Early life nociceptive stimulus and fentanyl exposure increase hippocampal neurogenesis and anxiety but do not affect spatial learning and memory.

This study aimed to determine whether preemptive fentanyl administration in neonatal rats reduces the impact of a nociceptive stimulus initiated during the first day of life (P1) on hippocampal neurogenesis, behavior, and learning. At P1, Wistar rat pups received either a subcutaneous injection of fentanyl (F) before intraplantar injection of complete Freund's adjuvant (CFA) (CFA + F group), an isolated injection of CFA (CFA group), or subcutaneous injection of fentanyl without CFA injection (F). Control animals received saline injections using the same route and volume as the treatment groups. Hippocampal neurogenesis was evaluated by 5' -bromo-2'-deoxyuridine (BrdU) staining on P10 and P39 to assess neuronal proliferation and survival, respectively. Anxiety behavior in adulthood was assessed using an open field test (OF) and an elevated plus maze test (EPM). Spatial memory was assessed on a Morris water maze test (MWM), where the animals were trained for seven days, beginning on P81, and the probe trial was performed to evaluate memory retention. Although the CFA + F group showed an increased number of proliferative cells on P10, this finding did not persist on P39. The CFA + F group spent more time in the closed arms in the EPM, revealing more anxious behavior, although the early noxious experience, both with and without fentanyl, did not alter neurogenesis in adolescence and learning in adulthood. This study highlights that the impact of pain in early life pain combined with fentanyl on hippocampal neurogenesis on P10 did not persist on P39. In addition, this combined intervention during the first week of life was associated with higher anxiety levels.

Posterior cingulate cortex/precuneus blood oxygen-level dependent signal changes during the repetition of an attention task in meditators and nonmeditators.

BACKGROUND AND PURPOSE: Among several cognitive advantages, meditation is thought to enhance practitioners' capacity for sustained attention. In the present study, we explored this question by testing meditation practitioners (meditators) and nonpractitioners (nonmeditators) on a task that requires sustained attention, the Stroop Word-Color Task (SWCT), while using functional MRI. PARTICIPANTS AND METHODS: Participants were all right-handed and included 23 regular meditators as well as 17 nonmeditators. Participants viewed color words (i.e. 'red,' 'blue,' or 'green') presented one at a time on the screen that were written in either the same color (congruent condition) or a different color (incongruent condition) and were asked to indicate the color of the print. Participants also viewed noncolor words written in unrelated colors (neutral condition). Both groups completed the same two acquisition runs. RESULTS: Although both meditators and nonmeditators gave faster responses on run 2 than run 1 for both the neutral and incongruent trials, nonmeditators showed decreased activation and meditators showed increased activation in precuneus/posterior cingulate cortex. These regions were previously shown to be activated in the SWCT and belong to default mode network as well as to cognitive control network. CONCLUSION: Attention to repetitive stimuli during two equal runs of SWCT is mediated by the precuneus/posterior cingulate cortex, and mental training through meditation may influence the activity of these regions during such tasks.

Effects of a 7-Day Meditation Retreat on the Brain Function of Meditators and Non-Meditators During an Attention Task.

