Fründ I, Busch NA, Schadow J, Körner U, Herrmann CS
From perception to action: phase-locked gamma oscillations correlate with reaction times in a speeded response task.
BMC Neurosci. 2007;827.
BACKGROUND: Phase-locked gamma oscillations have so far mainly been described in relation to perceptual processes such as sensation, attention or memory matching. Due to its very short latency ( approximately 90 ms) such oscillations are a plausible candidate for very rapid integration of sensory and motor processes. RESULTS: We measured EEG in 13 healthy participants in a speeded reaction task. Participants had to press a button as fast as possible whenever a visual stimulus was presented. The stimulus was always identical and did not have to be discriminated from other possible stimuli. In trials in which the participants showed a fast response, a slow negative potential over central electrodes starting approximately 800 ms before the response and highly phase-locked gamma oscillations over central and posterior electrodes between 90 and 140 ms after the stimulus were observed. In trials in which the participants showed a slow response, no slow negative potential was observed and phase-locked gamma oscillations were significantly reduced. Furthermore, for slow response trials the phase-locked gamma oscillations were significantly delayed with respect to fast response trials. CONCLUSION: These results indicate the relevance of phase-locked gamma oscillations for very fast (not necessarily detailed) integration processes. [Abstract/Link to Full Text]
Neuronal expression of muskelin in the rodent central nervous system.
Tagnaouti N, Loebrich S, Heisler F, Pechmann Y, Fehr S, De Arcangelis A, Georges-Labouesse E, Adams JC, Kneussel M
Neuronal expression of muskelin in the rodent central nervous system.
BMC Neurosci. 2007;828.
BACKGROUND: The kelch repeat protein muskelin mediates cytoskeletal responses to the extracellular matrix protein thrombospondin 1, (TSP1), that is known to promote synaptogenesis in the central nervous system (CNS). Muskelin displays intracellular localization and affects cytoskeletal organization in adherent cells. Muskelin is expressed in adult brain and has been reported to bind the Cdk5 activator p39, which also facilitates the formation of functional synapses. Since little is known about muskelin in neuronal tissues, we here analysed the tissue distribution of muskelin in rodent brain and analysed its subcellular localization using cultured neurons from multiple life stages. RESULTS: Our data show that muskelin transcripts and polypeptides are expressed throughout the central nervous system with significantly high levels in hippocampus and cerebellum, a finding that resembles the tissue distribution of p39. At the subcellular level, muskelin is found in the soma, in neurite projections and the nucleus with a punctate distribution in both axons and dendrites. Immunostaining and synaptosome preparations identify partial localization of muskelin at synaptic sites. Differential centrifugation further reveals muskelin in membrane-enriched, rather than cytosolic fractions. CONCLUSION: Our results suggest that muskelin represents a multifunctional protein associated with membranes and/or large protein complexes in most neurons of the central nervous system. These data are in conclusion with distinct roles of muskelin's functional interaction partners. [Abstract/Link to Full Text]
Neuronal expression of muskelin in the rodent central nervous system.
BMC Neurosci. 2007;828.
BACKGROUND: The kelch repeat protein muskelin mediates cytoskeletal responses to the extracellular matrix protein thrombospondin 1, (TSP1), that is known to promote synaptogenesis in the central nervous system (CNS). Muskelin displays intracellular localization and affects cytoskeletal organization in adherent cells. Muskelin is expressed in adult brain and has been reported to bind the Cdk5 activator p39, which also facilitates the formation of functional synapses. Since little is known about muskelin in neuronal tissues, we here analysed the tissue distribution of muskelin in rodent brain and analysed its subcellular localization using cultured neurons from multiple life stages. RESULTS: Our data show that muskelin transcripts and polypeptides are expressed throughout the central nervous system with significantly high levels in hippocampus and cerebellum, a finding that resembles the tissue distribution of p39. At the subcellular level, muskelin is found in the soma, in neurite projections and the nucleus with a punctate distribution in both axons and dendrites. Immunostaining and synaptosome preparations identify partial localization of muskelin at synaptic sites. Differential centrifugation further reveals muskelin in membrane-enriched, rather than cytosolic fractions. CONCLUSION: Our results suggest that muskelin represents a multifunctional protein associated with membranes and/or large protein complexes in most neurons of the central nervous system. These data are in conclusion with distinct roles of muskelin's functional interaction partners. [Abstract/Link to Full Text]
Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding.
Bateman DA, McLaurin J, Chakrabartty A
Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding.
BMC Neurosci. 2007;829.
BACKGROUND: Aggregation of the amyloid peptides, Abeta40 and Abeta42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Abeta (Abeta40, Abeta42, and an Abeta mutant). RESULTS: Using confocal microscopy and flow cytometry with fluorescently labelled Abeta, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone Abeta42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Abeta40 associates over 24 hours. We show that a double mutation in Abeta42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Abeta cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Abeta40 or Abeta42. CONCLUSION: Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving Abeta imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Abeta association with neuronal cells. [Abstract/Link to Full Text]
Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding.
BMC Neurosci. 2007;829.
BACKGROUND: Aggregation of the amyloid peptides, Abeta40 and Abeta42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Abeta (Abeta40, Abeta42, and an Abeta mutant). RESULTS: Using confocal microscopy and flow cytometry with fluorescently labelled Abeta, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone Abeta42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Abeta40 associates over 24 hours. We show that a double mutation in Abeta42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Abeta cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Abeta40 or Abeta42. CONCLUSION: Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving Abeta imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Abeta association with neuronal cells. [Abstract/Link to Full Text]
Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin.
Caudle RM, Mannes AJ, Keller J, Perez FM, Suckow SK, Neubert JK
Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin.
BMC Neurosci. 2007;830.
BACKGROUND: Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing. RESULTS: The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 microg) injected intrathecally produce thermal hyperalgesia. At higher doses (10 microg) peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons. CONCLUSION: The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury. [Abstract/Link to Full Text]
Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin.
BMC Neurosci. 2007;830.
BACKGROUND: Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing. RESULTS: The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 microg) injected intrathecally produce thermal hyperalgesia. At higher doses (10 microg) peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons. CONCLUSION: The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury. [Abstract/Link to Full Text]
Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection.
Li J, Bentsman G, Potash MJ, Volsky DJ
Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection.
BMC Neurosci. 2007;831.
