Neuroscience
Hippocampal theta rhythms follow the beat of their own drum.
Publication Date: 2009 Dec PMID: 19935726
Authors: Colgin, L. L. - Moser, E. I.
Journal: Nat Neurosci
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Authors: Colgin, L. L. - Moser, E. I.
Journal: Nat Neurosci
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Pigment epithelium-derived growth factor: modulating adult neural stem cell self-renewal.
Publication Date: 2009 Dec PMID: 19935725
Authors: Chojnacki, A. - Weiss, S.
Journal: Nat Neurosci
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Authors: Chojnacki, A. - Weiss, S.
Journal: Nat Neurosci
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Neuronal death or dismemberment mediated by Sox14.
Publication Date: 2009 Dec PMID: 19935724
Authors: Osterloh, J. M. - Freeman, M. R.
Journal: Nat Neurosci
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Authors: Osterloh, J. M. - Freeman, M. R.
Journal: Nat Neurosci
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Scientists talking to the public: is there anyone out there?
Publication Date: 2009 Dec PMID: 19935723
Authors: Ringach, D. L.
Journal: Nat Neurosci
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Authors: Ringach, D. L.
Journal: Nat Neurosci
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Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses.
Publication Date: 2009 Nov 22 PMID: 19935655
Authors: Abramov, E. - Dolev, I. - Fogel, H. - Ciccotosto, G. D. - Ruff, E. - Slutsky, I.
Journal: Nat Neurosci
Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.
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Authors: Abramov, E. - Dolev, I. - Fogel, H. - Ciccotosto, G. D. - Ruff, E. - Slutsky, I.
Journal: Nat Neurosci
Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.
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Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system.
Publication Date: 2009 Nov 22 PMID: 19935654
Authors: Ohno, M. - Hiraoka, Y. - Matsuoka, T. - Tomimoto, H. - Takao, K. - Miyakawa, T. - Oshima, N. - Kiyonari, H. - Kimura, T. - Kita, T. - Nishi, E.
Journal: Nat Neurosci
Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1(-/-) mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters. We also found hypomyelination in the peripheral nervous system (PNS) of Nrd1(-/-) mice. Neuron-specific overexpression of NRDc induced hypermyelination, indicating that the level of neuronal NRDc regulates myelin thickness. Consistent with these findings, Nrd1(-/-) mice had impaired motor activities and cognitive deficits. Furthermore, NRDc enhanced ectodomain shedding of neuregulin1 (NRG1), which is a master regulator of myelination in the PNS. On the basis of these data, we propose that NRDc regulates axonal maturation and myelination in the CNS and PNS, in part, through the modulation of NRG1 shedding.
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Authors: Ohno, M. - Hiraoka, Y. - Matsuoka, T. - Tomimoto, H. - Takao, K. - Miyakawa, T. - Oshima, N. - Kiyonari, H. - Kimura, T. - Kita, T. - Nishi, E.
Journal: Nat Neurosci
Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1(-/-) mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters. We also found hypomyelination in the peripheral nervous system (PNS) of Nrd1(-/-) mice. Neuron-specific overexpression of NRDc induced hypermyelination, indicating that the level of neuronal NRDc regulates myelin thickness. Consistent with these findings, Nrd1(-/-) mice had impaired motor activities and cognitive deficits. Furthermore, NRDc enhanced ectodomain shedding of neuregulin1 (NRG1), which is a master regulator of myelination in the PNS. On the basis of these data, we propose that NRDc regulates axonal maturation and myelination in the CNS and PNS, in part, through the modulation of NRG1 shedding.
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Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides.
Publication Date: 2009 Nov 22 PMID: 19935653
Authors: Leinders-Zufall, T. - Ishii, T. - Mombaerts, P. - Zufall, F. - Boehm, T.
Journal: Nat Neurosci
In addition to their role in the immune response, peptide ligands of major histocompatibility complex (MHC) molecules function as olfactory cues for subsets of vomeronasal sensory neurons (VSNs) in the mammalian nose. How MHC peptide diversity is recognized and encoded by these cells is unclear. We found that mouse VSNs expressing the vomeronasal receptor gene V2r1b (also known as Vmn2r26) detected MHC peptides at subpicomolar concentrations and exhibited combinatorial activation with overlapping specificities. In a given cell, peptide responsiveness was broad, but highly specific; peptides differing by a single amino-acid residue could be distinguished. Cells transcribing a V2r1b locus that has been disrupted by gene targeting no longer showed such peptide responses. Our results reveal fundamental parameters governing the response to MHC peptides by VSNs. We suggest that the peptide presentation system provided by MHC molecules co-evolves with the peptide recognition systems expressed by T cells and VSNs.