Meditation as a cognitive enhancement technique is of growing interest in the field of health and research on brain function. The Stroop Word-Color Task (SWCT) has been adapted for neuroimaging studies as an interesting paradigm for the understanding of cognitive control mechanisms. Performance in the SWCT requires both attention and impulse control, which is trained in meditation practices. We presented SWCT inside the MRI equipment to measure the performance of meditators compared with non-meditators before and after a meditation retreat. The aim of this study was to evaluate the effects of a 7-day Zen intensive meditation training (a retreat) on meditators and non-meditators in this task on performance level and neural mechanisms. Nineteen meditators and 14 non-meditators were scanned before and after a 7-day Zen meditation retreat. No significant differences were found between meditators and non-meditators in the number of the correct responses and response time (RT) during SWCT before and after the retreat. Probably, due to meditators training in attention, their brain activity in the contrast incongruent > neutral during the SWCT in the anterior cingulate, ventromedial prefrontal cortex/anterior cingulate, caudate/putamen/pallidum/temporal lobe (center), insula/putamen/temporal lobe (right) and posterior cingulate before the retreat, were reduced compared with non-meditators. After the meditation retreat, non-meditators had reduced activation in these regions, becoming similar to meditators before the retreat. This result could be interpreted as an increase in the brain efficiency of non-meditators (less brain activation in attention-related regions and same behavioral response) promoted by their intensive training in meditation in only 7 days. On the other hand, meditators showed an increase in brain activation in these regions after the same training. Intensive meditation training (retreat) presented distinct effects on the attention-related regions in meditators and non-meditators probably due to differences in expertise, attention processing as well as neuroplasticity.

The effects of mindfulness and relaxation training for insomnia (MRTI) on postmenopausal women: a pilot study.

OBJECTIVE: The aim of the study was to evaluate the effects of mindfulness and relaxation training for insomnia on insomnia and quality of life in postmenopausal women. METHODS: Thirty postmenopausal women aged 50 to 65 years, who were not using hormone therapy, and had a diagnosis of insomnia and an apnea-hypopnea index of less than 15, were randomly assigned to two groups: a mindfulness intervention group and a control group. They were assessed before the intervention, and 8 weeks after its completion using questionnaires assessing sleep quality (Pittsburgh Sleep Quality Index), insomnia (Insomnia Severity Index), quality of life in menopause (Menopause-Specific Quality of Life), menopausal symptoms (Kupperman Menopausal Index), and level of attention (Mindfulness Awareness Attention Scale). They were also assessed through ambulatory polysomnography. This is a pilot study and is limited by its small sample size. RESULTS: The results of the questionnaires showed significant differences in the group that received mindfulness training compared with the control group, namely, improvements in sleep quality, a reduction in the severity of insomnia, a better quality of life, improved attention levels, and a reduction in menopausal and vasomotor symptoms. Polysomnography results showed no differences between the groups. CONCLUSIONS: Eight weeks mindfulness meditation training improved sleep quality, quality of life, attention levels, and reduced vasomotor symptoms in postmenopausal women with insomnia.

Interação academia-indústria. Relato da experiência da Vale / Academy-industry interaction. Vale's experience report

RESUMO Abordamos aqui a nucleação de um modelo de inovação aberta na Vale (uma das maiores mineradoras do mundo) apresentando o contexto histórico em que se deu esse processo. Discutimos algumas das questões que possivelmente haviam até então dificultado a implantação de uma estrutura de pesquisa e desenvolvimento focando o longo prazo pela indústria no Brasil. Destacamos algumas das dificuldades encontradas ao longo do processo, bem como algumas das razões que levaram ao sucesso da iniciativa.

ABSTRACT We discuss how Vale (one of the world's largest diversified mining companies) implemented an organizational structure that enabled an open innovation model. We describe the historical perspective in which this process took place. In addition, we present some of the potential causes underlying the slow advance of Brazilian industry in undertaking long-term research and development agendas. Lastly, we list some of the obstacles encountered in this process, as well as some of the potential reasons that might have contributed to the success of the initiative.

Is mindfulness associated with insomnia after menopause?

OBJECTIVE: Mindfulness has been defined as being intentionally aware of internal and external experiences that occur at the present moment, without judgment. Techniques that develop mindfulness, such as meditation, have positive effects on reducing insomnia, a sleep disorder that is common both during and after menopause. Our aim was to establish whether postmenopausal women with insomnia are less mindful than postmenopausal women without sleep disorders. METHODS: Postmenopausal women aged 50 to 65 years who did not use hormone therapy were recruited for the study. The sample included 14 women with insomnia and 12 women without insomnia or any other sleep disorder. The groups were comparable in age, schooling, and anxiety level. To assess mindfulness, we used the validated Mindful Attention Awareness Scale and the attentiveness domain of the Positive and Negative Affect Schedule-Expanded Form. RESULTS: Participants with insomnia were less mindful than healthy women. The level of mindfulness was able to discriminate the group with insomnia from the healthy group, with 71.4% accuracy. CONCLUSIONS: Postmenopausal women with insomnia are less mindful than women without insomnia. Mindfulness-based interventions, such as meditation, may be beneficial for postmenopausal insomnia.

