hypergravity was most likely not the result of increased +Gz values resulting in a decreased oxygenation produced through hypergravity exposure. No significant relationship between prefrontal cortex activity and oxygenation measured by NIRS concludes that brain activity during exposure to hypergravity may be difficult to measure using NIRS. Instead, the increase in prefrontal cortex activity might be attributable to psychological stress, which could pose a problem for the use of a

  8. Characterization of electrically evoked field potentials in the medial prefrontal cortex and orbitofrontal cortex of the rat: modulation by monoamines

    PubMed Central

    Wallace, Joanne; Jackson, Rosanna K; Shotton, Tanya L; Munjal, Ishaana; McQuade, Richard; Gartside, Sarah E

    2015-01-01

    Medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) play critical roles in cognition and behavioural control. Glutamatergic, GABAergic, and monoaminergic dysfunction in the prefrontal cortex has been hypothesised to underlie symptoms in neuropsychiatric disorders. Here we characterised electrically-evoked field potentials in the mPFC and OFC. Electrical stimulation evoked field potentials in layer V/VI of the mPFC and layer V of the OFC. The earliest component (approximately 2 ms latency) was insensitive to glutamate receptor blockade and was presumed to be presynaptic. Later components were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX (20 μM) and were assumed to reflect monosynaptic (latency 4-6 ms) and polysynaptic activity (latency 6-40 ms) mediated by glutamate via AMPA/kainate receptor. In the mPFC, but not the OFC, the monosynaptic component was also partly blocked by 2-amino-5-phosphonopentanoic acid (AP-5 (50-100 μM) indicating the involvement of NMDA receptors. Bicuculline (3-10 μM) enhanced the monosynaptic component suggesting electrically-evoked and/or glutamate induced GABA release inhibits the monosynaptic component via GABAA receptor activation. There were complex effects of bicuculline on polysynaptic components. In the mPFC both the mono- and polysynaptic components were attenuated by 5-HT (10-100 μM) and NA (30 and 60 μM) and the monosynaptic component was attenuated by DA (100 μM). In the OFC the mono-and polysynaptic components were also attenuated by 5-HT (100 μM), NA (10-100 μM) but DA (10-100 μM) had no effect. We propose that these pharmacologically characterised electrically-evoked field potentials in the mPFC and OFC are useful models for the study of prefrontal cortical physiology and pathophysiology. PMID:23932190

  9. The Cortical Connectivity of the Prefrontal Cortex in the Monkey Brain

    PubMed Central

    Yeterian, Edward H.; Pandya, Deepak N.; Tomaiuolo, Francesco; Petrides, Michael

    2011-01-01

    One dimension of understanding the functions of the prefrontal cortex is knowledge of cortical connectivity. We have surveyed three aspects of prefrontal cortical connections: local projections (within the frontal lobe), the termination patterns of long association (post-Rolandic) projections, and the trajectories of major fiber pathways. The local connections appear to be organized in relation to dorsal (hippocampal origin) and ventral (paleocortical origin) architectonic trends. According to the proposal of a dual origin of the cerebral cortex, cortical areas can be traced as originating from archicortex (hippocampus) on the one hand, and paleocortex, on the other hand, in a stepwise manner (e.g., Sanides, 1969; Pandya and Yeterian, 1985). Prefrontal areas within each trend are connected with less architectonically differentiated areas, and, on the other hand, with more differentiated areas. Such organization may allow for the systematic exchange of information within each architectonic trend. The long connections of the prefrontal cortex with post-Rolandic regions seem to be organized preferentially in relation to dorsal and ventral prefrontal architectonic trends. Prefrontal areas are connected with post-Rolandic auditory, visual and somatosensory association areas, and with multimodal and paralimbic regions. This long connectivity likely works in conjunction with local connections to serve prefrontal cortical functions. The afferent and efferent connections of the prefrontal cortex with post-Rolandic regions are conveyed by specific long association pathways. These pathways as well appear to be organized in relation to dorsal and ventral prefrontal architectonic trends. Finally, although prefrontal areas have preferential connections in relation to dual architectonic trends, it is clear that there are interconnections between and among areas in each trend, which may provide a substrate for the overall integrative function of the prefrontal cortex. Prefrontal

  10. Response of dorsomedial prefrontal cortex predicts altruistic behavior

    PubMed Central

    Waytz, Adam; Zaki, Jamil; Mitchell, Jason P.

    2012-01-01

    Human beings have an unusual proclivity for altruistic behavior, and recent commentators have suggested that these prosocial tendencies arise from our unique capacity to understand the minds of others (i.e., to mentalize). The current studies test this hypothesis by examining the relation between altruistic behavior and the reflexive engagement of a neural system reliably associated with mentalizing. Results indicated that activity in the dorsomedial prefrontal cortex (dorsal MPFC)—a region consistently involved in understanding others’ mental states—predicts both monetary donations to others and time spent helping others. These findings address long-standing questions about the proximate source of human altruism by suggesting that prosocial behavior results, in part, from our broader tendency for social-cognitive thought. PMID:22649243

  11. Prefrontal cortex mediation of cognitive enhancement in rewarding motivational contexts.

    PubMed

    Jimura, Koji; Locke, Hannah S; Braver, Todd S

    2010-05-11

    Increasing the reward value of behavioral goals can facilitate cognitive processes required for goal achievement. This facilitation may be accomplished by the dynamic and flexible engagement of cognitive control mechanisms operating in distributed brain regions. It is still not clear, however, what are the characteristics of individuals, situations, and neural activation dynamics that optimize motivation-linked cognitive enhancement. Here we show that highly reward-sensitive individuals exhibited greater improvement of working memory performance in rewarding contexts, but exclusively on trials that were not rewarded. This effect was mediated by a shift in the temporal dynamics of activation within right lateral prefrontal cortex, from a transient to predominantly tonic mode, with an additional anticipatory transient boost. In contexts with intermittent rewards, a strategy of proactive cognitive control may enable globally optimal performance to facilitate reward attainment. Reward-sensitive individuals appear preferentially motivated to adopt this resource-demanding strategy, resulting in paradoxical benefits selectively for nonrewarded events. PMID:20421489

  12. Increased prefrontal cortex neurogranin enhances plasticity and extinction learning.

    PubMed

    Zhong, Ling; Brown, Joshua; Kramer, Audra; Kaleka, Kanwardeep; Petersen, Amber; Krueger, Jamie N; Florence, Matthew; Muelbl, Matthew J; Battle, Michelle; Murphy, Geoffrey G; Olsen, Christopher M; Gerges, Nashaat Z

    2015-05-13

    Increasing plasticity in neurons of the prefrontal cortex (PFC) has been proposed as a possible therapeutic tool to enhance extinction, a process that is impaired in post-traumatic stress disorder, schizophrenia, and addiction. To test this hypothesis, we generated transgenic mice that overexpress neurogranin (a calmodulin-binding protein that facilitates long-term potentiation) in the PFC. Neurogranin overexpression in the PFC enhanced long-term potentiation and increased the rates of extinction learning of both fear conditioning and sucrose self-administration. Our results indicate that elevated neurogranin function within the PFC can enhance local plasticity and increase the rate of extinction learning across different behavioral tasks. Thus, neurogranin can provide a molecular link between enhanced plasticity and enhanced extinction. PMID:25972176

  13. Damage to ventromedial prefrontal cortex impairs judgment of harmful intent

    PubMed Central

    Young, Liane; Bechara, Antoine; Tranel, Daniel; Damasio, Hanna; Hauser, Marc; Damasio, Antonio

    2011-01-01

    Summary Moral judgments, whether delivered in ordinary experience or in the courtroom, depend on our ability to infer intentions. We forgive unintentional or accidental harms and condemn failed attempts to harm. Prior work demonstrates that patients with damage to the ventromedial prefrontal cortex (VMPC) deliver abnormal judgments in response to moral dilemmas, and that these patients are especially impaired in triggering emotional responses to inferred or abstract events (e.g., intentions), as opposed to real or actual outcomes. We therefore predicted that VMPC patients would deliver abnormal moral judgments of harmful intentions in the absence of harmful outcomes, as in failed attempts to harm. This prediction was confirmed in the current study: VMPC patients judged attempted harms including attempted murder as more morally permissible relative to controls. These results highlight the critical role of the VMPC in processing harmful intent for moral judgment. PMID:20346759

  14. Abstract context representations in primate amygdala and prefrontal cortex

    PubMed Central

    Saez, A.; Rigotti, M.; Ostojic, S.; Fusi, S.; Salzman, C. D.

    2015-01-01

    Summary Neurons in prefrontal cortex (PFC) encode rules, goals and other abstract information thought to underlie cognitive, emotional, and behavioral flexibility. Here we show that the amygdala, a brain area traditionally thought to mediate emotions, also encodes abstract information that could underlie this flexibility. Monkeys performed a task in which stimulus-reinforcement contingencies varied between two sets of associations, each defining a context. Reinforcement prediction required identifying a stimulus and knowing the current context. Behavioral evidence indicated that monkeys utilized this information to perform inference and adjust their behavior. Neural representations in both amygdala and PFC reflected the linked sets of associations implicitly defining each context, a process requiring a level of abstraction characteristic of cognitive operations. Surprisingly, when errors were made, the context signal weakened substantially in the amygdala. These data emphasize the importance of maintaining abstract cognitive information in the amygdala to support flexible behavior. PMID:26291167

  15. Damage to the ventromedial prefrontal cortex reduces interpersonal disgust

    PubMed Central

    Ciaramelli, Elisa; Sperotto, Rebecca G.; Mattioli, Flavia

    2013-01-01

    Disgust for contaminating objects (core disgust), immoral behaviors (moral disgust) and unsavory others (interpersonal disgust), have been assumed to be closely related. It is not clear, however, whether different forms of disgust are mediated by overlapping or specific neural substrates. We report that 10 patients with damage to the ventromedial prefrontal cortex (vmPFC) avoided behaviors that normally elicit interpersonal disgust (e.g. using the scarf of a busker) less frequently than healthy and brain-damaged controls, whereas they avoided core and moral disgust elicitors at normal rates. These results indicate that different forms of disgust are dissociated neurally. We propose that the vmPFC is causally (and selectively) involved in mediating interpersonal disgust, shaping patterns of social avoidance and approach. PMID:22842816

  16. Increased Prefrontal Cortex Neurogranin Enhances Plasticity and Extinction Learning

    PubMed Central

    Zhong, Ling; Brown, Joshua; Kramer, Audra; Kaleka, Kanwardeep; Petersen, Amber; Krueger, Jamie N.; Florence, Matthew; Muelbl, Matthew J.; Battle, Michelle; Murphy, Geoffrey G.; Olsen, Christopher M.

    2015-01-01

    Increasing plasticity in neurons of the prefrontal cortex (PFC) has been proposed as a possible therapeutic tool to enhance extinction, a process that is impaired in post-traumatic stress disorder, schizophrenia, and addiction. To test this hypothesis, we generated transgenic mice that overexpress neurogranin (a calmodulin-binding protein that facilitates long-term potentiation) in the PFC. Neurogranin overexpression in the PFC enhanced long-term potentiation and increased the rates of extinction learning of both fear conditioning and sucrose self-administration. Our results indicate that elevated neurogranin function within the PFC can enhance local plasticity and increase the rate of extinction learning across different behavioral tasks. Thus, neurogranin can provide a molecular link between enhanced plasticity and enhanced extinction. PMID:25972176

  17. Behavioral effects of congenital ventromedial prefrontal cortex malformation

    PubMed Central

    2011-01-01

    Background A detailed behavioral profile associated with focal congenital malformation of the ventromedial prefrontal cortex (vmPFC) has not been reported previously. Here we describe a 14 year-old boy, B.W., with neurological and psychiatric sequelae stemming from focal cortical malformation of the left vmPFC. Case Presentation B.W.'s behavior has been characterized through extensive review Patience of clinical and personal records along with behavioral and neuropsychological testing. A central feature of the behavioral profile is severe antisocial behavior. He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance. Conclusions The vmPFC has a profound contribution to the development of human prosocial behavior. B.W. demonstrates how a congenital lesion to this cortical region severely disrupts this process. PMID:22136635

  18. Involvement of prefrontal cortex in scalar implicatures: evidence from magnetoencephalography

    PubMed Central

    Politzer-Ahles, Stephen; Gwilliams, Laura

    2015-01-01

    The present study investigated the neural correlates of the realisation of scalar inferences, i.e., the interpretation of some as meaning some but not all. We used magnetoencephalography, which has high temporal resolution, to measure neural activity while participants heard stories that included the scalar inference trigger some in contexts that either provide strong cues for a scalar inference or provide weaker cues. The middle portion of the lateral prefrontal cortex (Brodmann area 46) showed an increased response to some in contexts with fewer cues to the inference, suggesting that this condition elicited greater effort. While the results are not predicted by traditional all-or-nothing accounts of scalar inferencing that assume the process is always automatic or always effortful, they are consistent with more recent gradient accounts which predict that the speed and effort of scalar inferences is strongly modulated by numerous contextual factors. PMID:26247054

  19. The Behavioral Relevance of Task Information in Human Prefrontal Cortex.

    PubMed

    Cole, Michael W; Ito, Takuya; Braver, Todd S

    2016-06-01

    Human lateral prefrontal cortex (LPFC) is thought to play a critical role in enabling cognitive flexibility, particularly when performing novel tasks. However, it remains to be established whether LPFC representation of task-relevant information in such situations actually contributes to successful performance. We utilized pattern classification analyses of functional MRI activity to identify novelty-sensitive brain regions as participants rapidly switched between performance of 64 complex tasks, 60 of which were novel. In three of these novelty-sensitive regions-located within distinct areas of left anterior LPFC-trial-evoked activity patterns discriminated correct from error trials. Further, these regions also contained information regarding the task-relevant decision rule, but only for successfully performed trials. This suggests that left anterior LPFC may be particularly important for representing task information that contributes to the cognitive flexibility needed to perform successfully in novel task situations. PMID:25870233

  20. Insights into Human Behavior from Lesions to the Prefrontal Cortex

    PubMed Central

    Szczepanski, Sara M.; Knight, Robert T.

    2014-01-01

    SUMMARY The prefrontal cortex (PFC), a cortical region that was once thought to be functionally insignificant, is now known to play an essential role in the organization and control of goal-directed thought and behavior. Neuroimaging, neurophysiological, and modeling techniques have lead to tremendous advances in our understanding of PFC functions over the last few decades. It should be noted, however, that neurological, neuropathological, and neuropsychological studies have contributed some of the most essential, historical, and often prescient, conclusions regarding the functions of this region. Importantly, examination of patients with brain damage allows one to draw conclusions about whether a brain area is necessary for a particular function. Here, we provide a broad overview of PFC functions based upon behavioral and neural changes resulting from damage to PFC in both human patients and non-human primates. PMID:25175878

  1. Abstract Context Representations in Primate Amygdala and Prefrontal Cortex.

    PubMed

    Saez, A; Rigotti, M; Ostojic, S; Fusi, S; Salzman, C D

    2015-08-19

    Neurons in prefrontal cortex (PFC) encode rules, goals, and other abstract information thought to underlie cognitive, emotional, and behavioral flexibility. Here we show that the amygdala, a brain area traditionally thought to mediate emotions, also encodes abstract information that could underlie this flexibility. Monkeys performed a task in which stimulus-reinforcement contingencies varied between two sets of associations, each defining a context. Reinforcement prediction required identifying a stimulus and knowing the current context. Behavioral evidence indicated that monkeys utilized this information to perform inference and adjust their behavior. Neural representations in both amygdala and PFC reflected the linked sets of associations implicitly defining each context, a process requiring a level of abstraction characteristic of cognitive operations. Surprisingly, when errors were made, the context signal weakened substantially in the amygdala. These data emphasize the importance of maintaining abstract cognitive information in the amygdala to support flexible behavior. PMID:26291167

  2. Multiple component networks support working memory in prefrontal cortex.

    PubMed

    Markowitz, David A; Curtis, Clayton E; Pesaran, Bijan

    2015-09-01

    Lateral prefrontal cortex (PFC) is regarded as the hub of the brain's working memory (WM) system, but it remains unclear whether WM is supported by a single distributed network or multiple specialized network components in this region. To investigate this problem, we recorded from neurons in PFC while monkeys made delayed eye movements guided by memory or vision. We show that neuronal responses during these tasks map to three anatomically specific modes of persistent activity. The first two modes encode early and late forms of information storage, whereas the third mode encodes response preparation. Neurons that reflect these modes are concentrated at different anatomical locations in PFC and exhibit distinct patterns of coordinated firing rates and spike timing during WM, consistent with distinct networks. These findings support multiple component models of WM and consequently predict distinct failures that could contribute to neurologic dysfunction. PMID:26283366

  3. MDMA (ecstasy) modulates locomotor and prefrontal cortex sensory evoked activity.

    PubMed

    Atkins, Kristal; Burks, Tilithia; Swann, Alan C; Dafny, Nachum

    2009-12-11

    Ingestion of 3, 4-methylenedioxymethamphetamine (MDMA) leads to heightened response to sensory stimulation; thus, MDMA is referred to as "ecstasy" because it produces pleasurable enhancement of such sensation. There have been no electrophysiological studies that report the consequences of MDMA on sensory input. The present study was initiated to study the effects of acute and chronic MDMA on locomotor activity and sensory evoked field potential from freely behaving rats previously implanted with permanent electrodes in the prefrontal cortex (PFC). The main findings of this study are that: (1) acute MDMA augments locomotor behavior and attenuates the incoming sensory input, (2) chronic treatment of MDMA elicits behavioral sensitization, (3) chronic administration of MDMA results in attenuation of the baseline activity of the sensory evoked field potential, and (4) administration of rechallenge MDMA result in enhancement of the PFC sensory evoked field potential. PMID:19769950

  4. Medial prefrontal cortex predicts internally driven strategy shifts

    PubMed Central

    Schuck, Nicolas W.; Gaschler, Robert; Wenke, Dorit; Heinzle, Jakob; Frensch, Peter A.; Haynes, John-Dylan; Reverberi, Carlo

    2015-01-01

    Summary Many daily behaviors require us to actively focus on the current task and ignore all other distractions. Yet, ignoring everything else might hinder the ability to discover new ways to achieve the same goal. Here, we studied the neural mechanisms that support the spontaneous change to better strategies while an established strategy is executed. Multivariate neuroimaging analysis showed that before the spontaneous change to an alternative strategy, medial prefrontal cortex (MPFC) encoded information that was irrelevant for the current strategy but necessary for the later strategy. Importantly, this neural effect was related to future behavioral changes: information encoding in MPFC was changed only in participants who eventually switched their strategy and started before the actual strategy change. This allowed us to predict spontaneous strategy shifts ahead of time. These findings suggest that MPFC might internally simulate alternative strategies and sheds new light on the organization of PFC. PMID:25819613

  5. Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex.

