Electrical high frequency stimulation (HFS) in the subthalamic nucleus (STN) has been shown to have a therapeutic effect in several movement disorders.But, debilitating psychiatric effects like depression and suicidality are occasionally seen and might be caused by the changes in the serotoninergic activity.Previous studies could show that HFS of the STN results in inhibition of the serotonergic neurons originating in the dorsal raphe nucleus.The aim of this study was to characterize the effect of HFS (124 Hz, 0.5 mA) in the STN, on the extracellular levels of serotonin, dopamine and their metabolites HIAA, DOPAC and HVA in the caudate-putamen (CPu) in conscious and freely moving rats.Extracellular levels of the neurotransmitters and their metabolites were quantified using high performance liquid chromatography with electrochemical detection.Under HFS conditions, a significant reduction in the extracellular levels of serotonin was observed.Cessation of HFS showed a recovery back to basal levels.Dopamine levels were not affected, although significant increase of its metabolites DOPAC and HVA were measured.In the case of low frequency stimulation (LFS), levels of serotonin and its metabolite HIAA remained unchanged, while the levels of dopamine metabolites, DOPAC and HVA, showed a significant decline.These results demonstrate evidence for a strong linkage between HFS in the STN and reduction of the levels of serotonin in the caudate-putamen, which is likely responsible for psychiatric side effects seen in Parkinsonian patients who are treated with STN stimulation.
We studied the brain distribution of amyloid-β (Aβ) and phosphorylated tau (τ) in 20 consecutive autopsy cases between the ages of 51 and 65, with no history of neurologic disease during life. We note that early accumulations of Aβ and τ occur in distinct neuroanatomical distributions. In the locus ceruleus and medial temporal lobe allocortex τ often occurs in the absence of diffuse Aβ and that Aβ occurs in the neocortex in the absence of τ. In those cases with both Aβ and τ were present in the sections, there was no overlap at the microanatomical or cellular level. APOE genotype was also assessed, showing no specific relationship with the presence or distribution of Aβ and τ, although the numbers of cases were limited. These findings indicate that the early appearances of hallmark proteins of Alzheimer's disease are disconnected both in time and in space, suggesting that both are reactive phenomena with no mechanistic relationship in aging or preclinical disease.
Recent progress has greatly expanded our view of how signaling pathways regulate the actin cytoskeleton in post-synaptic spines.These studies reveal a complex interplay between pathways that highlight the role of the actin cytoskeleton during the development of spines as well as in response to stimuli that modify synaptic strength.This review discusses the results from these studies that include biochemical, cellular, and genetic approaches to understanding excitatory synapse formation and function.
Dendritic spines are highly specialized neuronal structures that are the major postsynaptic sites for excitatory input.These actin-rich expansions are highly versatile in adapting their morphology and density towards the support of synaptic transmission and plasticity.Among the chief factors known to be crucial in the modulation of the actin cytoskeleton, the Rho-GTPases and their associated signaling effectors are particularly important.This signaling system is involved in numerous regulatory processes, including cell morphology, structural dynamics and cell motility.Accordingly, the disruption of Rho-related signaling has a profound effect on the integrity of neurons, resulting in abnormalities with neurite outgrowth, dendritic arborization, spine properties and plasticity.These perturbations can dramatically alter normal synaptic function, including hippocampal long-term potentiation (LTP), resulting in cognitive defects.Additionally, Rho-GTPase-associated signaling disorders have also been implicated in numerous forms of mental retardation.Therefore, the elucidation of the underlying mechanisms involved in this pathway and their critical association with dendritic spines remains a major focus of research concerning the cellular basis of cognitive function.Here we will discuss our recent data obtained utilizing knockout animals deficient in the expression of PAKs (p21-activated kinases) and ROCKs (Rhokinases), predominant protein kinases known to be directly activated by the Rho-GTPases.A downstream target for both PAKs and ROCKs, LIMKs (Lin-11, Isl-1, and Mec-3 kinase), will also be discussed.While it is evident that these kinase families all serve towards spine and synaptic regulation, their individual roles in the achievement of this goal may be quite different.
