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Visual working memory (VWM) is a remarkable skill dependent on the brain's ability to construct and hold an internal representation of the world for later comparison with an external stimulus. The prefrontal cortex (PFC) and basal ganglia (BG) interact within a cortical and subcortical network supporting VWM. We used scalp electroencephalography in groups of patients with unilateral PFC or BG lesions to provide evidence that these regions play complementary but dissociable roles in VWM. PFC patients show behavioral and electrophysiological deficits manifested by attenuation of extrastriate attention and VWM-related neural activity only for stimuli presented to the contralesional visual field. In contrast, patients with BG lesions show behavioral and electrophysiological VWM deficits independent of the hemifield of stimulus presentation but have intact extrastriate attention activity. The results support a model wherein the PFC is critical for top-down intrahemispheric modulation of attention and VWM with the BG involved in global support of VWM processes. attention | electroencephalography | lesion | stroke doi/ 10.1073/pnas.1007277107

Individuals can learn by interacting with the environment and experiencing a difference between predicted and obtained outcomes (prediction error). However, many species also learn by observing the actions and outcomes of others. In contrast to individual learning, observational learning cannot be based on directly experienced outcome prediction errors. Accordingly, the behavioral and neural mechanisms of learning through observation remain elusive. Here we propose that human observational learning can be explained by two previously uncharacterized forms of prediction error, observational action prediction errors (the actual minus the predicted choice of others) and observational outcome prediction errors (the actual minus predicted outcome received by others). In a functional MRI experiment, we found that brain activity in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex respectively corresponded to these two distinct observational learning signals. prediction error | reward | vicarious learning | dorsolateral prefrontal cortex | ventromedial prefrontal cortex doi/ 10.1073/pnas.1003111107

In the medial prefrontal cortex, the prelimbic area is emerging as a major modulator of fear behavior, but the mechanisms remain unclear. Using a selective neocortical knockout mouse, virally mediated prelimbic cortical-specific gene deletion, and pharmacological rescue with a TrkB agonist, we examined the role of a primary candidate mechanism, BDNF, in conditioned fear. We found consistently robust deficits in consolidation of cued fear but no effects on acquisition, expression of unlearned fear, sensorimotor function, and spatial learning. This deficit in learned fear in the BDNF knockout mice was rescued with systemic administration of a TrkB receptor agonist, 7,8-dihydroxyflavone. These data indicate that prelimbic BDNF is critical for consolidation of learned fear memories, but it is not required for innate fear or extinction of fear. Moreover, use of site-specific, inducible BDNF deletions shows a powerful mechanism that may further our understanding of the pathophysiology of fear-related disorders. learning | plasticity | prefrontal cortex | Cre/LoxP | inducible knockout www.pnas.org/cgi/doi/10.1073/pnas.0909359107

Mathematics is based on highly abstract principles, or rules, of how to structure, process, and evaluate numerical information. If and how mathematical rules can be represented by single neurons, however, has remained elusive. We therefore recorded the activity of individual prefrontal cortex (PFC) neurons in rhesus monkeys required to switch flexibly between 'greater than' and 'less than' rules. The monkeys performed this task with different numerical quantities and generalized to set sizes that had not been presented previously, indicating that they had learned an abstract mathematical principle. The most prevalent activity recorded from randomly selected PFC neurons reflected the mathematical rules; purely sensory- and memory-related activity was almost absent. These data show that single PFC neurons have the capacity to represent flexible operations on most abstract numerical quantities. Our findings support PFC network models implementing specific 'rule-coding' units that control the flow of information between segregated input, memory, and output layers. We speculate that these neuronal circuits in the monkey lateral PFC could readily have been adopted in the course of primate evolution for syntactic processing of numbers in formalized mathematical systems. mathematics | monkey | number | single cell doi/10.1073/pnas.0909180107