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Authors: Leinders-Zufall, T. - Ishii, T. - Mombaerts, P. - Zufall, F. - Boehm, T.
Journal: Nat Neurosci
In addition to their role in the immune response, peptide ligands of major histocompatibility complex (MHC) molecules function as olfactory cues for subsets of vomeronasal sensory neurons (VSNs) in the mammalian nose. How MHC peptide diversity is recognized and encoded by these cells is unclear. We found that mouse VSNs expressing the vomeronasal receptor gene V2r1b (also known as Vmn2r26) detected MHC peptides at subpicomolar concentrations and exhibited combinatorial activation with overlapping specificities. In a given cell, peptide responsiveness was broad, but highly specific; peptides differing by a single amino-acid residue could be distinguished. Cells transcribing a V2r1b locus that has been disrupted by gene targeting no longer showed such peptide responses. Our results reveal fundamental parameters governing the response to MHC peptides by VSNs. We suggest that the peptide presentation system provided by MHC molecules co-evolves with the peptide recognition systems expressed by T cells and VSNs.
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Self-modulation of neocortical pyramidal neurons by endocannabinoids.
Publication Date: 2009 Dec PMID: 19915567
Authors: Marinelli, S. - Pacioni, S. - Cannich, A. - Marsicano, G. - Bacci, A.
Journal: Nat Neurosci
Control of pyramidal neuron excitability is vital for the functioning of the neocortex. Somatodendritic slow self-inhibition (SSI) allows inhibitory neurons to regulate their own activity, but the existence of similar mechanisms in excitatory cells has not been shown. We found that in rodents endocannabinoids mediated SSI and long-term modulation of inhibitory connections in layer 2/3 pyramidal neurons with a distinct dendritic morphology, suggesting that a glutamatergic network in cortical circuits is self-regulated.
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Authors: Marinelli, S. - Pacioni, S. - Cannich, A. - Marsicano, G. - Bacci, A.
Journal: Nat Neurosci
Control of pyramidal neuron excitability is vital for the functioning of the neocortex. Somatodendritic slow self-inhibition (SSI) allows inhibitory neurons to regulate their own activity, but the existence of similar mechanisms in excitatory cells has not been shown. We found that in rodents endocannabinoids mediated SSI and long-term modulation of inhibitory connections in layer 2/3 pyramidal neurons with a distinct dendritic morphology, suggesting that a glutamatergic network in cortical circuits is self-regulated.
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Attention improves performance primarily by reducing interneuronal correlations.
Publication Date: 2009 Dec PMID: 19915566
Authors: Cohen, M. R. - Maunsell, J. H.
Journal: Nat Neurosci
Visual attention can improve behavioral performance by allowing observers to focus on the important information in a complex scene. Attention also typically increases the firing rates of cortical sensory neurons. Rate increases improve the signal-to-noise ratio of individual neurons, and this improvement has been assumed to underlie attention-related improvements in behavior. We recorded dozens of neurons simultaneously in visual area V4 and found that changes in single neurons accounted for only a small fraction of the improvement in the sensitivity of the population. Instead, over 80% of the attentional improvement in the population signal was caused by decreases in the correlations between the trial-to-trial fluctuations in the responses of pairs of neurons. These results suggest that the representation of sensory information in populations of neurons and the way attention affects the sensitivity of the population may only be understood by considering the interactions between neurons.
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Authors: Cohen, M. R. - Maunsell, J. H.
Journal: Nat Neurosci
Visual attention can improve behavioral performance by allowing observers to focus on the important information in a complex scene. Attention also typically increases the firing rates of cortical sensory neurons. Rate increases improve the signal-to-noise ratio of individual neurons, and this improvement has been assumed to underlie attention-related improvements in behavior. We recorded dozens of neurons simultaneously in visual area V4 and found that changes in single neurons accounted for only a small fraction of the improvement in the sensitivity of the population. Instead, over 80% of the attentional improvement in the population signal was caused by decreases in the correlations between the trial-to-trial fluctuations in the responses of pairs of neurons. These results suggest that the representation of sensory information in populations of neurons and the way attention affects the sensitivity of the population may only be understood by considering the interactions between neurons.
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Endogenous rhythms in period1 mutant suprachiasmatic nuclei in vitro do not represent circadian behavior.