BACKGROUND: HIV-1 infects human astrocytes in vitro and in vivo but the frequency of infected cells is low and its biological significance is unknown. In studies in vitro, recombinant gp120 alone can induce profound effects on astrocyte biology, suggesting that HIV-1 interaction with astrocytes and its functional consequences extend beyond the limited levels of infection in these cells. Here we determined the relative efficiencies of HIV-1 binding and infection in human fetal astrocytes (HFA), mainly at the single cell level, using HIV-1 tagged with green fluorescence protein (GFP)-Vpr fusion proteins, termed HIV-GFP, to detect virus binding and HIV-1 expressing Rev and NefGFP fusion proteins to detect productive infection. RESULTS: Essentially all HFA in a population bound HIV-GFP specifically and independently of CCR5 and CXCR4. The dynamics of this binding at 37 degrees C resembled binding of an HIV fusion mutant to CD4-positive cells, indicating that most of HIV-GFP arrested infection of HFA at the stage of virus-cell fusion. Despite extensive binding, only about 1% of HFA were detectably infected by HIV-RevGFP or HIV-NefGFP, but this proportion increased to the majority of HFA when the viruses were pseudotyped with vesicular stomatitis virus envelope glycoprotein G, confirming that HFA impose a restriction upon HIV-1 entry. Exposure of HFA to HIV-1 through its native proteins rapidly induced synthesis of interleukin-6 and interleukin-8 with increased mRNA detected within 3 h and increased protein detected within 18 h of exposure. CONCLUSION: Our results indicate that HIV-1 binding to human astrocytes, although extensive, is not generally followed by virus entry and replication. Astrocytes respond to HIV-1 binding by rapidly increased cytokine production suggesting a role of this virus-brain cell interaction in HIV-1 neuropathogenesis. [Abstract/Link to Full Text]
Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection.
BMC Neurosci. 2007;831.
BACKGROUND: HIV-1 infects human astrocytes in vitro and in vivo but the frequency of infected cells is low and its biological significance is unknown. In studies in vitro, recombinant gp120 alone can induce profound effects on astrocyte biology, suggesting that HIV-1 interaction with astrocytes and its functional consequences extend beyond the limited levels of infection in these cells. Here we determined the relative efficiencies of HIV-1 binding and infection in human fetal astrocytes (HFA), mainly at the single cell level, using HIV-1 tagged with green fluorescence protein (GFP)-Vpr fusion proteins, termed HIV-GFP, to detect virus binding and HIV-1 expressing Rev and NefGFP fusion proteins to detect productive infection. RESULTS: Essentially all HFA in a population bound HIV-GFP specifically and independently of CCR5 and CXCR4. The dynamics of this binding at 37 degrees C resembled binding of an HIV fusion mutant to CD4-positive cells, indicating that most of HIV-GFP arrested infection of HFA at the stage of virus-cell fusion. Despite extensive binding, only about 1% of HFA were detectably infected by HIV-RevGFP or HIV-NefGFP, but this proportion increased to the majority of HFA when the viruses were pseudotyped with vesicular stomatitis virus envelope glycoprotein G, confirming that HFA impose a restriction upon HIV-1 entry. Exposure of HFA to HIV-1 through its native proteins rapidly induced synthesis of interleukin-6 and interleukin-8 with increased mRNA detected within 3 h and increased protein detected within 18 h of exposure. CONCLUSION: Our results indicate that HIV-1 binding to human astrocytes, although extensive, is not generally followed by virus entry and replication. Astrocytes respond to HIV-1 binding by rapidly increased cytokine production suggesting a role of this virus-brain cell interaction in HIV-1 neuropathogenesis. [Abstract/Link to Full Text]
Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation.
Sandstrom MI, Rebec GV
Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation.
BMC Neurosci. 2007;832.
BACKGROUND: A physiological increase in extracellular ascorbate (AA), an antioxidant vitamin found throughout the striatum, elevates extracellular glutamate (GLU). To determine the role of behavioral arousal in this interaction, microdialysis was used to measure striatal GLU efflux in rats tested in either a lights-off or lights-on condition while reverse dialysis either maintained the concentration of AA at 250 microM or increased it to 1000 microM to approximate endogenous changes. RESULTS: When lights were off, both locomotion and GLU increased regardless of AA dose. In contrast, animals in the lights-on condition were behaviorally inactive, and infusion of 1000, but not 250, microM AA significantly increased extracellular GLU. Interestingly, when ambient light returned to the lights-off group, 1000 microM prolonged the GLU increase relative to the 250 microM group. CONCLUSION: Our results not only support evidence that elevated striatal AA increases extracellular GLU but also indicate that this effect depends on behavioral state and the corresponding level of endogenous GLU release. [Abstract/Link to Full Text]
Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation.
BMC Neurosci. 2007;832.
BACKGROUND: A physiological increase in extracellular ascorbate (AA), an antioxidant vitamin found throughout the striatum, elevates extracellular glutamate (GLU). To determine the role of behavioral arousal in this interaction, microdialysis was used to measure striatal GLU efflux in rats tested in either a lights-off or lights-on condition while reverse dialysis either maintained the concentration of AA at 250 microM or increased it to 1000 microM to approximate endogenous changes. RESULTS: When lights were off, both locomotion and GLU increased regardless of AA dose. In contrast, animals in the lights-on condition were behaviorally inactive, and infusion of 1000, but not 250, microM AA significantly increased extracellular GLU. Interestingly, when ambient light returned to the lights-off group, 1000 microM prolonged the GLU increase relative to the 250 microM group. CONCLUSION: Our results not only support evidence that elevated striatal AA increases extracellular GLU but also indicate that this effect depends on behavioral state and the corresponding level of endogenous GLU release. [Abstract/Link to Full Text]
Asymmetric lateral inhibitory neural activity in the auditory system: a magnetoencephalographic study.
Okamoto H, Kakigi R, Gunji A, Pantev C
Asymmetric lateral inhibitory neural activity in the auditory system: a magnetoencephalographic study.
BMC Neurosci. 2007;833.
BACKGROUND: Decrements of auditory evoked responses elicited by repeatedly presented sounds with similar frequencies have been well investigated by means of electroencephalography and magnetoencephalography (MEG). However the possible inhibitory interactions between different neuronal populations remains poorly understood. In the present study, we investigated the effect of proceeding notch-filtered noises (NFNs) with different frequency spectra on a following test tone using MEG. RESULTS: Three-second exposure to the NFNs resulted in significantly different N1m responses to a 1000 Hz test tone presented 500 ms after the offset of the NFNs. The NFN with a lower spectral edge closest to the test tone mostly decreased the N1m amplitude. CONCLUSION: The decrement of the N1m component after exposure to the NFNs could be explained partly in terms of lateral inhibition. The results demonstrated that the amplitude of the N1m was more effectively influenced by inhibitory lateral connections originating from neurons corresponding to lower rather than higher frequencies. We interpret this effect of asymmetric lateral inhibition in the auditory system as an important contribution to reduce the asymmetric neural activity profiles originating from the cochlea. [Abstract/Link to Full Text]
Asymmetric lateral inhibitory neural activity in the auditory system: a magnetoencephalographic study.