The ability to hold multiple objects in memory is fundamental to intelligent behavior, but its neural basis remains poorly understood. It has been suggested that multiple items may be held in memory by oscillatory activity across neuronal populations, but yet there is little direct evidence. Here, we show that neuronal information about two objects held in short-term memory is enhanced at specific phases of underlying oscillatory population activity. We recorded neuronal activity from the prefrontal cortices of monkeys remembering two visual objects over a brief interval. We found that during this memory interval prefrontal population activity was rhythmically synchronized at frequencies around 32 and 3 Hz and that spikes carried the most information about the memorized objects at specific phases. Further, according to their order of presentation, optimal encoding of the first presented object was significantly earlier in the 32 Hz cycle than that for the second object. Our results suggest that oscillatory neuronal synchronization mediates a phase-dependent coding of memorized objects in the prefrontal cortex. Encoding at distinct phases may play a role for disambiguating information about multiple objects in short-term memory. oscillations | prefrontal cortex | synchronization | local field potential | delay activity doi/ 10.1073/pnas.0908193106

Reputation formation pervades human social life. In fact, many people go to great lengths to acquire a good reputation, even though building a good reputation is costly in many cases. Little is known about the neural underpinnings of this important social mechanism, however. In the present study, we show that disruption of the right, but not the left, lateral prefrontal cortex (PFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) diminishes subjects' ability to build a favorable reputation. This effect occurs even though subjects' ability to behave altruistically in the absence of reputation incentives remains intact, and even though they are still able to recognize both the fairness standards necessary for acquiring and the future benefits of a good reputation. Thus, subjects with a disrupted right lateral PFC no longer seem to be able to resist the temptation to defect, even though they know that this has detrimental effects on their future reputation. This suggests an important dissociation between the knowledge about one's own best interests and the ability to act accordingly in social contexts. These results link findings on the neural underpinnings of self-control and temptation with the study of human social behavior, and they may help explain why reputation formation remains less prominent in most other species with less developed prefrontal cortices. decision making | social interaction | transcranial magnetic stimulation doi/10.1073/pnas.0911619106

The prefrontal cortex r regulates behavior, cognition, and emotion by using working memory. Prefrontal functions are impaired by stress exposure. Acute, stress-induced deficits arise from excessive protein kinase C (PKC) signaling, which diminishes prefrontal neuronal firing. Chronic stress additionally produces architectural changes, reducing dendritic complexity and spine density of cortico-cortical pyramidal neurons, thereby disrupting excitatory working memory networks, in vitro studies have found that sustained PKC activity leads to spine loss from hippocampal-cultured neurons, suggesting that PKC may contribute to spine loss during chronic stress exposure. The present study tested whether inhibition of PKC with chelerythrine before daily stress would protect prefrontal spines and working memory. We found that inhibition of PKC rescued working memory impairments and reversed distal apical dendritic spine loss in layer II/III pyramidal neurons of rat prelimbic cortex. Greater spine density predicted better cognitive performance, the first direct correlation between pyramidal cell structure and working memory abilities. These findings suggest that PKC inhibitors may be neuroprotective in disorders with dysregulated PKC signaling such as bipolar disorder, schizophrenia, post-traumatic stress disorder, and lead poisoning--conditions characterized by impoverished prefrontal structural and functional integrity. bipolar disorder | post-traumatic stress disorder | working memory | chelerythrine | lead poisoning doi/ 10.1073/pnas.0908563106

