Showing papers in "European Journal of Neuroscience in 2007"

Mechanisms of selective inhibition in visual spatial attention are indexed by alpha-band EEG synchronization.

Abstract: Electroencephalographic studies in humans have demonstrated that orienting of visual attention induces a decrease in oscillatory alpha-band activity (alpha-desynchronization) over cortical areas tuned to the attended visual space. This is interpreted as reflecting intentionally enhanced excitability of these areas to facilitate upcoming visual processing. However, the inverse mechanism might also apply. Brain areas that process task-irrelevant space might be actively suppressed by increased alpha-activity (alpha-synchronization) to protect against input of distracter information. In the present study, we demonstrate that such suppression mechanisms are highly selective and are taking place even without distracters that need to be ignored. During voluntary orienting of attention, we found alpha-synchronization to dominate over desynchronization, to be topographically specific for each of eight attention positions, and to occur over areas processing unattended space in a retinotopically organized pattern. This indicates that alpha-synchronization is an important component of selective attention, serving active suppression of unattended positions during visual spatial orienting.

Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration

Abstract: Microtubule associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and related tauopathies; in this form it is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles. However, the nature of protein kinases and phosphatases and tau sites involved in this lesion has been elusive. We investigated self-assembly and microtubule assembly promoting activities of hyperphosphorylated tau isolated from Alzheimer disease brain cytosol, the AD abnormally hyperphosphorylated tau (AD P-tau) before and after dephosphorylation by phosphoseryl/phosphothreonyl protein phosphatase-2A (PP-2A), and then rephosphorylation by cyclic AMP-dependent protein kinase (PKA), calcium, calmodulin-dependent protein kinase II (CaMKII), glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent protein kinase 5 (cdk5) in different kinase combinations. We found that (i) dephosphorylation of AD P-tau by PP-2A inhibits its polymerization into PHF/straight filaments (SF) and restores its binding and ability to promote assembly of tubulin into microtubules; (ii) rephosphorylation of PP-2A-dephosphorylated AD P-tau by sequential phosphorylation by PKA, CaMKII and GSK-3beta or cdk5, and as well as by cdk5 and GSK-3beta, promotes its self-assembly into tangles of PHF similar to those seen in Alzheimer brain, and (iii) phosphorylation of tau sites required for this pathology are Thr231 and Ser262, along with several sites flanking the microtubule binding repeat region. Phosphorylation of recombinant human brain tau(441) yielded similar results as the PP-2A dephosphorylated AD P-tau, except that mostly SF were formed. The conditions for the abnormal hyperphosphorylation of tau that promoted its self-assembly also induced the microtubule assembly inhibitory activity. These findings suggest that activation of PP-2A or inhibition of either both GSK-3beta and cdk5 or one of these two kinases plus PKA or CaMKII might be required to inhibit Alzheimer neurofibrillary degeneration.

Rhythmic auditory stimulation modulates gait variability in Parkinson's disease.

Abstract: Patients with Parkinson's disease (PD) walk with a shortened stride length and high stride-to-stride variability, a measure associated with fall risk. Rhythmic auditory stimulation (RAS) improves stride length but the effects on stride-to-stride variability, a marker of fall risk, are unknown. The effects of RAS on stride time variability, swing time variability and spatial-temporal measures were examined during 100-m walks with the RAS beat set to 100 and 110% of each subject's usual cadence in 29 patients with idiopathic PD and 26 healthy age-matched controls. Carryover effects were also evaluated. During usual walking, variability was significantly higher (worse) in the patients with PD compared with the controls (P < 0.01). For the patients with PD, RAS at 100% improved gait speed, stride length and swing time (P < 0.02) but did not significantly affect variability. With RAS at 110%, reductions in variability were also observed (P < 0.03) and these effects persisted 2 and 15 min later. In the control subjects, the positive effects of RAS were not observed. For example, RAS increased stride time variability at 100 and 110%. These results demonstrate that RAS enables more automatic movement and reduces stride-to-stride variability in patients with PD. Further, these improvements are not simply a by-product of changes in speed or stride length. After walking with RAS, there also appears to be a carryover effect that supports the possibility of motor plasticity in the networks controlling rhythmicity in PD and the potential for using RAS as an intervention to improve mobility and reduce fall risk.

Fibromyalgia patients show an abnormal dopamine response to pain.

Abstract: Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.