Publication Date: 2009 Nov 18 PMID: 19923301
Authors: Pendergast, J. S. - Friday, R. C. - Yamazaki, S.
Journal: J Neurosci
The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) controls daily rhythms of behavior and physiology. Lesions of the SCN cause arrhythmicity of locomotor activity, and transplants of fetal SCN tissue restore rhythmic behavior that is consistent with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. While several studies have demonstrated that the circadian characteristics of in vitro SCN rhythms represent circadian behavior, others have shown that the periods of explanted SCN are not always congruent with locomotor activity. We find that the aberrant rhythms of ex vivo SCN lacking functional Period1 (Per1(-/-)) do not represent the behavioral rhythms of the mutant animals. Surprisingly, in C57BL/6J Per1(-/-) mice, the real-time circadian gene promoter activity rhythm is weak or absent in adult SCN slices in vitro even though the free-running wheel-running activity rhythm is indistinguishable from wild-type (Per1(+/+)) mice. While some neurons in Per1(-/-) SCN explants exhibit robust circadian rhythms, others have irregular and/or low-amplitude rhythms. Together, these data suggest that either a small population of rhythmic neurons in the Per1(-/-) SCN is sufficient to control wheel-running activity or that in vivo physiological factors can compensate for the aberrant endogenous rhythms of Per1(-/-) SCN.
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Authors: Pendergast, J. S. - Friday, R. C. - Yamazaki, S.
Journal: J Neurosci
The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) controls daily rhythms of behavior and physiology. Lesions of the SCN cause arrhythmicity of locomotor activity, and transplants of fetal SCN tissue restore rhythmic behavior that is consistent with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. While several studies have demonstrated that the circadian characteristics of in vitro SCN rhythms represent circadian behavior, others have shown that the periods of explanted SCN are not always congruent with locomotor activity. We find that the aberrant rhythms of ex vivo SCN lacking functional Period1 (Per1(-/-)) do not represent the behavioral rhythms of the mutant animals. Surprisingly, in C57BL/6J Per1(-/-) mice, the real-time circadian gene promoter activity rhythm is weak or absent in adult SCN slices in vitro even though the free-running wheel-running activity rhythm is indistinguishable from wild-type (Per1(+/+)) mice. While some neurons in Per1(-/-) SCN explants exhibit robust circadian rhythms, others have irregular and/or low-amplitude rhythms. Together, these data suggest that either a small population of rhythmic neurons in the Per1(-/-) SCN is sufficient to control wheel-running activity or that in vivo physiological factors can compensate for the aberrant endogenous rhythms of Per1(-/-) SCN.
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Functional heterogeneity at dopamine release sites.
Publication Date: 2009 Nov 18 PMID: 19923300
Authors: Daniel, J. A. - Galbraith, S. - Iacovitti, L. - Abdipranoto, A. - Vissel, B.
Journal: J Neurosci
Although drugs used to treat several neurological diseases are presumed to target synapses that secrete dopamine (DA), relatively little is known about synaptic vesicle (SV) release mechanisms at single DA synapses. We found that the relative probability of release (Pr) varied between individual DA synapses. Furthermore, DA terminals generally exhibited lower Pr than glutamatergic hippocampal (Hpc) terminals, suggesting that DA release is less reliable than the release of glutamate. Our mathematical model of fluorescence loss shows that Pr is regulated by two independent and heterogeneous elements. First, the size of the recycling SV pool regulates Pr. Second, Pr is also independently regulated by additional factors, which are reflected in the time constant of FM 1-43 destaining, tau. We found that the observed difference in Pr between Hpc and DA neurons results because the recycling SV pool is smaller in DA neurons than in Hpc neurons. However, tau does not vary between these two neuron populations. We also identified a population of functional nonsynaptic boutons in DA axons, which are not associated with a postsynaptic element and which are not functionally different from boutons that formed conventional synapses. Our work provides a new approach to the study of SV exocytosis in DA neurons and shows that synaptic terminals of DA neurons are functionally heterogeneous and differ from excitatory terminals in terms of Pr.
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Authors: Daniel, J. A. - Galbraith, S. - Iacovitti, L. - Abdipranoto, A. - Vissel, B.