BMC Neurosci. 2007;833.
BACKGROUND: Decrements of auditory evoked responses elicited by repeatedly presented sounds with similar frequencies have been well investigated by means of electroencephalography and magnetoencephalography (MEG). However the possible inhibitory interactions between different neuronal populations remains poorly understood. In the present study, we investigated the effect of proceeding notch-filtered noises (NFNs) with different frequency spectra on a following test tone using MEG. RESULTS: Three-second exposure to the NFNs resulted in significantly different N1m responses to a 1000 Hz test tone presented 500 ms after the offset of the NFNs. The NFN with a lower spectral edge closest to the test tone mostly decreased the N1m amplitude. CONCLUSION: The decrement of the N1m component after exposure to the NFNs could be explained partly in terms of lateral inhibition. The results demonstrated that the amplitude of the N1m was more effectively influenced by inhibitory lateral connections originating from neurons corresponding to lower rather than higher frequencies. We interpret this effect of asymmetric lateral inhibition in the auditory system as an important contribution to reduce the asymmetric neural activity profiles originating from the cochlea. [Abstract/Link to Full Text]
Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.
Lindberg J, Saetre P, Nishino S, Mignot E, Jazin E
Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.
BMC Neurosci. 2007;834.
BACKGROUND: Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals. RESULTS: By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. CONCLUSION: These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans. [Abstract/Link to Full Text]
Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.
BMC Neurosci. 2007;834.
BACKGROUND: Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals. RESULTS: By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. CONCLUSION: These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans. [Abstract/Link to Full Text]
Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of Lactate Dehydrogenase 5 a
Laughton JD, Bittar P, Charnay Y, Pellerin L, Kovari E, Magistretti PJ, Bouras C
Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of Lactate Dehydrogenase 5 and Pyruvate Dehydrogenase.
BMC Neurosci. 2007 May 23;8(1):35.
ABSTRACT: BACKGROUND: For a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally. The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC1.1.1.27) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation. RESULTS: In this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions. CONCLUSIONS: These observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons. [Abstract/Link to Full Text]
Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of Lactate Dehydrogenase 5 and Pyruvate Dehydrogenase.
BMC Neurosci. 2007 May 23;8(1):35.
ABSTRACT: BACKGROUND: For a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally. The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC1.1.1.27) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation. RESULTS: In this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions. CONCLUSIONS: These observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons. [Abstract/Link to Full Text]
Differential development of neuronal physiological responsiveness in two human neural stem cell lines.
Donato R, Miljan EA, Hines SJ, Aouabdi S, Pollock K, Patel S, Edwards FA, Sinden JD
Differential development of neuronal physiological responsiveness in two human neural stem cell lines.
BMC Neurosci. 2007;836.
BACKGROUND: Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX) that can be continuously expanded in monolayer culture. RESULTS: In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting membrane potentials of around -60 mV but do not display any voltage-activated conductances. As initially hypothesized, using standard methods (stdD) for differentiation, both cell lines can form neurons, astrocytes and oligodendrocytes according to immunohistological characteristics. However it became clear that this was not true for electrophysiological features which designate neurons, such as the firing of action potentials. We have thus developed a new differentiation protocol, designated 'pre-aggregation differentiation' (preD) which appears to favor development of electrophysiologically functional neurons and to lead to an increase in dopaminergic neurons in the ReNcell VM line. In contrast, the protocol used had little effect on the differentiation of ReNcell CX in which dopaminergic differentiation was not observed. Moreover, after a week of differentiation with the preD protocol, 100% of ReNcell VM featured TTX-sensitive Na+-channels and fired action potentials, compared to 25% after stdD. Currents via other voltage-gated channels did not appear to depend on the differentiation protocol. ReNcell CX did not display the same electrophysiological properties as the VM line, generating voltage-dependant K+ currents but no Na+ currents or action potentials under either stdD or preD differentiation. CONCLUSION: These data demonstrate that overexpression of myc in NSCs can be used to generate electrophysiologically active neurons in culture. Development of a functional neuronal phenotype may be dependent on parameters of isolation and differentiation of the cell lines, indicating that not all human NSCs are functionally equivalent. [Abstract/Link to Full Text]
Differential development of neuronal physiological responsiveness in two human neural stem cell lines.
BMC Neurosci. 2007;836.
BACKGROUND: Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX) that can be continuously expanded in monolayer culture. RESULTS: In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting membrane potentials of around -60 mV but do not display any voltage-activated conductances. As initially hypothesized, using standard methods (stdD) for differentiation, both cell lines can form neurons, astrocytes and oligodendrocytes according to immunohistological characteristics. However it became clear that this was not true for electrophysiological features which designate neurons, such as the firing of action potentials. We have thus developed a new differentiation protocol, designated 'pre-aggregation differentiation' (preD) which appears to favor development of electrophysiologically functional neurons and to lead to an increase in dopaminergic neurons in the ReNcell VM line. In contrast, the protocol used had little effect on the differentiation of ReNcell CX in which dopaminergic differentiation was not observed. Moreover, after a week of differentiation with the preD protocol, 100% of ReNcell VM featured TTX-sensitive Na+-channels and fired action potentials, compared to 25% after stdD. Currents via other voltage-gated channels did not appear to depend on the differentiation protocol. ReNcell CX did not display the same electrophysiological properties as the VM line, generating voltage-dependant K+ currents but no Na+ currents or action potentials under either stdD or preD differentiation. CONCLUSION: These data demonstrate that overexpression of myc in NSCs can be used to generate electrophysiologically active neurons in culture. Development of a functional neuronal phenotype may be dependent on parameters of isolation and differentiation of the cell lines, indicating that not all human NSCs are functionally equivalent. [Abstract/Link to Full Text]
Central administration of dipeptides, beta-alanyl-BCAAs, induces hyperactivity in chicks.
Tsuneyoshi Y, Tomonaga S, Asechi M, Morishita K, Denbow DM, Furuse M
Central administration of dipeptides, beta-alanyl-BCAAs, induces hyperactivity in chicks.
BMC Neurosci. 2007;837.