Glutamatergic neurons are present in the rat ventral tegmental area

Abstract: The ventral tegmental area (VTA) is thought to play an important role in reward function. Two populations of neurons, containing either dopamine (DA) or gamma-amino butyric acid (GABA), have been extensively characterized in this area. However, recent electrophysiological studies are consistent with the notion that neurons that utilize neurotransmitters other than DA or GABA are likely to be present in the VTA. Given the pronounced phenotypic diversity of neurons in this region, we have proposed that additional cell types, such as those that express the neurotransmitter glutamate may also be present in this area. Thus, by using in situ hybridization histochemistry we investigated whether transcripts encoded by genes for the two vesicular glutamate transporters, VGluT1 or VGluT2, were expressed in the VTA. We found that VGluT2 mRNA but not VGluT1 mRNA is expressed in the VTA. Neurons expressing VGluT2 mRNA were differentially distributed throughout the rostro-caudal and medio-lateral aspects of the VTA, with the highest concentration detected in rostro-medial areas. Phenotypic characterization with double in situ hybridization of these neurons indicated that they rarely co-expressed mRNAs for tyrosine hydroxylase (TH, marker for DAergic neurons) or glutamic acid decarboxylase (GAD, marker for GABAergic neurons). Based on the results described here, we concluded that the VTA contains glutamatergic neurons that in their vast majority are clearly non-DAergic and non-GABAergic.

Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats.

Abstract: Adolescent brain development seems to be important for the maturation of brain structures and behaviour. Intermittent binge ethanol drinking is common among adolescents, and this type of drinking can induce brain damage. Because we have demonstrated that chronic ethanol treatment induces inflammatory processes in the brain, we investigate whether intermittent ethanol intoxication enhances cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in adolescent rats, and whether these mediators induce brain damage and cause permanent cognitive dysfunctions. Adolescent rats were exposed to ethanol (3.0 g/kg) for two consecutive days at 48-h intervals over 14 days. Levels of COX-2, iNOS and cell death were assessed in the neocortex, hippocampus and cerebellum 24 h after the final ethanol administration. The following day or 20 days after the final injection (adult stage), animals were tested for different behavioural tests (conditional discrimination learning, rotarod, object recognition, beam-walking performance) to assess cognitive and motor functions. Our results show that intermittent ethanol intoxication upregulates COX-2 and iNOS levels, and increases cell death in the neocortex, hippocampus and cerebellum. Furthermore, animals treated with ethanol during adolescence exhibited behavioural deficits that were evident at the end of ethanol treatments and at the adult stage. Administration of indomethacin, a COX-2 inhibitor, abolishes the induction of COX-2 and iNOS expression and cell death, preventing ethanol-induced behavioural deficits. These findings indicate that binge pattern exposure to ethanol during adolescence induces brain damage by inflammatory processes and causes long-lasting neurobehavioural consequences. Accordingly, administering indomethacin protects against ethanol-induced brain damage and prevents detrimental ethanol effects on cognitive and motor processes.

The role of cingulate cortex in the detection of errors with and without awareness: a high-density electrical mapping study.

Abstract: Error-processing research has demonstrated that the brain uses a specialized neural network to detect errors during task performance but the brain regions necessary for conscious awareness of an error are poorly understood. In the present study we show that two well-known error-related event-related potential (ERP) components, the error-related negativity (ERN) and error positivity (Pe) have a differential relationship with awareness during performance of a manual response inhibition task optimized to examine error awareness. While the ERN was unaffected by the participants’ conscious experience of errors, the Pe was only seen when participants were aware of committing an error. Source localization of these components indicated that the ERN was generated by a caudal region of the anterior cingulate cortex (ACC) while the Pe was associated with contributions from a more anterior ACC region and the posterior cingulate–precuneus. Tonic EEG measures of cortical arousal were correlated with individual rates of error awareness and showed a specific relationship with the amplitude of the Pe. The latter finding is consistent with evidence that the Pe represents a P3-like facilitation of information processing modulated by subcortical arousal systems. Our data suggest that the ACC might participate in both preconscious and conscious error detection and that cortical arousal provides a necessary setting condition for error awareness. These findings may be particularly important in the context of clinical studies in which a proper understanding of self-monitoring deficits requires an explicit measurement of error awareness.