    PubMed

    Bryden, Daniel W; Burton, Amanda C; Barnett, Brian R; Cohen, Valerie J; Hearn, Taylor N; Jones, Emily A; Kariyil, Reshma J; Kunin, Alice; Kwak, Sae In; Lee, Jessica; Lubinski, Brooke L; Rao, Gautam K; Zhan, Ashley; Roesch, Matthew R

    2016-02-01

    Prenatal nicotine exposure (PNE) is linked to numerous psychiatric disorders including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex. Yet, it is unclear how neural activity in the medial prefrontal cortex (mPFC) is modulated during tasks that assess response inhibition or if these neural correlates, along with behavior, are affected by PNE. To address this issue, we recorded from single mPFC neurons in control and PNE rats as they performed a stop-signal task. We found that PNE rats were faster for all trial-types, made more premature responses, and were less likely to inhibit behavior on 'STOP' trials during which rats had to inhibit an already initiated response. Activity in mPFC was modulated by response direction and was positively correlated with accuracy and movement time in control but not PNE rats. Although the number of single neurons correlated with response direction was significantly reduced by PNE, neural activity observed on general STOP trials was largely unaffected. However, dramatic behavioral deficits on STOP trials immediately following non-conflicting (GO) trials in the PNE group appear to be mediated by the loss of conflict monitoring signals in mPFC. We conclude that prenatal nicotine exposure makes rats impulsive and disrupts firing of mPFC neurons that carry signals related to response direction and conflict monitoring. PMID:26189451

  6. NUCLEUS REUNIENS OF THE MIDLINE THALAMUS: LINK BETWEEN THE MEDIAL PREFRONTAL CORTEX AND THE HIPPOCAMPUS

    PubMed Central

    Vertes, Robert P.; Hoover, Walter B.; Szigeti-Buck, Klara; Leranth, Csaba

    2016-01-01

    The medial prefrontal cortex and the hippocampus serve well recognized roles in memory processing. The hippocampus projects densely to, and exerts strong excitatory actions on, the medial prefrontal cortex. Interestingly, the medial prefrontal cortex, in rats and other species, has no direct return projections to the hippocampus, and few projections to parahippocampal structures including the entorhinal cortex. It is well established that the nucleus reuniens of the midline thalamus is the major source of thalamic afferents to the hippocampus. Since the medial prefrontal cortex also distributes to nucleus reuniens, we examined medial prefrontal connections with populations of nucleus reuniens neurons projecting to hippocampus. We used a combined anterograde and retrograde tracing procedure at the light and electron microscopic levels. Specifically, we made Phaseolus vulgaris-leuccoagglutinin (PHA-L) injections into the medial prefrontal cortex and Fluorogold injections into the hippocampus (CA1/subiculum) and examined termination patterns of anterogradely PHA-L labeled fibers on retrogradely FG labeled cells of nucleus reuniens. At the light microscopic level, we showed that fibers from the medial prefrontal cortex form multiple putative synaptic contacts with dendrites of hippocampally projecting neurons throughout the extent of nucleus reuniens. At ultrastructural level, we showed that medial prefrontal cortical fibers form asymmetric contacts predominantly with dendritic shafts of hippocampally projecting reuniens cells. These findings indicate that nucleus reuniens represents a critical link between the medial prefrontal cortex and the hippocampus. We discuss the possibility that nucleus reuniens gates the flow of information between the medial prefrontal cortex and hippocampus dependent upon attentive/arousal states of the organism. PMID:17292803

  7. Milnacipran Remediates Impulsive Deficits in Rats with Lesions of the Ventromedial Prefrontal Cortex

    PubMed Central

    Tsutsui-Kimura, Iku; Yoshida, Takayuki; Izumi, Takeshi; Yoshioka, Mitsuhiro

    2015-01-01

    Background: Deficits in impulse control are often observed in psychiatric disorders in which abnormalities of the prefrontal cortex are observed, including attention-deficit/hyperactivity disorder and bipolar disorder. We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats. However, whether milnacipran could suppress elevated impulsive action in rats with lesions of the ventromedial prefrontal cortex, which is functionally comparable with the human prefrontal cortex, remains unknown. Methods: Selective lesions of the ventromedial prefrontal cortex were made using quinolinic acid in rats previously trained on a 3-choice serial reaction time task. Sham rats received phosphate buffered saline. Following a period of recovery, milnacipran (0 or 10mg/kg/d × 14 days) was orally administered 60 minutes prior to testing on the 3-choice task. After 7 days of drug cessation, Western blotting, immunohistochemistry, electrophysiological analysis, and morphological analysis were conducted. Results: Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug. Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats. Conclusions: The findings of this study suggest that milnacipran treatment could be a novel strategy for the treatment of psychiatric disorders that are associated with a lack of impulse control. PMID:25522418

  8. Linking trait-based phenotypes to prefrontal cortex activation during inhibitory control.

    PubMed

    Rodrigo, Achala H; Di Domenico, Stefano I; Graves, Bryanna; Lam, Jaeger; Ayaz, Hasan; Bagby, R Michael; Ruocco, Anthony C

    2016-01-01

    Inhibitory control is subserved in part by discrete regions of the prefrontal cortex whose functionality may be altered according to specific trait-based phenotypes. Using a unified model of normal range personality traits, we examined activation within lateral and medial aspects of the prefrontal cortex during a manual go/no-go task. Evoked hemodynamic oxygenation within the prefrontal cortex was measured in 106 adults using a 16-channel continuous-wave functional near-infrared spectroscopy system. Within lateral regions of the prefrontal cortex, greater activation was associated with higher trait levels of extraversion, agreeableness and conscientiousness, and lower neuroticism. Higher agreeableness was also related to more activation in the medial prefrontal cortex during inhibitory control. These results suggest that personality traits reflecting greater emotional stability, extraversion, agreeableness and conscientiousness may be associated with more efficient recruitment of control processes subserved by lateral regions of the prefrontal cortex. These findings highlight key links between trait-based phenotypes and neural activation patterns in the prefrontal cortex underlying inhibitory control. PMID:26163672

  9. Ventromedial prefrontal cortex and the regulation of physiological arousal.

    PubMed

    Zhang, Sheng; Hu, Sien; Chao, Herta H; Ide, Jaime S; Luo, Xi; Farr, Olivia M; Li, Chiang-shan R

    2014-07-01

    Neuroimaging studies show a correlation between activity of the ventromedial prefrontal cortex (vmPFC) and skin conductance measurements. However, little is known whether this brain region plays a causal role in regulating physiological arousal. To address this question, we employed Granger causality analysis (GCA) to establish causality between cerebral blood oxygenation level-dependent and skin conductance signals in 24 healthy adults performing a cognitive task during functional magnetic resonance imaging. The results showed that activity of the vmPFC not only negatively correlated with skin conductance level (SCL) but also Granger caused SCL, thus establishing the direction of influence. Importantly, across participants, the strength of Granger causality was negatively correlated to phasic skin conductance responses elicited by external events during the behavioral task. In contrast, activity of the dorsal anterior cingulate cortex positively correlated with SCL but did not show a causal relationship in GCA. These new findings indicate that the vmPFC plays a causal role in regulating physiological arousal. Increased vmPFC activity leads to a decrease in skin conductance. The findings may also advance our understanding of dysfunctions of the vmPFC in mood and anxiety disorders that involve altered control of physiological arousal. PMID:23620600

  10. Dynamic Construction of Stimulus Values in the Ventromedial Prefrontal Cortex

    PubMed Central

    Harris, Alison; Adolphs, Ralph; Camerer, Colin; Rangel, Antonio

    2011-01-01

    Signals representing the value assigned to stimuli at the time of choice have been repeatedly observed in ventromedial prefrontal cortex (vmPFC). Yet it remains unknown how these value representations are computed from sensory and memory representations in more posterior brain regions. We used electroencephalography (EEG) while subjects evaluated appetitive and aversive food items to study how event-related responses modulated by stimulus value evolve over time. We found that value-related activity shifted from posterior to anterior, and from parietal to central to frontal sensors, across three major time windows after stimulus onset: 150–250 ms, 400–550 ms, and 700–800 ms. Exploratory localization of the EEG signal revealed a shifting network of activity moving from sensory and memory structures to areas associated with value coding, with stimulus value activity localized to vmPFC only from 400 ms onwards. Consistent with these results, functional connectivity analyses also showed a causal flow of information from temporal cortex to vmPFC. Thus, although value signals are present as early as 150 ms after stimulus onset, the value signals in vmPFC appear relatively late in the choice process, and seem to reflect the integration of incoming information from sensory and memory related regions. PMID:21695081

  11. Successful Face Recognition is Associated with Increased Prefrontal Cortex Activation in Autism Spectrum Disorder

    PubMed Central

    Herrington, John D.; Riley, Meghan E.; Grupe, Daniel W.; Schultz, Robert T.

    2014-01-01

    This study examines whether deficits in visual information processing in ASD can be offset by the recruitment of brain structures involved in selective attention. During functional MRI, 12 children with ASD and 19 control participants completed a selective attention one-back task in which images of faces and houses were superimposed. When attending to faces, the ASD group showed increased activation relative to control participants within multiple prefrontal cortex areas, including dorsolateral prefrontal cortex (DLPFC). DLPFC activation in ASD was associated with increased response times for faces. These data suggest that prefrontal cortex activation may represent a compensatory mechanism for diminished visual information processing abilities. PMID:25234479

  12. Lesions to right prefrontal cortex impair real-world planning through premature commitments.

    PubMed

    Goel, Vinod; Vartanian, Oshin; Bartolo, Angela; Hakim, Lila; Ferraro, Anna Maria; Isella, Valeria; Appollonio, Ildebrando; Drei, Silvia; Nichelli, Paolo

    2013-03-01

    While it is well accepted that the left prefrontal cortex plays a critical role in planning and problem-solving tasks, very little is known about the role of the right prefrontal cortex. We addressed this issue by testing five neurological patients with focal lesions to right prefrontal cortex on a real-world travel planning task, and compared their performance with the performance of five neurological patients with focal lesions to left prefrontal cortex, five neurological patients with posterior lesions, and five normal controls. Only patients with lesions to right prefrontal cortex generated substandard solutions compared to normal controls. Examination of the underlying cognitive processes and strategies revealed that patients with lesions to right prefrontal cortex approached the task at an excessively precise, concrete level compared to normal controls, and very early locked themselves into substandard solutions relative to the comparison group. In contrast, the behavior of normal controls was characterized by a judicious interplay of concrete and abstract levels/modes of representations. We suggest that damage to the right prefrontal system impairs the encoding and processing of more abstract and vague representations that facilitate lateral transformations, resulting in premature commitment to precise concrete patterns, and hasty albeit substandard conclusions (because the space of possibilities has not been properly explored). PMID:23266766

  13. Prefrontal Cortex Activation and Young Driver Behaviour: A fNIRS Study

    PubMed Central

    Foy, Hannah J.; Runham, Patrick; Chapman, Peter

    2016-01-01

    Road traffic accidents consistently show a significant over-representation for young, novice and particularly male drivers. This research examines the prefrontal cortex activation of young drivers and the changes in activation associated with manipulations of mental workload and inhibitory control. It also considers the explanation that a lack of prefrontal cortex maturation is a contributing factor to the higher accident risk in this young driver population. The prefrontal cortex is associated with a number of factors including mental workload and inhibitory control, both of which are also related to road traffic accidents. This experiment used functional near infrared spectroscopy to measure prefrontal cortex activity during five simulated driving tasks: one following task and four overtaking tasks at varying traffic densities which aimed to dissociate workload and inhibitory control. Age, experience and gender were controlled for throughout the experiment. The results showed that younger drivers had reduced prefrontal cortex activity compared to older drivers. When both mental workload and inhibitory control increased prefrontal cortex activity also increased, however when inhibitory control alone increased there were no changes in activity. Along with an increase in activity during overtaking manoeuvres, these results suggest that prefrontal cortex activation is more indicative of workload in the current task. There were no differences in the number of overtakes completed by younger and older drivers but males overtook significantly more than females. We conclude that prefrontal cortex activity is associated with the mental workload required for overtaking. We additionally suggest that the reduced activation in younger drivers may be related to a lack of prefrontal maturation which could contribute to the increased crash risk seen in this population. PMID:27227990

  14. Prefrontal Cortex Glutamate Correlates with Mental Perspective-Taking

    PubMed Central

    Montag, Christiane; Schubert, Florian; Heinz, Andreas; Gallinat, Jürgen

    2008-01-01

    Background Dysfunctions in theory of mind and empathic abilities have been suggested as core symptoms in major psychiatric disorders including schizophrenia and autism. Since self monitoring, perspective taking and empathy have been linked to prefrontal (PFC) and anterior cingulate cortex (ACC) function, neurotransmitter variations in these areas may account for normal and pathological variations of these functions. Converging evidence indicates an essential role of glutamatergic neurotransmission in psychiatric diseases with pronounced deficits in empathy. However, the role of the glutamate system for different dimensions of empathy has not been investigated so far. Methodology/Principal Findings Absolute concentrations of cerebral glutamate in the ACC, left dorsolateral PFC and left hippocampus were determined by 3-tesla proton magnetic resonance spectroscopy (1H-MRS) in 17 healthy individuals. Three dimensions of empathy were estimated by a self-rating questionnaire, the Interpersonal Reactivity Index (IRI). Linear regression analysis showed that dorsolateral PFC glutamate concentration was predicted by IRI factor “perspective taking” (T = −2.710, p = 0.018; adjusted alpha-level of 0.017, Bonferroni) but not by “empathic concern” or “personal distress”. No significant relationship between IRI subscores and the glutamate levels in the ACC or left hippocampus was detected. Conclusions/Significance This is the first study to investigate the role of the glutamate system for dimensions of theory of mind and empathy. Results are in line with recent concepts that executive top-down control of behavior is mediated by prefrontal glutamatergic projections. This is a preliminary finding that needs a replication in an independent sample. PMID:19060949

  15. Prefrontal cortex white matter tracts in prodromal Huntington disease.

    PubMed

    Matsui, Joy T; Vaidya, Jatin G; Wassermann, Demian; Kim, Regina Eunyoung; Magnotta, Vincent A; Johnson, Hans J; Paulsen, Jane S

    2015-10-01

    Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e., prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATRs), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage. Hum Brain Mapp 36:3717-3732, 2015. © 2015 Wiley Periodicals, Inc. PMID:26179962

  16. Intentional signal in prefrontal cortex generalizes across different sensory modalities.

    PubMed

    Choi, Kyuwan; Torres, Elizabeth B

    2014-07-01

    Biofeedback-EEG training to learn the mental control of an external device (e.g., a cursor on the screen) has been an important paradigm to attempt to understand the involvements of various areas of the brain in the volitional control and the modulation of intentional thought processes. Often the areas to adapt and to monitor progress are selected a priori. Less explored, however, has been the notion of automatically emerging activation in a particular area or subregions within that area recruited above and beyond the rest of the brain. Likewise, the notion of evoking such a signal as an amodal, abstract one remaining robust across different sensory modalities could afford some exploration. Here we develop a simple binary control task in the context of brain-computer interface (BCI) and use a Bayesian sparse probit classification algorithm to automatically uncover brain regional activity that maximizes task performance. We trained and tested 19 participants using the visual modality for instructions and feedback. Across training blocks we quantified coupling of the frontoparietal nodes and selective involvement of visual and auditory regions as a function of the real-time sensory feedback. The testing phase under both forms of sensory feedback revealed automatic recruitment of the prefrontal cortex with a parcellation of higher strength levels in Brodmann's areas 9, 10, and 11 significantly above those in other brain areas. We propose that the prefrontal signal may be a neural correlate of externally driven intended direction and discuss our results in the context of various aspects involved in the cognitive control of our thoughts. PMID:24259543

  17. Guanfacine Modulates the Influence of Emotional Cues on Prefrontal Cortex Activation for Cognitive Control

    PubMed Central

    Clerkin, Suzanne M.; Fan, Jin; Halperin, Jeffrey M.; Newcorn, Jeffrey H.

    2012-01-01

    Rationale Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic α2 adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established. Objectives This study tested the effect of the postsynaptic α2 adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex. Methods Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, crossover design. Results Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces, but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response-related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions. Conclusions These results provide evidence that guanfacine stimulation of postsynaptic α2 adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the α2 adrenoceptor agonist treatment of attention-deficit hyperactivity disorder (ADHD). PMID:23086020

  18. microRNA Profiles in Parkinson's Disease Prefrontal Cortex

    PubMed Central

    Hoss, Andrew G.; Labadorf, Adam; Beach, Thomas G.; Latourelle, Jeanne C.; Myers, Richard H.

    2016-01-01

    Objective: The goal of this study was to compare the microRNA (miRNA) profile of Parkinson's disease (PD) frontal cortex with normal control brain, allowing for the identification of PD specific signatures as well as study the disease-related phenotypes of onset age and dementia. Methods: Small RNA sequence analysis was performed from prefrontal cortex for 29 PD samples and 33 control samples. After sample QC, normalization and batch correction, linear regression was employed to identify miRNAs altered in PD, and a PD classifier was developed using weighted voting class prediction. The relationship of miRNA levels to onset age and PD with dementia (PDD) was also characterized in case-only analyses. Results: One twenty five miRNAs were differentially expressed in PD at a genome-wide level of significance (FDR q < 0.05). A set of 29 miRNAs classified PD from non-diseased brain (93.9% specificity, 96.6% sensitivity). The majority of differentially expressed miRNAs (105/125) showed an ordinal relationship from control, to PD without dementia (PDN), to PDD. Among PD brains, 36 miRNAs classified PDD from PDN (sensitivity = 81.2%, specificity = 88.9%). Among differentially expressed miRNAs, miR-10b-5p had a positive association with onset age (q = 4.7e-2). Conclusions: Based on cortical miRNA levels, PD brains were accurately classified from non-diseased brains. Additionally, the PDD miRNA profile exhibited a more severe pattern of alteration among those differentially expressed in PD. To evaluate the clinical utility of miRNAs as potential clinical biomarkers, further characterization and testing of brain-related miRNA alterations in peripheral biofluids is warranted. PMID:26973511

  19. Prefrontal Cortex Cognitive Deficits in Children Treated Early and Continuously for PKU.

    ERIC Educational Resources Information Center

    Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda

    1997-01-01

    Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…

  20. Altered Functional Connectivity of the Insular Cortex across Prefrontal Networks in Cocaine Addiction

    PubMed Central

    Cisler, Josh M.; Elton, Amanda; Kennedy, Ashley P.; Young, Jonathan; Smitherman, Sonet; James, George Andrew; Kilts, Clinton D.

    2013-01-01

    Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. 41 participants with cocaine dependence and 19 control participants underwent a resting-state 3T fMRI scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial PFC, inferior frontal gyrus, and bilateral dlPFC. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision-making processes presumably mediated by prefrontal networks in the cocaine dependence process. PMID:23684980

  1. The hierarchical organization of the lateral prefrontal cortex

    PubMed Central

    Nee, Derek Evan; D'Esposito, Mark

    2016-01-01

    Higher-level cognition depends on the lateral prefrontal cortex (LPFC), but its functional organization has remained elusive. An influential proposal is that the LPFC is organized hierarchically whereby progressively rostral areas of the LPFC process/represent increasingly abstract information facilitating efficient and flexible cognition. However, support for this theory has been limited. Here, human fMRI data revealed rostral/caudal gradients of abstraction in the LPFC. Dynamic causal modeling revealed asymmetrical LPFC interactions indicative of hierarchical processing. Contrary to dominant assumptions, the relative strength of efferent versus afferent connections positioned mid LPFC as the apex of the hierarchy. Furthermore, cognitive demands induced connectivity modulations towards mid LPFC consistent with a role in integrating information for control operations. Moreover, the strengths of these dynamics were related to trait-measured higher-level cognitive ability. Collectively, these results suggest that the LPFC is hierarchically organized with the mid LPFC positioned to synthesize abstract and concrete information to control behavior. DOI: http://dx.doi.org/10.7554/eLife.12112.001 PMID:26999822

  2. Architecture of Explanatory Inference in the Human Prefrontal Cortex

    PubMed Central

    Barbey, Aron K.; Patterson, Richard

    2011-01-01

    Causal reasoning is a ubiquitous feature of human cognition. We continuously seek to understand, at least implicitly and often explicitly, the causal scenarios in which we live, so that we may anticipate what will come next, plan a potential response and envision its outcome, decide among possible courses of action in light of their probable outcomes, make midstream adjustments in our goal-related activities as our situation changes, and so on. A considerable body of research shows that the lateral prefrontal cortex (PFC) is crucial for causal reasoning, but also that there are significant differences in the manner in which ventrolateral PFC, dorsolateral PFC, and anterolateral PFC support causal reasoning. We propose, on the basis of research on the evolution, architecture, and functional organization of the lateral PFC, a general framework for understanding its roles in the many and varied sorts of causal reasoning carried out by human beings. Specifically, the ventrolateral PFC supports the generation of basic causal explanations and inferences; dorsolateral PFC supports the evaluation of these scenarios in light of some given normative standard (e.g., of plausibility or correctness in light of real or imagined causal interventions); and anterolateral PFC supports explanation and inference at an even higher level of complexity, coordinating the processes of generation and evaluation with further cognitive processes, and especially with computations of hedonic value and emotional implications of possible behavioral scenarios – considerations that are often critical both for understanding situations causally and for deciding about our own courses of action. PMID:21845182

  3. Distinct Value Signals in Anterior and Posterior Ventromedial Prefrontal Cortex

    PubMed Central

    Smith, David V.; Hayden, Benjamin Y.; Truong, Trong-Kha; Song, Allen W.; Platt, Michael L.; Huettel, Scott A.

    2010-01-01

    The core feature of an economic exchange is a decision to trade one good for another, based on a comparison of relative value. Economists have long recognized, however, that the value an individual ascribes to a good during decision making (i.e., their relative willingness to trade for that good) does not always map onto the reward they actually experience. Here, we show that experienced value and decision value are represented in distinct regions of ventromedial prefrontal cortex (VMPFC) during the passive consumption of rewards. Participants viewed two categories of rewards – images of faces that varied in their attractiveness and monetary gains and losses – while being scanned using functional magnetic resonance imaging (fMRI). An independent market task, in which participants exchanged some of the money that they earned for brief views of attractive faces, determined the relative decision value associated with each category. We found that activation of anterior VMPFC increased with increasing experienced value, but not decision value, for both reward categories. In contrast, activation of posterior VMPFC predicted each individual's relative decision value for face and monetary stimuli. These results indicate not only that experienced value and decision value are represented in distinct regions of VMPFC, but also that decision value signals are evident even in the absence of an overt choice task. These results endorse the idea that decisions are made by comparing neural representations of the value of different goods encoded in posterior VMPFC in a common, relative currency. PMID:20164333

  4. The role of the medial prefrontal cortex in social categorization.

    PubMed

    Molenberghs, Pascal; Morrison, Samantha

    2014-03-01

    Group membership is an important aspect of our everyday behavior. Recently, we showed that existing relevant in-group labels increased activation in the medial prefrontal cortex (MPFC) compared with out-group labels, suggesting a role of the MPFC in social categorization. However, the question still remains whether this increase in MPFC activation for in-group representation is solely related with previous experience with the in-group. To test this, we randomly assigned participants to a red or blue team and in a subsequent functional magnetic resonance imaging experiment they categorized red and blue team words as belonging to either the in-group or the out-group. Results showed that even under these minimal conditions increased activation was found in the MPFC when participants indicated that they belonged to a group, as compared with when they did not. This effect was found to be associated with the level of group identification. These results confirm the role of MPFC in social categorization. PMID:23175678

  5. Electrical stimulation of the dorsolateral prefrontal cortex improves memory monitoring.

    PubMed

    Chua, Elizabeth F; Ahmed, Rifat

    2016-05-01

    The ability to accurately monitor one's own memory is an important feature of normal memory function. Converging evidence from neuroimaging and lesion studies have implicated the dorsolateral prefrontal cortex (DLPFC) in memory monitoring. Here we used high definition transcranial direct stimulation (HD-tDCS), a non-invasive form of brain stimulation, to test whether the DLPFC has a causal role in memory monitoring, and the nature of that role. We used a metamemory monitoring task, in which participants first attempted to recall the answer to a general knowledge question, then gave a feeling-of-knowing (FOK) judgment, followed by a forced choice recognition task. When participants received DLPFC stimulation, their feeling-of-knowing judgments were better predictors of memory performance, i.e., they had better memory monitoring accuracy, compared to stimulation of a control site, the anterior temporal lobe (ATL). Effects of DLPFC stimulation were specific to monitoring accuracy, as there was no significant increase in memory performance, and if anything, there was poorer memory performance with DLPFC stimulation. Thus we have demonstrated a causal role for the DLPFC in memory monitoring, and showed that electrically stimulating the left DLPFC led people to more accurately monitor and judge their own memory. PMID:26970142

  6. Nature experience reduces rumination and subgenual prefrontal cortex activation

    PubMed Central

    Bratman, Gregory N.; Hamilton, J. Paul; Hahn, Kevin S.; Daily, Gretchen C.; Gross, James J.