Fragile X syndrome, the most common form of inherited mental retardation is caused by silencing of the Fmr1 (fragile x mental retardation-1) gene.Two mammalian homologues of Fmr1 have been identified: fragile X-related Protein 1 (Fxr1) and Protein 2Fxr2.Aberrations in dendritic spines of Fragile X syndrome patients and Fmr1 null mice implicate FMRP in synapse fo rmation and function.However, no structural analysis has been performed on Fxr2 null mice.Here we examined dendritic spines in brains of Fxr2 KO mouse.We report that at the age of 2 weeks, unlike in the Fmr1 null mice, spines in the somatosensory cortex and the hippocampus of Fxr2 null mice are less dense compared to wild type mice.On the other hand, there is an increase in spine length similar to that reported in the Fmr1 null mice.These differences in spine density and morphology are no longer detected by the age of 4 weeks.Our results indicate for the first time that Fxr2 plays a role in spine development and further suggest that Fxr2 has only partially overlapping function with Fmr1.
In the past several years, a multitude of genes has been linked to mental retardations in humans, in particular the most commonly occurring X-linked mental retardations.An emerging idea is that structural and functional abnormalities in spines and synapses are a common feature of mental retardations.Consistent with this concept, a number of genes that control synaptic function have been implicated in X-linked mental retardations.In this review we discuss aberrations in spine and synapse structure and function in X-linked human mental retardations and corresponding mouse models with mutations in genes that modulate synaptic structure and function.A thorough understanding of these synaptic structures and abnormalities would enhance our knowledge of the normal process of learning and understand how synaptic aberrations contribute to cognitive deficits such as those observed in mental retardations.
Objective: In this prospective study, we examined the association between azathioprine dose, levels of its phosphoribosylated metabolites, and the activity of thiopurine methyltransferase in patients with multiple sclerosis (MS).Materials/Methods: Clinical data and blood samples were collected from 27 MS patients who were undergoing azathioprine treatment.In red blood cells, thiopurine methyltransferase (TPMT) activity was determined, and after hydrolysis and cleavage of the phosphoribosyl residue, amounts of 6-thioguanine (6-TG), 6-methyl-thioguanine (6-MTG), 6methylmercaptopurine (6-MMP) were measured.For clinical evaluation, the expanded disability status score (EDSS) and the multiple sclerosis functional composite (MSFC) were performed.Laboratory and clinical examinations were conducted twice with a 6-month-intervall.Results: Over a broad range of daily azathioprine dose, nearly constant levels of the immunosuppressive-active 6-TG (nucleotides) were found.There was, however, a marked relationship between daily azathioprine dose and 6-MMP nucleotide levels.Especially patients receiving an azathioprine dose of more than 1.5 mg/kg per day in particular presented an exponential increase in 6-MMP levels when TPMT activity was higher than 45 U/g Hb.All the biochemical measurements gave similar results when performed 6 months later.Conclusions: Patients with the combination of a high TPMT-activity and an azathioprine dose of more than 1.5 mg/kg/d exhibit significantly increased 6-MMP nucleotide levels.These patients are thus at risk for hepatotoxic side effects.Determination of TPMT activity before azathioprine therapy and monitoring of its metabolites might provide guidance for dose individualization.
To determine whether fishes respond to menthol, Japanese medaka Oryzias latipes, goldfish Carassius auratus, and zebrafish Danio rerio were exposed to various types of menthol receptors agonists and the behavioral responses to these drugs were observed.Waterbone application of dl-menthol (0.5 mM) induced surgical anesthesia in 100% of medaka, 90% of goldfish, and 100% of zebrafish.The percentage of response increased dose-dependently from 0.2 mM to 0.5 mM.There were no differences in either percentage or latency of the response in surgical anesthesia among dl-, d-, and l-types of menthol.A high (3.0 mM) concentration of any of the three types of menthol induced rapid movement followed by the anesthetic response.Rapid movement was observed with allyl isothiocyanate, a cold nociceptor agonist, but not with icilin, a cold receptor agonist, in medaka and goldfish.Both allyl isothiocyanate and icilin failed to induce surgical anesthesia.To determine the involvement of -aminobutyric acid (GABA) system in menthol-induced surgical anesthesia, the effect of the receptors antagonist for the GABA A was tested.Pretreatment with a specific GABA A receptor antagonist prolonged the latency of the anesthetic response to menthol, but not to cold-water stimulation, in medaka and goldfish.These results demonstrate that menthol can play a role in the induction of surgical anesthesia in fishes, related at least in part to the activation of GABA A receptors, and of rapid movement possibly via cold nociceptors.
