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Could learning that uses cognitive control to judiciously use relevant information while ignoring distractions generally improve brain function, beyond forming explicit memories? According to a neuroplasticity hypothesis for how some cognitive behavioural therapies are effective, cognitive control training (CCT) changes neural circuit information processing1–3. Here we investigated whether CCT persistently alters hippocampal neural circuit function. We show that mice learned and remembered a conditioned place avoidance during CCT that required ignoring irrelevant locations of shock. CCT facilitated learning new tasks in novel environments for several weeks, relative to unconditioned controls and control mice that avoided the same place during reduced distraction. CCT rapidly changes entorhinal cortex-to-dentate gyrus synaptic circuit function, resulting in an excitatory–inhibitory subcircuit change that persists for months. CCT increases inhibition that attenuates the dentate response to medial entorhinal cortical input, and through disinhibition, potentiates the response to strong inputs, pointing to overall signal-to-noise enhancement. These neurobiological findings support the neuroplasticity hypothesis that, as well as storing item–event associations, CCT persistently optimizes neural circuit information processing. Studies in mice show that cognitive control training rapidly improves brain circuit function and enhances subsequent learning, which both persist for months.

PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we examined the amount and distribution of PKMζ in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKMζ increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. During the initial expression of the memory, we tagged principal cells with immediate-early gene Arc promoter-driven transcription of fluorescent proteins. The subset of memory-tagged CA1 cells selectively increases expression of PKMζ during memory storage, and the increase persists in dendritic compartments within stratum radiatum for 1 month, indicating long-term storage of information in the CA3-to-CA1 pathway. We conclude that persistent increases in PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other protein kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in kinase protein expression. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we examined the amount and distribution of PKMζ in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 h. During spatial memory storage, PKMζ increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. The subset of CA1 pyramidal cells that are tagged by immediate early gene Arc-driven transcription of fluorescent proteins, whose expression increases during initial memory formation, also expresses the persistent increase of PKMζ during memory storage. In the memory-tagged cells, the increased PKMζ expression persists in dendritic compartments within stratum radiatum for 1 month, indicating the long-term storage of information in the CA3-to-CA1 pathway during remote spatial memory. We conclude that persistent increases in PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

SUMMARYCognitive control, the judicious use of relevant information while ignoring distractions, is a feature of everyday cognitive experience, but its neurobiology is understudied. We investigated whether cognitive control training (CCT) changes hippocampal neural circuit function in mice, beyond the changes caused by place learning and memory formation. Mice learned and remembered a conditioned place avoidance during CCT that required ignoring irrelevant locations of shock. They were compared to controls that learned the same place avoidance under lower cognitive control demands. Weeks after CCT, mice learn new tasks in novel environments faster than controls; they learned to learn. We investigated entorhinal cortex-to-dentate gyrus neural circuit changes and report that CCT rapidly changes synaptic circuit function, resulting in an excitatory-inhibitory subcircuit change that persists for months. CCT increases inhibition that attenuates the dentate response to medial entorhinal cortical input, and through disinhibition, potentiates the response to strong inputs, pointing to overall signal-to-noise enhancement. These neurobiological findings support a neuroplasticity hypothesis that, beyond storing item/event associations, CCT persistently optimizes neural circuit information processing.

Objective Functional imaging studies of panic disorder subjects suggest an increased activation of the cingulate regions of the brain. Aim of the current study was to explore the white matter connectivity differences between subjects with panic disorder and healthy comparison subjects. Method Structural white matter connectivity, as determined from fractional anisotropy (FA) values obtained by diffusion tensor imaging, was assessed for anterior and posterior cingulate regions in 24 panic disorder patients and 24 age and sex-matched healthy comparison subjects. Results Subjects with panic disorder exhibited significantly greater FA values in left anterior and right posterior cingulate regions (by 13.3% and 19.6%, respectively) relative to comparison subjects. White matter connectivity for these two cingulate regions was also positively correlated with clinical severity, as determined by Panic Disorder Severity Scale. FA values in left anterior cingulate region negatively correlated with the time of Trail Making Tests and positively with Digit Symbol Substitution Test. Conclusions Findings suggest a potential ‘enhancement’ in white matter connectivity in left anterior and right posterior cingulate regions in panic disorder, and that these changes may play an important role in mediating clinical symptoms of panic disorder.