    2015-01-01

    Urbanization has many benefits, but it also is associated with increased levels of mental illness, including depression. It has been suggested that decreased nature experience may help to explain the link between urbanization and mental illness. This suggestion is supported by a growing body of correlational and experimental evidence, which raises a further question: what mechanism(s) link decreased nature experience to the development of mental illness? One such mechanism might be the impact of nature exposure on rumination, a maladaptive pattern of self-referential thought that is associated with heightened risk for depression and other mental illnesses. We show in healthy participants that a brief nature experience, a 90-min walk in a natural setting, decreases both self-reported rumination and neural activity in the subgenual prefrontal cortex (sgPFC), whereas a 90-min walk in an urban setting has no such effects on self-reported rumination or neural activity. In other studies, the sgPFC has been associated with a self-focused behavioral withdrawal linked to rumination in both depressed and healthy individuals. This study reveals a pathway by which nature experience may improve mental well-being and suggests that accessible natural areas within urban contexts may be a critical resource for mental health in our rapidly urbanizing world. PMID:26124129

  7. Regulation of prefrontal cortex myelination by the microbiota.

    PubMed

    Hoban, A E; Stilling, R M; Ryan, F J; Shanahan, F; Dinan, T G; Claesson, M J; Clarke, G; Cryan, J F

    2016-01-01

    The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC. PMID:27045844

  8. Context-Dependent Duration Signals in the Primate Prefrontal Cortex.

    PubMed

    Genovesio, Aldo; Seitz, Lucia K; Tsujimoto, Satoshi; Wise, Steven P

    2016-08-01

    The activity of some prefrontal (PF) cortex neurons distinguishes short from long time intervals. Here, we examined whether this property reflected a general timing mechanism or one dependent on behavioral context. In one task, monkeys discriminated the relative duration of 2 stimuli; in the other, they discriminated the relative distance of 2 stimuli from a fixed reference point. Both tasks had a pre-cue period (interval 1) and a delay period (interval 2) with no discriminant stimulus. Interval 1 elapsed before the presentation of the first discriminant stimulus, and interval 2 began after that stimulus. Both intervals had durations of either 400 or 800 ms. Most PF neurons distinguished short from long durations in one task or interval, but not in the others. When neurons did signal something about duration for both intervals, they did so in an uncorrelated or weakly correlated manner. These results demonstrate a high degree of context dependency in PF time processing. The PF, therefore, does not appear to signal durations abstractedly, as would be expected of a general temporal encoder, but instead does so in a highly context-dependent manner, both within and between tasks. PMID:26209845

  9. The hierarchical organization of the lateral prefrontal cortex.

    PubMed

    Nee, Derek Evan; D'Esposito, Mark

    2016-01-01

    Higher-level cognition depends on the lateral prefrontal cortex (LPFC), but its functional organization has remained elusive. An influential proposal is that the LPFC is organized hierarchically whereby progressively rostral areas of the LPFC process/represent increasingly abstract information facilitating efficient and flexible cognition. However, support for this theory has been limited. Here, human fMRI data revealed rostral/caudal gradients of abstraction in the LPFC. Dynamic causal modeling revealed asymmetrical LPFC interactions indicative of hierarchical processing. Contrary to dominant assumptions, the relative strength of efferent versus afferent connections positioned mid LPFC as the apex of the hierarchy. Furthermore, cognitive demands induced connectivity modulations towards mid LPFC consistent with a role in integrating information for control operations. Moreover, the strengths of these dynamics were related to trait-measured higher-level cognitive ability. Collectively, these results suggest that the LPFC is hierarchically organized with the mid LPFC positioned to synthesize abstract and concrete information to control behavior. PMID:26999822

  10. Nature experience reduces rumination and subgenual prefrontal cortex activation.

    PubMed

    Bratman, Gregory N; Hamilton, J Paul; Hahn, Kevin S; Daily, Gretchen C; Gross, James J

    2015-07-14

    Urbanization has many benefits, but it also is associated with increased levels of mental illness, including depression. It has been suggested that decreased nature experience may help to explain the link between urbanization and mental illness. This suggestion is supported by a growing body of correlational and experimental evidence, which raises a further question: what mechanism(s) link decreased nature experience to the development of mental illness? One such mechanism might be the impact of nature exposure on rumination, a maladaptive pattern of self-referential thought that is associated with heightened risk for depression and other mental illnesses. We show in healthy participants that a brief nature experience, a 90-min walk in a natural setting, decreases both self-reported rumination and neural activity in the subgenual prefrontal cortex (sgPFC), whereas a 90-min walk in an urban setting has no such effects on self-reported rumination or neural activity. In other studies, the sgPFC has been associated with a self-focused behavioral withdrawal linked to rumination in both depressed and healthy individuals. This study reveals a pathway by which nature experience may improve mental well-being and suggests that accessible natural areas within urban contexts may be a critical resource for mental health in our rapidly urbanizing world. PMID:26124129

  11. Action planning in a virtual context after prefrontal cortex damage.

    PubMed

    Zalla, T; Plassiart, C; Pillon, B; Grafman, J; Sirigu, A

    2001-01-01

    Patients with frontal lobe lesions are known to encounter severe problems in the organisation of their behaviour in everyday life. Script generation tasks assess the subject's conceptual ability to formulate and evaluate a coherent and structured plan of action. In the present study, we investigated to what extent neuropsychological deficits observed at the conceptual level of action knowledge lead to impairments in action execution. We examined seven patients with prefrontal cortex damage and sixteen normal subjects. Subjects were first asked to verbally formulate a plan of action and then to use this knowledge for 'executing' the actions in a virtual 3-dimensional interactive apartment presented on a computer screen. The results indicated that the presence of the realistic context improved patients' performance. However, specific impairments were observed in patients in the execution condition, namely actions slips, omissions, failure in initiating actions and purposeless displacements. Moreover, an analysis of planning time showed that, differently of the patients group, normal subjects spent more time during plan execution as compared to plan generation. These results suggest that after a frontal lobe lesion a defective formulation of a routine plan might affect the execution of the corresponding course of actions. PMID:11369400

  12. Medial prefrontal cortex subserves diverse forms of self-reflection.

    PubMed

    Jenkins, Adrianna C; Mitchell, Jason P

    2011-01-01

    The ability to think about oneself--to self--reflect--is one of the defining features of the human mind. Recent research has suggested that this ability may be subserved by a particular brain region: the medial prefrontal cortex (MPFC). However, although humans can contemplate a variety of different aspects of themselves, including their stable personality traits, current feelings, and physical attributes, no research has directly examined the extent to which these different forms of self-reflection are subserved by common mechanisms. To address this question, participants were scanned using functional magnetic resonance imaging (fMRI) while making judgments about their own personality traits, current mental states, and physical attributes as well as those of another person. Whereas some brain regions responded preferentially during only one form of self-reflection, a robust region of MPFC was engaged preferentially during self-reflection across all three types of judgment. These results suggest that--although dissociable--diverse forms of self-referential thought draw on a shared cognitive process subserved by MPFC. PMID:20711940

  13. Regulation of prefrontal cortex myelination by the microbiota

    PubMed Central

    Hoban, A E; Stilling, R M; Ryan, F J; Shanahan, F; Dinan, T G; Claesson, M J; Clarke, G; Cryan, J F

    2016-01-01

    The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC. PMID:27045844

  14. Architecture of explanatory inference in the human prefrontal cortex.

    PubMed

    Barbey, Aron K; Patterson, Richard

    2011-01-01

    Causal reasoning is a ubiquitous feature of human cognition. We continuously seek to understand, at least implicitly and often explicitly, the causal scenarios in which we live, so that we may anticipate what will come next, plan a potential response and envision its outcome, decide among possible courses of action in light of their probable outcomes, make midstream adjustments in our goal-related activities as our situation changes, and so on. A considerable body of research shows that the lateral prefrontal cortex (PFC) is crucial for causal reasoning, but also that there are significant differences in the manner in which ventrolateral PFC, dorsolateral PFC, and anterolateral PFC support causal reasoning. We propose, on the basis of research on the evolution, architecture, and functional organization of the lateral PFC, a general framework for understanding its roles in the many and varied sorts of causal reasoning carried out by human beings. Specifically, the ventrolateral PFC supports the generation of basic causal explanations and inferences; dorsolateral PFC supports the evaluation of these scenarios in light of some given normative standard (e.g., of plausibility or correctness in light of real or imagined causal interventions); and anterolateral PFC supports explanation and inference at an even higher level of complexity, coordinating the processes of generation and evaluation with further cognitive processes, and especially with computations of hedonic value and emotional implications of possible behavioral scenarios - considerations that are often critical both for understanding situations causally and for deciding about our own courses of action. PMID:21845182

  15. Lateral Prefrontal Cortex Contributes to Fluid Intelligence Through Multinetwork Connectivity.

    PubMed

    Cole, Michael W; Ito, Takuya; Braver, Todd S

    2015-10-01

    Our ability to effectively adapt to novel circumstances--as measured by general fluid intelligence--has recently been tied to the global connectivity of lateral prefrontal cortex (LPFC). Global connectivity is a broad measure that summarizes both within-network connectivity and across-network connectivity. We used additional graph theoretical measures to better characterize the nature of LPFC connectivity and its relationship with fluid intelligence. We specifically hypothesized that LPFC is a connector hub with an across-network connectivity that contributes to fluid intelligence independent of within-network connectivity. We verified that LPFC was in the top 10% of brain regions in terms of across-network connectivity, suggesting it is a strong connector hub. Importantly, we found that the LPFC across-network connectivity predicted individuals' fluid intelligence and this correlation remained statistically significant when controlling for global connectivity (which includes within-network connectivity). This supports the conclusion that across-network connectivity independently contributes to the relationship between LPFC connectivity and intelligence. These results suggest that LPFC contributes to fluid intelligence by being a connector hub with a truly global multisystem connectivity throughout the brain. PMID:26165732

  16. Susceptibility to social pressure following ventromedial prefrontal cortex damage.

    PubMed

    Chen, Kuan-Hua; Rusch, Michelle L; Dawson, Jeffrey D; Rizzo, Matthew; Anderson, Steven W

    2015-11-01

    Social pressure influences human behavior including risk taking, but the psychological and neural underpinnings of this process are not well understood. We used the human lesion method to probe the role of ventromedial prefrontal cortex (vmPFC) in resisting adverse social pressure in the presence of risk. Thirty-seven participants (11 with vmPFC damage, 12 with brain damage outside the vmPFC and 14 without brain damage) were tested in driving simulator scenarios requiring left-turn decisions across oncoming traffic with varying time gaps between the oncoming vehicles. Social pressure was applied by a virtual driver who honked aggressively from behind. Participants with vmPFC damage were more likely to select smaller and potentially unsafe gaps under social pressure, while gap selection by the comparison groups did not change under social pressure. Participants with vmPFC damage also showed prolonged elevated skin conductance responses (SCR) under social pressure. Comparison groups showed similar initial elevated SCR, which then declined prior to making left-turn decisions. The findings suggest that the vmPFC plays an important role in resisting explicit and immediately present social pressure with potentially negative consequences. The vmPFC appears to contribute to the regulation of emotional responses and the modulation of decision making to optimize long-term outcomes. PMID:25816815

  17. Flexible neural mechanisms of cognitive control within human prefrontal cortex.

    PubMed

    Braver, Todd S; Paxton, Jessica L; Locke, Hannah S; Barch, Deanna M

    2009-05-01

    A major challenge in research on executive control is to reveal its functional decomposition into underlying neural mechanisms. A typical assumption is that this decomposition occurs solely through anatomically based dissociations. Here we tested an alternative hypothesis that different cognitive control processes may be implemented within the same brain regions, with fractionation and dissociation occurring on the basis of temporal dynamics. Regions within lateral prefrontal cortex (PFC) were examined that, in a prior study, exhibited contrasting temporal dynamics between older and younger adults during performance of the AX-CPT cognitive control task. The temporal dynamics in younger adults fit a proactive control pattern (primarily cue-based activation), whereas in older adults a reactive control pattern was found (primarily probe-based activation). In the current study, we found that following a period of task-strategy training, these older adults exhibited a proactive shift within a subset of the PFC regions, normalizing their activity dynamics toward young adult patterns. Conversely, under conditions of penalty-based monetary incentives, the younger adults exhibited a reactive shift some of the same regions, altering their temporal dynamics toward the older adult baseline pattern. These experimentally induced crossover patterns of temporal dynamics provide strong support for dual modes of cognitive control that can be flexibly shifted within PFC regions, via modulation of neural responses to changing task conditions or behavioral goals. PMID:19380750

  18. Repeated cocaine administration promotes long-term potentiation induction in rat medial prefrontal cortex.

    PubMed

    Huang, Chiung-Chun; Lin, Hsiao-Ju; Hsu, Kuei-Sen

    2007-08-01

    Although drug-induced adaptations in the prefrontal cortex (PFC) may contribute to several core aspects of addictive behaviors, it is not clear yet whether drugs of abuse elicit changes in synaptic plasticity at the PFC excitatory synapses. Here we report that, following repeated cocaine administration (15 mg/kg/day intraperitoneal injection for 5 consecutive days) with a 3-day withdrawal, excitatory synapses to layer V pyramidal neurons in rat medial prefrontal cortex (mPFC) become highly sensitive to the induction of long-term potentiation (LTP) by repeated correlated presynaptic and postsynaptic activity. This promoted LTP induction is caused by cocaine-induced reduction of gamma-aminobutyric acid (GABA)(A) receptor-mediated inhibition of mPFC pyramidal neurons. In contrast, in slices from rats treated with saline or a single dose of cocaine, the same LTP induction protocol did not induce significant LTP unless the blockade of GABA(A) receptors. Blockade of the D1-like receptors specifically prevented the cocaine-induced enhancement of LTP. Repeated cocaine exposure reduced the GABA(A) receptor-mediated synaptic currents in mPFC pyramidal neurons. Biotinylation experiments revealed a significant reduction of surface GABA(A) receptor alpha1 subunit expression in mPFC slices from repeated cocaine-treated rats. These findings support an important role for cocaine-induced enhancement of synaptic plasticity in the PFC in the development of drug-associated behavioral plasticity. PMID:17050645

  19. Effects of Physical Exercise on Working Memory and Prefrontal Cortex Function in Post-Stroke Patients.

    PubMed

    Moriya, M; Aoki, C; Sakatani, K

    2016-01-01

    Physical exercise enhances prefrontal cortex activity and improves working memory performance in healthy older adults, but it is not clear whether this remains the case in post-stroke patients. Therefore, the aim of this study was to examine the acute effect of physical exercise on prefrontal cortex activity in post-stroke patients using near-infrared spectroscopy (NIRS). We studied 11 post-stroke patients. The patients performed Sternberg-type working memory tasks before and after moderate intensity aerobic exercise (40 % of maximal oxygen uptake) with a cycling ergometer for 15 min. We measured the NIRS response at the prefrontal cortex during the working memory task. We evaluated behavioral performance (response time and accuracy) of the working memory task. It was found that physical exercise improved behavioral performance of the working memory task compared with the control condition (p < 0.01). In addition, NIRS analysis indicated that physical exercise enhanced prefrontal cortex activation, particularly in the right prefrontal cortex (p < 0.05), during the working memory task compared with the control condition. These findings suggest that the moderate-intensity aerobic exercise enhances prefrontal cortex activity and improves working memory performance in post-stroke patients. PMID:27526144

  20. TMS-induced neural noise in sensory cortex interferes with short-term memory storage in prefrontal cortex

    PubMed Central

    Bancroft, Tyler D.; Hogeveen, Jeremy; Hockley, William E.; Servos, Philip

    2014-01-01

    In a previous study, Harris et al. (2002) found disruption of vibrotactile short-term memory after applying single-pulse transcranial magnetic stimulation (TMS) to primary somatosensory cortex (SI) early in the maintenance period, and suggested that this demonstrated a role for SI in vibrotactile memory storage. While such a role is compatible with recent suggestions that sensory cortex is the storage substrate for working memory, it stands in contrast to a relatively large body of evidence from human EEG and single-cell recording in primates that instead points to prefrontal cortex as the storage substrate for vibrotactile memory. In the present study, we use computational methods to demonstrate how Harris et al.'s results can be reproduced by TMS-induced activity in sensory cortex and subsequent feedforward interference with memory traces stored in prefrontal cortex, thereby reconciling discordant findings in the tactile memory literature. PMID:24634653

  1. Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex

    PubMed Central

    López-Ramos, Juan Carlos; Guerra-Narbona, Rafael; Delgado-García, José M.

    2015-01-01

    Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals’ avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations. PMID:25688195

  2. Noradrenergic control of error perseveration in medial prefrontal cortex

    PubMed Central

    Caetano, Marcelo S.; Jin, Lu E.; Harenberg, Linda; Stachenfeld, Kimberly L.; Arnsten, Amy F. T.; Laubach, Mark

    2013-01-01

    The medial prefrontal cortex (mPFC) plays a key role in behavioral variability, action monitoring, and inhibitory control. The functional role of mPFC may change over the lifespan due to a number of aging-related issues, including dendritic regression, increased cAMP signaling, and reductions in the efficacy of neuromodulators to influence mPFC processing. A key neurotransmitter in mPFC is norepinephrine. Previous studies have reported aging-related changes in the sensitivity of mPFC-dependent tasks to noradrenergic agonist drugs, such as guanfacine. Here, we assessed the effects of yohimbine, an alpha-2 noradrenergic antagonist, in cohorts of younger and older rats in a classic test of spatial working memory (using a T-maze). Older rats (23–29 mo.) were impaired by a lower dose of yohimbine compared to younger animals (5–10 mo.). To determine if the drug acts on alpha-2 noradrenergic receptors in mPFC and if its effects are specific to memory-guided performance, we made infusions of yohimbine into mPFC of a cohort of young rats (6 mo.) using an operant delayed response task. The task involved testing rats in blocks of trials with memory- and stimulus-guided performance. Yohimbine selectively impaired memory-guided performance and was associated with error perseveration. Infusions of muscimol (a GABA-A agonist) at the same sites also selectively impaired memory-guided performance, but did not lead to error perseveration. Based on these results, we propose several potential interpretations for the role for the noradrenergic system in the performance of delayed response tasks, including the encoding of previous response locations, task rules (i.e., using a win-stay strategy instead of a win-shift strategy), and performance monitoring (e.g., prospective encoding of outcomes). PMID:23293590

  3. Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

    PubMed Central

    Schiller, Daniela; Kanen, Jonathan W.; LeDoux, Joseph E.; Monfils, Marie-H.; Phelps, Elizabeth A.

    2013-01-01

    Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala–PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC–amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders. PMID:24277809

  4. Disconnection Between Amygdala and Medial Prefrontal Cortex in Psychotic Disorders.

    PubMed

    Mukherjee, Prerona; Sabharwal, Amri; Kotov, Roman; Szekely, Akos; Parsey, Ramin; Barch, Deanna M; Mohanty, Aprajita

    2016-07-01

    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. PMID:26908926

  5. Medial Prefrontal Cortex: Adding Value to Imagined Scenarios

    PubMed Central

    Lin, Wen-Jing; Horner, Aidan J.; Bisby, James A.; Burgess, Neil

    2016-01-01

    The medial prefrontal cortex (mPFC) is consistently implicated in the network supporting autobiographical memory. Whereas more posterior regions in this network have been related to specific processes, such as the generation of visuospatial imagery or the association of items and contexts, the functional contribution of the mPFC remains unclear. However, the involvement of mPFC in estimation of value during decision-making suggests that it might play a similar role in memory. We investigated whether mPFC activity reflects the subjective value of elements in imagined scenarios. Participants in an MRI scanner imagined scenarios comprising a spatial context, a physiological state of need (e.g., thirst), and two items that could be congruent (e.g., drink) or incongruent (e.g., food) with the state of need. Memory for the scenarios was tested outside the scanner. Our manipulation of subjective value by imagined need was verified by increased subjective ratings of value for congruent items and improved subsequent memory for them. Consistent with our hypothesis, fMRI signal in mPFC reflected the modulation of an item’s subjective value by the imagined physiological state, suggesting the mPFC selectively tracked subjective value within our imagination paradigm. Further analyses showed uncorrected effects in non-mPFC regions, including increased activity in the insula when imagining states of need, the caudate nucleus when imagining congruent items, and the anterior hippocampus/amygdala when imagining subsequently remembered items. We therefore provide evidence that the mPFC plays a role in constructing the subjective value of the components of imagined scenarios and thus potentially in reconstructing the value of components of autobiographical recollection. PMID:26042501

  6. Medial prefrontal cortex stimulation modulates the processing of conditioned fear

    PubMed Central

    Guhn, Anne; Dresler, Thomas; Andreatta, Marta; Müller, Laura D.; Hahn, Tim; Tupak, Sara V.; Polak, Thomas; Deckert, Jürgen; Herrmann, Martin J.