Journal: J Neurosci
Although drugs used to treat several neurological diseases are presumed to target synapses that secrete dopamine (DA), relatively little is known about synaptic vesicle (SV) release mechanisms at single DA synapses. We found that the relative probability of release (Pr) varied between individual DA synapses. Furthermore, DA terminals generally exhibited lower Pr than glutamatergic hippocampal (Hpc) terminals, suggesting that DA release is less reliable than the release of glutamate. Our mathematical model of fluorescence loss shows that Pr is regulated by two independent and heterogeneous elements. First, the size of the recycling SV pool regulates Pr. Second, Pr is also independently regulated by additional factors, which are reflected in the time constant of FM 1-43 destaining, tau. We found that the observed difference in Pr between Hpc and DA neurons results because the recycling SV pool is smaller in DA neurons than in Hpc neurons. However, tau does not vary between these two neuron populations. We also identified a population of functional nonsynaptic boutons in DA axons, which are not associated with a postsynaptic element and which are not functionally different from boutons that formed conventional synapses. Our work provides a new approach to the study of SV exocytosis in DA neurons and shows that synaptic terminals of DA neurons are functionally heterogeneous and differ from excitatory terminals in terms of Pr.
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In vivo quantification of myelin changes in the vertebrate nervous system.
Publication Date: 2009 Nov 18 PMID: 19923299
Authors: Wang, Y. - Wu, C. - Caprariello, A. V. - Somoza, E. - Zhu, W. - Wang, C. - Miller, R. H.
Journal: J Neurosci
Destruction or changes associated with myelin membranes in the CNS play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. A long-standing goal has been to detect and quantify myelin content in vivo. For this reason, we have developed a myelin-imaging technique based on positron emission tomography (PET). PET is a quantitative imaging modality that has been widely used in clinical settings for direct assessment of biological processes at the molecular level. However, lack of myelin-imaging probes has hampered the use of PET for imaging of myelination in the CNS. Here, we report a myelin-imaging agent, termed Case Imaging Compound (CIC) that readily penetrates the blood-brain barrier and preferentially localizes to myelinated regions of the brain. After radiolabeling with positron-emitting carbon-11, [(11)C]CIC-PET was conducted in longitudinal studies using a lysolethicin-induced rat model of focal demyelination and subsequent remyelination. Quantitative analysis showed that the retention of [(11)C]CIC correlates with the level of demyelination/remyelination. These studies indicate that, for the first time, [(11)C]CIC-PET can be used as an imaging marker of myelination, which has the potential to be translated into clinical studies in multiple sclerosis and other myelin-related diseases for early diagnosis, subtyping, and efficacy evaluation of therapeutic treatments aimed at myelin repair.
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Authors: Wang, Y. - Wu, C. - Caprariello, A. V. - Somoza, E. - Zhu, W. - Wang, C. - Miller, R. H.
Journal: J Neurosci
Destruction or changes associated with myelin membranes in the CNS play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. A long-standing goal has been to detect and quantify myelin content in vivo. For this reason, we have developed a myelin-imaging technique based on positron emission tomography (PET). PET is a quantitative imaging modality that has been widely used in clinical settings for direct assessment of biological processes at the molecular level. However, lack of myelin-imaging probes has hampered the use of PET for imaging of myelination in the CNS. Here, we report a myelin-imaging agent, termed Case Imaging Compound (CIC) that readily penetrates the blood-brain barrier and preferentially localizes to myelinated regions of the brain. After radiolabeling with positron-emitting carbon-11, [(11)C]CIC-PET was conducted in longitudinal studies using a lysolethicin-induced rat model of focal demyelination and subsequent remyelination. Quantitative analysis showed that the retention of [(11)C]CIC correlates with the level of demyelination/remyelination. These studies indicate that, for the first time, [(11)C]CIC-PET can be used as an imaging marker of myelination, which has the potential to be translated into clinical studies in multiple sclerosis and other myelin-related diseases for early diagnosis, subtyping, and efficacy evaluation of therapeutic treatments aimed at myelin repair.
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Novel repression of Kcc2 transcription by REST-RE-1 controls developmental switch in neuronal chloride.
Publication Date: 2009 Nov 18 PMID: 19923298
Authors: Yeo, M. - Berglund, K. - Augustine, G. - Liedtke, W.