Adolescence is characterized by increased vulnerability to developing neuropsychiatric disorders and involves a period of prefrontal cortical dendritic refinement and synaptic pruning that culminates in cytoskeletal stabilization in adulthood. The Abl-related gene (Arg) acts through p190RhoGAP to inhibit the RhoA GTPase and stabilize cortical dendritic arbors beginning in adolescence. Cortical axons, dendrites, and synapses develop normally in Arg-deficient ([arg.sup.-/-]) mice, but adult dendrites destabilize and regress; thus, [arg.sup.-/-] mice present a model of adolescent-onset dendritic simplification. We show that [arg.sup.-/-] mice are impaired in a reversal task and that deficits are grossly exacerbated by low-dose cocaine administration. Although ventral prefrontal dopamine D2 receptor levels predict 'perseverative' error counts in wild-type mice, no such relationship is found in [arg.sup.-/-] mice. Moreover, [arg.sup.-/-] mice are insensitive to the disruptive effects of the D2/D3 antagonist haloperidol in reversal but show normal sensitivity to its locomotor-depressant actions. Arg deficiency and orbitofrontal cortical Arg inhibition via STI-571 infusion also enhance the psychomotor stimulant actions of cocaine. These findings provide evidence that stabilization of dendritic structure beginning in adolescence is critical for the development of adaptive and flexible behavior after cocaine exposure. D2 | orbital cortex | prefrontal cortex | reversal learning

Electrical recordings in humans and monkeys show attentional enhancement of evoked responses and gamma synchrony in ventral stream cortical areas. Does this synchrony result from intrinsic activity in visual cortex or from inputs from other structures? Using paired recordings in the frontal eye field (FEF) and area V4, we found that attention to a stimulus in their joint receptive field leads to enhanced oscillatory coupling between the two areas, particularly at gamma frequencies. This coupling appeared to be initiated by FEF and was time-shifted by about 8 to 13 milliseconds across a range of frequencies. Considering the expected conduction and synaptic delays between the areas, this time-shifted coupling at gamma frequencies may optimize the postsynaptic impact of spikes from one area upon the other, improving cross-area communication with attention.

Working memory capacity, the maximum number of items that we can transiently store in working memory, is a good predictor of our general cognitive abilities. Neural activity in both dorsolateral prefrontal cortex and posterior parietal cortex has been associated with memory retention during visuospatial working memory tasks. The parietal cortex is thought to store the memories. However, the role of the dorsolateral prefrontal cortex, a top-down control area, during pure information retention is debated, and the mechanisms regulating capacity are unknown. Here, we propose that a major role of the dorsolateral prefrontal cortex in working memory is to boost parietal memory capacity. Furthermore, we formulate the boosting mechanism computationally in a biophysical cortical microcircuit model and derive a simple, explicit mathematical formula relating memory capacity to prefrontal and parietal model parameters. For physiologically realistic parameter values, lateral inhibition in the parietal cortex limits mnemonic capacity to a maximum of 2-7 items. However, at high loads inhibition can be counteracted by excitatory prefrontal input, thus boosting parietal capacity. Predictions from the model were confirmed in an fMRI study. Our results show that although memories are stored in the parietal cortex, interindividual differences in memory capacity are partly determined by the strength of prefrontal top-down control. The model provides a mechanistic framework for understanding top-down control of working memory and specifies two different contributions of prefrontal and parietal cortex to working memory capacity. computer model | fMRI | lateral inhibition | prefrontal | short-term memory | parietal

Cognitive shifting is the ability to adapt to changes in the environment. Extensive research has revealed that the prefrontal cortex plays an important role in cognitive shifting. Adult neuroimaging studies have shown that the inferior prefrontal cortex is activated during cognitive shifting tasks. Developmental studies have shown that cognitive shifting changes significantly during preschool years. It is known that 3-year-old children often perseverate to previous mental sets, whereas 5-year-old children do not. Developmental psychologists assume that maturation of the prefrontal cortex plays an essential role in the development of shifting; however, direct supporting evidence is lacking. We used near-infrared spectroscopy and showed that inferior prefrontal activation is associated with successful shifting in young children. We also showed that even preschool children display adult-like inferior prefrontal activation during a simple cognitive shifting task. This report demonstrates the neural origins of cognitive shifting in young children. These results have the potential to contribute to our understanding of cognitive and brain development in both typically and atypically developed children. cognitive development | inferior prefrontal cortex | near-infrared spectroscopy | preschool children | executive function

Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression, BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnftranscription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF. activity-dependent | GABAergic interneuron | knockout mice | parvalbumin | cortical inhibition

Individual variation in the experience and expression of pleasure may relate to differential patterns of lateral frontal activity. Brain electrical measures have been used to study the asymmetric involvement of lateral frontal cortex in positive emotion, but the excellent time resolution of these measures has not been used to capture second-by-second changes in ongoing emotion until now. The relationship between pleasure and second-by-second lateral frontal activity was examined with the use of hierarchical linear modeling in a sample of 128 children ages 6-10 years. Electroencephalographic activity was recorded during 'pop-out toy,' a standardized task that elicits pleasure. The task consisted of 3 epochs: an anticipation period sandwiched between 2 play periods. The amount of pleasure expressed during the task predicted the pattern of nonlinear change in lateral frontal activity. Children who expressed increasing amounts of pleasure during the task exhibited increasing left lateral frontal activity during the task, whereas children who expressed contentment exhibited increasing right/decreasing left activity. These findings indicate that task-dependent changes in pleasure relate to dynamic, nonlinear changes in lateral frontal activity as the task unfolds. Keywords: pleasure, EEG, lateral frontal cortex

Relatively little is known about the long-term neurobiological sequelae of chronic stress, which predisposes susceptible patients to neuropsychiatric conditions affecting the prefrontal cortex (PFC). Animal models and human neuroimaging experiments provide complementary insights, yet efforts to integrate the two are often complicated by limitations inherent in drawing comparisons between unrelated studies with disparate designs. Translating from a rodent model of chronic stress where we have shown reversible disruption of PFC function, we show that psychosocial stress induces long-lasting but reversible impairments in behavioral and functional magnetic resonance imaging (fMRI) measures of PFC function in humans. Twenty healthy adults, exposed to 1 month of psychosocial stress, confirmed by a validated rating scale, were scanned while performing a PFC-dependent attention-shifting task. One month later, they returned for a second scanning session after a period of reduced stress, and their performance was compared with a twice-scanned, matched group of low-stress controls. Psychosocial stress selectively impaired attentional control and disrupted functional connectivity within a frontoparietal network that mediates attention shifts. These effects were reversible: after one month of reduced stress, the same subjects showed no significant differences from controls. These results highlight the plasticity of PFC networks in healthy human subjects and suggest one mechanism by which disrupted plasticity may contribute to cognitive impairments characteristic of stress-related neuropsychiatric conditions in susceptible individuals. chronic stress | dorsolateral prefrontal cortex | functional connectivity analysis | perceived stress scale

The primary challenge associated with the development of an LC/MS/MS-based assay for simultaneous determination of biogenic monoamine neurotransmitters such as norepinephrine (NE), dopamine (DA), serotonin (5-HT), and normetanephrine (NM) in rat brain microdialysates is to improve detection sensitivity. In this work, a UPLC/ MS/MS-based method combined with a diethyl labeling technique was developed for simultaneous determination of a panel of monoamines in rat prefrontal cortex microdialysates. The chromatographic run time is 3.5 min/ sample. The limits of detection of the UPLC/MS/MS-based method for NE, DA, 5-HT/and NM, with/without diethyl labeling of monoamines, are 0.005/0.4 (30/2367 pM), 0.005/0.1 (33/653 pM), 0.005/0.2 (28/1136 pM), and 0.002/0.2 ng/mL (11/1092 pM), respectively. Diethyl labeling of amino groups of monoamines affords 20-100 times increased detection sensitivity of corresponding native monoamines during the UPLC/MS/MS analysis. This could result from the following: (1) improved fragmentation patterns; (2) increased hydrophobicity and concomitantly increased ionization efficiency in ESI MS and MS/MS analysis; (3) reduced matrix interference. This labeling reaction employs a commercially available reagent, acetaldehyde-[d.sub.4], to label the amine groups on the monoamines via reductive amination. It is also simple, fast (~25-min reaction time), specific, and quantitative under mild reaction conditions. Data are also presented from the application of this assay to monitor the drug-induced changes of monoamine concentrations in rat prefrontal cortex microdialysate samples followed by administration of SKF 81297, a selective D1 dopamine receptor agonist known to elevate the extracellular level of the neurotransmitters DA and NE in the central nervous system.