    2014-01-01

    The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT). PMID:24600362

  7. Noradrenergic control of error perseveration in medial prefrontal cortex.

    PubMed

    Caetano, Marcelo S; Jin, Lu E; Harenberg, Linda; Stachenfeld, Kimberly L; Arnsten, Amy F T; Laubach, Mark

    2012-01-01

    The medial prefrontal cortex (mPFC) plays a key role in behavioral variability, action monitoring, and inhibitory control. The functional role of mPFC may change over the lifespan due to a number of aging-related issues, including dendritic regression, increased cAMP signaling, and reductions in the efficacy of neuromodulators to influence mPFC processing. A key neurotransmitter in mPFC is norepinephrine. Previous studies have reported aging-related changes in the sensitivity of mPFC-dependent tasks to noradrenergic agonist drugs, such as guanfacine. Here, we assessed the effects of yohimbine, an alpha-2 noradrenergic antagonist, in cohorts of younger and older rats in a classic test of spatial working memory (using a T-maze). Older rats (23-29 mo.) were impaired by a lower dose of yohimbine compared to younger animals (5-10 mo.). To determine if the drug acts on alpha-2 noradrenergic receptors in mPFC and if its effects are specific to memory-guided performance, we made infusions of yohimbine into mPFC of a cohort of young rats (6 mo.) using an operant delayed response task. The task involved testing rats in blocks of trials with memory- and stimulus-guided performance. Yohimbine selectively impaired memory-guided performance and was associated with error perseveration. Infusions of muscimol (a GABA-A agonist) at the same sites also selectively impaired memory-guided performance, but did not lead to error perseveration. Based on these results, we propose several potential interpretations for the role for the noradrenergic system in the performance of delayed response tasks, including the encoding of previous response locations, task rules (i.e., using a win-stay strategy instead of a win-shift strategy), and performance monitoring (e.g., prospective encoding of outcomes). PMID:23293590

  8. Prefrontal cortex contributions to episodic retrieval monitoring and evaluation.

    PubMed

    Cruse, Damian; Wilding, Edward L

    2009-11-01

    Although the prefrontal cortex (PFC) plays roles in episodic memory judgments, the specific processes it supports are not understood fully. Event-related potential (ERP) studies of episodic retrieval have revealed an electrophysiological modulation - the right-frontal ERP old/new effect - which is thought to reflect activity in PFC. The functional significance of this old/new effect remains a matter of debate, and this study was designed to test two accounts: (i) that the effect indexes processes linked to the monitoring or evaluation of the products of retrieval in service of task demands, or (ii) that it indexes the number of internal decisions required for a task judgment. Participants studied words in one of two colours. In a subsequent retrieval task, old (studied) and new words were presented in a neutral colour. Participants made initial old/new judgments, along with study colour judgments to words thought to be old. They also indicated their confidence (high/low) in the colour decision. Right-frontal ERP old/new effects were larger for high than for low confidence correct colour judgments, and the magnitude of the right-frontal effect was correlated with the proportions of low confidence judgments that were made. Because the numbers of decisions associated with these response categories are equivalent, these findings do not support a decision-based account of the right-frontal ERP old/new effect. Rather, the correlation between confidence and the magnitude of the effect links it with retrieval monitoring and evaluation processes. PMID:19523968

  9. Differential Effects of Insular and Ventromedial Prefrontal Cortex Lesions on Risky Decision-Making

    ERIC Educational Resources Information Center

    Clark, L.; Bechara, A.; Damasio, H.; Aitken, M. R. F.; Sahakian, B. J.; Robbins, T. W.

    2008-01-01

    The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear…

  10. Category-dependent and category-independent goal-value codes in human ventromedial prefrontal cortex.

    PubMed

    McNamee, Daniel; Rangel, Antonio; O'Doherty, John P

    2013-04-01

    To choose between manifestly distinct options, it is suggested that the brain assigns values to goals using a common currency. Although previous studies have reported activity in ventromedial prefrontal cortex (vmPFC) correlating with the value of different goal stimuli, it remains unclear whether such goal-value representations are independent of the associated stimulus categorization, as required by a common currency. Using multivoxel pattern analyses on functional magnetic resonance imaging (fMRI) data, we found a region of medial prefrontal cortex to contain a distributed goal-value code that is independent of stimulus category. More ventrally in the vmPFC, we found spatially distinct areas of the medial orbitofrontal cortex to contain unique category-dependent distributed value codes for food and consumer items. These results implicate the medial prefrontal cortex in the implementation of a common currency and suggest a ventral versus dorsal topographical organization of value signals in the vmPFC. PMID:23416449

  11. Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex

    PubMed Central

    Romanski, L. M.; Tian, B.; Fritz, J.; Mishkin, M.; Goldman-Rakic, P. S.; Rauschecker, J. P.

    2009-01-01

    ‘What’ and ‘where’ visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory–prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively. PMID:10570492

  12. Effect of fish oil intake on glucose levels in rat prefrontal cortex, as measured by microdialysis

    PubMed Central

    2013-01-01

    Background Brain glucose sensing may contribute to energy homeostasis control. The prefrontal cortex (PFC) participates in the hedonic component of feeding control. As high-fat diets may disrupt energy homeostasis, we evaluated in male Wistar rats whether intake of high-fat fish-oil diet modified cortical glucose extracellular levels and the feeding induced by intracerebroventricular glucose or PFC glucoprivation. Methods Glucose levels in PFC microdialysates were measured before and after a 30-min meal. Food intake was measured in animals receiving intracerebroventricular glucose followed, 30-min. later, by 2-deoxy-D-glucose injected into the PFC. Results The fish-oil group showed normal body weight and serum insulin while fat pads weight and glucose levels were increased. Baseline PFC glucose and 30-min. carbohydrates intake were similar between the groups. Feeding-induced PFC glucose levels increased earlier and more pronouncedly in fish-oil than in control rats. Intracerebroventricular glucose inhibited feeding consistently in the control but not in the fish-oil group. Local PFC glucoprivation with 2-DG attenuated glucose-induced hypophagia. Conclusions The present experiments have shown that, following food intake, more glucose reached the prefrontal cortex of the rats fed the high-fat fish-oil diet than of the rats fed the control diet. However, when administered directly into the lateral cerebral ventricle, glucose was able to consistently inhibit feeding only in the control rats. The findings indicate that, an impairment of glucose transport into the brain does not contribute to the disturbances induced by the high-fat fish-oil feeding. PMID:24369745

  13. Effect of VGLUT inhibitors on glutamatergic synaptic transmission in the rodent hippocampus and prefrontal cortex.

    PubMed

    Neale, S A; Copeland, C S; Salt, T E

    2014-07-01

    Vesicular glutamate transporters (VGLUTs) are known to be important in the uptake of glutamate into vesicles in the presynaptic terminal; thereby playing a role in synaptic function. VGLUT dysfunction has also been suggested in neurological and psychiatric disorders such as epilepsy and schizophrenia. A number of compounds have been identified as VGLUT inhibitors; however, little is known as to how these compounds affect synaptic transmission. We therefore investigated the effects of structurally unrelated VGLUT inhibitors on synaptic transmission in the rodent hippocampus and prefrontal cortex. In the CA1 and dentate gyrus regions of the in vitro slice preparation of mouse hippocampus, AMPA receptor-mediated field excitatory postsynaptic potentials (fEPSPs) were evoked in response to Schaffer collateral/commissural pathway stimulation. Application of the VGLUT inhibitors Rose Bengal (RB), Congo Red (CR) or Chicago Sky Blue 6B (CB) resulted in a concentration-related reduction of fEPSP amplitudes. RB (30μM) or CB (300μM) also depressed NMDA receptor-mediated responses in the CA1 region. The naturally occurring kynurenine Xanthurenic Acid (XA) is reported to be a VGLUT inhibitor. We found XA attenuated both AMPA and NMDA receptor-mediated synaptic transmission. The potency order of the VGLUT inhibitors was consistent with literature Ki values for VGLUT inhibition. Impaired glutamatergic neurotransmission is believed to contribute to schizophrenia, and VGLUTs have also been implicated in this disease. We therefore investigated the effect of VGLUT inhibition in the prefrontal cortex. Application of the VGLUT inhibitors RB or CB resulted in a concentration-dependent reduction in the amplitude of glutamate receptor-mediated fEPSPs recorded in layer V/VI in response to stimulation in the forceps minor. We conclude that VGLUT inhibitors can modulate glutamatergic synaptic transmission in the PFC and hippocampus. This could be important in the pathophysiology of nervous

  14. Oxidant/antioxidant effects of chronic exposure to predator odor in prefrontal cortex, amygdala, and hypothalamus.

    PubMed

    Mejia-Carmona, G E; Gosselink, K L; Pérez-Ishiwara, G; Martínez-Martínez, A

    2015-08-01

    The incidence of anxiety-related diseases is increasing these days, hence there is a need to understand the mechanisms that underlie its nature and consequences. It is known that limbic structures, mainly the prefrontal cortex and amygdala, are involved in the processing of anxiety, and that projections from prefrontal cortex and amygdala can induce activity of the hypothalamic-pituitary-adrenal axis with consequent cardiovascular changes, increase in oxygen consumption, and ROS production. The compensatory reaction can include increased antioxidant enzymes activities, overexpression of antioxidant enzymes, and genetic shifts that could include the activation of antioxidant genes. The main objective of this study was to evaluate the oxidant/antioxidant effect that chronic anxiogenic stress exposure can have in prefrontal cortex, amygdala, and hypothalamus by exposition to predator odor. Results showed (a) sensitization of the HPA axis response, (b) an enzymatic phase 1 and 2 antioxidant response to oxidative stress in amygdala, (c) an antioxidant stability without elevation of oxidative markers in prefrontal cortex, (d) an elevation in phase 1 antioxidant response in hypothalamus. Chronic exposure to predator odor has an impact in the metabolic REDOX state in amygdala, prefrontal cortex, and hypothalamus, with oxidative stress being prevalent in amygdala as this is the principal structure responsible for the management of anxiety. PMID:25981530

  15. Study the left prefrontal cortex activity of Chinese children with dyslexia in phonological processing by NIRS

    NASA Astrophysics Data System (ADS)

    Zhang, Zhili; Li, Ting; Zheng, Yi; Luo, Qingming; Song, Ranran; Gong, Hui

    2006-02-01

    Developmental dyslexia, a kind of prevalent psychological disease, represents that dyslexic children have unexpected difficulties in phonological processing and recognition test of Chinese characters. Some functional imaging technologies, such as fMRI and PET, have been used to study the brain activities of the children with dyslexia whose first language is English. In this paper, a portable, 16-channel, continuous-wave (CW) NIRS instrument was used to monitor the concentration changes of each hemoglobin species when Chinese children did the task of phonological processing and recognition test. The NIRS recorded the hemodynamic changes in the left prefrontal cortex of the children. 20 dyslexia-reading children (10~12 years old) and 20 normal-reading children took part in the phonological processing of Chinese characters including the phonological awareness section and the phonological decoding section. During the phonological awareness section, the changed concentration of deoxy-hemoglobin in dyslexia-reading children were significantly higher (p<0.05) than normal-reading children in the left ventrolateral prefrontal cortex (VLPFC). While in the phonological decoding section, both normal and dyslexic reading children had more activity in the left VLPFC, but only normal-reading children had activity in the left middorsal prefrontal cortex. In conclusion, both dyslexic and normal-reading children have activity in the left prefrontal cortex, but the degree and the areas of the prefrontal cortex activity are different between them when they did phonological processing.

  16. Effects of Mandibular Retrusive Deviation on Prefrontal Cortex Activation: A Functional Near-Infrared Spectroscopy Study

    PubMed Central

    Otsuka, Takero; Yamasaki, Ryuichi; Shimazaki, Tateshi; Sasaguri, Kenichi; Kawata, Toshitsugu

    2015-01-01

    The objective of this study was to evaluate occlusal condition by assessing brain activity in the prefrontal cortex, which is associated with emotion. Functional near-infrared spectroscopy (fNIRS) was used to detect changes in cerebral blood flow in the prefrontal cortex of 12 healthy volunteers. The malocclusion model was a custom-made splint that forced the mandible into retrusion. A splint with no modification was used as a control. The cortical activation during clenching was compared between the retrusive position condition and the control condition. A visual analog scale score for discomfort was also obtained during clenching and used to evaluate the interaction between fNIRS data and psychiatric changes. Activation of the prefrontal cortex was significantly greater during clenching in the mandibular retrusive condition than during clenching in the control condition. Furthermore, Spearman rank-correlation coefficient revealed a parallel relation between prefrontal cortex activation and visual analog scale score for discomfort. These results indicate that fNIRS can be used to objectively evaluate the occlusal condition by evaluating activity in the prefrontal cortex. PMID:26075235

  17. Reversible online control of habitual behavior by optogenetic perturbation of medial prefrontal cortex.

    PubMed

    Smith, Kyle S; Virkud, Arti; Deisseroth, Karl; Graybiel, Ann M

    2012-11-13

    Habits tend to form slowly but, once formed, can have great stability. We probed these temporal characteristics of habitual behaviors by intervening optogenetically in forebrain habit circuits as rats performed well-ingrained habitual runs in a T-maze. We trained rats to perform a maze habit, confirmed the habitual behavior by devaluation tests, and then, during the maze runs (ca. 3 s), we disrupted population activity in a small region in the medial prefrontal cortex, the infralimbic cortex. In accordance with evidence that this region is necessary for the expression of habits, we found that this cortical disruption blocked habitual behavior. Notably, however, this blockade of habitual performance occurred on line, within an average of three trials (ca. 9 s of inhibition), and as soon as during the first trial (<3 s). During subsequent weeks of training, the rats acquired a new behavioral pattern. When we again imposed the same cortical perturbation, the rats regained the suppressed maze-running that typified the original habit, and, simultaneously, the more recently acquired habit was blocked. These online changes occurred within an average of two trials (ca. 6 s of infralimbic inhibition). Measured changes in generalized performance ability and motivation to consume reward were unaffected. This immediate toggling between breaking old habits and returning to them demonstrates that even semiautomatic behaviors are under cortical control and that this control occurs online, second by second. These temporal characteristics define a framework for uncovering cellular transitions between fixed and flexible behaviors, and corresponding disturbances in pathologies. PMID:23112197

  18. Functional activity and effective connectivity of the posterior medial prefrontal cortex during processing of incongruent mental states.

    PubMed

    Schuwerk, Tobias; Döhnel, Katrin; Sodian, Beate; Keck, Ingo R; Rupprecht, Rainer; Sommer, Monika

    2014-07-01

    The neurocognitive components of Theory of Mind reasoning remain poorly understood. In particular the role of the posterior medial prefrontal cortex in the processing of other's mental states such as beliefs that are incongruent with one's own knowledge of reality is not clear-cut. It is unknown whether this region is involved in computing discrepant mental states or in subsequently resolving a response conflict between the discrepant others' and one's own beliefs. To test this, we adapted a false belief paradigm for the separate inspection of functional brain activity related to (1) the computation of diverging beliefs and (2) the subsequent consideration and selection of another's or one's own belief. Based on statistical parametric findings from functional neuroimaging, we employed dynamic causal modelling combined with Bayesian model selection to further characterize the interplay of resulting brain regions. In the initial computation of diverging beliefs, the posterior medial prefrontal cortex (pMPFC) and the bilateral temporoparietal cortex were crucially involved. The findings suggest that the bilateral temporal cortex engages in the construction and adjustment of diverging mental states by encoding relevant environmental information. The pMPFC inhibits this stimulus-bound processing which helps to compute discrepant mental states and process another's false belief decoupled from one's own perception of reality. In the subsequent question phase the right temporoparietal cortex showed increased activity related to switching to and reconsidering another's beliefs in order to select the correct response. PMID:24115202

  19. Preferential encoding of visual categories in parietal cortex compared with prefrontal cortex.

    PubMed

    Swaminathan, Sruthi K; Freedman, David J

    2012-02-01

    The ability to recognize the behavioral relevance, or category membership, of sensory stimuli is critical for interpreting the meaning of events in our environment. Neurophysiological studies of visual categorization have found categorical representations of stimuli in prefrontal cortex (PFC), an area that is closely associated with cognitive and executive functions. Recent studies have also identified neuronal category signals in parietal areas that are typically associated with visual-spatial processing. It has been proposed that category-related signals in parietal cortex and other visual areas may result from 'top-down' feedback from PFC. We directly compared neuronal activity in the lateral intraparietal (LIP) area and PFC in monkeys performing a visual motion categorization task. We found that LIP showed stronger, more reliable and shorter latency category signals than PFC. These findings suggest that LIP is strongly involved in visual categorization and argue against the idea that parietal category signals arise as a result of feedback from PFC during this task. PMID:22246435

  20. Activation of beta2-Adrenoceptor Enhances Synaptic Potentiation and Behavioral Memory via cAMP-PKA Signaling in the Medial Prefrontal Cortex of Rats

    ERIC Educational Resources Information Center

    Zhou, Hou-Cheng; Sun, Yan-Yan; Cai, Wei; He, Xiao-Ting; Yi, Feng; Li, Bao-Ming; Zhang, Xue-Han

    2013-01-01

    The prefrontal cortex (PFC) plays a critical role in cognitive functions, including working memory, attention regulation, behavioral inhibition, as well as memory storage. The functions of PFC are very sensitive to norepinephrine (NE), and even low levels of endogenously released NE exert a dramatic influence on the functioning of the PFC.…

  1. Biological and social influences on cognitive control processes dependent on prefrontal cortex.

    PubMed

    Diamond, Adele

    2011-01-01

    Cognitive control functions ("executive functions" [EFs] such as attentional control, self-regulation, working memory, and inhibition) that depend on prefrontal cortex (PFC) are critical for success in school and in life. Many children begin school lacking needed EF skills. Disturbances in EFs occur in many mental health disorders, such as ADHD and depression. This chapter addresses modulation of EFs by biology (genes and neurochemistry) and the environment (including school programs) with implications for clinical disorders and for education. Unusual properties of the prefrontal dopamine system contribute to PFC's vulnerability to environmental and genetic variations that have little effect elsewhere. EFs depend on a late-maturing brain region (PFC), yet they can be improved even in infants and preschoolers, without specialists or fancy equipment. Research shows that activities often squeezed out of school curricula (play, physical education, and the arts) rather than detracting from academic achievement help improve EFs and enhance academic outcomes. Such practices may also head off problems before they lead to diagnoses of EF impairments, including ADHD. Many issues are not simply education issues or health issues; they are both. PMID:21489397

  2. Emotional and Utilitarian Appraisals of Moral Dilemmas Are Encoded in Separate Areas and Integrated in Ventromedial Prefrontal Cortex

    PubMed Central

    Montaser-Kouhsari, Leila; Woodward, James; Rangel, Antonio

    2015-01-01

    Moral judgment often requires making difficult tradeoffs (e.g., is it appropriate to torture to save the lives of innocents at risk?). Previous research suggests that both emotional appraisals and more deliberative utilitarian appraisals influence such judgments and that these appraisals often conflict. However, it is unclear how these different types of appraisals are represented in the brain, or how they are integrated into an overall moral judgment. We addressed these questions using an fMRI paradigm in which human subjects provide separate emotional and utilitarian appraisals for different potential actions, and then make difficult moral judgments constructed from combinations of these actions. We found that anterior cingulate, insula, and superior temporal gyrus correlated with emotional appraisals, whereas temporoparietal junction and dorsomedial prefrontal cortex correlated with utilitarian appraisals. Overall moral value judgments were represented in an anterior portion of the ventromedial prefrontal cortex. Critically, the pattern of responses and functional interactions between these three sets of regions are consistent with a model in which emotional and utilitarian appraisals are computed independently and in parallel, and passed to the ventromedial prefrontal cortex where they are integrated into an overall moral value judgment. SIGNIFICANCE STATEMENT Popular accounts of moral judgment often describe it as a battle for control between two systems, one intuitive and emotional, the other rational and utilitarian, engaged in winner-take-all inhibitory competition. Using a novel fMRI paradigm, we identified distinct neural signatures of emotional and utilitarian appraisals and used them to test different models of how they compete for the control of moral behavior. Importantly, we find little support for competitive inhibition accounts. Instead, moral judgments resembled the architecture of simple economic choices: distinct regions represented emotional

  3. Emotional and Utilitarian Appraisals of Moral Dilemmas Are Encoded in Separate Areas and Integrated in Ventromedial Prefrontal Cortex.

    PubMed

    Hutcherson, Cendri A; Montaser-Kouhsari, Leila; Woodward, James; Rangel, Antonio

    2015-09-01

    Moral judgment often requires making difficult tradeoffs (e.g., is it appropriate to torture to save the lives of innocents at risk?). Previous research suggests that both emotional appraisals and more deliberative utilitarian appraisals influence such judgments and that these appraisals often conflict. However, it is unclear how these different types of appraisals are represented in the brain, or how they are integrated into an overall moral judgment. We addressed these questions using an fMRI paradigm in which human subjects provide separate emotional and utilitarian appraisals for different potential actions, and then make difficult moral judgments constructed from combinations of these actions. We found that anterior cingulate, insula, and superior temporal gyrus correlated with emotional appraisals, whereas temporoparietal junction and dorsomedial prefrontal cortex correlated with utilitarian appraisals. Overall moral value judgments were represented in an anterior portion of the ventromedial prefrontal cortex. Critically, the pattern of responses and functional interactions between these three sets of regions are consistent with a model in which emotional and utilitarian appraisals are computed independently and in parallel, and passed to the ventromedial prefrontal cortex where they are integrated into an overall moral value judgment. Significance statement: Popular accounts of moral judgment often describe it as a battle for control between two systems, one intuitive and emotional, the other rational and utilitarian, engaged in winner-take-all inhibitory competition. Using a novel fMRI paradigm, we identified distinct neural signatures of emotional and utilitarian appraisals and used them to test different models of how they compete for the control of moral behavior. Importantly, we find little support for competitive inhibition accounts. Instead, moral judgments resembled the architecture of simple economic choices: distinct regions represented emotional

  4. Amygdala Perfusion Is Predicted by Its Functional Connectivity with the Ventromedial Prefrontal Cortex and Negative Affect

    PubMed Central

    Coombs III, Garth; Loggia, Marco L.; Greve, Douglas N.; Holt, Daphne J.