Journal: J Neurosci
Transcriptional upregulation of Kcc2b, the gene variant encoding the major isoform of the KCC2 chloride transporter, underlies a rapid perinatal decrease in intraneuronal chloride concentration (chloride shift), which is necessary for GABA to act inhibitory. Here we identify a novel repressor element-1 (RE-1) site in the 5' regulatory region of Kcc2b. In primary cortical neurons, which recapitulate the chloride shift in culture, the novel upstream RE-1 together with a known intronic RE-1 site function in concerted interaction to suppress Kcc2b transcription. With critical relevance for the chloride shift, only in the presence of the dual RE-1 site could inhibition of REST upregulate Kcc2b transcription. For this, we confirmed increased KCC2 protein expression and decreased intraneuronal chloride. Kcc2b developmental upregulation was potentiated by BDNF application, which was fully dependent on the presence of dual RE-1. In addition, the developmental chloride shift and GABA switch, from excitatory to inhibitory action, was accelerated by REST inhibition and slowed by REST overexpression. These results identify the REST-dual RE-1 interaction as a novel mechanism of transcriptional Kcc2b upregulation that significantly contributes to the ontogenetic shift in chloride concentration and GABA action in cortical neurons, which is fundamental for brain function in health and disease. Thus, we present here a new logic for the perinatal chloride shift, which is critical for establishment of GABAergic cortical inhibitory neurotransmission.
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Authors: Yeo, M. - Berglund, K. - Augustine, G. - Liedtke, W.
Journal: J Neurosci
Transcriptional upregulation of Kcc2b, the gene variant encoding the major isoform of the KCC2 chloride transporter, underlies a rapid perinatal decrease in intraneuronal chloride concentration (chloride shift), which is necessary for GABA to act inhibitory. Here we identify a novel repressor element-1 (RE-1) site in the 5' regulatory region of Kcc2b. In primary cortical neurons, which recapitulate the chloride shift in culture, the novel upstream RE-1 together with a known intronic RE-1 site function in concerted interaction to suppress Kcc2b transcription. With critical relevance for the chloride shift, only in the presence of the dual RE-1 site could inhibition of REST upregulate Kcc2b transcription. For this, we confirmed increased KCC2 protein expression and decreased intraneuronal chloride. Kcc2b developmental upregulation was potentiated by BDNF application, which was fully dependent on the presence of dual RE-1. In addition, the developmental chloride shift and GABA switch, from excitatory to inhibitory action, was accelerated by REST inhibition and slowed by REST overexpression. These results identify the REST-dual RE-1 interaction as a novel mechanism of transcriptional Kcc2b upregulation that significantly contributes to the ontogenetic shift in chloride concentration and GABA action in cortical neurons, which is fundamental for brain function in health and disease. Thus, we present here a new logic for the perinatal chloride shift, which is critical for establishment of GABAergic cortical inhibitory neurotransmission.
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Overexpression of the wild-type SPT1 subunit lowers Desoxysphingolipid levels and rescues the phenotype of HSAN1.
Publication Date: 2009 Nov 18 PMID: 19923297
Authors: Eichler, F. S. - Hornemann, T. - McCampbell, A. - Kuljis, D. - Penno, A. - Vardeh, D. - Tamrazian, E. - Garofalo, K. - Lee, H. J. - Kini, L. - Selig, M. - Frosch, M. - Gable, K. - von Eckardstein, A. - Woolf, C. J. - Guan, G. - Harmon, J. M. - Dunn, T. M. - Brown, R. H. Jr
Journal: J Neurosci
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1(C133W)) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1(C133W), but not in the wild-type, double-transgenic tgSPTLC1(WT + C133W) or SPTLC1(+/-) mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.
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Authors: Eichler, F. S. - Hornemann, T. - McCampbell, A. - Kuljis, D. - Penno, A. - Vardeh, D. - Tamrazian, E. - Garofalo, K. - Lee, H. J. - Kini, L. - Selig, M. - Frosch, M. - Gable, K. - von Eckardstein, A. - Woolf, C. J. - Guan, G. - Harmon, J. M. - Dunn, T. M. - Brown, R. H. Jr
Journal: J Neurosci
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1(C133W)) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1(C133W), but not in the wild-type, double-transgenic tgSPTLC1(WT + C133W) or SPTLC1(+/-) mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.
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The neural-glial purinergic receptor ensemble in chronic pain states.
Publication Date: 2009 Nov 13 PMID: 19914722
Authors: Jarvis, M. F.
Journal: Trends Neurosci
Chronic pain is characterized by enhanced sensory neurotransmission that underlies increased sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful. Evidence from neurophysiological and pharmacological studies demonstrates that ATP produces pain by directly enhancing neuronal excitability via the activation of specific ligand-gated ion channels, the P2X3 and P2X2/3 receptors. In addition, ATP activates CNS glial cells (e.g. microglia) in response to persistent nociceptive stimulation. This latter effect involves several distinct receptor-mediated signaling pathways linked to the P2X4, P2X7 and P2Y(12) receptors. This review summarizes new data that places these purinergic signaling events in a mechanistic context that illustrates the ability of ATP to initiate and maintain states of heightened sensory neuron excitability associated with persistent pain.