Kinin B1 receptor gene ablation affects hypothalamic CART productionb.

A role for the kinin B1 receptor in energy-homeostatic processes was implicated in previous studies; notably, the studies where kinin B1 receptor knockout mice (B1-/-) were shown to have impaired adiposity, impaired leptin and insulin production, lower feed efficiency, protection from liver steatosis and diet-induced obesity when fed a high fat diet (HFD). In particular, in a model where the B1 receptor is expressed exclusively in the adipose tissue, it rescues the plasma insulin concentration and the weight gain seen in wild type mice. Taking into consideration that leptin participates in the formation of hypothalamic nuclei, which modulate energy expenditure, and feeding behavior, we hypothesized that these brain regions could also be altered in B1-/- mice. We observed for the first time a difference in the gene expression pattern of cocaine and amphetamine related transcript (CART) in the (lateral hypothalamic area (LHA) resulting from the deletion of the kinin B1 receptor gene. The correlation between CART expression in the LHA and the thwarting of diet-induced obesity corroborates independent correlations between CART and obesity. Furthermore, it seems to indicate that the mechanism underlying the 'lean' phenotype of B1-/- mice does not stem solely from changes in peripheral tissues but may also receive contributions from changes in the hypothalamic machinery involved in energy homeostasis processes.

Experimental model of facial paralysis by nerve compression in primates (Callithrix sp.): a new model of facial paralysis in small nonhuman primates.

CONCLUSION: We conclude that facial nerve injury induced by compression is associated with a reasonable time window (4 weeks) that allows possible neurotrophic effects to be analyzed. Additionally, there are no hints of cross-innervation by the contralateral facial nerve or parallel innervation by other nerves in the hemiface ipsilateral to the injured nerve. OBJECTIVE: The aim of this work was to develop an experimental model of facial nerve injury in nonhuman primates (Callithrix sp.). METHODS: In this study, individuals of the non-human primate species Callithrix sp. were subjected to three different types of facial nerve injury, and they were observed for 27 days after surgery by video to record their facial movements. RESULTS: Two types of nerve compression caused severe initial facial paralysis followed by gradual recovery until normal levels were reached at the end of the evaluation period. Injury induced by nerve resection was followed by a complete lack of facial movement recovery.

Hippocampal gene expression analysis using the ORESTES methodology shows that homer 1a mRNA is upregulated in the acute period of the pilocarpine epilepsy model.

In the study of temporal lobe epilepsy (TLE) the characterization of genes expressed in the hippocampus is of central importance for understanding their roles in epileptogenic mechanisms. Although several large-scale studies on TLE gene expression have been reported, precise assignment of individual genes associated with this syndrome is still debatable. Here we investigated differentially expressed genes by comparison of mRNAs from normal and epileptic rat hippocampus in the pilocarpine model of epilepsy. For this we used a powerful EST sequencing methodology, ORESTES (Open Reading frame Expressed Sequence Tags), which generates sequence datasets enriched for mRNAs open reading frames (ORFs) rather than simple 5' and 3' ends of mRNAs. Analysis of our sequences shows that ORESTES readily enables the identification of epilepsy associated ORFs. PFAM analysis of protein motifs present in our ORESTES epilepsy database revealed diverse important protein family domains, such as cytoskeletal, cell signaling and protein kinase domains, which could be involved in processes underlying epileptogenesis. More importantly, we show that the expression of homer 1a, known to be coupled to mGluR and NMDA synaptic transmission, is associated with pilocarpine induced status epilepticus (SE). The combined use of the pilocarpine model of epilepsy with the ORESTES technique can significantly contribute to the identification of specific genes and proteins related to TLE. This is the first study applying a large-scale method for rapid shotgun sequencing directed to ORFs in epilepsy research.