    2014-01-01

    Background Previous studies have shown that the activity of the amygdala is elevated in people experiencing clinical and subclinical levels of anxiety and depression (negative affect). It has been proposed that a reduction in inhibitory input to the amygdala from the prefrontal cortex and resultant over-activity of the amygdala underlies this association. Prior studies have found relationships between negative affect and 1) amygdala over-activity and 2) reduced amygdala-prefrontal connectivity. However, it is not known whether elevated amygdala activity is associated with decreased amygdala-prefrontal connectivity during negative affect states. Methods Here we used resting-state arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in combination to test this model, measuring the activity (regional cerebral blood flow, rCBF) and functional connectivity (correlated fluctuations in the BOLD signal) of one subregion of the amygdala with strong connections with the prefrontal cortex, the basolateral nucleus (BLA), and subsyndromal anxiety levels in 38 healthy subjects. Results BLA rCBF was strongly correlated with anxiety levels. Moreover, both BLA rCBF and anxiety were inversely correlated with the strength of the functional coupling of the BLA with the caudal ventromedial prefrontal cortex. Lastly, BLA perfusion was found to be a mediator of the relationship between BLA-prefrontal connectivity and anxiety. Conclusions These results show that both perfusion of the BLA and a measure of its functional coupling with the prefrontal cortex directly index anxiety levels in healthy subjects, and that low BLA-prefrontal connectivity may lead to increased BLA activity and resulting anxiety. Thus, these data provide key evidence for an often-cited circuitry model of negative affect, using a novel, multi-modal imaging approach. PMID:24816735

  5. Successful face recognition is associated with increased prefrontal cortex activation in autism spectrum disorder.

    PubMed

    Herrington, John D; Riley, Meghan E; Grupe, Daniel W; Schultz, Robert T

    2015-04-01

    This study examines whether deficits in visual information processing in autism-spectrum disorder (ASD) can be offset by the recruitment of brain structures involved in selective attention. During functional MRI, 12 children with ASD and 19 control participants completed a selective attention one-back task in which images of faces and houses were superimposed. When attending to faces, the ASD group showed increased activation relative to control participants within multiple prefrontal cortex areas, including dorsolateral prefrontal cortex (DLPFC). DLPFC activation in ASD was associated with increased response times for faces. These data suggest that prefrontal cortex activation may represent a compensatory mechanism for diminished visual information processing abilities in ASD. PMID:25234479

  6. The role of the prefrontal cortex in controlling gender-stereotypical associations: a TMS investigation.

    PubMed

    Cattaneo, Zaira; Mattavelli, Giulia; Platania, Elisa; Papagno, Costanza

    2011-06-01

    Stereotypes associated with gender, race, ethnicity and religion are powerful forces in human social interactions. Previous neuroimaging and neuropsychological studies point to a role of the prefrontal cortex in controlling stereotypical responses. Here we used transcranial magnetic stimulation (TMS) in combination with an Implicit Association Test (IAT) to highlight the possible causal role of the left dorsolateral prefrontal cortex (DLPFC) and the right anterior dorsomedial prefrontal cortex (aDMPFC) in controlling gender-stereotypical responses. Young male and female participants were tested. Our results showed that applying TMS over the left DLPFC and the right aDMPFC increased the gender-stereotypical bias in male participants compared to when TMS was applied to a control site (vertex). This suggests that both the left DLPFC and the right aDMPFC play a direct role in stereotyping. Females did not show a significant gender bias on the IAT; correspondingly their responses were unaffected by TMS. PMID:21338690

  7. Mindful attention to breath regulates emotions via increased amygdala-prefrontal cortex connectivity.

    PubMed

    Doll, Anselm; Hölzel, Britta K; Mulej Bratec, Satja; Boucard, Christine C; Xie, Xiyao; Wohlschläger, Afra M; Sorg, Christian

    2016-07-01

    Mindfulness practice is beneficial for emotion regulation; however, the neural mechanisms underlying this effect are poorly understood. The current study focuses on effects of attention-to-breath (ATB) as a basic mindfulness practice on aversive emotions at behavioral and brain levels. A key finding across different emotion regulation strategies is the modulation of amygdala and prefrontal activity. It is unclear how ATB relevant brain areas in the prefrontal cortex integrate with amygdala activation during emotional stimulation. We proposed that, during emotional stimulation, ATB down-regulates activation in the amygdala and increases its integration with prefrontal regions. To address this hypothesis, 26 healthy controls were trained in mindfulness-based attention-to-breath meditation for two weeks and then stimulated with aversive pictures during both attention-to-breath and passive viewing while undergoing fMRI. Data were controlled for breathing frequency. Results indicate that (1) ATB was effective in regulating aversive emotions. (2) Left dorso-medial prefrontal cortex was associated with ATB in general. (3) A fronto-parietal network was additionally recruited during emotional stimulation. (4) ATB down regulated amygdala activation and increased amygdala-prefrontal integration, with such increased integration being associated with mindfulness ability. Results suggest amygdala-dorsal prefrontal cortex integration as a potential neural pathway of emotion regulation by mindfulness practice. PMID:27033686

  8. The endocannabinoid system is altered in the post-mortem prefrontal cortex of alcoholic subjects.

    PubMed

    Erdozain, Amaia M; Rubio, Marina; Valdizan, Elsa M; Pazos, Angel; Meana, J Javier; Fernández-Ruiz, Javier; Alexander, Stephen P H; Callado, Luis F

    2015-07-01

    There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non-suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non-alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences in CB1 mRNA relative expression among the four experimental groups. Conversely, our results showed an increase in CB1 receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 ± 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels of MAGL activity, regardless of the cause of death. A significant decrease in the active form of ERK and CREB levels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for the ECS in the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease. PMID:25041461

  9. Language and Memory Improvements following tDCS of Left Lateral Prefrontal Cortex

    PubMed Central

    Hussey, Erika K.; Ward, Nathan; Christianson, Kiel; Kramer, Arthur F.

    2015-01-01

    Recent research demonstrates that performance on executive-control measures can be enhanced through brain stimulation of lateral prefrontal regions. Separate psycholinguistic work emphasizes the importance of left lateral prefrontal cortex executive-control resources during sentence processing, especially when readers must override early, incorrect interpretations when faced with temporary ambiguity. Using transcranial direct current stimulation, we tested whether stimulation of left lateral prefrontal cortex had discriminate effects on language and memory conditions that rely on executive-control (versus cases with minimal executive-control demands, even in the face of task difficulty). Participants were randomly assigned to receive Anodal, Cathodal, or Sham stimulation of left lateral prefrontal cortex while they (1) processed ambiguous and unambiguous sentences in a word-by-word self-paced reading task and (2) performed an n-back memory task that, on some trials, contained interference lure items reputed to require executive-control. Across both tasks, we parametrically manipulated executive-control demands and task difficulty. Our results revealed that the Anodal group outperformed the remaining groups on (1) the sentence processing conditions requiring executive-control, and (2) only the most complex n-back conditions, regardless of executive-control demands. Together, these findings add to the mounting evidence for the selective causal role of left lateral prefrontal cortex for executive-control tasks in the language domain. Moreover, we provide the first evidence suggesting that brain stimulation is a promising method to mitigate processing demands encountered during online sentence processing. PMID:26528814

  10. Recency gets larger as lesions move from anterior to posterior locations within the ventromedial prefrontal cortex.

    PubMed

    Hochman, Guy; Yechiam, Eldad; Bechara, Antoine

    2010-11-12

    In the past two decades neuroimaging research has substantiated the important role of the prefrontal cortex (PFC) in decision-making. In the current study, we use the complementary lesion based approach to deepen our knowledge concerning the specific cognitive mechanisms modulated by prefrontal activity. Specifically, we assessed the brain substrates implicated in two decision making dimensions in a sample of prefrontal cortex patients: (a) the tendency to differently weigh recent compared to past experience; and (b) the tendency to differently weigh gains compared to losses. The participants performed the Iowa Gambling Task, a complex experience-based decision-making task, which was analyzed with a formal cognitive model (the Expectancy-Valance model). The results indicated that decisions become influenced by more recent, as opposed to older, events when the damage reaches the posterior sectors of the ventromedial prefrontal cortex (VMPC). Furthermore, the degree of this recency deficit was related to the size of the lesion. These results suggest that the posterior area of the prefrontal cortex directly modulates the capacity to use time-delayed information. In contrast, we did not find similar modulation for the sensitivity to gains versus losses. PMID:20412820

  11. Catecholamine receptors differentially mediate impulsive choice in the medial prefrontal and orbitofrontal cortex.

    PubMed

    Pardey, Margery C; Kumar, Natasha N; Goodchild, Ann K; Cornish, Jennifer L

    2013-02-01

    Impulsivity is characteristic of several mental health disorders and is largely mediated by the prefrontal cortex subregions: the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Dopamine (DA) and norepinephrine (NE) are known to modulate activity of the prefrontal cortex, however their direct role in impulsive choice is not known. The aim of the present study was to investigate the effect of microinjecting DA or NE compounds in the mPFC or OFC on impulsive choice as measured by a delayed reinforcement (DR) task in male Wistar Kyoto rats. Following training in the DR task, rats were pretreated with DA D(1) and D(2) receptor antagonists (SCH23390 3 μg/side, raclopride 3 or 6 μg/side) or NE α(1) and α(2) receptor agonists (phenylephrine 0.1 or 0.3 μg/side, guanfacine 1 or 3 μg/side, respectively) into the mPFC or OFC and the effect on impulsive behavior was assessed. Pretreatment with raclopride into the mPFC or OFC significantly increased impulsive choice, however only pretreatment with SCH23390 into the mPFC, and not the OFC, significantly increased impulsive choice. Pretreatment with the NE receptor agonists had no effect on impulsive choice. This study suggests that DA receptors, but not NE receptors, differentially mediate impulsive choice in sub-regions of the prefrontal cortex. PMID:23135240

  12. Transcranial direct current stimulation over prefrontal cortex diminishes degree of risk aversion.

    PubMed

    Ye, Hang; Chen, Shu; Huang, Daqiang; Wang, Siqi; Jia, Yongmin; Luo, Jun

    2015-06-26

    Previous studies have established that transcranial direct current stimulation (tDCS) is a powerful technique for manipulating the activity of the human cerebral cortex. Many studies have found that weighing the risks and benefits in decision-making involves a complex neural network that includes the dorsolateral prefrontal cortex (DLPFC). We studied whether participants change the balance of risky and safe responses after receiving tDCS applied over the right and left prefrontal cortex. A total of 60 healthy volunteers performed a risk task while they received either anodal tDCS over the right prefrontal cortex, with cathodal over the left; anodal tDCS over the left prefrontal cortex, with cathodal over the right; or sham stimulation. The participants tended to choose less risky options after receiving sham stimulation, demonstrating that the task might be highly influenced by the "wealth effect". There was no statistically significant change after either right anodal/left cathodal or left anodal/right cathodal tDCS, indicating that both types of tDCS impact the participants' degrees of risk aversion, and therefore, counteract the wealth effect. We also found gender differences in the participants' choices. These findings extend the notion that DLPFC activity is critical for risk decision-making. Application of tDCS to the right/left DLPFC may impact a person's attitude to taking risks. PMID:25956033

  13. Impaired Cognition after Stimulation of P2Y1 Receptors in the Rat Medial Prefrontal Cortex

    PubMed Central

    Koch, Holger; Bespalov, Anton; Drescher, Karla; Franke, Heike; Krügel, Ute

    2015-01-01

    We hypothesize that cortical ATP and ADP accumulating in the extracellular space, eg during prolonged network activity, contribute to a decline in cognitive performance in particular via stimulation of the G protein-coupled P2Y1 receptor (P2Y1R) subtype. Here, we report first evidence on P2Y1R-mediated control of cognitive functioning in rats using bilateral microinfusions of the selective agonist MRS2365 into medial prefrontal cortex (mPFC). MRS2365 attenuated prepulse inhibition of the acoustic startle reflex while having no impact on startle amplitude. Stimulation of P2Y1Rs deteriorated performance accuracy in the delayed non-matching to position task in a delay dependent manner and increased the rate of magazine entries consistent with both working memory disturbances and impaired impulse control. Further, MRS2365 significantly impaired performance in the reversal learning task. These effects might be related to MRS2365-evoked increase of dopamine observed by microdialysis to be short-lasting in mPFC and long-lasting in the nucleus accumbens. P2Y1Rs were identified on pyramidal cells and parvalbumin-positive interneurons, but not on tyrosine hydroxylase-positive fibers, which argues for an indirect activation of dopaminergic afferents in the cortex by MRS2365. Collectively, these results suggest that activation of P2Y1Rs in the mPFC impairs inhibitory control and behavioral flexibility mediated by increased mesocorticolimbic activity and local disinhibition. PMID:25027332

  14. Post-traumatic stress disorder: The role of medial prefrontal cortex and amygdala

    PubMed Central

    Koenigs, Michael; Grafman, Jordan

    2009-01-01

    Post-traumatic stress disorder (PTSD) is characterized by recurrent distressing memories of an emotionally traumatic event. In this review, we present neuroscientific data highlighting the function of two brain areas—the amygdala and ventromedial prefrontal cortex (vmPFC)—in PTSD and related emotional processes. A convergent body of human and non-human studies suggests that the amygdala mediates the acquisition and expression of conditioned fear and the enhancement of emotional memory, whereas the vmPFC mediates the extinction of conditioned fear and the volitional regulation of negative emotion. It has been theorized that the vmPFC exerts inhibition on the amygdala, and that a defect in this inhibition could account for the symptoms of PTSD. This theory is supported by functional imaging studies of PTSD patients, who exhibit hypoactivity in vmPFC but hyperactivity in amygdala. A recent study of brain-injured and trauma-exposed combat veterans confirms that amygdala damage reduces the likelihood of developing PTSD. But contrary to the prediction of the top-down inhibition model, vmPFC damage also reduces the likelihood of developing PTSD. The putative roles of amygdala and vmPFC in the pathophysiology of PTSD, as well as implications for potential treatments, are discussed in light of these results. PMID:19359671

  15. Sustained Attentional States Require Distinct Temporal Involvement of the Dorsal and Ventral Medial Prefrontal Cortex

    PubMed Central

    Luchicchi, Antonio; Mnie-Filali, Ouissame; Terra, Huub; Bruinsma, Bastiaan; de Kloet, Sybren F.; Obermayer, Joshua; Heistek, Tim S.; de Haan, Roel; de Kock, Christiaan P. J.; Deisseroth, Karl; Pattij, Tommy; Mansvelder, Huibert D.

    2016-01-01

    Attending the sensory environment for cue detection is a cognitive operation that occurs on a time scale of seconds. The dorsal and ventral medial prefrontal cortex (mPFC) contribute to separate aspects of attentional processing. Pyramidal neurons in different parts of the mPFC are active during cognitive behavior, yet whether this activity is causally underlying attentional processing is not known. We aimed to determine the precise temporal requirements for activation of the mPFC subregions during the seconds prior to cue detection. To test this, we used optogenetic silencing of dorsal or ventral mPFC pyramidal neurons at defined time windows during a sustained attentional state. We find that the requirement of ventral mPFC pyramidal neuron activity is strictly time-locked to stimulus detection. Inhibiting the ventral mPFC 2 s before or during cue presentation reduces response accuracy and hampers behavioral inhibition. The requirement for dorsal mPFC activity on the other hand is temporally more loosely related to a preparatory attentional state, and short lapses in pyramidal neuron activity in dorsal mPFC do not affect performance. This only occurs when the dorsal mPFC is inhibited during the entire preparatory period. Together, our results reveal that a dissociable temporal recruitment of ventral and dorsal mPFC is required during attentional processing.

  16. Norepinephrine Drives Persistent Activity in Prefrontal Cortex via Synergistic α1 and α2 Adrenoceptors

    PubMed Central

    Jego, Sonia; Adamantidis, Antoine; Séguéla, Philippe

    2013-01-01

    Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons. PMID:23785477

  17. Mindfulness training modulates value signals in ventromedial prefrontal cortex through input from insular cortex

    PubMed Central

    Kirk, Ulrich; Gu, Xiaosi; Harvey, Ann H.; Fonagy, Peter; Montague, P. Read

    2014-01-01

    Neuroimaging research has demonstrated that ventromedial prefrontal cortex (vmPFC) encodes value signals that can be modulated by top-down cognitive input such as semantic knowledge, price incentives, and monetary favors suggesting that such biases may have an identified biological basis. It has been hypothesized that mindfulness training (MT) provides one path for gaining control over such top-down influences; yet, there have been no direct tests of this hypothesis. Here, we probe the behavioral and neural effects of MT on value signals in vmPFC in a randomized longitudinal design of 8 weeks of MT on an initially naïve subject cohort. The impact of this within-subject training was assessed using two paradigms: one that employed primary rewards (fruit juice) in a simple conditioning task and another that used a well-validated art-viewing paradigm to test bias of monetary favors on preference. We show that MT behaviorally censors the top-down bias of monetary favors through a measurable influence on value signals in vmPFC. MT also modulates value signals in vmPFC to primary reward delivery. Using a separate cohort of subjects we show that 8 weeks of active control training (ACT) generates the same behavioral impact also through an effect on signals in the vmPFC. Importantly, functional connectivity analyses show that value signals in vmPFC are coupled with bilateral posterior insula in the MT groups in both paradigms, but not in the ACT groups. These results suggest that MT integrates interoceptive input from insular cortex in the context of value computations of both primary and secondary rewards. PMID:24956066

  18. Chronic Treatment with a Clinically Relevant Dose of Methylphenidate Increases Glutamate Levels in Cerebrospinal Fluid and Impairs Glutamatergic Homeostasis in Prefrontal Cortex of Juvenile Rats.

    PubMed

    Schmitz, Felipe; Pierozan, Paula; Rodrigues, André F; Biasibetti, Helena; Coelho, Daniella M; Mussulini, Ben Hur; Pereira, Mery S L; Parisi, Mariana M; Barbé-Tuana, Florencia; de Oliveira, Diogo L; Vargas, Carmen R; Wyse, Angela T S

    2016-05-01

    The understanding of the consequences of chronic treatment with methylphenidate is very important since this psychostimulant is extensively prescribed to preschool age children, and little is known about the mechanisms underlying the persistent changes in behavior and neuronal function related with the use of methylphenidate. In this study, we initially investigate the effect of early chronic treatment with methylphenidate on amino acids profile in cerebrospinal fluid and prefrontal cortex of juvenile rats, as well as on glutamatergic homeostasis, Na(+),K(+)-ATPase function, and balance redox in prefrontal cortex of rats. Wistar rats at early age received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9 % saline solution (controls), once a day, from the 15th to the 45th day of age. Twenty-four hours after the last injection, the animals were decapitated and the cerebrospinal fluid and prefrontal cortex were obtained. Results showed that methylphenidate altered amino acid profile in cerebrospinal fluid, increasing the levels of glutamate. Glutamate uptake was decreased by methylphenidate administration, but GLAST and GLT-1 were not altered by this treatment. In addition, the astrocyte marker GFAP was not altered by MPH. The activity and immunocontent of catalytic subunits (α1, α2, and α3) of Na(+),K(+)-ATPase were decreased in prefrontal cortex of rats subjected to methylphenidate treatment, as well as changes in α1 and α2 gene expression of catalytic α subunits of Na(+),K(+)-ATPase were also observed. CAT activity was increased and SOD/CAT ratio and sulfhydryl content were decreased in rat prefrontal cortex. Taken together, our results suggest that chronic treatment with methylphenidate at early age induces excitotoxicity, at least in part, due to inhibition of glutamate uptake probably caused by disturbances in the Na(+),K(+)-ATPase function and/or in protein damage observed in the prefrontal cortex. PMID:26001762

  19. Early detection and late cognitive control of emotional distraction by the prefrontal cortex

    PubMed Central

    García-Pacios, Javier; Garcés, Pilar; Del Río, David; Maestú, Fernando

    2015-01-01

    Unpleasant emotional distraction can impair the retention of non-emotional information in working memory (WM). Research links the prefrontal cortex with the successful control of such biologically relevant distractors, although the temporal changes in this brain mechanism remain unexplored. We use magnetoencephalography to investigate the temporal dynamics of the cognitive control of both unpleasant and pleasant distraction, in the millisecond (ms) scale. Behavioral results demonstrate that pleasant events do not affect WM maintenance more than neutral ones. Neuroimaging results show that prefrontal cortices are recruited for the rapid detection of emotional distraction, at early latencies of the processing (70-130 ms). Later in the processing (360-450 ms), the dorsolateral, the medial and the orbital sections of the prefrontal cortex mediate the effective control of emotional distraction. In accordance with the behavioral performance, pleasant distractors do not require higher prefrontal activity than neutral ones. These findings extend our knowledge about the brain mechanisms of coping with emotional distraction in WM. In particular, they show for the first time that overriding the attentional capture triggered by emotional distractors, while maintaining task-relevant elements in mind, is based on the early detection of such linked-to-survival information and on its later cognitive control by the prefrontal cortex. PMID:26067780

  20. Lower neuronal variability in the monkey dorsolateral prefrontal than posterior parietal cortex.

    PubMed

    Qi, Xue-Lian; Constantinidis, Christos

    2015-10-01

    The dorsolateral prefrontal and posterior parietal cortex are two brain areas involved in cognitive functions such as spatial attention and working memory. When tested with identical tasks, only subtle differences in firing rate are present between neurons recorded in the two areas. In this article we report that major differences in neuronal variability characterize the two areas during working memory. The Fano factors of spike counts in dorsolateral prefrontal neurons were consistently lower than those of the posterior parietal cortex across a range of tasks, epochs, and conditions in the same monkeys. Variability differences were observed despite minor differences in firing rates between the two areas in the tasks tested and higher overall firing rate in the prefrontal than in the posterior parietal sample. Other measures of neuronal discharge variability, such as the coefficient of variation of the interspike interval, displayed the same pattern of lower prefrontal variability. Fano factor values were negatively correlated with performance in the working memory task, suggesting that higher neuronal variability was associated with diminished task performance. The results indicate that information involving remembered stimuli is more reliably represented in the prefrontal than the posterior parietal cortex based on the variability of neuronal responses, and suggest functional differentiation between the two areas beyond differences in firing rate. PMID:26269556

  1. Lateralized effect of rapid-rate transcranial magnetic stimulation of the prefrontal cortex on mood.

    PubMed

    Pascual-Leone, A; Catalá, M D; Pascual-Leone Pascual, A

    1996-02-01

    We studied the effects of rapid-rate transcranial magnetic stimulation (rTMS) of different scalp positions on mood. Ten normal volunteers rated themselves before and after rTMS on five analog scales labeled "Tristeza" (Sadness), "Ansiedad" (Anxiety), "Alegria" (Happiness), "Cansancio" (Tiredness), and "Dolor/Malestar" (Pain/Discomfort). rTMS was applied to the right lateral prefrontal, left prefrontal, or midline frontal cortex in trains of 5 seconds' duration at 10 Hz and 110% of the subject's motor threshold intensity. Each stimulation position received 10 trains separated by a 25-second pause. No clinically apparent mood changes were evoked by rTMS to any of the scalp positions in any subject. However, left prefrontal rTMS resulted in a significant increase in the Sadness ratings (Tristeza) and a significant decrease in the Happiness ratings ("Alegria") as compared with right prefrontal and midfrontal cortex stimulation. These results show differential effects of rTMS of left and right prefrontal cortex stimulation on mood and illustrate the lateralized control of mood in normal volunteers. PMID:8614521

  2. Anatomical insights into the interaction of emotion and cognition in the prefrontal cortex

    PubMed Central

    Ray, Rebecca; Zald, David H.