In the prefrontal cortex, NMDA receptors are important for normal prefrontal functions such as working memory, and their dysfunction plays a key role in the pathological processes of psychiatric disorders such as schizophrenia. Little is known, however, about the synaptic properties of NMDA receptors in the local circuits of recurrent excitation, a leading candidate mechanism underlying working memory. We investigated the NMDA receptor-mediated currents at monosynaptic connections between pairs of layer 5 pyramidal neurons. We found that NMDA receptor-mediated currents at prefrontal synapses in the adult, but not young, rats exhibit a twofold Longer decay time-constant and temporally summate a train of stimuli more effectively, compared to those in the primary visual cortex. Experiments with pharmacological, immunocytochemical, and biochemical approaches further suggest that, in the adult animals, neurons express significantly more NR2B subunits in the prefrontal cortex than the visual cortex. The NR2B-rich synapses in the prefrontal circuitry may be critically implicated in online cognitive computations and plasticity in learning, as well as psychiatric disorders. cortical development | persistent activity | working memory | recurrent excitation

Cognitive deficits in schizophrenia are thought to derive from a hypofunction of the prefrontal cortex (PFC), but the origin of the hypofunction is unclear. To explore the nature of this deficit, we genetically modified mice to model the increase in striatal dopamine [D.sub.2] receptors ([D.sub.2]Rs) observed in patients with schizophrenia. Previously, we reported deficits in spatial working memory tasks in these mice, congruent with the working memory deficits observed in schizophrenia. However, patients with schizophrenia suffer from deficits in many executive functions, including associative learning, planning, problem solving, and nonspatial working memory. We therefore developed operant tasks to assay two executive functions, conditional associative learning (CAL) and nonspatial working memory. Striatal [D.sub.2]R-overexpressing mice show a deficit in CAL because of perseverative behavior, caused by interference from the previous trial. [D.sub.2]R up-regulation during development was sufficient to cause this deficit, because switching off the transgene in adulthood did not rescue the phenotype. We validated prefrontal dependency of CAL by using neurotoxic lesions. Lesions of the medial PFC including the anterior cingulate, infralimbic, and prelimbic cortices impair CAL because of increased interference from previously rewarded trials, exactly as observed in [D.sub.2]R transgenic mice. In contrast, lesions restricted to the infra-limbic and prelimbic cortices have no effect on CAL but impair performance in the nonspatial working memory task. These assays not only give us insight into how excess striatal [D.sub.2]Rs affect cognition but also provide tools for studying cognitive endophenotypes in mice. cognitive symptoms | dopamine [D.sub.2] receptors | genetic mouse models | schizophrenia | prefrontal cortex lesion

This article analyzes the effortful control of automatic processing related to social and emotional behavior, including control over evolved modules designed to solve problems of survival and reproduction that were recurrent over evolutionary time. The inputs to effortful control mechanisms include a wide range of nonrecurrent information--information resulting not from evolutionary regularities but from explicit appraisals of costs and benefits. Effortful control mechanisms are associated with the ventromedial prefrontal cortex and the ventral anterior cingulated cortex. These mechanisms are largely separate from mechanisms of cognitive control (termed executive function) and working memory, and they enable effortful control of behavior in the service of long range goals. Individual differences in effortful control are associated with measures of conscientiousness in the Five Factor Model of personality. Research in the areas of aggression, ethnocentrism, sexuality, reward seeking, and emotion regulation is reviewed indicating effortful control of automatic, implicit processing based on explicit appraisals of the context. Evidence is reviewed indicating that evolutionary pressure for cooperation may be a critical adaptive function accounting for the evolution of explicit processing. Keywords: Effortful control, explicit processing, evolutionary psychology, conscientiousness, prefrontal cortex