Long-term behavioural and molecular alterations associated with maternal separation in rats

Abstract: In this study we addressed whether certain behavioural measures, endocrine levels and specific stress-related proteins exhibit long-term alterations in adult rats following repeated postnatal maternal separation. Rats were subjected to daily maternal separation for 15 min (HMS15) or 180 min (HMS180) from postnatal day 2-14. Adult HMS180 animals were hypoactive and had increased levels of stereotypy compared to HMS15 and normal animal facility-reared (AFR) animals. HMS180 animals also had augmented plasma adrenocorticotropin (ACTH) and corticosterone (CORT) concentrations following an acute stressor, compared to the other two groups. We assessed persistent changes in proteins regulated by stress in hippocampus, cortex, ventral tegmental area, nucleus accumbens, striatum and amygdala. Western blotting analysis revealed a decrease in the levels of mature brain-derived neurotrophic factor (BDNF) in hippocampus and striatum, but an increase in the ventral tegmental area in the HMS180 rats. Levels of pro-BDNF were significantly increased in the ventral tegmental area of HMS180 animals but were unchanged in other brain regions compared to the other two groups. Levels of the transcription factors cAMP response element binding protein (CREB) and DeltaFosB were unchanged in all of the brain regions studied in the maternally separated rats. These data show that maternal separation induces long-term changes in BDNF expression, and more specifically the processing of BDNF, in the hippocampus, striatum and ventral tegmental area. Recognition of these adaptations begins to define the brain regions, and neural circuitry, associated with persistent alterations induced by early life stressors and the development of mood disorders.

Challenging the omnipotence of the suprachiasmatic timekeeper: are circadian oscillators present throughout the mammalian brain?

Abstract: The suprachiasmatic nucleus of the hypothalamus (SCN) is the master circadian pacemaker or clock in the mammalian brain. Canonical theory holds that the output from this single, dominant clock is responsible for driving most daily rhythms in physiology and behaviour. However, important recent findings challenge this uniclock model and reveal clock-like activities in many neural and non-neural tissues. Thus, in addition to the SCN, a number of areas of the mammalian brain including the olfactory bulb, amygdala, lateral habenula and a variety of nuclei in the hypothalamus, express circadian rhythms in core clock gene expression, hormone output and electrical activity. This review examines the evidence for extra-SCN circadian oscillators in the mammalian brain and highlights some of the essential properties and key differences between brain oscillators. The demonstration of neural pacemakers outside the SCN has wide-ranging implications for models of the circadian system at a whole-organism level.

Glycogen synthase kinase-3 inhibition is integral to long-term potentiation.

Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine ⁄threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3b is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3b phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3b. The LTP deficits can be attenuated ⁄rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3b in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer’s and other dementias.

Dissociation of sustained attention from central executive functions: local activity and interregional connectivity in the theta range

Abstract: Human brain oscillatory activity was analysed in the electroencephalographic theta frequency range (4-7 Hz) while subjects executed complex sequential finger movements with varying task difficulty and memory load. Local frontal-midline theta activity was associated with the general level of cognitive demand, with the highest amplitudes in the most demanding condition. Using low-resolution electromagnetic tomography analysis (LORETA), this theta activity was localized in the anterior cingulate gyrus including the cingulate motor area. These results suggest that local theta activity in the anterior cingulate gyrus represents correlates of an attentional system that allocate cognitive resources. In addition, interregional connectivity in the theta frequency range was modulated by memory-related executive functions independently of task difficulty. Connectivity analyses revealed a more distributed long-range network including frontal and parietal cortices during execution of novel compared with well-trained finger movement sequences. Thus, these results are compatible with a model in which theta long-range coupling indicates integration of sensory information into executive control components of complex motor behaviour.

Improved isometric force endurance after transcranial direct current stimulation over the human motor cortical areas

Abstract: Neuromuscular fatigue is the exercise-dependent decrease in the ability of muscle fibres to generate force. To investigate whether manipulation of brain excitability by transcranial direct current stimulation (tDCS; 1.5 mA, 10 min, 0.026 C ⁄cm 2 ) modulates neuromuscular fatigue, we evaluated the effect of brain polarization over the right motor areas of the cerebral cortex of healthy subjects on the endurance time for a submaximal isometric contraction of left elbow flexors. In 24 healthy volunteers the study protocol comprised an assessment of the maximum voluntary contraction (MVC) for the left elbow flexors and a fatiguing isometric contraction (35% of MVC), before and immediately after brain polarization. One hour elapsed between baseline (T0) and postconditioning (T1) evaluation. After tDCS, MVC remained unchanged from baseline (mean ± SEM; anodal tDCS: T0, 154.4 ± 18.07; T1, 142.8 ± 16.62 N; cathodal tDCS: T0, 156 ± 18.75; T1, 141.86 ± 17.53 N; controls: T0, 148.8 ± 6.64; T1, 137.6 ± 7.36 N; P > 0.1). Conversely, endurance time decreased significantly less after anodal than after cathodal tDCS or no stimulation ()21.1 ± 5.5%, )35.7 ± 3.3% and )39.3 ± 3.3%, respectively; P < 0.05). None of the evaluated electromyographic variables changed after tDCS. Anodal tDCS could improve endurance time by directly modulating motor cortical excitability, modulating premotor areas, decreasing fatigue-related muscle pain, increasing motivation and improving synergist muscle coupling. Our findings, showing that anodal tDCS over the motor areas of the cerebral cortex improves muscle endurance, open the way to increasing muscle endurance and decreasing muscle fatigue in normal (i.e. sports medicine) and pathological conditions.

Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses.

Abstract: Synaptic adhesion molecules are thought to play a critical role in the formation, function and plasticity of neuronal networks. Neuroligins (NL1-4) are a family of presumptive postsynaptic cell adhesion molecules. NL1 and NL2 isoforms are concentrated at glutamatergic and GABAergic synapses, respectively, but the cellular expression and synaptic localization of the endogenous NL3 and NL4 isoforms are unknown. We generated a panel of NL isoform-specific antibodies and examined the expression, developmental regulation and synaptic specificity of NL3. We found that NL3 was enriched in brain, where NL3 protein levels increased during postnatal development, coinciding with the peak of synaptogenesis. Subcellular fractionation revealed a concentration of NL3 in synaptic plasma membranes and postsynaptic densities. In cultured hippocampal neurons, endogenous NL3 was highly expressed and was localized at both glutamatergic and GABAergic synapses. Clustering of NL3 in hippocampal neurons by neurexin-expressing cells resulted in coaggregation of NL3 with glutamatergic and GABAergic scaffolding proteins. Finally, individual synapses contained colocalized NL2 and NL3 proteins, and coimmunoprecipitation studies revealed the presence of NL1-NL3 and NL2-NL3 complexes in brain extracts. These findings suggest that rodent NL3 is a synaptic adhesion molecule that is a shared component of glutamatergic and GABAergic synapses.

Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells

Abstract: Neural stem/progenitor cells (NSPCs) proliferate and differentiate depending on their intrinsic properties and local environment. It has been recognized that astrocytes promote neurogenic differentiation of NSPCs, suggesting the importance of cell-cell interactions between glial cells and NSPCs. Recent studies have demonstrated that microglia, one type of glial cells, play an important role in neurogenesis. However, little is known about how activated microglia control the proliferation and differentiation of NSPCs. In this study, we investigated the possibility that microglia-derived soluble factors regulate the behaviour of NSPCs. To this end, NSPCs and microglial cultures were obtained from rat embryonic day 16 subventricular zone (SVZ) and rat postnatal 1 day cortex, respectively, and the conditioned medium from microglia was prepared. Microglial-conditioned medium had no significant effect on the proliferation of NSPCs. In contrast, it increased the percentage of cells positive for a marker of astrocytes, glial fibrillary acidic protein (GFAP) during differentiation. The induction of astrocytic differentiation by microglial-conditioned medium was reduced by the inhibition of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK) pathways. Furthermore, microglia-derived interleukin (IL)-6 and leukaemia inhibitory factor (LIF) were identified as essential molecules for this astrocytic differentiation using neutralizing antibodies and recombinant cytokines. Our results suggest that microglia as well as astrocytes contribute to the integrity of the local environment of NSPCs, and at least IL-6 and LIF released by activated microglia promote astrocytic differentiation of NSPCs via the activation of the JAK/STAT and MAPK pathways.

ERP correlates of conscious error recognition: aware and unaware errors in an antisaccade task

Abstract: Event-related potential (ERP) studies identified the error-related negativity (Ne/ERN) and the error positivity (Pe) to be associated with performance errors. However, the functional significance of these components is not yet resolved. With the present study we intended to further investigate to what extent these components are related to error awareness. ERPs were recorded during an antisaccade task, and error awareness was obtained from accuracy ratings on each trial. In accordance with earlier findings, aware and unaware errors did not differ in Ne/ERN amplitude. Whereas the late Pe (400-600 ms) shows an increased parietal positivity for aware compared with unaware errors, the early Pe (200-300 ms) shows no dissociation between aware and unaware errors. These data lend further support to the view that the Ne/ERN and the (late) Pe reflect different processes in performance monitoring. In fact the present results provide a clear replication of [S. Nieuwenhuis et al. (2001) Psychophysiology, 38, 752-760], showing that the Pe is associated with error awareness and remedial action. Furthermore, it has been shown that this is only true for the late Pe, whereas the early Pe like the Ne/ERN is not modulated by error awareness.