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Authors: Jarvis, M. F.
Journal: Trends Neurosci
Chronic pain is characterized by enhanced sensory neurotransmission that underlies increased sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful. Evidence from neurophysiological and pharmacological studies demonstrates that ATP produces pain by directly enhancing neuronal excitability via the activation of specific ligand-gated ion channels, the P2X3 and P2X2/3 receptors. In addition, ATP activates CNS glial cells (e.g. microglia) in response to persistent nociceptive stimulation. This latter effect involves several distinct receptor-mediated signaling pathways linked to the P2X4, P2X7 and P2Y(12) receptors. This review summarizes new data that places these purinergic signaling events in a mechanistic context that illustrates the ability of ATP to initiate and maintain states of heightened sensory neuron excitability associated with persistent pain.
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Post-transcriptional control of neurofilaments: New roles in development, regeneration and neurodegenerative disease.
Publication Date: 2009 Nov 9 PMID: 19906448
Authors: Szaro, B. G. - Strong, M. J.
Journal: Trends Neurosci
Neurofilament (NF) protein expression is coupled to axon development and the maintenance of neuronal homeostasis. Here, we present evidence that this tight regulation depends critically on post-transcriptionally regulated changes in NF mRNA transport, translation and stability. Recent studies have shown that post-transcriptional mechanisms modulate increases in NF gene transcription during axon regeneration to yield the final pattern of NF protein expression. Other recent work has found that post-transcriptional control of NFs shares elements with that of other axonal proteins and that its dysregulation contributes to amyotrophic lateral sclerosis. Such studies herald a novel approach to understanding how neurons coordinate the expressions of functionally related proteins and provide new insights into how the dysregulation of this control can lead to disease.
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Authors: Szaro, B. G. - Strong, M. J.
Journal: Trends Neurosci
Neurofilament (NF) protein expression is coupled to axon development and the maintenance of neuronal homeostasis. Here, we present evidence that this tight regulation depends critically on post-transcriptionally regulated changes in NF mRNA transport, translation and stability. Recent studies have shown that post-transcriptional mechanisms modulate increases in NF gene transcription during axon regeneration to yield the final pattern of NF protein expression. Other recent work has found that post-transcriptional control of NFs shares elements with that of other axonal proteins and that its dysregulation contributes to amyotrophic lateral sclerosis. Such studies herald a novel approach to understanding how neurons coordinate the expressions of functionally related proteins and provide new insights into how the dysregulation of this control can lead to disease.
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More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory.
Publication Date: 2009 Nov 2 PMID: 19889466
Authors: Mozzachiodi, R. - Byrne, J. H.
Journal: Trends Neurosci
Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage.
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Authors: Mozzachiodi, R. - Byrne, J. H.
Journal: Trends Neurosci
Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage.
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Molecular layers underlying cytoskeletal remodelling during cortical development.
Publication Date: 2009 Nov 19 PMID: 19837469
Authors: Heng, J. I. - Chariot, A. - Nguyen, L.
Journal: Trends Neurosci
During neural development, the cytoskeleton of newborn neurons undergoes extensive and dynamic remodelling to facilitate the sequential steps of neurogenesis, cell migration and terminal differentiation. It is clear from studying the mechanisms that precipitate these functions that different configurations of the cytoskeleton prefigure the correct execution of each step and define cohorts of proteins the functions of which are indispensable for the control of neuronal migration but not terminal differentiation. These combinatorial protein functions are also predetermined by regulated gene expression and the precise subcellular localisation of their protein products. Here, we expand on this view in the context of recent data on how the cytoskeleton is regulated during the maturation of cortical neurons within the developing brain.
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Authors: Heng, J. I. - Chariot, A. - Nguyen, L.
Journal: Trends Neurosci
During neural development, the cytoskeleton of newborn neurons undergoes extensive and dynamic remodelling to facilitate the sequential steps of neurogenesis, cell migration and terminal differentiation. It is clear from studying the mechanisms that precipitate these functions that different configurations of the cytoskeleton prefigure the correct execution of each step and define cohorts of proteins the functions of which are indispensable for the control of neuronal migration but not terminal differentiation. These combinatorial protein functions are also predetermined by regulated gene expression and the precise subcellular localisation of their protein products. Here, we expand on this view in the context of recent data on how the cytoskeleton is regulated during the maturation of cortical neurons within the developing brain.
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Angiotensins in Alzheimer's disease - friend or foe?