Functional near-infrared spectroscopy (fNIRS) is an emerging technique for monitoring the concentration changes of oxy- and deoxy-hemoglobin (oxy-Hb and deoxy-Hb) in the brain. An important consideration in fNIRS-based neuroimaging modality is to conduct group-level analysis from a set of time series measured from a group of subjects. We investigate the feasibility of multilevel statistical inference for fNIRS. As a case study, we search for hemodynamic activations in the prefrontal cortex during Stroop interference. Hierarchical general linear model (GLM) is used for making this multilevel analysis. Activation patterns both at the subject and group level are investigated on a comparative basis using various classical and Bayesian inference methods. All methods showed consistent left lateral prefrontal cortex activation for oxy-Hb during interference condition, while the effects were much less pronounced for deoxy-Hb. Our analysis showed that mixed effects or Bayesian models are more convenient for faithful analysis of fNIRS data. We arrived at two important conclusions. First, fNIRS has the capability to identify activations at the group level, and second, the mixed effects or Bayesian model is the appropriate mechanism to pass from subject to group-level inference. Index Terms--General linear model (GLM), near-infrared spectroscopy, statistical inference, Stroop task.

The Identity Style Inventory-Revised for a Sixth-Grade Reading Level (ISI-6G) was administered to samples of community college students (N=99) and middle school and high school students (N=320). Tests of between-groups differences indicated that the college sample had a significantly lower mean diffuse-avoidant score on the ISI-6G than the middle and high school sample. In terms of actual assignment to identity styles, college students were significantly more likely to be classified as informational or normative, while the younger students were more likely to be diffuse-avoidant. The mean ages of participants for each of the three identity styles were compared, and it was found that diffuse-avoidant participants had the lowest mean age (15.54 years), while individuals with an informational orientation had the highest mean age (17.20 years). Results suggest that, in general, identity style evolves with age and maturity and the general trajectory or progression involves movement away from a diffuse-avoidant orientation. Findings are discussed in terms of current knowledge of neurocognitive development during adolescence and early adulthood. Keywords Identity * Identity style * Brain development * Executive function * Prefrontal cortex * Cross-sectional

Cognitively demanding tasks that evoke activation in the brain's central-executive network (CEN) have been consistently shown to evoke decreased activation (deactivation) in the default-mode network (DMN). The neural mechanisms underlying this switch between activation and deactivation of large-scale brain networks remain completely unknown. Here, we use functional magnetic resonance imaging (fMRI) to investigate the mechanisms underlying switching of brain networks in three different experiments. We first examined this switching process in an auditory event segmentation task. We observed significant activation of the CEN and deactivation of the DMN, along with activation of a third network comprising the right fronto-insular cortex (rFIC) and anterior cingulate cortex (ACC), when participants perceived salient auditory event boundaries. Using chronometric techniques and Granger causality analysis, we show that the rFIC-ACC network, and the rFIC, in particular, plays a critical and causal role in switching between the CEN and the DMN. We replicated this causal connectivity pattern in two additional experiments: (i) a visual attention 'oddball' task and (ii) a task-free resting state. These results indicate that the rFIC is likely to play a major role in switching between distinct brain networks across task paradigms and stimulus modalities. Our findings have important implications for a unified view of network mechanisms underlying both exogenous and endogenous cognitive control. brain networks | cognitive control | insula | attention | prefrontal cortex