Phosphorylation of the alpha subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus.

In response to different cellular stresses, a family of protein kinases phosphorylates eIF2alpha (alpha subunit of eukaryotic initiation factor-2), contributing to regulation of both general and genespecific translation proposed to alleviate cellular injury or alternatively induce apoptosis. Recently, we reported eIF2alpha(P) (phosphorylated eIF2alpha) in the brain during SE (status epilepticus) induced by pilocarpine in mice, an animal model of TLE (temporal lobe epilepsy) [Carnevalli, Pereira, Longo, Jaqueta, Avedissian, Mello and Castilho (2004) Neurosci. Lett. 357, 191-194]. We show in the present study that one eIF2alpha kinase family member, PKR (double-stranded-RNA-dependent protein kinase), is activated in the cortex and hippocampus at 30 min of SE, reflecting the levels of eIF2alpha(P) in these areas. In PKR-deficient animals subjected to SE, eIF2alpha phosphorylation was clearly evident coincident with activation of a secondary eIF2alpha kinase, PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. The extent of eIF2alpha phosphorylation correlated with the inhibition of protein synthesis in the brain, as determined from polysome profiles. We also found that C57BL/6 mice, which enter SE upon pilocarpine administration but are more resistant to seizure-induced neuronal degeneration, showed very low levels of eIF2alpha(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2alpha contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2alpha phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.

Effect of moxibustion at acupoints Ren-12 (Zhongwan), St-25 (Tianshu), and St-36 (Zuzanli) in the prevention of gastric lesions induced by indomethacin in Wistar rats.

This study was aimed at assessing the physical characteristics underlying the action of moxibustion at acupoints Ren-12 (Zhongwan), St-25 (Tianshu), and St-36 (Zuzanli) in preventing acute injuries of the gastric mucous membrane induced by indomethacin in Wistar rats. Induction of gastric lesions, by means of intragastric administration of indomethacin (100 mg/kg), in adult male Wistar rats was followed by treatment with moxibustion using Artemisia vulgaris dried leaves at 60 or 45 degrees C, heating with Artemisia vulgaris charcoal at 50 degrees C, heating with a regular tobacco cigar at 50 degrees C, and heating with a regular water pad at 50 degrees C, The effects of the different heating protocols over the gastric lesions were then compared. In addition, another group of animals was pretreated with capsaicin (100 mg/kg, s.c.), in order to lesion C fibers and, 15 days later, subjected to indomethacin administration and moxibustion treatment. Moxibustion was significantly more efficient at 60 degrees C than at 45 degrees C in preventing gastric lesions triggered by indomethacin. Moxibustion applied in acupoints provided a significant reduction of the lesion area, which was two times less than that of animals stimulated in a nonacupoint (sham group). Comparing the therapeutic effects provided by different forms of heating over the gastric lesions, the burning of dry leaves of Artemisia vulgaris was significantly more efficient in preventing gastric lesions than moxibustion made with Artemisia charcoal or tobacco (cigar) or by heating the animal with a water pad. Desensitization of the afferent sensory C fibers by capsaicin significantly diminished the ability of moxibustion to block the lesions in the gastric mucous membrane. Moxibustion can efficiently prevent indomethacin-induced gastric lesions in rats and this effect is dependent on the temperature, the material used for moxibustion, the use of acupuncture points, and the integrity of C fibers.

Serotonin involvement in the electroacupuncture- and moxibustion-induced gastric emptying in rats.