    2011-01-01

    Ray, R. and D. Zald. Anatomical insights into the interaction of emotion and cognition in the prefrontal cortex. NEUROSCI BIOBEHAV REV 36(X) XXX-XXX, 2011. -Psychological research increasingly indicates that emotional processes interact with other aspects of cognition. Studies have demonstrated both the ability of emotional stimuli to influence a broad range of cognitive operations, and the ability of humans to use top-down cognitive control mechanisms to regulate emotional responses. Portions of the prefrontal cortex appear to play a significant role in these interactions. However, the manner in which these interactions are implemented remains only partially elucidated. In the present review we describe the anatomical connections between ventral and dorsal prefrontal areas as well as their connections with limbic regions. Only a subset of prefrontal areas are likely to directly influence amygdalar processing, and as such models of prefrontal control of emotions and models of emotional regulation should be constrained to plausible pathways of influence. We also focus on how the specific pattern of feedforward and feedback connections between these regions may dictate the nature of information flow between ventral and dorsal prefrontal areas and the amygdala. These patterns of connections are inconsistent with several commonly expressed assumptions about the nature of communications between emotion and cognition. PMID:21889953

  3. Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function

    PubMed Central

    Butts, Kelly A.; Weinberg, Joanne; Young, Allan H.; Phillips, Anthony G.

    2011-01-01

    Enhanced dopamine efflux in the prefrontal cortex is a well-documented response to acute stress. However, the underlying mechanism(s) for this response is unknown. Using in vivo microdialysis, we demonstrate that blocking glucocorticoid receptors locally within the rat prefrontal cortex results in a reduction in stress-evoked dopamine efflux. In contrast, blocking glucocorticoid receptors in the ventral tegmental area did not affect stress-evoked dopamine efflux in the prefrontal cortex. Additionally, local administration of corticosterone into the prefrontal cortex increased prefrontal dopamine efflux. The functional impact of enhanced dopamine efflux evoked by acute stress was demonstrated using a cognitive task dependent on the prefrontal cortex and sensitive to impairment in working memory. Notably, stress-induced impairments in cognition were attenuated by blockade of glucocorticoid receptors in the prefrontal cortex. Taken together, these data demonstrate that glucocorticoids act locally within the prefrontal cortex to modulate mesocortical dopamine efflux leading to the cognitive impairments observed during acute stress. PMID:22032926

  4. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls

    NASA Technical Reports Server (NTRS)

    Akbarian, S.; Huntsman, M. M.; Kim, J. J.; Tafazzoli, A.; Potkin, S. G.; Bunney, W. E. Jr; Jones, E. G.; Bloom, F. E. (Principal Investigator)

    1995-01-01

    The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of

  5. Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex.

    PubMed

    Rotaru, Diana C; Olezene, Cameron; Miyamae, Takeaki; Povysheva, Nadezhda V; Zaitsev, Aleksey V; Lewis, David A; Gonzalez-Burgos, Guillermo

    2015-03-15

    In rodent cortex GABAA receptor (GABAAR)-mediated synapses are a significant source of input onto GABA neurons, and the properties of these inputs vary among GABA neuron subtypes that differ in molecular markers and firing patterns. Some features of cortical interneurons are different between rodents and primates, but it is not known whether inhibition of GABA neurons is prominent in the primate cortex and, if so, whether these inputs show heterogeneity across GABA neuron subtypes. We thus studied GABAAR-mediated miniature synaptic events in GABAergic interneurons in layer 3 of monkey dorsolateral prefrontal cortex (DLPFC). Interneurons were identified on the basis of their firing pattern as fast spiking (FS), regular spiking (RS), burst spiking (BS), or irregular spiking (IS). Miniature synaptic events were common in all of the recorded interneurons, and the frequency of these events was highest in FS neurons. The amplitude and kinetics of miniature inhibitory postsynaptic potentials (mIPSPs) also differed between DLPFC interneuron subtypes in a manner correlated with their input resistance and membrane time constant. FS neurons had the fastest mIPSP decay times and the strongest effects of the GABAAR modulator zolpidem, suggesting that the distinctive properties of inhibitory synaptic inputs onto FS cells are in part conferred by GABAARs containing α1 subunits. Moreover, mIPSCs differed between FS and RS interneurons in a manner consistent with the mIPSP findings. These results show that in the monkey DLPFC GABAAR-mediated synaptic inputs are prominent in layer 3 interneurons and may differentially regulate the activity of different interneuron subtypes. PMID:25540225

  6. Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons.

    PubMed

    Konstantoudaki, X; Chalkiadaki, K; Tivodar, S; Karagogeos, D; Sidiropoulou, K

    2016-05-13

    Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ∼50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period. PMID:26926965

  7. Exercise-induced stress resistance is independent of exercise controllability and the medial prefrontal cortex.

    PubMed

    Greenwood, Benjamin N; Spence, Katie G; Crevling, Danielle M; Clark, Peter J; Craig, Wendy C; Fleshner, Monika

    2013-02-01

    Exercise increases resistance against stress-related disorders such as anxiety and depression. Similarly, the perception of control is a powerful predictor of neurochemical and behavioral responses to stress, but whether the experience of choosing to exercise, and exerting control over that exercise, is a critical factor in producing exercise-induced stress resistance is unknown. The current studies investigated whether the protective effects of exercise against the anxiety- and depression-like consequences of stress are dependent on exercise controllability and a brain region implicated in the protective effects of controllable experiences, the medial prefrontal cortex. Adult male Fischer 344 rats remained sedentary, were forced to run on treadmills or motorised running wheels, or had voluntary access to wheels for 6 weeks. Three weeks after exercise onset, rats received sham surgery or excitotoxic lesions of the medial prefrontal cortex. Rats were exposed to home cage or uncontrollable tail shock treatment three weeks later. Shock-elicited fear conditioning and shuttle box escape testing occurred the next day. Both forced and voluntary wheel running, but not treadmill training, prevented the exaggerated fear conditioning and interference with escape learning produced by uncontrollable stress. Lesions of the medial prefrontal cortex failed to eliminate the protective effects of forced or voluntary wheel running. These data suggest that exercise controllability and the medial prefrontal cortex are not critical factors in conferring the protective effects of exercise against the affective consequences of stressor exposure, and imply that exercise perceived as forced may still benefit affect and mental health. PMID:23121339

  8. Prefrontal Cortex: Role in Acquisition of Overlapping Associations and Transitive Inference

    ERIC Educational Resources Information Center

    DeVito, Loren M.; Lykken, Christine; Kanter, Benjamin R.; Eichenbaum, Howard

    2010-01-01

    "Transitive inference" refers to the ability to judge from memory the relationships between indirectly related items that compose a hierarchically organized series, and this capacity is considered a fundamental feature of relational memory. Here we explored the role of the prefrontal cortex in transitive inference by examining the performance of…

  9. Attention, Emotion, and Deactivation of Default Activity in Inferior Medial Prefrontal Cortex

    ERIC Educational Resources Information Center

    Geday, Jacob; Gjedde, Albert

    2009-01-01

    Attention deactivates the inferior medial prefrontal cortex (IMPC), but it is uncertain if emotions can attenuate this deactivation. To test the extent to which common emotions interfere with attention, we measured changes of a blood flow index of brain activity in key areas of the IMPC with positron emission tomography (PET) of labeled water…

  10. Orbital and Ventromedial Prefrontal Cortex Functioning in Parkinson's Disease: Neuropsychological Evidence

    ERIC Educational Resources Information Center

    Poletti, Michele; Bonuccelli, Ubaldo

    2012-01-01

    A recent paper (Zald & Andreotti, 2010) reviewed neuropsychological tasks that assess the function of the orbital and ventromedial portions of the prefrontal cortex (OMPFC). Neuropathological studies have shown that the function of the OMPFC should be preserved in the early stages of Parkinson's disease (PD) but becomes affected in the advanced…

  11. Prefrontal Cortex Lesions and Sex Differences in Fear Extinction and Perseveration

    ERIC Educational Resources Information Center

    Baran, Sarah E.; Armstrong, Charles E.; Niren, Danielle C.; Conrad, Cheryl D.

    2010-01-01

    Electrolytic lesions of the medial prefrontal cortex (PFCX) were examined using fear conditioning to assess the recall of fear extinction and performance in the Y-maze, open field, and object location/recognition in male and female Sprague-Dawley rats. Rats were conditioned to seven tone/footshocks, followed by extinction after 1-h and 24-h…

  12. Hippocampal Train Stimulation Modulates Recall of Fear Extinction Independently of Prefrontal Cortex Synaptic Plasticity and Lesions

    ERIC Educational Resources Information Center

    Garcia, Rene; Farinelli, Melissa; Deschaux, Olivier; Hugues, Sandrine; Thevenet, Aurelie

    2006-01-01

    It has been shown that long-term potentiation (LTP) develops in the connection between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) and between the hippocampus (HPC) and the mPFC following fear extinction, and correlates with extinction retention. However, recent lesion studies have shown that combined lesions of the MD…

  13. Role of Medial Prefrontal Cortex Narp in the Extinction of Morphine Conditioned Place Preference

    ERIC Educational Resources Information Center

    Blouin, Ashley M.; Han, Sungho; Pearce, Anne M.; Cheng, KaiLun; Lee, JongAh J.; Johnson, Alexander W.; Wang, Chuansong; During, Matthew J.; Holland, Peter C.; Shaham, Yavin; Baraban, Jay M.; Reti, Irving M.

    2013-01-01

    Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus…

  14. MEDIAL PREFRONTAL CORTEX LESIONS AND SPATIAL DELAYED ALTERNATION IN THE RAT: RECOVERY OR SPARING?

    EPA Science Inventory

    In Experiment 1, Long-Evans rat pups received medial prefrontal cortex (PFC) aspirations or sham surgery on Postnatal Day 10 (PND10) and were then trained on PND23 to perform one of two T-maze tasks: iscrete-trials delayed alternation (DA) or simple position discrimination (PD). ...

  15. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

    ERIC Educational Resources Information Center

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory…

  16. Reduced Prefrontal Cortex Hemodynamic Response in Adults with Methamphetamine Induced Psychosis: Relevance for Impulsivity.

    PubMed

    Yamamuro, Kazuhiko; Kimoto, Sohei; Iida, Junzo; Kishimoto, Naoko; Nakanishi, Yoko; Tanaka, Shohei; Ota, Toyosaku; Makinodan, Manabu; Kishimoto, Toshifumi

    2016-01-01

    Patients with methamphetamine abuse/dependence often exhibit high levels of impulsivity, which may be associated with the structural abnormalities and functional hypoactivities observed in the frontal cortex of these subjects. Although near-infrared spectroscopy (NIRS) is a simple and non-invasive method for characterizing the clinical features of various psychiatric illnesses, few studies have used NIRS to directly investigate the association between prefrontal cortical activity and inhibitory control in patients with methamphetamine-induced psychosis (MAP). Using a 24-channel NIRS system, we compared hemodynamic responses during the Stroop color-word task in 14 patients with MAP and 21 healthy controls matched for age, sex and premorbid IQ. In addition, we used the Barrett Impulsivity Scale-11 (BIS-11) to assess impulsivity between subject groups. The MAP group exhibited significantly less activation in the anterior and frontopolar prefrontal cortex accompanied by lower Stroop color-word task performance, compared with controls. Moreover, BIS-11 scores were significantly higher in the MAP group, and were negatively correlated with the hemodynamic responses in prefrontal cortex. Our data suggest that reduced hemodynamic responses in the prefrontal cortex might reflect higher levels of impulsivity in patients with MAP, providing new insights into disrupted inhibitory control observed in MAP. PMID:27050450

  17. Disruption of the Perineuronal Net in the Hippocampus or Medial Prefrontal Cortex Impairs Fear Conditioning

    ERIC Educational Resources Information Center

    Hylin, Michael J.; Orsi, Sara A.; Moore, Anthony N.; Dash, Pramod K.

    2013-01-01

    The perineuronal net (PNN) surrounds neurons in the central nervous system and is thought to regulate developmental plasticity. A few studies have shown an involvement of the PNN in hippocampal plasticity and memory storage in adult animals. In addition to the hippocampus, plasticity in the medial prefrontal cortex (mPFC) has been demonstrated to…

  18. Prefrontal Cortex and Hippocampus Subserve Different Components of Working Memory in Rats

    ERIC Educational Resources Information Center

    Yoon, Taejib; Okada, Jeffrey; Jung, Min W.; Kim, Jeansok J.

    2008-01-01

    Both the medial prefrontal cortex (mPFC) and hippocampus are implicated in working memory tasks in rodents. Specifically, it has been hypothesized that the mPFC is primarily engaged in the temporary storage and processing of information lasting from a subsecond to several seconds, while the hippocampal function becomes more critical as the working…

  19. Hippocampus and Medial Prefrontal Cortex Contributions to Trace and Contextual Fear Memory Expression over Time

    ERIC Educational Resources Information Center

    Beeman, Christopher L.; Bauer, Philip S.; Pierson, Jamie L.; Quinn, Jennifer J.

    2013-01-01

    Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion…

  20. The Neuropsychology of Ventral Prefrontal Cortex: Decision-Making and Reversal Learning

    ERIC Educational Resources Information Center

    Clark, L.; Cools, R.; Robbins, T. W.

    2004-01-01

    Converging evidence from human lesion, animal lesion, and human functional neuroimaging studies implicates overlapping neural circuitry in ventral prefrontal cortex in decision-making and reversal learning. The ascending 5-HT and dopamine neurotransmitter systems have a modulatory role in both processes. There is accumulating evidence that…

  1. Performance-Related Activity in Medial Rostral Prefrontal Cortex (Area 10) during Low-Demand Tasks

    ERIC Educational Resources Information Center

    Gilbert, Sam J.; Simons, Jon S.; Frith, Christopher D.; Burgess, Paul W.

    2006-01-01

    Neuroimaging studies have frequently observed relatively high activity in medial rostral prefrontal cortex (PFC) during rest or baseline conditions. Some accounts have attributed this high activity to the occurrence of unconstrained stimulus-independent and task-unrelated thought processes during baseline conditions. Here, the authors investigated…

  2. Medial Prefrontal Cortex Is Selectively Involved in Response Selection Using Visual Context in the Background

    ERIC Educational Resources Information Center

    Lee, Inah; Shin, Ji Yun

    2012-01-01

    The exact roles of the medial prefrontal cortex (mPFC) in conditional choice behavior are unknown and a visual contextual response selection task was used for examining the issue. Inactivation of the mPFC severely disrupted performance in the task. mPFC inactivations, however, did not disrupt the capability of perceptual discrimination for visual…

  3. Selection for Position: The Role of Left Ventrolateral Prefrontal Cortex in Sequencing Language

    ERIC Educational Resources Information Center

    Thothathiri, Malathi; Schwartz, Myrna F.; Thompson-Schill, Sharon L.

    2010-01-01

    Patients with damage involving left ventrolateral prefrontal cortex (left VLPFC) often show syntactic deficits. They also show exaggerated interference effects during a variety of non-syntactic tasks, including picture naming and working memory. Conceivably, both deficits could arise from inadequate biasing of competitive interactions during…

  4. Reduced Prefrontal Cortex Hemodynamic Response in Adults with Methamphetamine Induced Psychosis: Relevance for Impulsivity

    PubMed Central

    Yamamuro, Kazuhiko; Kimoto, Sohei; Iida, Junzo; Kishimoto, Naoko; Nakanishi, Yoko; Tanaka, Shohei; Ota, Toyosaku; Makinodan, Manabu; Kishimoto, Toshifumi

    2016-01-01

    Patients with methamphetamine abuse/dependence often exhibit high levels of impulsivity, which may be associated with the structural abnormalities and functional hypoactivities observed in the frontal cortex of these subjects. Although near-infrared spectroscopy (NIRS) is a simple and non-invasive method for characterizing the clinical features of various psychiatric illnesses, few studies have used NIRS to directly investigate the association between prefrontal cortical activity and inhibitory control in patients with methamphetamine-induced psychosis (MAP). Using a 24-channel NIRS system, we compared hemodynamic responses during the Stroop color-word task in 14 patients with MAP and 21 healthy controls matched for age, sex and premorbid IQ. In addition, we used the Barrett Impulsivity Scale-11 (BIS-11) to assess impulsivity between subject groups. The MAP group exhibited significantly less activation in the anterior and frontopolar prefrontal cortex accompanied by lower Stroop color-word task performance, compared with controls. Moreover, BIS-11 scores were significantly higher in the MAP group, and were negatively correlated with the hemodynamic responses in prefrontal cortex. Our data suggest that reduced hemodynamic responses in the prefrontal cortex might reflect higher levels of impulsivity in patients with MAP, providing new insights into disrupted inhibitory control observed in MAP. PMID:27050450

  5. Abnormal Amygdala and Prefrontal Cortex Activation to Facial Expressions in Pediatric Bipolar Disorder

    ERIC Educational Resources Information Center

    Garrett, Amy S.; Reiss, Allan L.; Howe, Meghan E.; Kelley, Ryan G.; Singh, Manpreet K.; Adleman, Nancy E.; Karchemskiy, Asya; Chang, Kiki D.

    2012-01-01

    Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late…

  6. Effect of Prefrontal Cortex Damage on Resolving Lexical Ambiguity in Text

    ERIC Educational Resources Information Center

    Frattali, Carol; Hanna, Rebecca; McGinty, Anita Shukla; Gerber, Lynn; Wesley, Robert; Grafman, Jordan; Coelho, Carl

    2007-01-01

    The function of suppression of context-inappropriate meanings during lexical ambiguity resolution was examined in 25 adults with prefrontal cortex damage (PFCD) localized to the left (N = 8), right (N = 6), or bilaterally (N = 11); and 21 matched Controls. Results revealed unexpected inverse patterns of suppression between PFCD and Control groups,…

  7. Prefrontal Cortex Is Critical for Contextual Processing: Evidence from Brain Lesions

    ERIC Educational Resources Information Center

    Fogelson, Noa; Shah, Mona; Scabini, Donatella; Knight, Robert T.

    2009-01-01

    We investigated the role of prefrontal cortex (PFC) in local contextual processing using a combined event-related potentials and lesion approach. Local context was defined as the occurrence of a short predictive series of visual stimuli occurring before delivery of a target event. Targets were preceded by either randomized sequences of standards…

  8. Social and Nonsocial Functions of Rostral Prefrontal Cortex: Implications for Education

    ERIC Educational Resources Information Center

    Gilbert, Sam J.; Burgess, Paul W.

    2008-01-01

    In this article, we discuss the role of rostral prefrontal cortex (approximating Brodmann Area 10) in two domains relevant to education: executive function (particularly prospective memory, our ability to realize delayed intentions) and social cognition (particularly our ability to reflect on our own mental states and the mental states of others).…

  9. Controllability modulates the anticipatory response in the human ventromedial prefrontal cortex.

    PubMed

    Kerr, Deborah L; McLaren, Donald G; Mathy, Robin M; Nitschke, Jack B

    2012-01-01

    Research has consistently shown that control is critical to psychological functioning, with perceived lack of control considered to play a crucial role in the manifestation of symptoms in psychiatric disorders. In a model of behavioral control based on non-human animal work, Maier et al. (2006) posited that the presence of control activates areas of the ventromedial prefrontal cortex (vmPFC), which in turn inhibit the normative stress response in the dorsal raphe nucleus and amygdala. To test Maier's model in humans, we investigated the effects of control over potent aversive stimuli by presenting video clips of snakes to 21 snake phobics who were otherwise healthy with no comorbid psychopathologies. Based on prior research documenting that disrupted neural processing during the anticipation of adverse events can be influenced by different forms of cognitive processing such as perceptions of control, analyses focused on the anticipatory activity preceding the videos. We found that phobics exhibited greater vmPFC activity during the anticipation of snake videos when they had control over whether the videos were presented as compared to when they had no control over the presentation of the videos. In addition, observed functional connectivity between the vmPFC and the amygdala is consistent with previous work documenting vmPFC inhibition of the amygdala. Our results provide evidence to support the extension of Maier's model of behavioral control to include anticipatory function in humans. PMID:23550176

  10. Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception.

    PubMed

    Jurik, Angela; Auffenberg, Eva; Klein, Sabine; Deussing, Jan M; Schmid, Roland M; Wotjak, Carsten T; Thoeringer, Christoph K

    2015-12-01

    Visceral pain represents a major clinical challenge in the management of many gastrointestinal disorders, eg, pancreatitis. However, cerebral neurobiological mechanisms underlying visceral nociception are poorly understood. As a representative model of visceral nociception, we applied cerulein hyperstimulation in C57BL6 mice to induce acute pancreatitis and performed a behavioral test battery and c-Fos staining of brains. We observed a specific pain phenotype and a significant increase in c-Fos immunoreactivity in the paraventricular nucleus of the thalamus (PVT), the periaqueductal gray, and the medial prefrontal cortex (mPFC). Using neuronal tracing, we observed projections of the PVT to cortical layers of the mPFC with contacts to inhibitory GABAergic neurons. These inhibitory neurons showed more activation after cerulein treatment suggesting thalamocortical "feedforward inhibition" in visceral nociception. The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by designer receptors exclusively activated by designer drugs, selectively and cell type specifically expressed in target neurons using adeno-associated virus-mediated gene transfer. Pharmacogenetic inhibition of PVT but not periaqueductal gray neurons attenuated visceral pain and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception. These data reveal novel insights into central pain processing that underlies visceral nociception and may trigger the development of novel, potent centrally acting analgesic drugs. PMID:26262826

  11. Na(+), K(+)-ATPase dysfunction causes cerebrovascular endothelial cell degeneration in rat prefrontal cortex slice cultures.