BACKGROUND: Carnosine (beta-alanyl-L-histidine) is a putative neurotransmitter and has a possible role in neuron-glia cell interactions. Previously, we reported that carnosine induced hyperactivity in chicks when intracerebroventricularly (i.c.v.) administered. In the present study, we focused on other beta-alanyl dipeptides to determine if they have novel functions. RESULTS: In Experiment 1, i.c.v. injection of beta-alanyl-L-leucine, but not beta-alanyl-glycine, induced hyperactivity behavior as observed with carnosine. Both carnosine and beta-alanyl-L-leucine stimulated corticosterone release. Thus, dipeptides of beta-alanyl-branched chain amino acids were compared in Experiment 2. The i.c.v. injection of beta-alanyl-L-isoleucine caused a similar response as beta-alanyl-L-leucine, but beta-alanyl-L-valine was somewhat less effective than the other two dipeptides. beta-Alanyl-L-leucine strongly stimulated, and the other two dipeptides tended to stimulate, corticosterone release. CONCLUSION: These results suggest that central beta-alanyl-branched chain amino acid stimulates activity in chicks through the hypothalamus-pituitary-adrenal axis. We named beta-alanyl-L-leucine, beta-alanyl-L-isoleucine and beta-alanyl-L-valine as Excitin-1, Excitin-2 and Excitin-3, respectively. [Abstract/Link to Full Text]
Central administration of dipeptides, beta-alanyl-BCAAs, induces hyperactivity in chicks.
BMC Neurosci. 2007;837.
BACKGROUND: Carnosine (beta-alanyl-L-histidine) is a putative neurotransmitter and has a possible role in neuron-glia cell interactions. Previously, we reported that carnosine induced hyperactivity in chicks when intracerebroventricularly (i.c.v.) administered. In the present study, we focused on other beta-alanyl dipeptides to determine if they have novel functions. RESULTS: In Experiment 1, i.c.v. injection of beta-alanyl-L-leucine, but not beta-alanyl-glycine, induced hyperactivity behavior as observed with carnosine. Both carnosine and beta-alanyl-L-leucine stimulated corticosterone release. Thus, dipeptides of beta-alanyl-branched chain amino acids were compared in Experiment 2. The i.c.v. injection of beta-alanyl-L-isoleucine caused a similar response as beta-alanyl-L-leucine, but beta-alanyl-L-valine was somewhat less effective than the other two dipeptides. beta-Alanyl-L-leucine strongly stimulated, and the other two dipeptides tended to stimulate, corticosterone release. CONCLUSION: These results suggest that central beta-alanyl-branched chain amino acid stimulates activity in chicks through the hypothalamus-pituitary-adrenal axis. We named beta-alanyl-L-leucine, beta-alanyl-L-isoleucine and beta-alanyl-L-valine as Excitin-1, Excitin-2 and Excitin-3, respectively. [Abstract/Link to Full Text]
Scale-invariance of receptive field properties in primary visual cortex.
Teichert T, Wachtler T, Michler F, Gail A, Eckhorn R
Scale-invariance of receptive field properties in primary visual cortex.
BMC Neurosci. 2007 Jun 11;8(1):38.
ABSTRACT: BACKGROUND: Our visual system enables us to recognize visual objects across a wide range of spatial scales. The neural mechanisms underlying these abilities are still poorly understood. Size- or scale-independent representation of visual objects might be supported by processing in primary visual cortex (V1). Neurons in V1 are selective for spatial frequency and thus represent visual information in specific spatial wavebands. We tested whether different receptive field properties of neurons in V1 scale with preferred spatial wavelength. Specifically, we investigated the size of the area that enhances responses, i.e., the grating summation field, the size of the inhibitory surround, and the distance dependence of signal coupling, i.e., the linking field. RESULTS: We found that the sizes of both grating summation field and inhibitory surround increase with preferred spatial wavelength. For the summation field this increase, however, is not strictly linear. No evidence was found that size of the linking field depends on preferred spatial wavelength. CONCLUSIONS: Our data show that some receptive field properties are related to preferred spatial wavelength. This speaks in favor of the hypothesis that processing in V1 supports scale-invariant visual performance. However, not all properties of receptive fields in V1 scale with preferred spatial wavelength. Spatial wavelength independence of the linking field implies constant spatial range of signal coupling between neurons with different spatial wavelengths. This might be important for encoding extended broad-band visual features such as edges. [Abstract/Link to Full Text]
Scale-invariance of receptive field properties in primary visual cortex.
BMC Neurosci. 2007 Jun 11;8(1):38.
ABSTRACT: BACKGROUND: Our visual system enables us to recognize visual objects across a wide range of spatial scales. The neural mechanisms underlying these abilities are still poorly understood. Size- or scale-independent representation of visual objects might be supported by processing in primary visual cortex (V1). Neurons in V1 are selective for spatial frequency and thus represent visual information in specific spatial wavebands. We tested whether different receptive field properties of neurons in V1 scale with preferred spatial wavelength. Specifically, we investigated the size of the area that enhances responses, i.e., the grating summation field, the size of the inhibitory surround, and the distance dependence of signal coupling, i.e., the linking field. RESULTS: We found that the sizes of both grating summation field and inhibitory surround increase with preferred spatial wavelength. For the summation field this increase, however, is not strictly linear. No evidence was found that size of the linking field depends on preferred spatial wavelength. CONCLUSIONS: Our data show that some receptive field properties are related to preferred spatial wavelength. This speaks in favor of the hypothesis that processing in V1 supports scale-invariant visual performance. However, not all properties of receptive fields in V1 scale with preferred spatial wavelength. Spatial wavelength independence of the linking field implies constant spatial range of signal coupling between neurons with different spatial wavelengths. This might be important for encoding extended broad-band visual features such as edges. [Abstract/Link to Full Text]
Functional distribution of Ca2+-coupled P2 purinergic receptors among adrenergic and noradrenergic bovine adrenal chromaffin cells.
Tome AR, Castro E, Santos RM, Rosario LM
Functional distribution of Ca2+-coupled P2 purinergic receptors among adrenergic and noradrenergic bovine adrenal chromaffin cells.
BMC Neurosci. 2007 Jun 14;8(1):39.