Publication Date: 2009 Dec PMID: 19796831
Authors: Kehoe, P. G. - Miners, S. - Love, S.
Journal: Trends Neurosci
The renin-angiotensin system (RAS) is an important regulator of blood pressure. Observational and experimental studies suggest that alterations in blood pressure and components of the brain RAS contribute to the development and progression of Alzheimer's disease (AD), resulting in changes that can lead or contribute to cognitive decline. The complexity of the RAS and diversity of its interactions with neurological processes have recently become apparent but large gaps in our understanding still remain. Modulation of activity of components of the brain RAS offers substantial opportunities for the treatment and prevention of dementia, including AD. This paper reviews molecular, genetic, experimental and clinical data as well as the therapeutic opportunities that relate to the involvement of the RAS in AD.
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Authors: Kehoe, P. G. - Miners, S. - Love, S.
Journal: Trends Neurosci
The renin-angiotensin system (RAS) is an important regulator of blood pressure. Observational and experimental studies suggest that alterations in blood pressure and components of the brain RAS contribute to the development and progression of Alzheimer's disease (AD), resulting in changes that can lead or contribute to cognitive decline. The complexity of the RAS and diversity of its interactions with neurological processes have recently become apparent but large gaps in our understanding still remain. Modulation of activity of components of the brain RAS offers substantial opportunities for the treatment and prevention of dementia, including AD. This paper reviews molecular, genetic, experimental and clinical data as well as the therapeutic opportunities that relate to the involvement of the RAS in AD.
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Molecular dissection of reactive astrogliosis and glial scar formation.
Publication Date: 2009 Dec PMID: 19782411
Authors: Sofroniew, M. V.
Journal: Trends Neurosci
Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders.
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Authors: Sofroniew, M. V.
Journal: Trends Neurosci
Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders.
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An evolutionarily adaptive neural architecture for social reasoning.
Publication Date: 2009 Dec PMID: 19782410
Authors: Barbey, A. K. - Krueger, F. - Grafman, J.
Journal: Trends Neurosci
Recent progress in cognitive neuroscience highlights the involvement of the prefrontal cortex (PFC) in social cognition. Accumulating evidence demonstrates that representations within the lateral PFC enable people to coordinate their thoughts and actions with their intentions to support goal-directed social behavior. Despite the importance of this region in guiding social interactions, remarkably little is known about the functional organization and forms of social inference processed by the lateral PFC. Here, we introduce a cognitive neuroscience framework for understanding the inferential architecture of the lateral PFC, drawing upon recent theoretical developments in evolutionary psychology and emerging neuroscience evidence about how this region can orchestrate behavior on the basis of evolutionarily adaptive social norms for obligatory, prohibited and permissible courses of action.
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Authors: Barbey, A. K. - Krueger, F. - Grafman, J.
Journal: Trends Neurosci
Recent progress in cognitive neuroscience highlights the involvement of the prefrontal cortex (PFC) in social cognition. Accumulating evidence demonstrates that representations within the lateral PFC enable people to coordinate their thoughts and actions with their intentions to support goal-directed social behavior. Despite the importance of this region in guiding social interactions, remarkably little is known about the functional organization and forms of social inference processed by the lateral PFC. Here, we introduce a cognitive neuroscience framework for understanding the inferential architecture of the lateral PFC, drawing upon recent theoretical developments in evolutionary psychology and emerging neuroscience evidence about how this region can orchestrate behavior on the basis of evolutionarily adaptive social norms for obligatory, prohibited and permissible courses of action.
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Making a neuron: Cdk5 in embryonic and adult neurogenesis.
Publication Date: 2009 Nov PMID: 19782409
Authors: Jessberger, S. - Gage, F. H. - Eisch, A. J. - Lagace, D. C.
Journal: Trends Neurosci
Cyclin-dependent kinase 5 (Cdk5) has been implicated in the migration, maturation and survival of neurons born during embryonic development. New evidence suggests that Cdk5 has comparable but also distinct functions in adult neurogenesis. Here we summarize accumulating evidence on the role of Cdk5 in regulation of the cell cycle, migration, survival, maturation and neuronal integration. We specifically highlight the many similarities and few tantalizing differences in the roles of Cdk5 in the embryonic and adult brain. We discuss the signaling pathways that might contribute to Cdk5 action in regulating embryonic and adult neurogenesis, highlighting future research directions that will help to clarify the mechanisms underlying lifelong neurogenesis in the mammalian brain.