Retrosplenial and hippocampal brain regions in human navigation: complementary functional contributions to the formation and use of cognitive maps.

Abstract: The ability to orientate within familiar environments relies on the formation and use of a mental representation of the environment, namely a cognitive map. Neuropsychological and neuroimaging studies suggest that the retrosplenial and hippocampal brain regions are involved in topographical orientation. We combined functional magnetic resonance imaging with a virtual-reality paradigm to investigate the functional interaction of the hippocampus and retrosplenial cortex during the formation and utilization of cognitive maps by human subjects. We found that the anterior hippocampus is involved during the formation of the cognitive map, while the posterior hippocampus is involved when using it. In conjunction with the hippocampus, the retrosplenial cortex was active during both the formation and the use of the cognitive map. In accordance with earlier studies in non-human animals, these findings suggest that, while navigating within the environment, the retrosplenial cortex complements the hippocampal contribution to topographical orientation by updating the individual's location as the frame of reference changes.

Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex.

Abstract: Stimulation with weak electrical direct currents has been shown to be capable of inducing stimulation-polarity-dependent prolonged diminutions or elevations of cortical excitability, most probably elicited by a hyper- or depolarization of resting membrane potentials. The aim of the present study was to test if cognitive task and motor exercise practiced during the stimulation are able to modify transcranial direct current stimulation-induced plasticity in the left primary motor cortex in 12 healthy subjects. Motor evoked potentials were recorded before and after 10 min of anodal and cathodal transcranial direct current stimulation. In Experiment 1, subjects were required to sit passively during the stimulation, in Experiment 2 the subject's attention was directed towards a cognitive test and in Experiment 3 subjects were instructed to push a ball in their right hand. Both the cognitive task and motor exercise modified transcranial direct current stimulation-induced plasticity; when performing the cognitive task during stimulation the motor cortex excitability was lower after anodal stimulation and higher after cathodal stimulation, compared with the passive condition. When performing the motor exercise, the motor cortex excitability was lower after both anodal and cathodal stimulation, compared with the passive condition. Our results show that transcranial direct current stimulation-induced plasticity is highly dependent on the state of the subject during stimulation.

The development of the social brain in human infancy

Abstract: Much research has focused on how the adult human brain processes the social world, yet until recently little was known about the early development of these abilities. Developmental studies inform debates about the specificity of social functions in the adult cortex. This review highlights recent work, mainly based on electroencephalography/event-related potential methods, examining the precursors of the human social brain network during infancy in several domains such as face and eye gaze processing, the perception of emotions, decoding biological motion, perceiving human actions and joint attention. The findings illustrate that the human brain is fundamentally adapted to develop within a social context, and that this context contributes to many of the specializations seen in the adult cortex.

Neural adaptation reveals state-dependent effects of transcranial magnetic stimulation

Abstract: Transcranial magnetic stimulation (TMS) is now widely used as a 'virtual' lesion paradigm to investigate behavioural functions, but the mechanisms through which it influences neural processing are unclear. To understand the differential effects of TMS on spatially overlapping populations of neurons we manipulated the relative activity levels of visual neurons by adapting subjects to a range of visual stimuli. By applying TMS to the visual cortex representing the central visual field we have shown in two experiments that the behavioural and perceptual effects of TMS depend on the state of adaptation of the neural population stimulated by TMS. Specifically, we have demonstrated that within the stimulated area TMS perceptually facilitates the attributes encoded by the less active neural population. We have demonstrated the generality of this principle for both suprathreshold and subthreshold TMS as well as for colour and orientation-contingent colour using both subjective reports and psychophsyical measures. These findings can explain how TMS disrupts cognitive functions and therefore have implications for all studies which use TMS to disrupt behaviour.

Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress.

Abstract: In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis. Rats received mifepristone on the last 4 days of a 21-day chronic unpredictable and inescapable stress regimen. Neurogenesis was analysed by stereological quantification of adult-generated cell survival (bromodeoxyuridine), young neuronal survival (doublecortin) and cell proliferation (Ki-67). The results show that only 4 days of mifepristone treatment normalized the stress-induced reductions in neurogenesis. Importantly, mifepristone by itself had no effect on neurogenesis. We conclude that, contrary to other compounds interfering with the effects of chronic stress on neurogenesis, like antidepressants, the normalizing effects of mifepristone on neurogenesis are rapid and particularly potent in a high stress environment. This neurogenic action of mifepristone could potentially contribute to its clinical mechanism of action.

Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus

Abstract: Novel spatially restricted genetic manipulations can be used to assess contributions made by synaptic plasticity to learning and memory, not just selectively within the hippocampus, but even within specific hippocampal subfields. Here we generated genetically modified mice (NR1ΔDG mice) exhibiting complete loss of the NR1 subunit of the N-methyl-d-aspartate receptor specifically in the granule cells of the dentate gyrus. There was no evidence of any reduction in NR1 subunit levels in any of the other hippocampal subfields, or elsewhere in the brain. NR1ΔDG mice displayed severely impaired long-term potentiation (LTP) in both medial and lateral perforant path inputs to the dentate gyrus, whereas LTP was unchanged in CA3-to-CA1 cell synapses in hippocampal slices. Behavioural assessment of NR1ΔDG mice revealed a spatial working memory impairment on a three-from-six radial arm maze task despite normal hippocampus-dependent spatial reference memory acquisition and performance of the same task. This behavioural phenotype resembles that of NR1ΔCA3 mice but differs from that of NR1ΔCA1 mice which do show a spatial reference memory deficit, consistent with the idea of subfield-specific contributions to hippocampal information processing. Furthermore, this pattern of selective functional loss and sparing is the same as previously observed with the global GluR-A l-α-amino-3-hydroxy-5-methyl-4-isoxazelopropionate receptor subunit knockout, a mutation which blocks the expression of hippocampal LTP. The present results show that dissociations between spatial working memory and spatial reference memory can be induced by disrupting synaptic plasticity specifically and exclusively within the dentate gyrus subfield of the hippocampal formation.

Candidate pheromone receptors provide the basis for the response of distinct antennal neurons to pheromonal compounds.

Abstract: Males of the moth species Heliothis virescens are able to detect the female-released pheromone with remarkable sensitivity and specificity, distinguishing between highly related pheromonal compounds. In the past, electrophysiological studies succeeded in assigning sensory hairs to identified compounds revealing three functional types of long sensilla trichodea housing neurons specifically responding to distinct semiochemicals. The specific responsiveness implies that the sensory neurons express different receptor types tuned to pheromone components. In this study we demonstrate that heterologously expressed candidate pheromone receptors from Heliothis responded to several pheromonal compounds, including the major sex-pheromone component Z-11-hexadecenal indicating a limited specificity of each receptor type. Nonetheless, based on functional analysis and in situ hybridization studies the analysed receptor types could tentatively be assigned to types of long sensilla trichodea, containing the pheromone-binding proteins (PBPs) HvirPBP1 and HvirPBP2 in the sensillum lymph. Substituting organic solvent with PBPs to solubilize the hydrophobic pheromone compounds in functional assays revealed an increase in sensitivity and especially specificity. It was found that in the presence of HvirPBP2, cells expressing the receptor type HR13 specifically responded to the main component of the sex pheromone blend only. The data provide further evidence that a combination of a distinct receptor type and binding protein underlie the specific response observed in the detection of a pheromone component in vivo.

General and outcome-specific forms of Pavlovian-instrumental transfer: the effect of shifts in motivational state and inactivation of the ventral tegmental area.

Abstract: This study compared the contribution of the general activating and specific cueing properties of Pavlovian stimuli to Pavlovian-instrumental transfer (PIT) and the role of the ventral tegmental area (VTA) in mediating these effects. In Experiment 1, hungry rats initially received Pavlovian training, in which three distinct auditory stimuli predicted the delivery of three different food outcomes. Next, the rats were trained to perform two instrumental actions, each earning a unique outcome selected from the three used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Presentation of a stimulus that had been paired with the same outcome as an action increased its performance relative to the other action, demonstrating that PIT effects can be outcome selective. In contrast, presentation of the stimulus that predicted the outcome that was not earned during instrumental training facilitated the performance of both actions indiscriminately. This effect, but not the outcome-selective effect, was abolished by a shift from a hungry to a relatively sated state. Experiment 2 examined the effects of inactivation of the VTA on these two forms of PIT. VTA inactivation was found to attenuate PIT but, unlike satiety, did not appear to differentially affect the general or the outcome-selective forms of PIT. The VTA appears therefore to play an important but general role in the initiation of instrumental actions, enabling cues to influence performance whether they enhance responding by changes in arousal or by retrieving particular actions based on their consequences.

Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice

Abstract: The entry of therapeutic compounds into the brain and spinal cord is normally restricted by barrier mechanisms in cerebral blood vessels (blood-brain barrier) and choroid plexuses (blood-CSF barrier). In the injured brain, ruptured cerebral blood vessels circumvent these barrier mechanisms by allowing blood contents to escape directly into the brain parenchyma. This process may contribute to the secondary damage that follows the initial primary injury. However, this localized compromise of barrier function in the injured brain may also provide a 'window of opportunity' through which drugs that do not normally cross the blood-brain barriers are able to do so. This paper describes a systematic study of barrier permeability in a mouse model of traumatic brain injury using both small and large inert molecules that can be visualized or quantified. The results show that soon after trauma, both large and small molecules are able to enter the brain in and around the injury site. Barrier restriction to large (protein-sized) molecules is restored by 4-5 h after injury. In contrast, smaller molecules (286-10,000 Da) are still able to enter the brain as long as 4 days postinjury. Thus the period of potential secondary damage from barrier disruption and the period during which therapeutic compounds have direct access to the injured brain may be longer than previously thought.

Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context‐induced reinstatement of cocaine‐seeking in rats

Abstract: The basolateral amygdala (BLA), dorsomedial prefrontal cortex (dmPFC) and dorsal hippocampus (DH) are critical elements of the neurocircuitry of drug context-induced reinstatement of cocaine-seeking; however, little is known about functional interactions between these brain regions. The present study tested the hypothesis that serial information processing by the BLA and dmPFC mediates drug context-induced cocaine-seeking, whereas the BLA and DH independently control this behaviour. Rats were trained to self-administer cocaine in a distinct environment (cocaine-paired context) followed by extinction training in a different environment (extinction context). On the test days, rats received unilateral microinfusions of baclofen + muscimol or of vehicle into the BLA and either the contralateral or ipsilateral dmPFC or DH. Cocaine-seeking behaviour (i.e. nonreinforced presses on the cocaine-associated lever) was then assessed in the cocaine-paired and extinction contexts. Following vehicle pretreatment, exposure to the cocaine-paired context reinstated extinguished cocaine-seeking behaviour. BLA-dmPFC asymmetrical inactivation attenuated cocaine-seeking behaviour relative to vehicle treatment; however, this impairment equaled that produced by ipsilateral BLA-dmPFC inactivation. Furthermore, unilateral inactivation of the BLA or dmPFC did not alter this behaviour. BLA-DH asymmetrical inactivation selectively attenuated cocaine-seeking behaviour relative to vehicle treatment whereas ipsilateral or unilateral inactivation of the BLA and DH did not alter this behaviour. These findings indicate that the BLA and DH exhibit sequential information processing within the relapse circuitry. In contrast, interactions between the BLA and dmPFC are more complex and include parallel loops of information processing and/or necessary interhemispheric input from the dmPFC to the BLA, probably in addition to direct intrahemispheric interactions.

Simulation of robustness against lesions of cortical networks

Abstract: Structure entails function, and thus a structural description of the brain will help to understand its function and may provide insights into many properties of brain systems, from their robustness and recovery from damage to their dynamics and even their evolution. Advances in the analysis of complex networks provide useful new approaches to understanding structural and functional properties of brain networks. Structural properties of networks recently described allow their characterization as small-world, random (exponential) and scale-free. They complement the set of other properties that have been explored in the context of brain connectivity, such as topology, hodology, clustering and hierarchical organization. Here we apply new network analysis methods to cortical interareal connectivity networks for the cat and macaque brains. We compare these corticocortical fibre networks to benchmark rewired, small-world, scale-free and random networks using two analysis strategies, in which we measure the effects of the removal of nodes and connections on the structural properties of the cortical networks. The structural decay of the brain networks is in most respects similar to that of scale-free networks. The results implicate highly connected hub-nodes and bottleneck connections as a structural basis for some of the conditional robustness of brain systems. This informs the understanding of the development of connectivity of the brain networks.

Umami: a delicious flavor formed by convergence of taste and olfactory pathways in the human brain.

Abstract: Umami taste is produced by glutamate acting on a fifth taste system. However, glutamate presented alone as a taste stimulus is not highly pleasant, and does not act synergistically with other tastes (sweet, salt, bitter and sour). We show here that when glutamate is given in combination with a consonant, savory, odour (vegetable), the resulting flavor can be much more pleasant. Moreover, we showed using functional brain imaging with fMRI that the glutamate taste and savory odour combination produced much greater activation of the medial orbitofrontal cortex and pregenual cingulate cortex than the sum of the activations by the taste and olfactory components presented separately. Supralinear effects were much less (and significantly less) evident for sodium chloride and vegetable odour. Further, activations in these brain regions were correlated with the pleasantness and fullness of the flavor, and with the consonance of the taste and olfactory components. Supralinear effects of glutamate taste and savory odour were not found in the insular primary taste cortex. We thus propose that glutamate acts by the nonlinear effects it can produce when combined with a consonant odour in multimodal cortical taste-olfactory convergence regions. We propose the concept that umami can be thought of as a rich and delicious flavor that is produced by a combination of glutamate taste and a consonant savory odour. Glutamate is thus a flavor enhancer because of the way that it can combine supralinearly with consonant odours in cortical areas where the taste and olfactory pathways converge far beyond the receptors.

Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum.

Abstract: Stroke is a neurodegenerative disorder and the leading cause of disability in adult humans. Treatments to support efficient recovery in stroke patients are lacking. Several studies have demonstrated the ability of grafted neural stem cells (NSCs) to partly improve impaired neurological functions in stroke-subjected animals. Recently, we reported that NSCs from human fetal striatum and cortex exhibit region-specific differentiation in vitro, but survive, migrate and form neurons to a similar extent after intrastriatal transplantation in newborn rats. Here, we have transplanted the same cells into the stroke-damaged striatum of adult rats. The two types of NSCs exhibited a similar robust survival (30%) at 1 month after transplantation, and migrated throughout the damaged striatum. Striatal NSCs migrated farther and occupied a larger volume of striatum. In the transplantation core, cells were undifferentiated and expressed nestin and, to a lesser extent, also GFAP, beta III-tubulin, DCX and calretinin, markers of immature neural lineage. Immunocytochemistry using markers of proliferation (p-H3 and Ki67) revealed a very low content of proliferating cells (< 1%) in the grafts. Human cells outside the transplantation core differentiated, exhibited mature neuronal morphology and expressed mature neuronal markers such as HuD, calbindin and parvalbumin. Interestingly, striatal NSCs generated a greater number of parvalbumin(+) and calbindin(+) neurons. Virtually none of the grafted cells differentiated into astrocytes or oligodendrocytes. Based on these data, human fetal striatum- and cortex-derived NSCs could be considered potentially safe and viable for transplantation, with strong neurogenic potential, for further exploration in animal models of stroke. (Less)

Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment.

Abstract: Depressive illness is associated with changes in amygdalar volume, and stressful life events are known to precipitate depressive episodes in this patient population. Stress affects amygdalar synaptic plasticity and several neurotransmitter systems have been implicated in stress-mediated changes in the brain, including the glutamatergic system. However, the role of the glutamatergic system in stress-mediated plasticity in the amygdala remains to be determined. Accordingly the current study examined the stress modulation of extracellular glutamate levels in the basolateral nucleus (BLA) and the central nucleus (CeA) of the amygdala by in vivo microdialysis. Acute stress increased extracellular glutamate levels in the BLA and CeA, although the dynamics of these stress-mediated changes were dramatically different in these amygdalar nuclei. Tetrodotoxin administration reduced basal, and completely eliminated stress-mediated increases in glutamate efflux in the amygdala, demonstrating that stress effects are dependent on local axonal depolarization. Moreover, stress-mediated increases in glutamate efflux in the BLA were inhibited by the antidepressant tianeptine but not by the selective serotonin-reuptake inhibitor fluoxetine. Collectively, these data demonstrate that stress-induced modulation of glutamate neurochemistry reflects a fundamental pathological change that may contribute to the aetiology and progression of depressive illness, and suggest that some antidepressants such as tianeptine may elicit their clinical effects by modulation of glutamatergic neurotransmission.

Functional microstates within human REM sleep: first evidence from fMRI of a thalamocortical network specific for phasic REM periods

Abstract: High thalamocortical neuronal activity characterizes both, wakefulness and rapid eye movement (REM) sleep, but apparently this network fulfills other roles than processing external information during REM sleep. To investigate thalamic and cortical reactivity during human REM sleep, we used functional magnetic resonance imaging with simultaneous polysomnographic recordings while applying acoustic stimulation. Our observations indicate two distinct functional substates within general REM sleep. Acoustic stimulation elicited a residual activation of the auditory cortex during tonic REM sleep background without rapid eye movements. By contrast, periods containing bursts of phasic activity such as rapid eye movements appear characterized by a lack of reactivity to sensory stimuli. We report a thalamocortical network including limbic and parahippocampal areas specifically active during phasic REM periods. Thus, REM sleep has to be subdivided into tonic REM sleep with residual alertness, and phasic REM sleep with the brain acting as a functionally isolated and closed intrinsic loop.