ABSTRACT: BACKGROUND: Adrenal chromaffin cells mediate acute responses to stress through the release of epinephrine. Chromaffin cell function is regulated by several receptors, present both in adrenergic (AD) and noradrenergic (NA) cells. Extracellular ATP exerts excitatory and inhibitory actions on chromaffin cells via ionotropic (P2X) and metabotropic (P2Y) receptors. We have taken advantage of the actions of the purinergic agonists ATP and UTP on cytosolic free Ca2+ concentration ([Ca2+]i) to determine whether P2X and P2Y receptors might be asymmetrically distributed among AD and NA chromaffin cells. RESULTS: The [Ca2+]i and the [Na+]i were recorded from immunolabeled bovine chromaffin cells by single-cell fluorescence imaging. Among the ATP-sensitive cells ~ 40 % did not yield [Ca2+]i responses to ATP in the absence of extracellular Ca2+ (Ca2+o), indicating that they expressed P2X receptors and did not express Ca2+- mobilizing P2Y receptors; the remainder expressed Ca2+-mobilizing P2Y receptors. Relative to AD-cells approximately twice as many NA-cells expressed P2X receptors while not expressing Ca2+- mobilizing P2Y receptors, as indicated by the proportion of cells lacking [Ca2+]i responses and exhibiting [Na+]i responses to ATP in the absence and presence of Ca2+o, respectively. The density of P2X receptors in NA-cells appeared to be 30-50 % larger, as suggested by comparing the average size of the [Na+]i and [Ca2+]i responses to ATP. Conversely, approximately twice as many AD-cells expressed Ca2+-mobilizing P2Y receptors, and they appeared to exhibit a higher (~ 20%) receptor density. UTP raised the [Ca2+]i in a fraction of the cells and did not raise the [Na+]i in any of the cells tested, confirming its specificity as a P2Y agonist. The cell density of UTP-sensitive P2Y receptors did not appear to vary among AD- and NA-cells. CONCLUSIONS: Although neither of the major purinoceptor types can be ascribed to a particular cell phenotype, P2X and Ca2+-mobilizing P2Y receptors are preferentially located to noradrenergic and adrenergic chromaffin cells, respectively. ATP might, in addition to an UTP-sensitive P2Y receptor, activate an UTP-insensitive P2Y receptor subtype. A model for a short-loop feedback interaction is presented whereby locally released ATP acts upon P2Y receptors in adrenergic cells, inhibiting Ca2+ influx and contributing to terminate evoked epinephrine secretion. [Abstract/Link to Full Text]
Functional distribution of Ca2+-coupled P2 purinergic receptors among adrenergic and noradrenergic bovine adrenal chromaffin cells.
BMC Neurosci. 2007 Jun 14;8(1):39.
ABSTRACT: BACKGROUND: Adrenal chromaffin cells mediate acute responses to stress through the release of epinephrine. Chromaffin cell function is regulated by several receptors, present both in adrenergic (AD) and noradrenergic (NA) cells. Extracellular ATP exerts excitatory and inhibitory actions on chromaffin cells via ionotropic (P2X) and metabotropic (P2Y) receptors. We have taken advantage of the actions of the purinergic agonists ATP and UTP on cytosolic free Ca2+ concentration ([Ca2+]i) to determine whether P2X and P2Y receptors might be asymmetrically distributed among AD and NA chromaffin cells. RESULTS: The [Ca2+]i and the [Na+]i were recorded from immunolabeled bovine chromaffin cells by single-cell fluorescence imaging. Among the ATP-sensitive cells ~ 40 % did not yield [Ca2+]i responses to ATP in the absence of extracellular Ca2+ (Ca2+o), indicating that they expressed P2X receptors and did not express Ca2+- mobilizing P2Y receptors; the remainder expressed Ca2+-mobilizing P2Y receptors. Relative to AD-cells approximately twice as many NA-cells expressed P2X receptors while not expressing Ca2+- mobilizing P2Y receptors, as indicated by the proportion of cells lacking [Ca2+]i responses and exhibiting [Na+]i responses to ATP in the absence and presence of Ca2+o, respectively. The density of P2X receptors in NA-cells appeared to be 30-50 % larger, as suggested by comparing the average size of the [Na+]i and [Ca2+]i responses to ATP. Conversely, approximately twice as many AD-cells expressed Ca2+-mobilizing P2Y receptors, and they appeared to exhibit a higher (~ 20%) receptor density. UTP raised the [Ca2+]i in a fraction of the cells and did not raise the [Na+]i in any of the cells tested, confirming its specificity as a P2Y agonist. The cell density of UTP-sensitive P2Y receptors did not appear to vary among AD- and NA-cells. CONCLUSIONS: Although neither of the major purinoceptor types can be ascribed to a particular cell phenotype, P2X and Ca2+-mobilizing P2Y receptors are preferentially located to noradrenergic and adrenergic chromaffin cells, respectively. ATP might, in addition to an UTP-sensitive P2Y receptor, activate an UTP-insensitive P2Y receptor subtype. A model for a short-loop feedback interaction is presented whereby locally released ATP acts upon P2Y receptors in adrenergic cells, inhibiting Ca2+ influx and contributing to terminate evoked epinephrine secretion. [Abstract/Link to Full Text]
The development of descending projections from the brainstem to the spinal cord in the fetal sheep.
Stockx EM, Anderson CR, Murphy SM, Cooke IR, Berger PJ
The development of descending projections from the brainstem to the spinal cord in the fetal sheep.
BMC Neurosci. 2007 Jun 18;8(1):40.
ABSTRACT: BACKGROUND: Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to when the marked change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus. CONCLUSIONS: The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord. [Abstract/Link to Full Text]
The development of descending projections from the brainstem to the spinal cord in the fetal sheep.
BMC Neurosci. 2007 Jun 18;8(1):40.
ABSTRACT: BACKGROUND: Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to when the marked change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus. CONCLUSIONS: The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord. [Abstract/Link to Full Text]
Selective stimulation of catecholamine release from bovine adrenal chromaffin cells by an ionotropic purinergic receptor sensitive to 2-methylthio ATP
Tome AR, Castro E, Santos RM, Rosario LM
Selective stimulation of catecholamine release from bovine adrenal chromaffin cells by an ionotropic purinergic receptor sensitive to 2-methylthio ATP.
BMC Neurosci. 2007 Jun 20;8(1):41.
