To the extent that recognition memory relies on interactions among widely distributed neural assemblies across the brain, phase synchronization between brain rhythms may play an important role in meditating those interactions. As the theta rhythm is known to modulate in power during the recognition memory process, we aimed to determine how the phase synchronization of the theta rhythms across the brain changes with recognition memory. Fourteen human participants performed a visual object recognition task in a virtual reality environment. Electroencephalograms were recorded from the scalp of the participants while they either recognized objects that had been presented previously or identified new objects. From the electroencephalogram recordings, we analyzed the phase-locking value of the theta rhythms, which indicates the degree of phase synchronization. We found that the overall phase-locking value recorded during the recognition of previously viewed objects was greater than that recorded during the identification of new objects. Specifically, the theta rhythms became strongly synchronized between the frontal and the left parietal areas during the recognition of previously viewed objects. These results suggest that the recognition memory process may involve an interaction between the frontal and the left parietal cortical regions mediated by theta phase synchronization.

Several studies have suggested an interaction between α-synuclein protein and iron in Parkinson's disease. The presence of iron together with α-synuclein in Lewy bodies, the increase of iron in the substantia nigra and the correlation between polymorphism of the several genes implicated in iron metabolism and Parkinson's disease, support a role for iron in the neurodegeneration. Analysis of post mortem brains revealed increased amount of insoluble α-synuclein protein despite unchanged/reduced levels of α-synuclein mRNA in Parkinson's disease. Interestingly, on the basis of the presence of a putative iron responsive element in the 5'-UTR, it has been suggested that there is a possible iron-dependent translational control of human α-synuclein mRNA. Considering the similarity between the sequences present in human α-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of α-synuclein mRNA. Here we used HEK293 cells treated with iron chelator deferoxamine or ferric ammonium citrate to verify the possible iron-dependent translational control of human α-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human α-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human α-synuclein expression is regulated by iron mainly at the translational level. This result not only supports a role for iron in the translational control of α-synuclein expression, but also suggests that iron chelation may be a valid approach to control α-synuclein levels in the brain.

In women, pain symptoms and nociceptive thresholds vary with the reproductive cycle, suggesting the role of estrogen receptors (ERs) in modulating nociception. Our previous data strongly suggest an interaction between ERs and ATP-induced purinergic (P2X3) as well as ERs and capsaicin-induced vanilloid (TRPV1) receptors at the level of dorsal root ganglion (DRG) neurons. In this study, we investigated the expression of P2X3 and TRPV1 receptors by western blotting and immunohistochemistry in lumbosacral DRGs from wild type, ERα, and ERβ knockout mice. We found a significant decrease for both P2X3 and TRPV1 in ERαKO and ERβKO. This phenomenon was visualized in L1, L2, L4, and L6 levels for P2X3 receptors and in L1, L2, and S2 levels for TRPV1 receptors. This tan interaction between P2X3/TRPV1 and ERs expression in sensory neurons may represent a novel mechanism that can explain the sex differences in nociception observed in clinical practice. The DRG is an important site of visceral afferent convergence and cross-sensitization and a potential target for designing new anti-nociceptive therapies.

Microglia are the most important immune cells within the highly specialized environment of the central nervous system. Upon activation, they transform from a resting 'ramified' into a fully functional 'amoeboid' phenotype with the ability to perform phagocytosis and generate free radicals. A combined flow cytometric assay for the simultaneous measurement of these two functions in porcine microglia in vitro is presented: reactive oxygen species are detected using hydroethidine; phagocytosis is assessed using fluorescein isothiocyanate-labeled latex beads. The combination of these two probes allowed us to distinguish four subpopulations within cultured porcine microglia on the basis of their functional activity. The effect of several exogenous stimuli [phorbol myristate acetate, conditioned medium, interferon γ (IFN-γ)] on the in-vitro functional properties of porcine microglia is investigated using this test. In particular for IFN-γ, a significant modulatory effect on the intracellular reactive oxygen species production and phagocytic activity was observed. This result suggests an alternative role of IFN-γ acting on cultured porcine microglia.