Background Previous brain imaging studies have reported hyperactivation of the amygdala and hypoactivation of the anterior cingulate in posttraumatic stress disorder (PTSD) patients, which is believed to be an underlying neural mechanism of the PTSD symptoms. The current study specifically focuses on the abnormal activity of the rostral anterior cingulate, using a paradigm which elicits an unexpected processing conflict caused by salient emotional stimuli. Methods Twelve survivors (seven men and five women) of the Taegu subway fire in 2003, who later developed PTSD, agreed to participate in this study. Twelve healthy volunteers (seven men and five women) were recruited for comparison. Functional brain images of all participants were acquired using functional magnetic resonance imaging while performing a same–different judgment task, which was modified to elicit an unexpected emotional processing conflict. Results PTSD patients, compared to comparison subjects, showed a decreased rostral anterior cingulate functioning when exposed to situations which induce an unexpected emotional processing conflict. Moreover, PTSD symptom severity was negatively correlated to the level of decrease in the rostral anterior cingulate activity. Conclusions The results of this study provide evidence that the rostral anterior cingulate functioning is impaired in PTSD patients during response-conflict situations that involve emotional stimuli.

Background: This study was conducted to investigate the relationship between patterns of temperament and character and self-reported psychopathology in adolescents from the community. Sampling and Methods: The Junior Temperament and Character Inventory (JTCI) and Youth Self-Report (YSR) instruments were administered to 623 Korean middle school students (boys/girls = 331/292; age = 13.3 ± 0.9 years old). Multiple linear regression analyses were used to evaluate the relationship between temperament and character based on Cloninger’s biogenetic theory of personality and youth psychopathology of internalizing and externalizing problems. Results: Internalizing problems of the YSR (withdrawn, somatic complaint and anxious/depressed scales) were significantly related to high Harm Avoidance and low Reward Dependence (JTCI temperament) and low Self-Directedness and high Self-Transcendence (JTCI character). Externalizing problems of the YSR (delinquency and aggression) were significantly associated with high Novelty Seeking and high Harm Avoidance (JTCI temperament) and low Self-Directedness, low Cooperativeness and high Self-Transcendence (JTCI character).Conclusions: Findings of the current study suggest that specific patterns of temperament and character potentially influence adolescents’ psychopathology in the community.

Background: The objective of this study was to evaluate the relationship between symptoms of attention deficit hyperactivity disorder (ADHD) and biogenetic temperament, as assessed by the Junior Temperament and Character Inventory (JTCI) in Korean elementary school children. Sampling and Methods: Five hundred and sixteen elementary school students (254 boys and 262 girls; age range 9–14 years, mean age 11.0 ± 1.0 years) were studied. The Junior Temperament and Character Inventory, both the self-rating and parent rating scales, the DuPaul ADHD rating scale (ARS-IV) for parents and teachers and the Child Behavior Checklist have been completed by study subjects. Children with high ARS-IV scores (the upper 10th percentile, n = 52) were defined to have ADHD. Fifty-two age- and sex-matched non-ADHD control subjects were selected randomly from a pool of 464 subjects. Results: Inattention and hyperactivity/impulsivity symptoms correlated positively with Novelty Seeking in both children and parent ratings. These symptoms correlated negatively with Persistence, Self-Directedness and Cooperativeness. Novelty Seeking also had significant correlations with attention problems, delinquent behavior, aggressive behavior, externalizing problems and social problems in the Child Behavior Checklist. The ADHD group (n = 52) had higher scores of Novelty Seeking and lower scores of Self-Directedness and Cooperativeness, compared with the control group. Conclusions: There were significant correlations between ADHD symptoms and Novelty Seeking. Current findings suggest that Novelty Seeking and ADHD share biogenetic backgrounds.

The objective of the current study was to evaluate structural changes of the corpus callosum (CC) in abstinence methamphetamine (MA) users. Shape and size of the CC in 27 MA users were compared to those of 18 healthy comparison subjects. To define the local curvature and width of the CC, medial model-based shape analysis was performed using CC skeletons extracted from a distance map. To define the local displacement of the CC, a boundary model-based shape analysis was performed. In addition, the size of regional areas of the CC was measured according to the Witelson's definition for comparison. In the medial model-based shape analysis, increased curvature in the genu (curvature angle difference = 4.1°) and decreased width in posterior midbody (width difference = 0.77 mm) and isthmus area (width difference = 0.86 mm) of the CC were observed in MA users relative to healthy comparison subjects. In the boundary model-based shape analysis, significant displacement was observed in MA users where there were differences in shape/width patterns by the medial model-based shape analysis. There were no differences in the size of regional areas of the CC between groups. Findings suggest that MA use is associated with regional changes in interhemispheric white matter tracts, which connect frontal and parietal cortices and that these frontal and parietal abnormalities may underlie clinical manifestations of the MA abuse.