ABSTRACT: BACKGROUND: 2-Methylthioadenosine 5-triphosphate (2-MeSATP), formerly regarded as a specific P2Y (metabotropic) purinergic receptor agonist, stimulates Ca2+ influx and evokes catecholamine release from adrenal chromaffin cells. These cells express P2Y and P2X (ionotropic) purinoceptors, with the latter providing an important Ca2+ influx pathway. Using single cell calcium imaging techniques, we have determined whether 2-MeSATP might be a specific P2X receptor agonist in bovine chromaffin cells and assessed the relative role of P2X and P2Y receptors on catecholamine secretion from these cells. RESULTS: ATP raised the [Ca2+]i in ~ 50 % of the cells. Removing extracellular Ca2+ suppressed the [Ca2+]i-raising ability of 2-MeSATP, observed in ~ 40 % of the ATP-sensitive cells. This indicates that 2-MeSATP behaves as a specific ionotropic purinoceptor agonist in bovine chromaffin cells. The 2-MeSATP-induced [Ca2+]i-rises were suppressed by PPADS. UTP raised the [Ca2+]i in ~ 40 % of the ATP-sensitive cells, indicating that these expressed Ca2+-mobilizing P2Y receptors. UTP-sensitive receptors may not be the only P2Y receptors present, as suggested by the observation that ~ 20 % of the ATP-sensitive pool did not respond to either 2-MeSATP or UTP. The average sizes of the ATP- and 2-MeSATP-evoked [Ca2+]i responses were identical in UTP-insensitive cells. 2-MeSATP stimulated Ca2+ influx and evoked catecholamine release, whereas UTP elicited Ca2+ release from intracellular stores but did not evoke secretion. 2-MeSATP-induced secretion was strongly inhibited by Cd2+ and suppressed by extracellular Ca2+ or Na+ removal. TTX inhibited 2-MeSATP-evoked secretion by ~ 20 %. CONCLUSIONS: 2-MeSATP is a specific P2X purinoceptor agonist and a potent secretagogue in bovine chromaffin cells. Activation of 2-MeSATP-sensitive receptors stimulates Ca2+ influx mainly via voltage-sensitive Ca2+ channels. For the most part, these are activated by the depolarization brought about by Na+ influx across P2X receptor pores. [Abstract/Link to Full Text]
Selective stimulation of catecholamine release from bovine adrenal chromaffin cells by an ionotropic purinergic receptor sensitive to 2-methylthio ATP.
BMC Neurosci. 2007 Jun 20;8(1):41.
ABSTRACT: BACKGROUND: 2-Methylthioadenosine 5-triphosphate (2-MeSATP), formerly regarded as a specific P2Y (metabotropic) purinergic receptor agonist, stimulates Ca2+ influx and evokes catecholamine release from adrenal chromaffin cells. These cells express P2Y and P2X (ionotropic) purinoceptors, with the latter providing an important Ca2+ influx pathway. Using single cell calcium imaging techniques, we have determined whether 2-MeSATP might be a specific P2X receptor agonist in bovine chromaffin cells and assessed the relative role of P2X and P2Y receptors on catecholamine secretion from these cells. RESULTS: ATP raised the [Ca2+]i in ~ 50 % of the cells. Removing extracellular Ca2+ suppressed the [Ca2+]i-raising ability of 2-MeSATP, observed in ~ 40 % of the ATP-sensitive cells. This indicates that 2-MeSATP behaves as a specific ionotropic purinoceptor agonist in bovine chromaffin cells. The 2-MeSATP-induced [Ca2+]i-rises were suppressed by PPADS. UTP raised the [Ca2+]i in ~ 40 % of the ATP-sensitive cells, indicating that these expressed Ca2+-mobilizing P2Y receptors. UTP-sensitive receptors may not be the only P2Y receptors present, as suggested by the observation that ~ 20 % of the ATP-sensitive pool did not respond to either 2-MeSATP or UTP. The average sizes of the ATP- and 2-MeSATP-evoked [Ca2+]i responses were identical in UTP-insensitive cells. 2-MeSATP stimulated Ca2+ influx and evoked catecholamine release, whereas UTP elicited Ca2+ release from intracellular stores but did not evoke secretion. 2-MeSATP-induced secretion was strongly inhibited by Cd2+ and suppressed by extracellular Ca2+ or Na+ removal. TTX inhibited 2-MeSATP-evoked secretion by ~ 20 %. CONCLUSIONS: 2-MeSATP is a specific P2X purinoceptor agonist and a potent secretagogue in bovine chromaffin cells. Activation of 2-MeSATP-sensitive receptors stimulates Ca2+ influx mainly via voltage-sensitive Ca2+ channels. For the most part, these are activated by the depolarization brought about by Na+ influx across P2X receptor pores. [Abstract/Link to Full Text]
Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression.
Tilley MR, Cagniard B, Zhuang X, Han DD, Tiao N, Gu HH
Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression.
BMC Neurosci. 2007 Jun 21;8(1):42.
ABSTRACT: BACKGROUND: The dopamine transporter (DAT) plays a critical role in regulating dopamine neurotransmission. Variations in DAT or changes in basal dopaminergic tone have been shown to alter behavior and drug responses. DAT is one of the three known high affinity targets for cocaine, a powerful psychostimulant that produces reward and stimulates locomotor activity in humans and animals. We have shown that cocaine no longer produces reward in knock-in mice with a cocaine insensitive mutant DAT (DAT-CI), suggesting that cocaine inhibition of DAT is critical for its rewarding effect. However, in DAT-CI mice, the mutant DAT has significantly reduced uptake activity resulting in elevated basal dopaminergic tone, which might cause adaptive changes that alter responses to cocaine. Therefore, the objective of this study is to determine how elevated dopaminergic tone affects how mice respond to cocaine. RESULTS: We examined the cocaine induced behavior of DAT knockdown mice that have DAT expression reduced by 90% when compared to the wild type mice. Despite a dramatic reduction of DAT expression and marked elevation in basal dopamine tone, cocaine produced reward, as measured by conditioned place preference, and stimulated locomotor activity in these mice. CONCLUSIONS: A reduction in DAT expression and elevation of dopaminergic tone do not lead to adaptive changes that abolish the rewarding and stimulating effects of cocaine. Therefore, the lack of reward to cocaine observed in DAT-CI mice is unlikely to have resulted from the reduced DAT activity but instead is likely due to the inability of cocaine to block the mutated DAT and increase extracellular dopamine. This study supports the conclusion that the blockade of DAT is required for cocaine reward and locomotor stimulation. [Abstract/Link to Full Text]
Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression.
BMC Neurosci. 2007 Jun 21;8(1):42.