OBJECTIVE: Electroacupuncture (EA) as well as moxibustion stimulation has been reported to produce an excitatory effect on the gastrointestinal motility of the rat. Serotonergic neurons of the mioenteric and submucous plexus are major participants in the gastrointestinal physiology. Here, we compared the outcomes of the stimulation of a specific set of acupoints with either acupuncture or moxibustion on the gastrointestinal motility and the role of serotonin (5-HT) in this effect. METHODS: To analyze the role of 5-HT on the gastrointestinal motility of the rat, we studied the flow of 25 glass beads administered to the stomach, after treatment of the animals with a serotonin inhibitor (para-chlorophenylalanine [pCPA]). Acupuncture stimulation was performed on acupoints St-36 (Zusanli) and Sp-6 (Sanyinjiao), with electrical stimulation, or on acupoints Ren-10 (Xiawan), Ren-12 (Zhongwan) and St-25 (Tianshu), with moxibustion. Animals subjected to sham stimulation were used as controls in addition to naive, unstimulated animals. RESULTS: Stimulation of the hind limb (St-36 and Sp-6) and abdominal (Ren-10, Ren-12, St-25) acupoints resulted in effective gastric emptying, as compared with sham-stimulated animals. Pretreatment of animals with pCPA abolished either the response provided by acupuncture stimulation in animal groups subjected to hind limb acupoints or the response provided by moxibustion stimulation in abdominal acupoints. CONCLUSION: Our data suggest that moxibustion in the abdominal points and EA in the hind limb require an intact serotonergic pathway. In addition, we suggest that this involvement of serotonin is a general feature of the mediated effects of acupuncture on gastric emptying of the rat.

A comparative study of the effects of electroacupuncture and moxibustion in the gastrointestinal motility of the rat.

We compared the outcomes of the stimulation of specific sets of acupoints with either acupuncture or moxibustion over peristalsis. Twenty-five plastic beads were orally administered in the stomach of the rats and 90 min later animals were sacrificed, the stomach and small intestine were opened, and the number of beads remaining in each segment was counted. Forty rats were immobilized for 20 min and stimulated at either abdominal or hindlimbs acupoints, with either electroacupuncture or moxibustion. Under this restraint (stress) condition electroacupuncture at hindlimb points or moxibustion at abdominal points significantly enhanced gastric emptying (P < 0.02) as well as intestinal motility compared with animals subjected only to immobilization and not stimulated with electroacupuncture or moxibustion. We conclude that the effects of different acupoints and modes of stimulation (electrical vs. moxibustion) over gastrointestinal motility in rats subjected to restraint-induced stress is not uniform and discuss the different neural pathways underlying these differences.

Phosphorylation of translation initiation factor eIF2alpha in the brain during pilocarpine-induced status epilepticus in mice.

In this work, we show extensive phosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha) occurring in the brain of mice subjected to 30 min of status epilepticus induced by pilocarpine. eIF2alpha(P) immunoreactivity was detected in the hippocampal pyramidal layer CA1 and CA3, cortex layer V, thalamus and amygdala. After 2 h of recovery, there was a marked decrease in total brain eIF2alpha(P), with the cortex layer V showing the most pronounced loss of anti-eIF2alpha(P) labeling, whereas the CA1 subregion had a significant increase in eIF2alpha(P). These results indicate that inhibition of protein synthesis in experimental models of epilepsy might be due to low levels of eIF2-GTP caused by the phosphorylation of eIF2alpha, and suggest that translational control may contribute to cell fate in the affected areas.

Analgesia and c-Fos expression in the periaqueductal gray induced by electroacupuncture at the Zusanli point in rats.