The objective of this study was to evaluate the relationship between attention deficit-hyperactivity/impulsivity symptoms and Internet addiction. In total, 535 elementary school students (264 boys, 271 girls; mean age, 11.0 +/- 1.0 years) were recruited. The presence or severity of Internet addiction was assessed by the Young's Internet Addiction test. Parents and teachers of the children completed the DuPaul's attention deficit hyperactivity disorder (ADHD) rating scale (ARS; Korean version, K-ARS) and Child Behavior Checklists. Children with the highest and lowest quartiles in K-ARS scores were defined to be in ADHD and non-ADHD groups, respectively. Five children (0.9%) met criteria for a definite Internet addiction and 75 children (14.0%) met criteria for a probable Internet addiction. K-ARS scores had significant positive correlations with Young's Internet Addiction test scores. The Internet addiction group had higher total scores of K-ARS and ADHD-related subcategories in the Child Behavior Checklists than the non-addiction group. The ADHD group had higher Internet addiction scores compared with the non-ADHD group. Therefore, significant associations have been found between the level of ADHD symptoms and the severity of Internet addiction in children. In addition, current findings suggest that the presence of ADHD symptoms, both in inattention and hyperactivity-impulsivity domains, may be one of the important risk factors for Internet addiction.

Calcitonin gene-related peptide (CGRP) acting within the bed nucleus of the stria terminalis (BNST) increases anxiety as well as neural activation in anxiety-related structures, and mediates behavioral stress responses. Similar effects have been described following intra-ventricular as well as intra-BNST infusions of the stress-responsive neuropeptide, corticotropin releasing factor (CRF). Interestingly, CGRP-positive terminals within the lateral division of the BNST form perisomatic baskets around neurons that express CRF, suggesting that BNST CGRP could exert its anxiogenic effects by increasing release of CRF from these neurons. With this in mind, the present set of experiments was designed to examine the role of CRFR1 signaling in the anxiogenic effects of CGRP within the BNST and to determine whether CRF from BNST neurons contributes to these effects. Consistent with previous studies, we found that 400 ng CGRP infused bilaterally into the BNST increased the acoustic startle response and induced anxiety-like behavior in the elevated plus maze compared to vehicle. Both of these effects were attenuated by 10 mg/kg PO of the CRFR1 antagonist, GSK876008. GSK876008 alone did not affect startle. An intra-BNST infusion of the CRFR1 antagonist CP376395 (2 μg) also blocked increases in acoustic startle induced by intra-BNST infusion of CGRP, as did virally-mediated siRNA knockdown of CRF expression locally within the BNST. Together, these results suggest that the anxiogenic effects of intra-BNST CGRP may be mediated by CRF from BNST neurons acting at local CRFR1 receptors.

Modern views on learning and memory accept the notion of biological constraints—that the formation of association is not uniform across all stimuli. Yet cellular evidence of the encoding of selective associations is lacking. Here, conditioned stimuli (CSs) and unconditioned stimuli (USs) commonly employed in two basic associative learning paradigms, fear conditioning and taste aversion conditioning, were delivered in a manner compatible with a functional cellular imaging technique (Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization [catFISH]) to identify biological constraints on CS–US convergence at the level of neurons in basolateral amygdala (BLA). Results indicate coincident Arc mRNA activation within BLA neurons after CS–US combinations that yield rapid, efficient learning, but not after CS–US combinations that do not.

Background: Associative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the existence and location of neurons in the brain that receive convergent information about the conditioned stimulus (CS) and unconditioned stimulus (US) during the acquisition of conditioned fear memory. Convergent activation of neurons is generally viewed as a key event for fear learning, yet there has been almost no direct evidence of this critical event in the mammalian brain. Methodology/Principal Findings: Here, we used Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH) to identify neurons activated during single trial contextual fear conditioning in rats. To conform to temporal requirements of catFISH analysis we used a novel delayed contextual fear conditioning protocol which yields significant single- trial fear conditioning with temporal parameters amenable to catFISH analysis. Analysis yielded clear evidence that a population of BLA neurons receives convergent CS and US information at the time of the learning, that this only occurs when the CS-US arrangement is supportive of the learning, and that this process requires N-methyl-D-aspartate receptor activation. In contrast, CS-US convergence was not observed in dorsal hippocampus. Conclusions/Significance: Based on the pattern of Arc activation seen in conditioning and control groups, we propose that a key requirement for CS-US convergence onto BLA neurons is the potentiation of US responding by prior exposure to a novel CS. Our results also support the view that contextual fear memories are encoded in the amygdala and that the role of dorsal hippocampus is to process and transmit contextual CS information.