Sensory epithelial cells in the organ of Corti survive throughout life.However, factors for sensory epithelial cell survival are poorly understood at the present time.Here we demonstrated that brain-derived neurotrophic factor (BDNF), a factor committing to neuronal survival, promotes the survival of sensory epithelial cells (OC1) through phosphatidylinositide 3'-OH kinase (PI3K)/protein kinase B (Akt) and/or nuclear factor kappa B (NF-B)/B cell lymphoma 2 (Bcl-2) pathways.BDNF activated PI3K/Akt kinases and increased NF-B/Bcl-2 activity or expression in association with the survival of OC1 cells in vitro.LY294002, a specific inhibitor for PI3K, and pyrrolidine dithiocarbamate (PDTC), an inhibitor for NF-B, abrogated the protective effect of BDNF on OC1 cells, causing the increased expression of caspase 3 and the apoptotic cell numbers in vitro.Similarly, a dominant negative mutant of I kappa B alpha (I B M, a specific inhibitor of NF-B) abrogated the protective effect of BDNF on OC1 cells.The data demonstrate that BDNF promotes the survival of sensory epithelial cells through the PI3K/Akt and NF-B/Bcl-2 signaling pathways.
This study investigated the extent to which audiovisual speech integration is special by comparing behavioral and neural measures using both speech and non-speech stimuli.An audiovisual recognition experiment presenting listeners with auditory, visual, and audiovisual stimuli was implemented.The auditory component consisted of sine wave speech, and the visual component consisted of point light displays, which include point-light dots that highlight a talker's points of articulation.In the first phase, listeners engaged in a discrimination task where they were unaware of the linguistic nature of the auditory and visual stimuli.In the second phase, they were informed that the auditory and visual stimuli were spoken utterances of /be/ ("bay") and /de/ ("day"), and they engaged in the same task.The neural dynamics of audiovisual integration was investigated by utilizing EEG, including mean Global Field Power and current density reconstruction (CDR).As predicted, support for divergent regions of multisensory integration between the speech and nonspeech stimuli was obtained, namely greater posterior parietal activation in the non-speech condition.Conversely, reaction-time measures indicated qualitatively similar multisensory integration across experimental conditions.
Co-localization of P2X4 and P2X7 subunits has been demonstrated in a number of tissues. It appears that these subunits form functionally interacting homomeric P2X4 and P2X7 receptors rather than heteromeric P2X4/7 receptors. We have recently reported that adult neural progenitor cells (NPCs) of the mouse subventricular zone (SVZ) possess P2X7 receptors. Cultured proliferating NPCs responded to higher concentrations of the prototypic P2X7 agonist diben- zoyl-ATP (Bz-ATP) with inward current, strongly inhibited by the selective P2X7 antagonist A438079, and moderately depressed by the P2X1-3,4 antagonist TNP-ATP, or the selective P2X4 antagonist 5-BDBD. Now we show in addition that ivermectin, a selective allosteric modulator of P2X4 receptors, uniformly potentiated the effect of lower Bz-ATP con- centrations; this potentiation was abolished by 5-BDBD. In conclusion, astrocyte-like cultured SVZ NPCs are endowed with P2X4 and P2X7 receptors shaping the characteristics of these cells with respect to ATP-dependent signalling.
Studies into the interactions between glia/immune cells and neurons have focused on the induction of patho-logical (neuropathic or inflammatory) pain. Growing evidence of close relationships between peripheral and central glia and pathological pain has emerged during the last 2 decades. Numerous experimental studies have showed the release of cytokines and inflammatory neuropeptides from peripheral and central terminals of primary sensory neurons and from ac-tivated peripheral and central glia after nerve injury (crush, ligation or transection), which in turn act in a paracrine or autocrine manner. Cytokines induce the synthesis of algogens (pain-inducing substances such as prostaglandin) which leads to the primary (peripheral) or secondary (central) sensitization responsible for hyperalgesia or allodynia under in-flammatory conditions. The review has also highlighted the role of thermo transient receptor potential (TRP) channels TRPV1, TRPA1 and TRPM8 in the induction of pathological pain. The noxious heat sensor TRPV1 has an overt role in noxious heat hyperalgesia or allodynia, whereas TRPA1 and TRPM8 seem to have roles in noxious cold or mechanical al-lodynia, although results are inconsistent. Close mutual interrelationships between immune and glial cells and thermoTRP channels via cytokines or pro-inflammatory neuropeptides cannot be ignored when attempting to explain the induction and continuation of pathological pain. Investigations on the initial signals sent to the central area (superficial dorsal horn) remote from injured (or infectious) sites are a key point to clarify the mechanisms of pathological pain.