    PubMed

    Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Katsuki, Hiroshi

    2016-08-01

    Cerebrovascular endothelial cell dysfunction resulting in imbalance of cerebral blood flow contributes to the onset of psychiatric disorders such as depression, schizophrenia and bipolar disorder. Although decrease in Na(+), K(+)-ATPase activity has been reported in the patients with schizophrenia and bipolar disorder, the contribution of Na(+), K(+)-ATPase to endothelial cell dysfunction remains poorly understood. Here, by using rat neonatal prefrontal cortex slice cultures, we demonstrated that pharmacological inhibition of Na(+), K(+)-ATPase by ouabain induced endothelial cell injury. Treatment with ouabain significantly decreased immunoreactive area of rat endothelial cell antigen-1 (RECA-1), a marker of endothelial cells, in a time-dependent manner. Ouabain also decreased Bcl-2/Bax ratio and phosphorylation level of glycogen synthase kinase 3β (GSK3β) (Ser9), which were prevented by lithium carbonate. On the other hand, ouabain-induced endothelial cell injury was exacerbated by concomitant treatment with LY294002, an inhibitor of phosphoinositide 3- (PI3-) kinase. We also found that xestospongin C, an inhibitor of inositol triphosphate (IP3) receptor, but not SEA0400, an inhibitor of Na(+), Ca(2+) exchanger (NCX), protected endothelial cells from cytotoxicity of ouabain. These results suggest that cerebrovascular endothelial cell degeneration induced by Na(+), K(+)-ATPase inhibition resulting in Ca(2+) release from endoplasmic reticulum (ER) and activation of GSK3β signaling underlies pathogenesis of these psychiatric disorders. PMID:27208492

  12. Children with High Functioning Autism show increased prefrontal and temporal cortex activity during error monitoring

    PubMed Central

    Goldberg, Melissa C.; Spinelli, Simona; Joel, Suresh; Pekar, James J.; Denckla, Martha B.; Mostofsky, Stewart H.

    2010-01-01

    Evidence exists for deficits in error monitoring in autism. These deficits may be particularly important because they may contribute to excessive perseveration and repetitive behavior in autism. We examined the neural correlates of error monitoring using fMRI in 8–12-year-old children with high-functioning autism (HFA, n=11) and typically developing children (TD, n=15) during performance of a Go/No-Go task by comparing the neural correlates of commission errors versus correct response inhibition trials. Compared to TD children, children with HFA showed increased BOLD fMRI signal in the anterior medial prefrontal cortex (amPFC) and the left superior temporal gyrus (STempG) during commission error (versus correct inhibition) trials. A follow-up region-of-interest analysis also showed increased BOLD signal in the right insula in HFA compared to TD controls. Our findings of increased amPFC and STempG activity in HFA, together with the increased activity in the insula, suggest a greater attention towards the internally-driven emotional state associated with making an error in children with HFA. Since error monitoring occurs across different cognitive tasks throughout daily life, an increased emotional reaction to errors may have important consequences for early learning processes. PMID:21151713

  13. Lesions of the Medial Prefrontal Cortex Abolish Conditioned Aversion Associated with Sexual Behavior in Male Rats

    PubMed Central

    Davis, Jon F.; Loos, Maarten; Di Sebastiano, Andrea R.; Brown, Jennifer L.; Lehman, Michael N.; Coolen, Lique M.

    2010-01-01

    BACKGROUND An inability to inhibit behaviors once they become maladaptive is a component of several psychiatric illnesses and the medial prefrontal cortex (mPFC) was identified as a potential mediator of behavioral inhibition. The current study tested if the mPFC is involved in inhibition of sexual behavior when associated with aversive outcomes. METHODS Using male rats, effects of lesions of the infralimbic (IL) and prelimbic (PL) areas of the mPFC on expression of sexual behavior and ability to inhibit mating were tested using a paradigm of copulation-contingent aversion. RESULTS mPFC lesions did not alter expression of sexual behavior. In contrast, mPFC lesions completely blocked the acquisition of sex-aversion conditioning and lesioned animals continued to mate, in contrast to the robust behavioral inhibition towards copulation in mPFC intact males, resulting in only 22% of intact males continuing to mate. However, rats with mPFC lesions were capable of forming a conditioned place preference to sexual reward and conditioned place aversion for lithium chloride, suggesting that these lesions did not alter associative learning or sensitivity for lithium chloride. DISCUSSION The current study indicates that animals with mPFC lesions are likely capable of forming the associations with aversive outcomes of their behavior, but lack the ability to suppress seeking of sexual reward in the face of aversive consequences. These data may contribute to a better understanding of a common pathology underlying impulse control disorders as compulsive sexual behavior has a high prevalence of comorbidity with psychiatric disorders and Parkinson’s Disease. PMID:20346444

  14. Is the self special in the dorsomedial prefrontal cortex? An fMRI study.

    PubMed

    Yaoi, Ken; Osaka, Naoyuki; Osaka, Mariko

    2009-01-01

    In recent years, several neuroimaging studies have suggested that the neural basis of the self-referential process1 is special, especially in the medial prefrontal cortex (MPFC). However, it remains controversial whether activity of the MPFC (and other related brain regions) appears only during the self-referential process. We investigated the neural correlates during the processing of references to the self, close other (friend), and distant other (prime minister) using fMRI. In comparison with baseline findings, referential processing to the three kinds of persons defined above showed common activation patterns in the dorsomedial prefrontal cortex (DMPFC), left middle temporal gyrus, left angular gyrus, posterior cingulate cortex and right cerebellum. Additionally, percent changes in BOLD signal in five regions of interest demonstrated the same findings. The result indicated that DMPFC was not special for the self-referential process, while there are common neural bases for evaluating the personalities of the self and others. PMID:19588282

  15. Individuals' and groups' intentions in the medial prefrontal cortex.

    PubMed

    Chaminade, Thierry; Kawato, Mitsuo; Frith, Chris

    2011-11-16

    Functional MRI signal was recorded while participants perceived stimuli presented using moving dots. In two conditions of interest, the motion of dots depicted intentions: dots representing the joints of an agent performing an action, and dots representing individual agents behaving contingently. The finding of a common cluster in the posterior part of the medial frontal cortex involved in intentional action representation validates the hypothesis that perception of these two conditions requires a similar internal representation. A cluster responding to the behaving group only is found in the anterior medial frontal cortex. These results support a division of the medial frontal cortex according to social stimuli attributes, with anterior areas responding to higher-order group behaviours integrating the action of multiple individual agents. PMID:21897305

  16. Visual space is compressed in prefrontal cortex before eye movements.

    PubMed

    Zirnsak, Marc; Steinmetz, Nicholas A; Noudoost, Behrad; Xu, Kitty Z; Moore, Tirin

    2014-03-27

    We experience the visual world through a series of saccadic eye movements, each one shifting our gaze to bring objects of interest to the fovea for further processing. Although such movements lead to frequent and substantial displacements of the retinal image, these displacements go unnoticed. It is widely assumed that a primary mechanism underlying this apparent stability is an anticipatory shifting of visual receptive fields (RFs) from their presaccadic to their postsaccadic locations before movement onset. Evidence of this predictive 'remapping' of RFs has been particularly apparent within brain structures involved in gaze control. However, critically absent among that evidence are detailed measurements of visual RFs before movement onset. Here we show that during saccade preparation, rather than remap, RFs of neurons in a prefrontal gaze control area massively converge towards the saccadic target. We mapped the visual RFs of prefrontal neurons during stable fixation and immediately before the onset of eye movements, using multi-electrode recordings in monkeys. Following movements from an initial fixation point to a target, RFs remained stationary in retinocentric space. However, in the period immediately before movement onset, RFs shifted by as much as 18 degrees of visual angle, and converged towards the target location. This convergence resulted in a threefold increase in the proportion of RFs responding to stimuli near the target region. In addition, like in human observers, the population of prefrontal neurons grossly mislocalized presaccadic stimuli as being closer to the target. Our results show that RF shifts do not predict the retinal displacements due to saccades, but instead reflect the overriding perception of target space during eye movements. PMID:24670771

  17. Dopaminergic dysregulation in prefrontal cortex of rhesus monkeys following cocaine self-administration.

    PubMed

    McIntosh, Scot; Howell, Leonard; Hemby, Scott E

    2013-01-01

    Chronic cocaine administration regulates the expression of several proteins related to dopaminergic signaling and synaptic function in the mesocorticolimbic pathway, including the prefrontal cortex. Functional abnormalities in the prefrontal cortex are hypothesized to be due in part to the expression of proteins involved in dopamine signaling and plasticity. Adult male rhesus monkeys self-administered cocaine (i.v.) under limited (n = 4) and extended access conditions (n = 6). The abundance of surrogate markers of dopamine signaling and plasticity in the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) were examined: glycosylated and non-glycosylated forms of the dopamine transporter (efficiency of dopamine transport), tyrosine hydroxylase (TH; marker of dopamine synthesis) and phosphorylated TH at Serine 30 and 40 (markers of enzyme activity), extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK 2), and phosphorylated ERK1 and ERK2 (phosphorylates TH Serine 31; markers of synaptic plasticity), and markers of synaptic integrity, spinophilin and post-synaptic density protein 95 (roles in dopamine signaling and response to cocaine). Extended cocaine access increased non-glycosylated and glycosylated DAT in DLPFC and OFC. While no differences in TH expression were observed between groups for any of the regions, extended access induced significant elevations in pTH(Ser31) in all regions. In addition, a slight but significant reduction in phosphorylated pTH(Ser40) was found in the DLPFC. Phosphorylated ERK2 was increased in all regions; however, pERK1 was decreased in ACC and OFC but increased in DLPFC. PSD-95 was increased in the OFC but not in DLPFC or ACC. Furthermore, extended cocaine self-administration elicited significant increases in spinophilin protein expression in all regions. Results from the study provide insight into the biochemical alterations occurring in primate prefrontal cortex

  18. Dopaminergic Dysregulation in Prefrontal Cortex of Rhesus Monkeys Following Cocaine Self-Administration

    PubMed Central

    McIntosh, Scot; Howell, Leonard; Hemby, Scott E.

    2013-01-01

    Chronic cocaine administration regulates the expression of several proteins related to dopaminergic signaling and synaptic function in the mesocorticolimbic pathway, including the prefrontal cortex. Functional abnormalities in the prefrontal cortex are hypothesized to be due in part to the expression of proteins involved in dopamine signaling and plasticity. Adult male rhesus monkeys self-administered cocaine (i.v.) under limited (n = 4) and extended access conditions (n = 6). The abundance of surrogate markers of dopamine signaling and plasticity in the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) were examined: glycosylated and non-glycosylated forms of the dopamine transporter (efficiency of dopamine transport), tyrosine hydroxylase (TH; marker of dopamine synthesis) and phosphorylated TH at Serine 30 and 40 (markers of enzyme activity), extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK 2), and phosphorylated ERK1 and ERK2 (phosphorylates TH Serine 31; markers of synaptic plasticity), and markers of synaptic integrity, spinophilin and post-synaptic density protein 95 (roles in dopamine signaling and response to cocaine). Extended cocaine access increased non-glycosylated and glycosylated DAT in DLPFC and OFC. While no differences in TH expression were observed between groups for any of the regions, extended access induced significant elevations in pTHSer31 in all regions. In addition, a slight but significant reduction in phosphorylated pTHSer40 was found in the DLPFC. Phosphorylated ERK2 was increased in all regions; however, pERK1 was decreased in ACC and OFC but increased in DLPFC. PSD-95 was increased in the OFC but not in DLPFC or ACC. Furthermore, extended cocaine self-administration elicited significant increases in spinophilin protein expression in all regions. Results from the study provide insight into the biochemical alterations occurring in primate prefrontal cortex. PMID

  19. Prefrontal Cortex Haemodynamics and Affective Responses during Exercise: A Multi-Channel Near Infrared Spectroscopy Study

    PubMed Central

    Tempest, Gavin D.; Eston, Roger G.; Parfitt, Gaynor

    2014-01-01

    The dose-response effects of the intensity of exercise upon the potential regulation (through top-down processes) of affective (pleasure-displeasure) responses in the prefrontal cortex during an incremental exercise protocol have not been explored. This study examined the functional capacity of the prefrontal cortex (reflected by haemodynamics using near infrared spectroscopy) and affective responses during exercise at different intensities. Participants completed an incremental cycling exercise test to exhaustion. Changes (Δ) in oxygenation (O2Hb), deoxygenation (HHb), blood volume (tHb) and haemoglobin difference (HbDiff) were measured from bilateral dorsal and ventral prefrontal areas. Affective responses were measured every minute during exercise. Data were extracted at intensities standardised to: below ventilatory threshold, at ventilatory threshold, respiratory compensation point and the end of exercise. During exercise at intensities from ventilatory threshold to respiratory compensation point, ΔO2Hb, ΔHbDiff and ΔtHb were greater in mostly ventral than dorsal regions. From the respiratory compensation point to the end of exercise, ΔO2Hb remained stable and ΔHbDiff declined in dorsal regions. As the intensity increased above the ventilatory threshold, inverse associations between affective responses and oxygenation in (a) all regions of the left hemisphere and (b) lateral (dorsal and ventral) regions followed by the midline (ventral) region in the right hemisphere were observed. Differential activation patterns occur within the prefrontal cortex and are associated with affective responses during cycling exercise. PMID:24788166

  20. Prefrontal cortex haemodynamics and affective responses during exercise: a multi-channel near infrared spectroscopy study.

    PubMed

    Tempest, Gavin D; Eston, Roger G; Parfitt, Gaynor

    2014-01-01

    The dose-response effects of the intensity of exercise upon the potential regulation (through top-down processes) of affective (pleasure-displeasure) responses in the prefrontal cortex during an incremental exercise protocol have not been explored. This study examined the functional capacity of the prefrontal cortex (reflected by haemodynamics using near infrared spectroscopy) and affective responses during exercise at different intensities. Participants completed an incremental cycling exercise test to exhaustion. Changes (Δ) in oxygenation (O2Hb), deoxygenation (HHb), blood volume (tHb) and haemoglobin difference (HbDiff) were measured from bilateral dorsal and ventral prefrontal areas. Affective responses were measured every minute during exercise. Data were extracted at intensities standardised to: below ventilatory threshold, at ventilatory threshold, respiratory compensation point and the end of exercise. During exercise at intensities from ventilatory threshold to respiratory compensation point, ΔO2Hb, ΔHbDiff and ΔtHb were greater in mostly ventral than dorsal regions. From the respiratory compensation point to the end of exercise, ΔO2Hb remained stable and ΔHbDiff declined in dorsal regions. As the intensity increased above the ventilatory threshold, inverse associations between affective responses and oxygenation in (a) all regions of the left hemisphere and (b) lateral (dorsal and ventral) regions followed by the midline (ventral) region in the right hemisphere were observed. Differential activation patterns occur within the prefrontal cortex and are associated with affective responses during cycling exercise. PMID:24788166

  1. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU.

    PubMed

    Diamond, A; Prevor, M B; Callender, G; Druin, D P

    1997-01-01

    To begin to study the importance of dopamine for executive function abilities dependent on prefrontal cortex during early childhood, the present investigation studied children in whom we predicted reduced dopamine in prefrontal cortex but otherwise normal brains. These are children treated early and continuously for the metabolic disorder phenylketonuria (PKU). Untreated PKU is the most common biochemical cause of mental retardation. The root problem is an inability to convert one amino acid, phenylalanine (Phe), into another, tyrosine (Tyr), the precursor of dopamine. Phe levels in the bloodstream soar; Tyr levels fall. Treatment with a diet low in Phe reduces the Phe:Tyr imbalance but cannot eliminate it. We hypothesized that the resultant modest elevation in the ratio of Phe to Tyr in the blood, which results in slightly less Tyr reaching the brain, uniquely affects the cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in Tyr. In a 4-year longitudinal study, we found that PKU children whose plasma Phe levels were three to five times normal (6-10 mg/dl) performed worse than other PKU children with lower Phe levels, matched controls, their own siblings, and children from the general population on tasks that required the working memory and inhibitory control abilities dependent on dorsolateral prefrontal cortex. The impairment was as evident in our oldest age range (3 1/2-7 years) as it was in the youngest (6-12 months). The higher a child's Phe level, the worse that child's performance. Girls were more adversely affected than boys. The deficit appears to be selective, affecting principally one neural system, since even PKU children with Phe levels three to five times normal performed well on the 13 control tasks. Clinical implications for the treatment of PKU and other neurodevelopmental disorders are discussed. PMID:9421921

  2. Perseverative Interference with Object-in-Place Scene Learning in Rhesus Monkeys with Bilateral Ablation of Ventrolateral Prefrontal Cortex

    ERIC Educational Resources Information Center

    Baxter, Mark G.; Browning, Philip G. F.; Mitchell, Anna S.

    2008-01-01

    Surgical disconnection of the frontal cortex and inferotemporal cortex severely impairs many aspects of visual learning and memory, including learning of new object-in-place scene memory problems, a monkey model of episodic memory. As part of a study of specialization within prefrontal cortex in visual learning and memory, we tested monkeys with…

  3. Damage To Dorsolateral Prefrontal Cortex Affects Tradeoffs Between Honesty And Self-Interest

    PubMed Central

    Zhu, Lusha; Jenkins, Adrianna C.; Set, Eric; Scabini, Donatella; Knight, Robert T.; Chiu, Pearl H.; King-Casas, Brooks; Hsu, Ming

    2014-01-01

    Substantial correlational evidence exists suggesting a critical role for prefrontal regions in honest and dishonest behavior, but causal evidence specifying the nature of this involvement remains absent. Here we show using the lesion method that damage to the human dorsolateral prefrontal cortex (DLPFC) decreased the effect of honesty concerns on behavior in economic games that pit honesty motives against self-interest, but did not affect decisions where honesty concerns were absent. These results point to a causal role for DLPFC in enabling honest behavior. PMID:25174003

  4. Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders

    PubMed Central

    Schubert, D; Martens, G J M; Kolk, S M

    2015-01-01

    The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies. PMID:25450230

  5. Working memory coding of analog stimulus properties in the human prefrontal cortex.

    PubMed

    Spitzer, Bernhard; Gloel, Matthias; Schmidt, Timo T; Blankenburg, Felix

    2014-08-01

    Building on evidence for working memory (WM) coding of vibrotactile frequency information in monkey prefrontal cortex, recent electroencephalography studies found frequency processing in human WM to be reflected by quantitative modulations of prefrontal upper beta activity (20-30 Hz) as a function of the to-be-maintained stimulus attribute. This kind of stimulus-dependent activity has been observed across different sensory modalities, suggesting a generalized role of prefrontal beta during abstract WM processing of quantitative magnitude information. However, until now the available empirical evidence for such quantitative WM representation remains critically limited to the retention of periodic stimulus frequencies. In the present experiment, we used retrospective cueing to examine the quantitative WM processing of stationary (intensity) and temporal (duration) attributes of a previously presented tactile stimulus. We found parametric modulations of prefrontal beta activity during cued WM processing of each type of quantitative information, in a very similar manner as had before been observed only for periodic frequency information. In particular, delayed prefrontal beta modulations systematically reflected the magnitude of the retrospectively selected stimulus attribute and were functionally linked to successful behavioral task performance. Together, these findings converge on a generalized role of stimulus-dependent prefrontal beta-band oscillations during abstract scaling of analog quantity information in human WM. PMID:23547134

  6. Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders.

    PubMed

    Schubert, D; Martens, G J M; Kolk, S M

    2015-07-01

    The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies. PMID:25450230

  7. Multisynaptic projections from the ventrolateral prefrontal cortex to hand and mouth representations of the monkey primary motor cortex.

    PubMed

    Miyachi, Shigehiro; Hirata, Yoshihiro; Inoue, Ken-ichi; Lu, Xiaofeng; Nambu, Atsushi; Takada, Masahiko

    2013-07-01

    Different sectors of the prefrontal cortex have distinct neuronal connections with higher-order sensory areas and/or limbic structures and are related to diverse aspects of cognitive functions, such as visual working memory and reward-based decision-making. Recent studies have revealed that the prefrontal cortex (PF), especially the lateral PF, is also involved in motor control. Hence, different sectors of the PF may contribute to motor behaviors with distinct body parts. To test this hypothesis anatomically, we examined the patterns of multisynaptic projections from the PF to regions of the primary motor cortex (MI) that represent the arm, hand, and mouth, using retrograde transsynaptic transport of rabies virus. Four days after rabies injections into the hand or mouth region, particularly dense neuron labeling was observed in the ventrolateral PF, including the convexity part of ventral area 46. After the rabies injections into the mouth region, another dense cluster of labeled neurons was seen in the orbitofrontal cortex (area 13). By contrast, rabies labeling of PF neurons was rather sparse in the arm-injection cases. The present results suggest that the PF-MI multisynaptic projections may be organized such that the MI hand and mouth regions preferentially receive cognitive information for execution of elaborate motor actions. PMID:23664864

  8. Persistent Interneuronopathy in the Prefrontal Cortex of Young Adult Offspring Exposed to Ethanol In Utero

    PubMed Central

    Skorput, Alexander G. J.; Gupta, Vivek P.; Yeh, Pamela W. L.