Light is an important environmental factor for regulation of mood. There is a high frequency of seasonal affective disorder in high latitudes where light exposure is limited, and bright light therapy is a successful antidepressant treatment. We recently showed that rats kept for 6 weeks in constant darkness (DD) have anatomical and behavioral features similar to depressed patients, including dysregulation of circadian sleep-waking rhythms and impairment of the noradrenergic (NA)-locus coeruleus (LC) system. Here, we analyzed the cell viability of neural systems related to the pathophysiology of depression after DD, including NA-LC, serotoninergic-raphe nuclei and dopaminergicventral tegmental area neurons, and evaluated the depressive behavioral profile of light-deprived rats. We found increased apoptosis in the three aminergic systems analyzed when compared with animals maintained for 6 weeks in 12:12 light-dark conditions. The most apoptosis was observed in NA-LC neurons, associated with a significant decrease in the number of cortical NA boutons. Behaviorally, DD induced a depression-like condition as measured by increased immobility in a forced swim test (FST). DD did not appear to be stressful (no effect on adrenal or body weights) but may have sensitized responses to subsequent stressors (increased fecal number during the FST). We also found that the antidepressant desipramine decreases these neural and behavioral effects of light deprivation. These findings indicate that DD induces neural damage in monoamine brain systems and this damage is associated with a depressive behavioral phenotype. Our results suggest a mechanism whereby prolonged limited light intensity could negatively impact mood. apoptosis | constant darkness | depression | forced swim test | prefrontal cortex

One useful strategy for inferring others' mental states (i.e., mentalizing) may be to use one's own thoughts, feelings, and desires as a proxy for those of other people. Such self-referential accounts of social cognition are supported by recent neuroimaging observations that a single brain region, ventromedial prefrontal cortex (vMPFC), is engaged both by tasks that require introspections about self and by tasks that require inferences about the minds of others perceived to be similar to self. To test whether people automatically refer to their own mental states when considering those of a similar other, we examined repetition-related suppression of vMPFC response during self-reflections that followed either an initial reflection about self or a judgment of another person. Consistent with the hypothesis that perceivers spontaneously engage in self-referential processing when mentalizing about particular individuals, vMPFC response was suppressed when self-reflections followed either an initial reflection about self or a judgment of a similar, but not a dissimilar, other. These results suggest that thinking about the mind of another person may rely importantly on reference to one's own mental characteristics. functional neuroimaging | mentalizing | self-reference | social cognition

Adolescence is a key period for the development of brain circuits underlying affective and behavioral regulation. It remains unclear, however, whether and how adolescent brain structure influences day-to-day affective behavior. Because of significant changes in the nature of family relations that also typically occur during adolescence, parent-child interactions provide a meaningful context where affective behavior and its regulation may be assessed. In a sample of 137 early adolescents, we investigated the relationship between aspects of the adolescents' brain structure and their affective behavior as assessed during observation of parent-child interactions. We found a significant positive association between volume of the amygdala and the duration of adolescent aggressive behavior during these interactions. We also found male-specific associations between the volume of prefrontal structures and affective behavior, with decreased leftward anterior paralimbic cortex volume asymmetry associated with increased duration of aggressive behavior, and decreased leftward orbitofrontal cortex volume asymmetry associated with increased reciprocity of dysphoric behavior. These findings suggest that adolescent brain structure is associated with affective behavior and its regulation in the context of family interactions, and that there may be gender differences in the neural mechanisms underlying affective and behavioral regulation during early adolescence. Particularly as adolescence marks a period of rapid brain maturation, our findings have implications for mental health outcomes that may be revealed later along the developmental trajectory. emotion | family interactions | neuroimaging | structural MRI | gender differences

Reaction time task rule congruency effects (RT-TRCEs) reflect faster responses to stimuli for which the competing task rules indicate the same correct response than to stimuli indicating conflicting responses. The authors tested the hypothesis that RT-TRCE reflects activated overlearned response category codes in long-term memory (such as up or left). The results support the hypothesis by showing that (a) RT-TRCE was absent for tasks for which there were no response codes ready beforehand, (b) RT-TRCE was present after these tasks were practiced, and (c) these practice effects were found only if the tasks permitted forming abstract response category codes. The increase in the RT-TRCE with response slowness, found only for familiar tasks, suggests that the abstract response category codes may be verbal or linguistic in these cases. The results are discussed in relation to task-switching theories and prefrontal functions. Keywords: task switching, working memory, congruency, practice, prefrontal functions