ABSTRACT: BACKGROUND: The dopamine transporter (DAT) plays a critical role in regulating dopamine neurotransmission. Variations in DAT or changes in basal dopaminergic tone have been shown to alter behavior and drug responses. DAT is one of the three known high affinity targets for cocaine, a powerful psychostimulant that produces reward and stimulates locomotor activity in humans and animals. We have shown that cocaine no longer produces reward in knock-in mice with a cocaine insensitive mutant DAT (DAT-CI), suggesting that cocaine inhibition of DAT is critical for its rewarding effect. However, in DAT-CI mice, the mutant DAT has significantly reduced uptake activity resulting in elevated basal dopaminergic tone, which might cause adaptive changes that alter responses to cocaine. Therefore, the objective of this study is to determine how elevated dopaminergic tone affects how mice respond to cocaine. RESULTS: We examined the cocaine induced behavior of DAT knockdown mice that have DAT expression reduced by 90% when compared to the wild type mice. Despite a dramatic reduction of DAT expression and marked elevation in basal dopamine tone, cocaine produced reward, as measured by conditioned place preference, and stimulated locomotor activity in these mice. CONCLUSIONS: A reduction in DAT expression and elevation of dopaminergic tone do not lead to adaptive changes that abolish the rewarding and stimulating effects of cocaine. Therefore, the lack of reward to cocaine observed in DAT-CI mice is unlikely to have resulted from the reduced DAT activity but instead is likely due to the inability of cocaine to block the mutated DAT and increase extracellular dopamine. This study supports the conclusion that the blockade of DAT is required for cocaine reward and locomotor stimulation. [Abstract/Link to Full Text]
Discontinuing treatment for psychiatric disorders.(sudden manias appear due to discontinuity)
COPYRIGHT 2006 Canadian Medical Association
The psychopharmacology of major psychiatric disorders involves the principle of optimal treatment, which includes appropriate drug selection, correct dosing, recognition and management of side effects, and appropriate duration of treatment. There is a substantial literature to support evidence-based decisions for all of these components of treatment in most major psychiatric syndromes. Less attention has been focused on drug discontinuation, especially in an era when longer-term treatment is recommended for most mood, anxiety and psychotic disorders. However, the rate and method of drug discontinuation can affect the course and prognosis of both mood and psychotic disorders. This is particularly relevant given the recommended use of relatively brief antidepressant treatment in bipolar disorder and the intermittent use of antipsychotic drugs in both mood and psychotic disorders. Moreover, up to 50% of patients will not comply with their prescription medication and will discontinue their drug treatments of their own accord. (1)
Analogous observations have been made in bipolar disorder and schizophrenia concerning drug discontinuation. Several studies have shown that discontinuation of lithium maintenance treatment in patients with bipolar disorder whose condition has been stabilized leads to...
Professional journal covering clinical and biological psychiatry and neuroscience.
An event-related functional MRI study of working memory in euthymic bipolar disorder.
An event-related functional MRI study of working memory in euthymic bipolar disorder.
COPYRIGHT 2007 Canadian Medical Association
Objective: Bipolar disorder (BD) is emerging as an illness marred by neurocognitive deficits, many of which do not resolve on recovery. Deficits affecting working memory (WM) in particular appear to be significant. WM comprises temporally separated biological processes that involve the on-line retention and manipulation of information. Previous neuroimaging studies have not sought to dissect the individual contributions of WM and examined WM subprocesses in euthymic BD. In this study, we investigated the encode, delay and response components of WM to identify the neural substrates and respective contributions to the WM deficits found in BD. Methods: We used event-related functional magnetic resonance imaging and a parametric WM task, incorporating 3 load conditions, to delineate individual WM subprocesses in 10 euthymic BD patients and 10 control subjects. Results: Patients exhibited attenuated patterns of activity, predominantly in frontal brain regions, across all WM components. Conclusions: Based on the attenuated activity observed in the patients, the clinical deficits in WM found in BD may reflect broad fronto-cortico-limbic dysfunction that is not confined to any single WM component. This is important in understanding the pathophysiology of BD and for future studies on executive functions in patients with this illness.
Objectif : On commence a reconnaitre que le trouble bipolaire (TB) est une maladie caracterisee par des deficits neurocognitifs dont beaucoup ne disparaissent pas au retablissement. Les deficits qui touchent la memoire de travail (MT) en particulier semblent importants. La MT comprend des processus biologiques separes temporalement mettant en cause la retention en ligne et la manipulation d'information. Les etudes anterieures de neuro-imagerie n'ont pas cherche a analyser les contributions individuelles de la MT et a examiner des sous-processus de la MT dans un cas de TB euthymique. Dans cette etude, nous nous sommes penches sur les composantes encodage, retard et reponse de la MT afin d'identifier les substrats neuraux et les contributions respectives au deficit de la MT que l'on retrouve dans des cas de TB. Methodes : Nous avons utilise l'imagerie par resonnance magnetique fonctionnelle reliee a un evenement et une tache MT parametrisee, comportant trois conditions de charge, afin de delimiter des sous-processus individuels de la MT chez 10 patients atteints d'un TB euthymique et 10 sujets temoins. Resultats : Les patients ont montre des tendances attenuees d'activite, principalement dans les regions frontales du cerveau, dans toutes les composantes de la MT. Conclusions : Compte tenu de l'attenuation de l'activite observee chez les patients, les deficits cliniques de la MT que l'on constate dans les cas de TB peuvent refleter un dysfonctionnement frontocorticolimbique general qui n'est pas confine a une seule composante de la MT. Cette constatation est importante si l'on veut comprendre la pathophysiologie du TB et pour des etudes futures des fonctions d'execution chez les patients atteints de cette maladie.