Electroencephalography amplitude, phase synchronization, and directionality of phase coupling within and between hemispheres were compared for different frequency components in 27 healthy individuals before and after 5 days of daily 1 Hz repetitive transcranial magnetic stimulation (rTMS), and at 2 weeks after the last session. Instantaneous amplitudes of α (8-13 Hz) and β (13-30 Hz) frequency components were increased after daily rTMS, the effects of which were declining over time, suggesting an adapting response with repeated rTMS sessions. The phase synchronization of electroencephalography increased significantly in the α frequency, especially the upper-α band (11-13 Hz), in both the frontal and the temporal areas, predominantly in the ipsilateral hemisphere. Asymmetric directional interactions of the upper-α band were stronger from the stimulated area to the contralateral hemisphere. No significant differences were found at 2 weeks after rTMS in any of these values. Focal 1 Hz rTMS induces an enhancement in the ipsilateral dominant corticocortical interaction drastically by interhemispheric asymmetric coupling from the stimulated cortical area with an adapting response with repeated sessions. This kind of method can be valuable for possible clinical applications in various neuropsychiatric conditions to study the therapeutic mechanisms of 1 Hz rTMS.

Abnormally expanded C9orf72 hexanucleotide repeats are found in up to 7% of patients with sporadic amyotrophic lateral sclerosis (SALS). It is not known whether the sporadic nature of the disease represents incomplete penetrance of the phenotype or expansion of the repeat in the SALS patient. The sizes of C9orf72 hexanucleotide repeats were measured in blood DNA of 43 SALS patients and their parents who had no symptoms of ALS. Two SALS patients (4.7%) had abnormally expanded (>30 repeats) C9orf72 repeats. Both of their fathers (one with dementia) also had abnormally expanded repeats. Nine SALS patients had intermediate-normal repeat sizes (7-30 repeats); in each of these, one parent had a similar repeat size. In the remaining 32 SALS patients, the repeat sizes were low-normal (<7 repeats). There was no evidence of repeat instability leading to abnormal numbers of repeats in any SALS patient in this trio cohort. Our results suggest that a simple monogenic mechanism is not likely to be the cause of C9orf72 repeat-related SALS.

TRPV1 is a nonselective cation channel in nociceptors. TRPV1 stimulation has been shown to lead to the activation of microglia and astrocytes in the dorsal horn of the spinal cord. However, information on the effect of TRPV1 stimulation on glial activation in the trigeminal nucleus caudalis (TNC) is lacking. Here, we stimulated TRPV1 in the trigeminal afferents by a repetitive injection of 10 mmol/l capsaicin into the whisker pad for 2 days (d2 group), 4 days (d4 group), or 6 days (d6 group). As a control (c group), the vehicle was injected for 2 days. Anti-Iba1 and anti-glial fibrillary acidic protein antibodies were used to immunostain microglia and astrocytes in the TNC, respectively. The ratio of the cross-sectional area immunoreactive for Iba1 to the entire area of the TNC was increased in the d2 group compared with the c group on the injected side. Microglia were recruited to the superficial layers of the TNC. The numbers of microglia were reduced in the d4 group and the d6 group compared with the d2 group. The ratio of the cross-sectional area immunoreactive for glial fibrillary acidic protein to the entire TNC showed a significant increase in d2 group and the d4 group compared with the c group on the injected side. Behavioral analysis indicated that mechanical allodynia began to develop after 2 days of capsaicin treatment and persisted for at least 6 days after the onset of the repetitive capsaicin injection. These data indicate that TRPV1 stimulation activates the microglia and astrocytes in temporally distinct ways and that the development of mechanical allodynia is independent of such glial activation.