Morphological studies show that repeated restraint stress leads to selective atrophy in the apical dendritic field of pyramidal cells in the medial prefrontal cortex (mPFC). However, the functional consequence of this selectivity remains unclear. The apical dendrite of layer V pyramidal neurons in the mPFC is a selective locus for the generation of increased excitatory postsynaptic currents (EPSCs) by serotonin (5-HT) and hypocretin (orexin). On that basis, we hypothesized that apical dendritic atrophy might result in a blunting of 5-HT- and hypocretin-induced excitatory responses. Using a combination of whole-cell recording and two-photon imaging in rat mPFC slices, we were able to correlate electrophysiological and morphological changes in the same layer V pyramidal neurons. Repeated mild restraint stress produced a decrement in both 5-HT-and hypocretin-induced EPSCs, an effect that was correlated with a decrease in apical tuft dendritic branch length and spine density in the distal tuft branches. Chronic treatment with the stress hormone corticosterone, while reducing 5-HT responses and generally mimicking the morphological effects of stress, failed to produce a significant decrease in hypocretin-induced EPSCs. Accentuating this difference, pretreatment of stressed animals with the glucocorticoid receptor antagonist RU486 blocked reductions in 5-HT-induced EPSCs but not hypocretin-induced EPSCs. We conclude: (i) stress-induced apical dendritic atrophy results in diminished responses to apically targeted excitatory inputs and (ii) corticosterone plays a greater role in stress-induced reductions in EPSCs evoked by 5-HT as compared with hypocretin, possibly reflecting the different pathways activated by the two transmitters. two-photon imaging | apical tuft | slice | spine | rat

Visual selection is influenced by items in working memory (WM) and priming from implicit memory when a stimulus is repeated across time. WM effects are typically held to be top-down in nature [Soto D, Heinke D, Humphreys GW, Blanco MJ (2005) J Exp Psychol Hum Percept Perform 31:248-261], whereas implicit priming may operate in a bottom-up manner [Theeuwes J, Reimann B, Mortier K (2006) Vis Cogn 14: 466-489]. How WM and implicit priming affects influence visual selection remains poorly understood, however. Here, we report functional MRI evidence that dissociates the neural mechanisms involved in these memory-based effects on selection. The reappearance of a stimulus held in WM enhanced activity in superior frontal gyrus, midtemporal, and occipital areas that are known to encode the prior occurrence of stimuli. In contrast, mere stimulus repetition elicited a suppressive response in the same regions. An additional finding was that a frontothalamic network was sensitive to the behavioral relevance of a match between the contents of WM and the visual search array, enhancing activity when the contents of WM matched the critical target of selection. Items held in WM influence selection by using neural coding distinct to effects of mere repetition. repetition priming | working memory | fMRI | anterior prefrontal cortex: BA10 | thalamus

What are the genetic and neural components that support adaptive learning from positive and negative outcomes? Here, we show with genetic analyses that three independent dopaminergic mechanisms contribute to reward and avoidance learning in humans. A polymorphism in the DARPP-32 gene, associated with striatal dopamine function, predicted relatively better probabilistic reward learning. Conversely, the C957T polymorphism of the DRD2 gene, associated with striatal D2 receptor function, predicted the degree to which participants learned to avoid choices that had been probabilistically associated with negative outcomes. The Val/Met polymorphism of the COMT gene, associated with prefrontal cortical dopamine function, predicted participants' ability to rapidly adapt behavior on a trial-to-trial basis. These findings support a neurocomputational dissociation between striatal and prefrontal dopaminergic mechanisms in reinforcement learning. Computational maximum likelihood analyses reveal independent gene effects on three reinforcement learning parameters that can explain the observed dissociations. basal ganglia | prefrontal cortex | computational model