Introduction
Bipolar disorder (BD) is a complex mental illness characterized by acute shifts in a person's mood, energy and ability to function. In BD, symptoms of depression and hypomania are more severe than the normal "ups and downs" experienced by healthy individuals, and episodes of apparent remission are deceptive, because impairments persist even while the patient is apparently well. (1-3) Traditionally, BD has been regarded as a disorder of mood and, as a consequence, initial studies focused on structural abnormalities in limbic-thalamocortical networks, which are known to subserve mood. Collectively, the prefrontal cortex, medial temporal lobe and subcortical structures have been targeted and structural abnormalities identified in each of these regions. (4-7) More recently, neuroimaging studies using positron emission tomography (PET) and single photon emission computed tomography (SPECT) have identified a wide range of metabolic dysfunctions involving the prefrontal cortex, cingulate, and temporal and parietal cortices. (8) Moreover, functional MRI (fMRI) studies have highlighted functional aberrations at various locations along limbic-thalamocortical circuits. (2,9-14) While the search for the precise structure-function relation underpinning the pathophysiology of BD has concentrated on mood-related circuits, it has been assumed that cognitive processes are unaffected and remain largely intact. Consequently, cognitive processes such as working memory (WM) have received far less attention than mood. This is surprising, given that many of the identified abnormalities occur in brain regions that clearly subserve functions other than emotional regulation. In BD, neurocognitive deficits have been identified3 that do not resolve during euthymia, (15) and deficits in WM in particular appear extensive. (16,17)
Working memory
The term "working memory" refers to a complex set of biological processes involved in the on-line retention and manipulation of information, (18) used by organisms to guide behaviour and successfully interact with the environment. WM plays a crucial role in many cognitive functions, such as spatial processing, reasoning, planning and language comprehension. Consequently, impairments in WM have a profound impact on cognition. Several studies have reported that dysfunctions in WM are the underlying cause of cognitive impairments observed in conditions such as schizophrenia, (19) unipolar depression (20) and Parkinson's disease. (21) It has been postulated that WM is not a unitary process but, instead, is composed of 3 independent components that operate dynamically. (18) According to this model, WM comprises a visuospatial sketchpad and phonological loop that stores and manipulates visuospatial and verbal information together with a central executive that regulates attention processes and controls information entry and the retention and release of memory from the visuospatial sketchpad and phonological loop. The precise neurobiological substrates of WM have yet to be elucidated. Results of recent neuroimaging studies lend tentative support for this 3-component model with the implication of such regions as the prefrontal cortex, (22) parietal cortex (23) and anterior cingulate. (24)
BD imaging studies
To date, only 2 WM fMRI studies have been conducted on patients with euthymic BD. (25,26) The first study (25) employed a 2-back WM task incorporated in a block design with 0-back as the baseline condition. The study reported that patients performed significantly worse than control subjects, with respect to the baseline condition 0-back. Despite performing poorly, patients showed qualitatively greater activation foci, compared with control subjects, across the entire brain; this pattern of activation persisted between group comparisons with healthy control subjects. The results from this study are counterintuitive, because poor performance would normally be associated with reduced activation, especially in regions associated with the WM. However, the paradigm employed in this study (2-back block design) did not draw on the load-capacity characteristics of the WM. The second study (26) used 2 separate WM paradigms, the 2-back (block design) and the Sternberg Task (parametric design), in an attempt to dissociate the central executive from the phonological loop. The authors reported no significant between-group differences in reaction time performance in either of the tasks. In direct contrast to the previous (25) study, the authors reported significantly decreased bilateral frontal, temporal and parietal activations for the BD group during the 2-back task, but no between-group differences were found during the Sternberg Task. The authors did not, however, adequately distinguish individual WM subprocesses; thus these findings may not be representative. Studies using the Sternberg Task reported reliable activations in frontal, parietal and subcortical areas. (27,28) However, to accurately elucidate the brain regions involved by such WM tasks, it is necessary to disentangle the contributions of subprocesses such as encode, delay and response execution, because each of these may preferentially engage separate brain regions. Although studies (25,26) have explored WM deficits in patients with BD using traditional n-back and Sternberg memory tasks, these studies that have used block-design paradigms...
Free articles on open access in The Journal of Neuroscience
The Journal of Neuroscience published an
editorial by Editor-in-Chief Gary Westbrook on the ongoing debate
about open access in the scientific community
(http://www.jneurosci.org/cgi/content/full/26/36/9077). This
issue included the first in a series of weekly Commentaries on
science publishing that will appear in issues leading up to the
2006 Annual Meeting of the Society for Neuroscience. Five
individuals who have been involved in various publishing
experiments and enterprises were invited to give their viewpoints
on the challenges facing scientific journals publishing. The
hope is that readers will find these opinion pieces intriguing,
while at the same time recognizing that the viewpoints expressed
are not necessarily those of The Journal or the Society
leadership.
Commentaries published to date in The Journal
John Willinsky
Why Open Access to Research and Scholarship?
J. Neurosci. 2006 26: 9078-9079; doi:10.1523/JNEUROSCI.2891-06.2006
<http://www.jneurosci.org/cgi/content/full/26/36/9078>
Richard K. Johnson
Will Research Sharing Keep Pace with the Internet?
J. Neurosci. 2006 26: 9349-9351; doi:10.1523/JNEUROSCI.3130-06.2006
[http://www.jneurosci.org/cgi/content/full/26/37/9349]
Paul Ginsparg
As We May Read
J. Neurosci. 2006 26: 9606-9608; doi:10.1523/JNEUROSCI.3161-06.2006
<http://www.jneurosci.org/cgi/content/full/26/38/9606> ]
In forthcoming Issues of The Journal:
Richard Smith: Reinventing the biomedical journal. (September 27)
Matthew Cockerill and Vitek Tracz: Open access and the future of the
scientific research article. (October 4)
The Society for Neuroscience also will host a Publishing
Roundtable at the 2006 Annual Meeting in Atlanta, which will be
moderated by incoming SfN President and former Editor-in-Chief of
The Journal of Neuroscience, David Van Essen. "(R)evolution in
scientific publishing: How will it affect you?" will be held
Monday, Oct 16, from 9:30 to 11:00 am. For details, please see
informacion for site
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HighWire Press is the largest archive of free full-text science on Earth! As of 10/13/06, we are assisting in the online publication of 1,456,917 free full-text articles and 3,707,713 total articles. There are 39 sites with free trial periods, and 35 completely free sites. 230 sites have free back issues, and 887 sites have pay per view!
Freely accessible scientific journals
• BioMed Central (medicine, biological sciences) http://www.biomedcentral.com/
• Directory of Open Access Journals (multidisciplinary) http://www.doaj.org/
• Electronic Journals Library (multidisciplinary) http://rzblx1.uni-regensburg.de/ezei...=1& bibid=UBR
•
• FreeMedicalJournals.com (medicine) http://www.freemedicaljournals.com/
• PubMed Central (medicine) http://www.pubmedcentral.nih.gov/
http://www.psychonomic.org/search/
Search for Psychonomic Society journal articles from 1991 to 2000.
free back issues
Animal Leaning and behavior
Behavior Research Methods, Instruments, & Computers
Memory & Cognition
Perception & Psychophysics
Psychobiology
Psychonomic Bulletin & Review
http://highwire.stanford.edu/lists/freeart.dtl
HighWire Press is the largest archive of free full-text science on Earth! As of 10/13/06, we are assisting in the online publication of 1,456,917 free full-text articles and 3,707,713 total articles. There are 39 sites with free trial periods, and 35 completely free sites. 230 sites have free back issues, and 887 sites have pay per view!
Freely accessible scientific journals
• BioMed Central (medicine, biological sciences) http://www.biomedcentral.com/
• Directory of Open Access Journals (multidisciplinary) http://www.doaj.org/
• Electronic Journals Library (multidisciplinary) http://rzblx1.uni-regensburg.de/ezei...=1& bibid=UBR
•
• FreeMedicalJournals.com (medicine) http://www.freemedicaljournals.com/
• PubMed Central (medicine) http://www.pubmedcentral.nih.gov/
http://www.psychonomic.org/search/
Search for Psychonomic Society journal articles from 1991 to 2000.
free back issues
Animal Leaning and behavior
Behavior Research Methods, Instruments, & Computers
Memory & Cognition
Perception & Psychophysics
Psychobiology
Psychonomic Bulletin & Review
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