We describe a simple Hadamard design for neural architecture with an equal number of input and output elements that is both error-tolerant and robust to missing information.The design provides a basis for calculation using a classification scheme based on the Chinese remainder theorem, producing an abstract representation of the physical world.The underlying co-prime arrays can be generated in a simple manner biologically and can evolve into more complex designs.The approach differs from previously described neural network constructions in that all connectivity is specified by design, with each correctly wired array producing a single output for each subset of inputs.The wiring is consistent with the "On-Off" schema observed for different senses because only about half the inputs can be active at any one time.The arrays can be tuned through by varying the number of simultaneous inputs required for activation within a range specified by the array size.The architecture is scalable.
Touching for shape recognition has been shown to activate occipital areas in addition to somatosensory areas. In this study we asked if this combination of somatosensory and other sensory processing areas also exist in other kinds of touch recognition. In particular, does touch for texture roughness matching activate other sensory processing areas apart from somatosensory areas? We addressed this question with functional magnetic resonance imaging (fMRI) using wooden abstract stimulus objects whose shape or texture were to be identified. The participants judged if pairs of objects had the same shape or the same texture. We found that the activated brain areas for texture and shape matching have similar underlying structures, a combination of the primary motor area and somatosensory areas. Areas associated with object-shape processing were activated between stimuli during shape matching and not texture roughness matching, while auditory areas were activated during encoding of texture and not for shape stimuli. Matching of textures also in- volves left BA47, an area associated with retrieval of relational information. We suggest that texture roughness is recog- nized in a framework of ordering. Left-lateralized activations favoring texture might reflect semantic processing associ- ated with grading roughness quantitatively, as opposed to the more qualitative distinctions between shapes.
In recent years, the neural substrates underlying outcome feedback processing have been investigated in several neuroimaging studies of feedback-based learning.However, what has been missed in these studies is that, the learning process itself also affects the way the feedback is being processed.In this study, we tried to investigate the changes in neural substrates underlying positive and negative feedback processing during goal-directed implicit learning using the Sugar Production Factory (SPF) task in conjunction with an event related functional magnetic resonance imaging.We found a significant learning-related decrease in activity of the right superior frontal gyrus (SFG) in response to positive feedback and a learning-related increase in activity of the precuneus in response to negative feedback.The results demonstrate the changing role of feedback during learning and suggest that learning-related changes in activity of the SFG and precuneus that have been previously reported in several implicit learning studies arise from changes in feedback processing after learning.In addition, the results suggest the important role of positive feedback in early stage and negative feedback in late stage of goal-directed implicit learning.
The goal of this study is to assess the role of membership and valence effects on errors performed in a racial implicit association test indexed by event-related potentials (ERPs).Non-indigenous participants performed an implicit association test (IAT) paradigm emphasizing the feedback of error due to misclassification of ingroup (non-indigenous) and outgroup (indigenous) faces as well as positive and negative words.As expected, participants responded to the compatible task with higher accuracy than to incompatible tasks.This is the first report demonstrating that IAT errors produce electrophysiological ERP modulation.Our results suggest that medial frontal negativity is modulated not only by IAT error of membership and valence classifications but also by IAT compatible and incompatible tasks.These results provide a basis for the future use of the misclassification error in the IAT recorded simultaneously with ERPs in other classic social psychology contexts.
Introduction: Moderate hypoxia has been implicated in the development of delirium.One mechanism may be an increase of Dopamine (DA) and Serotonin (5-HT) levels.Our previous studies indicated that hypoxia increased levels of both neurotransmitters (NT) and that nimodipine (NIMO) administered immediately after hypoxia preserved short term memory.We tested the hypothesis that these observations may be related to a NIMO dependent reduction of hypoxia induced NT elevation.Methods: Following IACUC approval, In Vivo microvoltammetry sensors (BRODERICK PROBE ® ) were implanted in the dorsal striatum of Na Pentobarbital anesthetized adult Sprague-Dawley rats.Extracellular NT levels were recorded for 15m during the establishment of baseline values in room air (N=6).Three sequential thirty-minute periods under hypoxia (10% O2) followed.First: under hypoxia alone; second after i.p. injection of NIMO (0.1mg/kg); and third following i.p. injection of NIMO (1.0mg/kg).Measurements were analyzed with ANOVA with post hoc Tukeys test.P-values less than 0.05 were considered significant.Results: NT levels are expressed as percentages of baseline values.Treatment values were averaged over each sequential thirty-minute period following each intervention.Moderate hypoxia resulted in the increase of DA to 172% (SEM=18) and 5-HT to 68% (SEM=4) above baseline.Under continuing hypoxia, NIMO (0.1mg/kg) caused DA levels to fall to 112% (SEM=14) and 5-HT to 13% (SEM=5) above baseline.NIMO (1.0mg/kg) caused DA levels to fall to 34% (SEM=6) above baseline and 5-HT to 20% (SEM=2) below baseline. Conclusion:Moderate hypoxia increased levels of DA and 5-HT in the striatum of rats.NIMO administration during ongoing hypoxia caused the levels of both neurotransmitters to fall towards baseline.The results may have implications for understanding and treating cognitive decline due to hypoxia.