The need to use anaesthetised or restrained animals in acupuncture research in laboratory animals may represent a confounding variable, since both anaesthesia and stress alter the pain threshold and the activity of pain-related brain areas. In the current study we assessed the participation of the periaqueductal gray (PAG) in electroacupuncture's (EA) analgesic effects applied to the Zusanli point (36S) under carefully controlled stress conditions. Repeated immobilisation protocols (6 days, 1 h/day and 13 days, 2 h/day) were used to diminish the influence of acute immobilisation stress on c-Fos expression and analgesia (tail-flick test) induced by electroacupuncture on the 36S point (EA36S). Animals submitted to immobilisation alone (IMMO) or to electroacupuncture (100 Hz, 2-4 V, faradic wave) on a non-point region (EANP) were compared with animals submitted to electroacupuncture on the 36S point. In animals not previously submitted to repeated immobilisation, electroacupuncture on the 36S point induced analgesia and c-Fos expression in the PAG was not different from that induced by electroacupuncture at a non-acupuncture point. In animals submitted to repeated immobilisation (repeated immobilisation for 6 days or repeated immobilisation for 13 days), however, electroacupuncture on point 36S led to higher levels of analgesia and c-Fos expression, specifically in the ventrolateral PAG (vlPAG), as compared with animal groups subjected only to immobilisation or to electroacupuncture on a non-point. Our findings endorse previous results, and point to a specific part of the PAG involved in the effects of electroacupuncture at the Zusanli point.

Sprouting of mossy fibers and the vacating of postsynaptic targets in the inner molecular layer of the dentate gyrus.

Aberrant mossy fiber sprouting, which presumably results from hilar mossy cell death after status epilepticus (SE), is a frequently studied feature of temporal lobe epilepsy. Although mossy fiber sprouting can be suppressed by the protein synthesis inhibitor cycloheximide, spontaneous seizures remain unaltered. We have investigated the mechanisms underlying the ability of cycloheximide to block SE-induced mossy fiber sprouting in the inner molecular layer of dentate gyrus (IML). Pilocarpine-induced SE in the presence of cycloheximide resulted in a reduced number of injured hilar cells compared to rats not pretreated with cycloheximide. Presumed mossy cells, identified by calcitonin gene related peptide (CGRP) immunohistochemistry, were not significantly reduced in either group 60 days after SE. Whereas controls had a strong band of CGRP-positive fibers (putative mossy cell axons) and no neo-Timm stained fibers in the IML, pilocarpine-treated rats had no CGRP fibers and strong neo-Timm staining. Cycloheximide-pilocarpine-treated animals, in contrast, had CGRP and neo-Timm staining similar to controls. Cycloheximide might protect hilar CGRP-positive cells during SE and, by allowing those cells to retain their normal axonal projection, prevent mossy fiber sprouting. The recently suggested "irritable" mossy cell hypothesis relies on the survival of mossy cells for network hyperexcitability. We hypothesized that CGRP may be a marker for a subpopulation of relatively resistant mossy cells in rats, which, if they survive injury, may become irritable and contribute to hyperexcitability. We suggest that cycloheximide prevents SE-induced mossy fiber sprouting by preventing the loss of hilar CGRP-positive cells (putative mossy cells).

O futuro da neuropsiquiatria: os novos metodos de investigacao e suas implicacoes no conhecimento do funcionamento cerebral / Neuropsychiatry future: news methods, investigational

No final deste seculo, somos inundados por inumeras descobertas geradas por novos metodos de investigacao em Neurociencias, com importantes implicacoes para o conhecimento sobre o funcionamento do cerebro humano. Nesta revisao, apresentamos alguns desses novos metodos - com enfase nas tecnicas de Genetica e Biologia Molecular e de Neuroimagem. Em seguida, sao discutidos achados de estudos recentes, nos quais essas tecnicas foram utilizadas em transtornos neuropsiquiatricos como a Doenca de Alzheimer, Parkinson e Huntington, Esquizofrenia e o Transtorno Obsessivo-Compulsivo. Conclui-se que o conhecimento gerado por esses novos metodos e suas potenciais implicacoes clinicas sao cruciais para o neurologista e o psiquiatra preocupados em desenvolver seu espirito critico para o proximo seculo