Diffusion tensor imaging (DTI) can be used to study the organization of brain white matter noninvasively. The aim of this study was to present a proof of concept for integrating DTI with high-resolution anatomical (T1) images to map and assess inter-regional connectivity across the entire cortex in a cohort of healthy participants and compared with patients with major depressive disorder. We used MRI data of 23 patients and 23 matched controls, assessed as part of baseline testing in the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Freesurfer was used to analyze the T1 images to automatically label 35 gyral-based areas for each hemisphere. DTI tractography was performed to parcellate intercortical tracts using each of these areas in seed-target combinations. We quantified fractional anisotropy, number-of-fiber connections, and fiber path length for each DTI connection, with the goal of identifying the best measure or combination of measures to characterize major depression. The best classification accuracy for the individual measures was achieved using the number-of-fibers data, whereas the combination model provided a slight improvement. The most discriminant features between the two groups were for white matter associated with the limbic, frontal, and thalamic projection fibers and as part of cortical connections between the left inferior temporal and the postcentral cortex; the left parstriangularis and the left superior frontal; the left cuneus and the corpus callosum; the left lingual and the right lateral occipital, the right superior parietal and the right superior temporal cortices; and the right inferior parietal and the right insula and postcentral cortices.

Pain was reported by 60-90% of patients with depression, and chronic pain states are often linked to depression. Animal models of pain/depression are generally lacking for the identification of centrally active drugs. In the present study, pain sensitivity was assessed in a mouse model of anxiety/depression on the basis of chronic corticosterone (CORT) administration through the drinking water (CORT model). We measured thermal hyperalgesia as shown by a decrease in the latency to hind paw licking in the hot plate test and cold allodynia reflected by a decrease in the time spent on the plate set at 20°C in the thermal preference plate test. Subsequently, we determined the effect of chronic administration of the selective serotonin reuptake inhibitor fluoxetine (an antidepressant known to reverse anxiety/depressive-like state in CORT-treated mice) on pain relief. Fluoxetine administration reduced both heat hyperalgesia and cold allodynia, thus unveiling a putative link between mood and nociception in the CORT model. This hypothesis is consistent with previous clinical studies reporting the analgesic efficacy of fluoxetine in depressed patients suffering from pain disorders. Together, these results suggest that the CORT model, with pain/anxiety/depressive-like state, is a good candidate for translational research.

Accumulated amyloid-β (Aβ) is a well-known cause of neuronal apoptosis in Alzheimer's disease and exerts its action partly by inducing mitochondrial dysfunction. Previous studies have suggested a neuroprotective role for mitochondrial ATP-sensitive potassium (KATP) channel openers against Aβ damages, but the molecular details were unclear. Recent evidence indicates that endoplasmic reticulum (ER) stress also plays an important role in the process of cell apoptosis. It remains to be determined whether KATP channel openers mediate their potential neuroprotective role by inhibiting ER stress pathways. The mRNA and protein expression levels of caspase-12, an ER-specific caspase, were observed. Here we showed that in response to the treatment with Aβ25-35 (10 μM) for 24 h the mRNA and protein expression levels of caspase-12 were significantly upregulated; however, this change could be partly reversed by pretreatment with diazoxide (1 mM) for 1 h. This effect was negated by 5-hydroxydecanoate, a selective mitochondrial KATP channel blocker. Our results indicate that the cytoprotective efficacy of diazoxide under Aβ25-35-induced insults is mediated, at least in part, by inhibition of ER stress. Demonstration of the neuroprotective action of diazoxide provides additional insights into the pathogenic mechanisms of Aβ25-35 toxicity and defines possible molecular targets for therapeutic intervention.

Recent studies show that electrophysiological markers of auditory processing such as the cortical 100 ms response (M100) and the mismatch field, derived from magnetoencephalography, might be used to identify children with autism spectrum disorders - M100 peak latency - and to stratify children with autism according to the degree of language impairment - mismatch field peak latency. The present study examined the latency of right superior temporal gyrus M100 and mismatch field in a cohort of children and young adolescents with specific language impairment (n=17), in comparison with age-matched and nonverbal intelligence quotient-matched typically developing controls (n=21). Neither group showed symptoms associated with autism. Although M100 latency (reflecting early auditory processing) did not distinguish controls from children with specific language impairment, the later 'change detection' mismatch field response was significantly delayed (by >50 ms) in the specific language impairment group. Linear discriminant analysis confirmed the role of mismatch field latency (92%) but not M100 latency (8%) in distinguishing groups. The present results lend support to the claim that a delayed M100 is specific to autism spectrum disorders (with relative independence of degree of language impairment) and that a delayed mismatch field reflects an abnormality more generally associated with language impairment, suggesting that mismatch field delay in the present specific language impairment group and previously reported in autistic children with language impairment may be indicative of a common neural system dysfunction.