This study explored differences in frontal white-matter (WM) integrity between methamphetamine (MA) abusers and healthy comparison subjects using diffusion tensor imaging (DTI). Fractional anisotropy (FA) values, which indicate WM integrity, were calculated for regions-of-interest in frontal WM on diffusion tensor images of 32 MA abusers and 30 healthy comparison subjects. Frontal executive functions were also assessed by the Wisconsin Card Sorting test (WCST). MA abusers had significantly lower FA values in bilateral frontal WM at the anterior commissure-posterior commissure (AC-PC) plane and the right frontal WM 5 mm above the AC-PC plane relative to healthy comparison subjects. MA abusers had more total, perseveration and non-perseveration errors in the WCST relative to healthy comparison subjects. FA values of the right frontal WM 5 mm above the AC-PC plane negatively correlated with the number of total and non-perseveration errors in the WCST in MA abusers. In the sub-analysis for gender differences, lower FA values in frontal WM and more errors in the WCST were found only in male MA abusers, not in female MA abusers, relative to comparison subjects of the respective gender. We report that frontal WM integrity of MA abusers is compromised. This finding may also be related to impairment in frontal executive function. In addition, the neurotoxic effect of MA on frontal WM may be less prominent in women than in men, possibly due to oestrogen's neuroprotective effect.

Previously, our group reported the altered white matter tract integrity of the left anterior cingulate in posttraumatic stress disorder (PTSD) in whole-brain exploration. Current study intended to explore whether the alteration was more prominent in any specific regions of the cingulum bundle. Diffusion tensor images of 21 PTSD subjects and 21 healthy comparison subjects were acquired. Eight isocubic regions of interest (ROIs), i.e. bilateral rostral, subgenual, dorsal, and upper cingulum bundle, were selected. Fractional anisotropy values in each ROI, which indicate the white matter tract integrity, were measured and compared between groups. Relative to comparison subjects, PTSD subjects had significantly smaller fractional anisotropy values in the left side of rostral, subgenual and dorsal cingulum bundle (26.7, 25.0, 22.2% decrease, respectively), but not in the right side ROIs. We report an asymmetrical alteration of the cingulum bundle in PTSD.

The authors first divided the midsagittal corpus callosum of 22 healthy volunteers using three different subdivision methods: Witelson's geometric subdivision, boundary model-based subdivision, and medial model-based subdivision. Next, subdivisions of the corpus callosum were clustered on the basis of homogeneity of the fractional anisotropy values as produced from diffusion tensor images. Nine subregions of corpus callosum, similar in location and size, were successfully clustered when medial model-based or boundary model-based subdivisions were applied. These nine subregions of the corpus callosum were different from the seven subregions defined by Witelson's geometric subdivision, especially at the anterior and posterior tips of the corpus callosum. Our method of corpus callosum division can be potentially utilized to assess structural changes in the midsagittal corpus callosum.

Background The current study was conducted to compare the prevalence, severity, and location of white matter signal hyperintensities (WMH) on brain magnetic resonance (MR) imaging in methamphetamine (MA) abusers. Methods Thirty-three MA abusers and 32 age- and gender-matched healthy comparison subjects were studied. Axial T-2 weighted images and fluid attenuated inversion recovery axial images were obtained using 3.0 T MR scanner. The severity of WMH was assessed separately for deep and periventricular WMH. Ordinal logistic regression models were used to assess the odds ratio for WMH. Results MA abusers had greater severity of WMH than the healthy comparison subjects (odds ratio: 7.06, 8.46, and 4.56 for all, deep, and periventricular WMH, respectively). Severity of deep WMH correlated with total cumulative dose of MA (p = 0.027). Male MA abusers had greater severity of WMH than female MA abusers (odds ratio = 10.00). While male MA abusers had greater severity of WMH than male comparison subjects (odds ratio = 18.86), there was no significant difference in WMH severity between female MA abusers and female comparison subjects. Conclusions The current study reports increased WMH in MA abusers, which may be related to MA-induced cerebral perfusion deficits. In addition, female MA abusers had less severe WMH than male MA abusers, possibly due to estrogen's protective effect against ischemic or neurotoxic effects of MA.

Authors explored grey-matter density in 29 methamphetamine abusers and 20 healthy comparison subjects using voxel-based morphometry. Grey-matter density changes and performances on the Wisconsin Card Sorting test (WCST) were also compared between 11 short-term (6 months) and 18 long-term (or=6 months) abstinent methamphetamine abusers. Methamphetamine abusers had lower grey-matter density in the right middle frontal cortex (corrected p0.05) and more total errors in the WCST (p0.01) relative to healthy comparison subjects. Grey-matter density decrease in the right middle frontal cortex correlated with total errors in the WCST in methamphetamine abusers (r=-0.45). Long-term abstinent abusers had significantly less right middle frontal grey-matter density decrease (p0.01) and total errors in the WCST (p0.01) than short-term abstinent abusers, but more than the healthy comparison subjects. We report that methamphetamine abusers have prefrontal grey-matter deficit, which may, in part, recover with long-term abstinence.