The precise control for maintenance of a normal intracellular calcium concentration in eukaryote cells is accomplished by several systems located at the plasma membrane, as well as several internal membrane systems.Neurons are especially sensitive to changes in these control systems, since when fail and calcium homeostasis disturbed, the cell's metabolism is immediately modified and a pathological condition emerges.Such a condition has been associated with epileptogenesis, and especially to those mechanisms associated to calcium entrance or ON mechanisms.On the other hand, calcium extrusion mechanisms or OFF mechanisms, have been investigated to a lesser extent and therefore remain much less understood.Here, we present a review of these calcium extrusion systems located at the plasma membrane considered to be critical in the process of epileptogenesis; first of all the plasma membrane calcium ATPase (PMCA) as the catalytic moiety of the enzyme that moves calcium outwards in an energy-dependent fashion, and the Na + /Ca 2+ exchanger (NCX) coupled to the (Na + /K + )-ATPase.Based on present knowledge considering the wide range of isoforms found for PMCA and NCX and their specific kinetic characteristics, a hypothesis for their participation on the OFF mechanisms related to the genesis of epilepsy is discussed.
Adenosine has been proposed as an endogenous anticonvulsant which can play an important role in seizure initiation, propagation and arrest.Extracellular ATP and adenosine are able to modulate synaptic activity through activation of P2 (P2X and P2Y) and P1 receptors (A 1 , A 2A , A 2B , and A 3 ), respectively.Besides the release of adenosine per se, the levels of ATP and adenosine in the synaptic cleft are controlled by a complex cascade of cell surface-localized enzymes collectively known as ectonucleotidases.These enzymes are capable of hydrolyzing nucleoside triphosphates, diphosphates and monophosphates to their respective nucleosides.There are four major families of ectonucleotidases: ectonucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase.All these members have specific physiological functions in the brain.In this review, the involvement of ectonucleotidases in the pathophysiology of brain disorders, such as seizures and epilepsy, is discussed.A brief introduction about the general characteristics of these enzymes is followed by a discussion about the role of ectonucleotidases in epilepsy and seizures and the implications for future treatments.
Adenosine has anticonvulsant effects in various models of seizures. Alpha-2 adrenoceptors have also demonstrated different effects in different models of epilepsy. In this study, the role of alpha-2 adrenoceptors in the anticonvulsant effects of adenosine in mice was determined according to the method of intravenous pentylenetetrazole-induced seizure. In this study, N6-cyclohexyladenosine (CHA) (a selective A1 receptor agonist), clonidine (an alpha-2 adrenoceptors agonist), yohimbine (an alpha-2 adrenoceptors antagonist) and 8-cyclopentyl-1,3-dimethylxanthine (8-CPT) (a selective A1 receptor antagonist) were used. CHA at doses of 0.5, 1 and 2 mg/kg significantly increased seizure threshold with the maximum anticonvulsant effect at 2 mg/kg. Yohimbine (0.1, 1 and 10 mg/kg), clonidine (0.1, 0.5, 1 and 2 mg/kg) and 8-CPT (0.5, 1, 2 and 4 mg/kg) had no effect on seizure by itself. Combination of yohimbine (10 mg/kg) and CHA (0.25 mg/kg) increased clonic seizure latency showing that yohimbine and CHA have an additive effect. Increasing the seizure threshold created by combining ineffective doses of yohimbine (10 mg/kg) and CHA (0.25 mg/kg) was completely inhibited by 8-CPT (4 mg/kg) or clonidine (1 and 2 mg/kg). Clonidine (0.5, 1 and 2 mg/kg) inhibited the anticonvulsant effects of CHA (2 mg/kg). Combination of 8-CPT (1 mg/kg) and clonidine (0.5 mg/kg) which completely inhibited the anticonvulsant effect of CHA (2 mg/kg) indicates that 8-CPT and clonidine have an additive effect. In conclusion, adenosine and yohimbine exhibit an additive effect on the enhancement of the pentylenetetrazole-induced seizure threshold in mice, indicating the interaction of alpha-2 adrenoceptors and A1 adenosine receptors.