Male Bengalese finches have a complex song-sequence pattern containing multiple elements. Learning and producing songs require memorization of the phonology and the sequence of elements. We tested the auditory memory of male finches for their own songs to determine whether the auditory memory included the sequence of elements. An immediate early gene ZENK is induced by auditory processing in the secondary auditory area of the caudomedial nidopallium (NCM) and the caudomedial mesopallium (CMM) in response to song presentations. Repeated presentations of the same song result in a decrease in ZENK expression in these areas, reflecting habituation to auditory processing. We examined sequential differences in auditory processing using the habituation-dishabituation method. After repeatedly presenting the male finches' own song stimulus, we changed the stimulus to a shuffled sequence of songs. If the shuffled songs induced ZENK expression, it indicated that the auditory areas had been dishabituated by the sequential differences. The shuffled songs caused intermediate ZENK expression in the NCM when compared with the expression by a conspecific new song and that by the same song. The tendency toward intermediate expression was similar in the CMM; however, a significant difference was observed between the conspecific song and shuffled songs. These results suggest that the sequential difference caused a partial dishabituation in the NCM. Thus, the auditory areas processed not only the phonology but also the sequence of songs.

This review article presents a summary of recent efforts to understand brain temperature and its regulation under different conditions. Brain temperature has a crucial influence on brain processes. Its regulation is the outcome of the balance of core and arterial blood temperatures, cerebral blood flow, brain metabolism, functional conditions, and external temperature. However, the relationship between these factors is not fully understood and several uncertainties remain. There are no satisfactory normative data on temperatures throughout the brain, but new technologies promise to fill this gap. Brain temperature changes with brain functional activation and under pathological conditions in ways that are not understood. A full understanding of brain temperature control is mandatory to optimize attempts at brain cooling during clinical conditions such as stroke and head injury.

Research suggests that emotional intelligence capacities may be related to the functional integrity of the corticolimbic regions including the ventromedial prefrontal cortex, insula, and amygdala. No study has yet examined regional brain volumes in relation to the two dominant models of emotional intelligence: the Ability model, which posits a set of specific demonstrable capabilities for solving emotional problems, and the Trait model, which proposes a set of stable emotional competencies that can be assessed through subjectively rated self-report scales. In 36 healthy participants, we correlated scores on the Mayer-Salovey-Caruso Emotional Intelligence Test (an Ability measure) and the Bar-On Emotional Quotient Inventory (a Trait measure) with regional brain volumes using voxel-based morphometry. Total Mayer-Salovey-Caruso Emotional Intelligence Test scores were positively correlated with the left insula grey matter volume. The Strategic emotional intelligence subscale correlated positively with the left ventromedial prefrontal cortex and insular volume. In contrast, for the Bar-On Emotional Quotient Inventory, Stress Management scores correlated positively with the bilateral ventromedial prefrontal cortex volume. Amygdala volumes were unrelated to emotional intelligence measures. Findings support the role of the ventromedial prefrontal cortex and insula as key nodes in the emotional intelligence circuitry.

This study examined the effects of pulsed radiofrequency (PRF) on sciatic nerve ligation-induced mechanical pain hypersensitivity in rats. The nociceptive threshold was evaluated using the paw pressure vocalization test. Seven days after nerve ligation, animals receiving a single PRF session (120 s/2 Hz/45 V/42°C) on L4-5-6 dorsal root ganglia ipsilateral to a chronic constriction injury (CCI) showed a reduced sensory hypersensitivity at H4 6 and 1 day after PRF as compared with animals without PRF. One day after PRF, the effect of morphine (2 mg/kg, subcutaneous) increased the nociceptive threshold in the no PRF/CCI group and more extensively in PRF/CCI animals. These results showed that PRF might represent an interesting strategy not only to reduce neuropathic pain but also to enhance the efficacy of morphine in patients with neuropathic pain, well known to be opioid resistant.