    2015-01-01

    Gestational exposure to ethanol has been reported to alter the disposition of tangentially migrating GABAergic cortical interneurons, but much remains to be elucidated. Here we first established the migration of interneurons as a proximal target of ethanol by limiting ethanol exposure in utero to the gestational window when tangential migration is at its height. We then asked whether the aberrant tangential migration of GABAergic interneurons persisted as an enduring interneuronopathy in the medial prefrontal cortex (mPFC) later in the life of offspring prenatally exposed to ethanol. Time pregnant mice with Nkx2.1Cre/Ai14 embryos harboring tdTomato-fluorescent medial ganglionic eminence (MGE)-derived cortical GABAergic interneurons were subjected to a 3 day binge-type 5% w/w ethanol consumption regimen from embryonic day (E) 13.5–16.5, spanning the peak of corticopetal interneuron migration in the fetal brain. Our binge-type regimen increased the density of MGE-derived interneurons in the E16.5 mPFC. In young adult offspring exposed to ethanol in utero, this effect persisted as an increase in the number of mPFC layer V parvalbumin-immunopositive interneurons. Commensurately, patch-clamp recording in mPFC layer V pyramidal neurons uncovered enhanced GABA-mediated spontaneous and evoked synaptic transmission, shifting the inhibitory/excitatory balance toward favoring inhibition. Furthermore, young adult offspring exposed to the 3 day binge-type ethanol regimen exhibited impaired reversal learning in a modified Barnes maze, indicative of decreased PFC-dependent behavioral flexibility, and heightened locomotor activity in an open field arena. Our findings underscore that aberrant neuronal migration, inhibitory/excitatory imbalance, and thus interneuronopathy contribute to indelible abnormal cortical circuit form and function in fetal alcohol spectrum disorders. SIGNIFICANCE STATEMENT The significance of this study is twofold. First, we demonstrate that a time

  9. DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

    PubMed

    Barbier, Estelle; Tapocik, Jenica D; Juergens, Nathan; Pitcairn, Caleb; Borich, Abbey; Schank, Jesse R; Sun, Hui; Schuebel, Kornel; Zhou, Zhifeng; Yuan, Qiaoping; Vendruscolo, Leandro F; Goldman, David; Heilig, Markus

    2015-04-15

    Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism. PMID:25878287

  10. Stimulation of α1-adrenoceptors facilitates GABAergic transmission onto pyramidal neurons in the medial prefrontal cortex.

    PubMed

    Luo, F; Tang, H; Cheng, Z-Y

    2015-08-01

    Whereas activation of α1-adrenoceptors (α1-ARs) modulates glutamatergic transmission, the roles of α1-ARs in GABAergic transmission in the medial prefrontal cortex (mPFC) are elusive. Here, we examined the effects of the α1-AR agonist phenylephrine (Phe) on GABAergic transmission onto pyramidal neurons in the deep layers of the mPFC. We found that bath application of Phe dose-dependently increased the amplitude of evoked IPSCs (eIPSCs). Phe increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Ca(2+) influx through T-type voltage-gated calcium channels is required for Phe-induced increases in GABA release. Phe increases GABA release probability and the number of releasable vesicles. Phe depolarizes the fast-spiking (FS) interneurons without effects on the firing rate of action potentials (APs) of interneurons. Phe-induced depolarization is independent of extracellular Na(+), Ca(2+) and T-type calcium channels, but requires inward rectifier K(+) channels (Kirs). The present study demonstrates that Phe enhances GABAergic transmission onto mPFC pyramidal neurons through inhibiting interneurons Kirs, which further depolarizes interneurons leading to increase in Ca(2+) influx via T-type calcium channels. Our results may provide a cellular and molecular mechanism that helps explain α1-AR-induced PFC dysfunction. PMID:25943480

  11. Functional anatomy of ventromedial prefrontal cortex: Implications for mood and anxiety disorders

    PubMed Central

    Myers-Schulz, Blake; Koenigs, Michael

    2014-01-01

    In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with mood and anxiety disorders. The results of such studies could have significant implications for the development of novel treatments for these disorders. A challenge currently facing the field is to assimilate the large and growing corpus of imaging data to inform a systems-level model of the neural circuitry underlying the disorders. One prominent theoretical perspective highlights the top-down inhibition of amygdala by ventromedial prefrontal cortex (vmPFC) as a crucial neural mechanism that may be defective in certain mood and anxiety disorders, such as major depression and post-traumatic stress disorder. In this article we provide a critical review of animal and human data related to this model. In particular, we emphasize the considerable body of research that challenges the veracity (or at least completeness) of the predominant model. We propose a framework for constructing a more comprehensive model of vmPFC function, with the goal of fostering further progress in understanding the neuropathophysiological basis of mood and anxiety disorders. PMID:21788943

  12. Sensory Deprivation during Early Postnatal Period Alters the Density of Interneurons in the Mouse Prefrontal Cortex

    PubMed Central

    Ueno, Hiroshi; Suemitsu, Shunsuke; Matsumoto, Yosuke; Okamoto, Motoi

    2015-01-01

    Early loss of one sensory system can cause improved function of other sensory systems. However, both the time course and neuronal mechanism of cross-modal plasticity remain elusive. Recent study using functional MRI in humans suggests a role of the prefrontal cortex (PFC) in cross-modal plasticity. Since this phenomenon is assumed to be associated with altered GABAergic inhibition in the PFC, we have tested the hypothesis that early postnatal sensory deprivation causes the changes of inhibitory neuronal circuit in different regions of the PFC of the mice. We determined the effects of sensory deprivation from birth to postnatal day 28 (P28) or P58 on the density of parvalbumin (PV), calbindin (CB), and calretinin (CR) neurons in the prelimbic, infralimbic, and dorsal anterior cingulate cortices. The density of PV and CB neurons was significantly increased in layer 5/6 (L5/6). Moreover, the density of CR neurons was higher in L2/3 in sensory deprived mice compared to intact mice. These changes were more prominent at P56 than at P28. These results suggest that long-term sensory deprivation causes the changes of intracortical inhibitory networks in the PFC and the changes of inhibitory networks in the PFC may contribute to cross-modal plasticity. PMID:26161272

  13. Evidence for Competition for Target Innervation in the Medial Prefrontal Cortex.

    PubMed

    Guirado, Ramon; Umemori, Juzoh; Sipilä, Pia; Castrén, Eero

    2016-03-01

    Inputs to sensory cortices are known to compete for target innervation through an activity-dependent mechanism during critical periods. To investigate whether this principle also applies to association cortices such as the medial prefrontal cortex (mPFC), we produced a bilateral lesion during early development to the ventral hippocampus (vHC), an input to the mPFC, and analyzed the intensity of the projection from another input, the basolateral amgydala (BLA). We found that axons from the BLA had a higher density of "en passant" boutons in the mPFC of lesioned animals. Furthermore, the density of neurons labeled with retrograde tracers was increased, and neurons projecting from the BLA to the mPFC showed increased expression of FosB. Since neonatal ventral hippocampal lesion has been used as an animal model of schizophrenia, we investigated its effects on behavior and found a negative correlation between the density of retrogradely labeled neurons in the BLA and the reduction of the startle response in the prepulse inhibition test. Our results not only indicate that the inputs from the BLA and the vHC compete for target innervation in the mPFC during postnatal development but also that subsequent abnormal rewiring might underlie the pathophysiology of neuropsychiatric disorders such as schizophrenia. PMID:26637448

  14. DNA Methylation in the Medial Prefrontal Cortex Regulates Alcohol-Induced Behavior and Plasticity

    PubMed Central

    Tapocik, Jenica D.; Juergens, Nathan; Pitcairn, Caleb; Borich, Abbey; Schank, Jesse R.; Sun, Hui; Schuebel, Kornel; Zhou, Zhifeng; Yuan, Qiaoping; Vendruscolo, Leandro F.; Goldman, David; Heilig, Markus

    2015-01-01

    Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism. PMID:25878287

  15. Interfering with activity in the dorsomedial prefrontal cortex via TMS affects social impressions updating.

    PubMed

    Ferrari, Chiara; Vecchi, Tomaso; Todorov, Alexander; Cattaneo, Zaira

    2016-08-01

    In our everyday social interactions we often need to deal with others' unpredictable behaviors. Integrating unexpected information in a consistent representation of another agent is a cognitively demanding process. Several neuroimaging studies point to the medial prefrontal cortex (mPFC) as a critical structure in mediating social evaluations. Our aim here was to shed light on the possible causal role of the mPFC in the dynamic process of forming and updating social impressions about others. We addressed this issue by suppressing activity in the mPFC by means of 1 Hz offline transcranial magnetic stimulation (TMS) prior to a task requiring participants to evaluate other agents' trustworthiness after reading about their social behavior. In two different experiments, we found that inhibiting activity in the mPFC increased perceived trustworthiness when inconsistent information about one agent's behavior was provided. In turn, when only negative or positive behaviors of a person were described, TMS over the mPFC did not affect judgments. Our results indicate that the mPFC is causally involved in mediating social impressions updating-at least in cases in which judgment is uncertain due to conflicting information to be processed. PMID:27012713

  16. Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex

    PubMed Central

    McClatchy, Daniel B.; Savas, Jeffrey N.; Martínez-Bartolomé, Salvador; Park, Sung Kyu; Maher, Pamela; Powell, Susan B.; Yates, John R.

    2015-01-01

    Prepulse inhibition (PPI) is an example of sensorimotor gating and deficits in PPI have been demonstrated in schizophrenia patients. Phencyclidine (PCP) suppression of PPI in animals has been studied to elucidate the pathological elements of schizophrenia. However, the molecular mechanisms underlying PCP treatment or PPI in the brain are still poorly understood. In this study, quantitative phosphoproteomic analysis was performed on the prefrontal cortex from rats that were subjected to PPI after being systemically injected with PCP or saline. PCP down-regulated phosphorylation events were significantly enriched in proteins associated with long-term potentiation (LTP). Importantly, this dataset identifies functionally novel phosphorylation sites on known LTP-associated signaling molecules. In addition, mutagenesis of a significantly altered phosphorylation site on xCT (SLC7A11), the light chain of system xc-, the cystine/glutamate antiporter, suggests that PCP also regulates the activity of this protein. Finally, new insights were also derived on PPI signaling independent of PCP treatment. This is the first quantitative phosphorylation proteomic analysis providing new molecular insights into sensorimotor gating. PMID:25869802

  17. Interhemispheric Dorsolateral Prefrontal Cortex Connectivity is Associated with Individual Differences in Pain Sensitivity in Healthy Controls.

    PubMed

    Sevel, Landrew S; Letzen, Janelle E; Staud, Roland; Robinson, Michael E

    2016-06-01

    The dorsolateral prefrontal cortex (DLPFC) is implicated in pain modulation through multiple psychological processes. Recent noninvasive brain stimulation studies suggest that interhemispheric DLPFC connectivity influences pain tolerance and discomfort by altering interhemispheric inhibition. The structure and role of interhemispheric DLPFC connectivity in pain processing have not been investigated. The present study used dynamic causal modeling (DCM) for fMRI to investigate transcallosal DLPFC connectivity during painful stimulation in healthy volunteers. DCM parameters were used to predict individual differences in sensitivity to noxious heat stimuli. Bayesian model selection results indicated that influences among the right DLPFC (rDLPFC) and left DLPFC (lDLPFC) are modulated during painful stimuli. Regression analyses revealed that greater rDLPFC→lDLPFC couplings were associated with higher suprathreshold pain temperatures. These results highlight the role of interhemispheric connectivity in pain modulation and support the preferential role of the right hemisphere in pain processing. Knowledge of these mechanisms may improve understanding of abnormal pain modulation in chronic pain populations. PMID:26916416

  18. Evidence for Competition for Target Innervation in the Medial Prefrontal Cortex

    PubMed Central

    Guirado, Ramon; Umemori, Juzoh; Sipilä, Pia; Castrén, Eero

    2016-01-01

    Inputs to sensory cortices are known to compete for target innervation through an activity-dependent mechanism during critical periods. To investigate whether this principle also applies to association cortices such as the medial prefrontal cortex (mPFC), we produced a bilateral lesion during early development to the ventral hippocampus (vHC), an input to the mPFC, and analyzed the intensity of the projection from another input, the basolateral amgydala (BLA). We found that axons from the BLA had a higher density of “en passant” boutons in the mPFC of lesioned animals. Furthermore, the density of neurons labeled with retrograde tracers was increased, and neurons projecting from the BLA to the mPFC showed increased expression of FosB. Since neonatal ventral hippocampal lesion has been used as an animal model of schizophrenia, we investigated its effects on behavior and found a negative correlation between the density of retrogradely labeled neurons in the BLA and the reduction of the startle response in the prepulse inhibition test. Our results not only indicate that the inputs from the BLA and the vHC compete for target innervation in the mPFC during postnatal development but also that subsequent abnormal rewiring might underlie the pathophysiology of neuropsychiatric disorders such as schizophrenia. PMID:26637448

  19. Differential expression of immediate early genes Zif268 and c-Fos in the hippocampus and prefrontal cortex following spatial learning and glutamate receptor antagonism.

    PubMed

    Farina, Francesca R; Commins, Sean

    2016-07-01

    The objective of this study was to examine the effects of NMDAR and AMPAR antagonism on the expression of Zif268 and c-Fos in the hippocampus and medial prefrontal cortex during spatial memory encoding in rats trained in the Morris water maze. NMDAR inhibition impaired navigation and significantly attenuated expression of Zif268, but not c-Fos, in area CA1. AMPAR channel blockade had little effect on learning or IEG expression. Overall, Zif268 and c-Fos displayed markedly different patterns of hippocampal and prefrontal expression, with Zif268 being more closely linked to spatial learning. PMID:27071329

  20. Differences in time course activation of dorsolateral prefrontal cortex associated with low or high risk choices in a gambling task

    PubMed Central

    Bembich, Stefano; Clarici, Andrea; Vecchiet, Cristina; Baldassi, Giulio; Cont, Gabriele; Demarini, Sergio

    2014-01-01

    Prefrontal cortex plays an important role in decision making (DM), supporting choices in the ordinary uncertainty of everyday life. To assess DM in an unpredictable situation, a playing card task, such as the Iowa Gambling Task (IGT), has been proposed. This task is supposed to specifically test emotion-based learning, linked to the integrity of the ventromedial prefrontal cortex (VMPFC). However, the dorsolateral prefrontal cortex (DLPFC) has demonstrated a role in IGT performance too. Our aim was to study, by multichannel near-infrared spectroscopy, the contribution of DLPFC to the IGT execution over time. We tested the hypothesis that low and high risk choices would differentially activate DLPFC, as IGT execution progressed. We enrolled 11 healthy adults. To identify DLPFC activation associated with IGT choices, we compared regional differences in oxy-hemoglobin variation, from baseline to the event. The time course of task execution was divided in four periods, each one consisting of 25 choices, and DLPFC activation was distinctly analyzed for low and high risk choices in each period. We found different time courses in DLPFC activation, associated with low or high risk choices. During the first period, a significant DLPFC activation emerged with low risk choices, whereas, during the second period, we found a cortical activation with high risk choices. Then, DLPFC activation decreased to non-significant levels during the third and fourth period. This study shows that DLPFC involvement in IGT execution is differentiated over time and according to choice risk level. DLPFC is activated only in the first half of the task, earlier by low risk and later by high risk choices. We speculate that DLPFC may sustain initial and more cognitive functions, such as attention shifting and response inhibition. The lack of DLPFC activation, as the task progresses, may be due to VMPFC activation, not detectable by fNIRS, which takes over the IGT execution in its second half. PMID

  1. Cognitive findings after transient global amnesia: role of prefrontal cortex.

    PubMed

    Le Pira, Francesco; Giuffrida, Salvatore; Maci, Tiziana; Reggio, Ester; Zappalà, Giuseppe; Perciavalle, Vincenzo

    2005-01-01

    The aim of this study is to verify, after recovery, the presence of specific patterns of cognitive dysfunctions in Transient Global Amnesia (TGA). Fourteen patients with the diagnosis of TGA were submitted to a battery of neuropsychological tests and compared to a matched control group. We found significant qualitative and quantitative differences between TGA patients and controls in the California Verbal Learning Test (CLVT) and Rey-Osterrieth Complex Figure Test. Our data support the presence of selective cognitive dysfunctions after the clinical recovery. Moreover, for Verbal Fluency, Digit Span Backward, and Number of Clusters in the CVLT short-term memory test, the relation resulted as positively related with the temporal interval from the TGA episode. Reduction of categorical learning, attention, and qualitative alterations of spatial strategy seem to postulate a planning defect due to a prefrontal impairment. PMID:16422663

  2. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex

    PubMed Central

    Kvitsiani, D.; Ranade, S.; Hangya, B.; Taniguchi, H.; Huang, JZ.; Kepecs, A.

    2013-01-01

    Neurons in prefrontal cortex exhibit diverse behavioural correlates1–4, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically-defined inhibitory interneuron classes, the perisomatically-targeting parvalbumin (Pv) and the dendritically-targeting somatostatin (Som) neurons5–8 in anterior cingulate cortex (ACC) of mice performing a reward foraging task. Here we show that Pv and a subtype of Som neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory impact and behavioural correlates. Out of a number of events pertaining to behaviour, a subtype of Som neurons selectively responded at reward approach, while Pv neurons responded at reward leaving encoding preceding stay duration. These behavioural correlates of Pv and Som neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to ACC9–11. Furthermore, Pv neurons could fire in millisecond synchrony exerting fast and powerful inhibition on principal cell firing, while the inhibitory impact of Som neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of and inputs to principal neurons12–16. These results suggest a connection between the circuit-level function of different interneuron-types in regulating the flow of information, and the behavioural functions served by the cortical circuits. Moreover these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity. PMID:23708967

  3. Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

    PubMed

    McCarthy, Deirdre M; Bhide, Pradeep G

    2012-01-01

    Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. PMID:22572769

  4. rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex

    PubMed Central

    Cho, Sang Soo; Strafella, Antonio P.

    2009-01-01

    Background Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson's disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of non-invasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC) (areas 9/46) stimulation on prefrontal dopamine (DA). Methodology/Principal Findings Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [11C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [11C]FLB 457 binding potential (BP) in the ipsilateral subgenual anterior cingulate cortex (ACC) (BA 25/12), pregenual ACC (BA 32) and medial orbitofrontal cortex (BA 11). There were no significant changes in [11C]FLB 457 BP following right DLPFC rTMS. Conclusions/Significance To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [11C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help to identify the neurobiological effects of TMS for the treatment of different neurological and psychiatric diseases. PMID:19696930

  5. Theta coupling between V4 and prefrontal cortex predicts visual short-term memory performance.

    PubMed

    Liebe, Stefanie; Hoerzer, Gregor M; Logothetis, Nikos K; Rainer, Gregor

    2012-03-01

    Short-term memory requires communication between multiple brain regions that collectively mediate the encoding and maintenance of sensory information. It has been suggested that oscillatory synchronization underlies intercortical communication. Yet, whether and how distant cortical areas cooperate during visual memory remains elusive. We examined neural interactions between visual area V4 and the lateral prefrontal cortex using simultaneous local field potential (LFP) recordings and single-unit activity (SUA) in monkeys performing a visual short-term memory task. During the memory period, we observed enhanced between-area phase synchronization in theta frequencies (3-9 Hz) of LFPs together with elevated phase locking of SUA to theta oscillations across regions. In addition, we found that the strength of intercortical locking was predictive of the animals' behavioral performance. This suggests that theta-band synchronization coordinates action potential communication between V4 and prefrontal cortex that may contribute to the maintenance of visual short-term memories. PMID:22286175

  6. Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty.

    PubMed

    Karlsson, Mattias P; Tervo, Dougal G R; Karpova, Alla Y

    2012-10-01

    Regions within the prefrontal cortex are thought to process beliefs about the world, but little is known about the circuit dynamics underlying the formation and modification of these beliefs. Using a task that permits dissociation between the activity encoding an animal's internal state and that encoding aspects of behavior, we found that transient increases in the volatility of activity in the rat medial prefrontal cortex accompany periods when an animal's belief is modified after an environmental change. Activity across the majority of sampled neurons underwent marked, abrupt, and coordinated changes when prior belief was abandoned in favor of exploration of alternative strategies. These dynamics reflect network switches to a state of instability, which diminishes over the period of exploration as new stable representations are formed. PMID:23042898

  7. Identification of prefrontal cortex (BA10) activation while performing Stroop test using diffuse optical tomography

    NASA Astrophysics Data System (ADS)

    Khadka, Sabin; Chityala, Srujan R.; Tian, Fenghua; Liu, Hanli

    2011-03-01

    Stroop test is commonly used as a behavior-testing tool for psychological examinations that are related to attention and cognitive control of the human brain. Studies have shown activations in Broadmann area 10 (BA10) of prefrontal cortex (PFC) during attention and cognitive process. The use of diffuse optical tomography (DOT) for human brain mapping is becoming more prevalent. In this study we expect to find neural correlates between the performed cognitive tasks and hemodynamic signals detected by a DOT system. Our initial observation showed activation of oxy-hemoglobin concentration in BA 10, which is consistent with some results seen by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Our study demonstrates the possibility of combining DOT with Stroop test to quantitatively investigate cognitive functions of the human brain at the prefrontal cortex.

  8. Prefrontal cortex involvement in creative problem solving in middle adolescence and adulthood.

    PubMed

    Kleibeuker, Sietske W; Koolschijn, P Cédric M P; Jolles, Dietsje D; Schel, Margot A; De Dreu, Carsten K W; Crone, Eveline A

    2013-07-01

    Creative cognition, defined as the generation of new yet appropriate ideas and solutions, serves important adaptive purposes. Here, we tested whether and how middle adolescence, characterized by transformations toward life independency and individuality, is a more profitable phase than adulthood for creative cognition. Behavioral and neural differences for creative problem solving in adolescents (15-17 years) and adults (25-30 years) were measured while performing a matchstick problem task (MPT) in the scanner and the creative ability test (CAT), a visuo-spatial divergent thinking task, outside the scanner. Overall performances were comparable, although MPT performance indicated an advantage for adolescents in creative problem solving. In addition, adolescents showed more activation in lateral prefrontal cortex (ventral and dorsal) during creative problem solving compared to adults. These areas correlated with performances on the MPT and the CAT performance. We discuss that extended prefrontal cortex activation in adolescence is important for exploration and aids in creative cognition. PMID:23624336

  9. Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

    PubMed Central

    Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

  10. Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats.

    PubMed

    Achterberg, E J Marijke; van Kerkhof, Linda W M; Damsteegt, Ruth; Trezza, Viviana; Vanderschuren, Louk J M J

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111