Human placental decidua basalis-derived mesenchymal stem cells (DBMSCs) have been identified as valuable sources for cell transplantation. In this study, we found that DBMSCs could be induced to form neural stem cells in the form of neurospheres. These neurospheres were further differentiated into dopamine neuron-like cells with a cocktail of cytokines. The differentiated DBMSCs were verified through the presence of a neuron-like morphology, the expression of specific dopamine neuron makers, and the production of dopamine. In addition, this differentiation capacity of DBMSCs was not affected by long-term culture, and the cells maintained a normal karyotype in vitro. The dopamine neuronal differentiation and the relative safety transplantation potential of DBMSCs may facilitate stem cell therapeutic approaches to Parkinson's disease.

Chondroitin sulfate proteoglycans are formed in scar tissue after a spinal cord injury and inhibit axon regrowth. The production of neurocan, one of these chondroitin sulfate proteoglycans, in cultured spinal cord astrocytes increased after the addition of epidermal growth factor (EGF) in a dose-dependent manner (2-200 ng/ml). In astrocytes stimulated by 20 ng/ml of EGF, neurocan production was inhibited after the addition of the p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580: 3-10 μM) in a dose-dependent manner. These results suggest that the activation of p38 MAPK is one of the mechanisms of neurocan production in EGF-stimulated astrocytes. The p38 MAPK inhibitor may reduce neurocan production and accelerate axonal regrowth after a spinal cord injury.

Our previous studies have shown that substantial amounts of 8-oxoguanine are present in the DNA and RNA in the hippocampi of old senescence-accelerated mice (SAMP8); however, oxidative damage to DNA and RNA in the other regions of the brain from a month after birth to the onset of aging has not been examined completely. In this study, we analyzed the amount of 8-oxoguanine in DNA and RNA in the temporal and frontal lobes of SAMP8 during aging by the immunohistochemical method. Compared with age-matched control acceleration-resistant mice (SAMR1), 8- and 12-month-old SAMP8 had increased amounts of 8-oxoguanine in the DNA and RNA in the frontal lobe, whereas in the temporal lobe, this trend began to appear as early as 4 months. The levels of 8-oxoguanine in the temporal lobe were significantly higher than those in the frontal lobe. These results indicate that nucleic acid oxidative damage occurs as an age-associated phenomenon, and can occur more easily in the temporal lobe than in the frontal lobe of SAMP8.

In our everyday life, processing complex dynamic scenes such as crowds and traffic is of critical importance. Further, it is well documented that there is an age-related decline in complex perceptual-cognitive processing, which can be reversed with training. It has been suggested that a specific dynamic scene perceptual-cognitive training procedure [the three-dimensional multiple object tracking speed task (3D-MOT)] helps observers manage socially relevant stimuli such as human body movements as seen in crowds or during sports activities. Here, we test this assertion by assessing whether training older observers on 3D-MOT can improve biological motion (BM) perception. Research has shown that healthy older adults require more distance in virtual space between themselves and a point-light walker to integrate BM information than younger adults. Their performances decreased markedly at a distance as far away as 4 m (critical for collision avoidance), whereas performance in young adults remained constant up to 1 m. We trained observers between 64 and 73 years of age on the 3D-MOT speed task and looked at BM perception at 4 and 16 m distances in virtual space. We also had a control group trained on a visual task and a third group without training. The perceptual-cognitive training eliminated the difference in BM perception between 4 and 16 m after only a few weeks, whereas the two control groups showed no transfer. This demonstrates that 3D-MOT training could be a good generic process for helping certain observers deal with socially relevant dynamic scenes.