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Authors: Jessberger, S. - Gage, F. H. - Eisch, A. J. - Lagace, D. C.
Journal: Trends Neurosci
Cyclin-dependent kinase 5 (Cdk5) has been implicated in the migration, maturation and survival of neurons born during embryonic development. New evidence suggests that Cdk5 has comparable but also distinct functions in adult neurogenesis. Here we summarize accumulating evidence on the role of Cdk5 in regulation of the cell cycle, migration, survival, maturation and neuronal integration. We specifically highlight the many similarities and few tantalizing differences in the roles of Cdk5 in the embryonic and adult brain. We discuss the signaling pathways that might contribute to Cdk5 action in regulating embryonic and adult neurogenesis, highlighting future research directions that will help to clarify the mechanisms underlying lifelong neurogenesis in the mammalian brain.
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Cingulate cortex: diverging data from humans and monkeys.
Publication Date: 2009 Nov PMID: 19781794
Authors: Cole, M. W. - Yeung, N. - Freiwald, W. A. - Botvinick, M.
Journal: Trends Neurosci
Cognitive neuroscience research relies, in part, on homologies between the brains of human and non-human primates. A quandary therefore arises when presumed anatomical homologues exhibit different functional properties. Such a situation has recently arisen in the case of the anterior cingulate cortex (ACC). In humans, numerous studies suggest a role for ACC in detecting conflicts in information processing. Studies of macaque monkey ACC, in contrast, have failed to find conflict-related responses. We consider several interpretations of this discrepancy, including differences in research methodology and cross-species differences in functional neuroanatomy. New directions for future research are outlined, emphasizing the importance of distinguishing illusory cross-species differences from the true evolutionary differences that make our species unique.
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Authors: Cole, M. W. - Yeung, N. - Freiwald, W. A. - Botvinick, M.
Journal: Trends Neurosci
Cognitive neuroscience research relies, in part, on homologies between the brains of human and non-human primates. A quandary therefore arises when presumed anatomical homologues exhibit different functional properties. Such a situation has recently arisen in the case of the anterior cingulate cortex (ACC). In humans, numerous studies suggest a role for ACC in detecting conflicts in information processing. Studies of macaque monkey ACC, in contrast, have failed to find conflict-related responses. We consider several interpretations of this discrepancy, including differences in research methodology and cross-species differences in functional neuroanatomy. New directions for future research are outlined, emphasizing the importance of distinguishing illusory cross-species differences from the true evolutionary differences that make our species unique.
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Critical role of nociceptor plasticity in chronic pain.
Publication Date: 2009 Dec PMID: 19781793
Authors: Reichling, D. B. - Levine, J. D.
Journal: Trends Neurosci
The transition from acute to chronic pain states might be the most important challenge in research to improve clinical treatment of debilitating pain. We describe a recently identified mechanism of neuronal plasticity in primary afferent nociceptive nerve fibers (nociceptors) by which an acute inflammatory insult or environmental stressor can trigger long-lasting hypersensitivity of nociceptors to inflammatory cytokines. This phenomenon, "hyperalgesic priming," depends on the epsilon isoform of protein kinase C (PKCvarepsilon) and a switch in intracellular signaling pathways that mediate cytokine-induced nociceptor hyperexcitability. We discuss the impact of this discovery on our understanding of, and ultimately our ability to treat, a variety of enigmatic and debilitating pain conditions, including those associated with repetitive injury, and generalized pain conditions, such as fibromyalgia.
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Authors: Reichling, D. B. - Levine, J. D.
Journal: Trends Neurosci
The transition from acute to chronic pain states might be the most important challenge in research to improve clinical treatment of debilitating pain. We describe a recently identified mechanism of neuronal plasticity in primary afferent nociceptive nerve fibers (nociceptors) by which an acute inflammatory insult or environmental stressor can trigger long-lasting hypersensitivity of nociceptors to inflammatory cytokines. This phenomenon, "hyperalgesic priming," depends on the epsilon isoform of protein kinase C (PKCvarepsilon) and a switch in intracellular signaling pathways that mediate cytokine-induced nociceptor hyperexcitability. We discuss the impact of this discovery on our understanding of, and ultimately our ability to treat, a variety of enigmatic and debilitating pain conditions, including those associated with repetitive injury, and generalized pain conditions, such as fibromyalgia.
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Disruption of the ether-a-go-go K+ channel gene BEC1/KCNH3 enhances cognitive function.
Publication Date: 2009 Nov 18 PMID: 19923296
Authors: Miyake, A. - Takahashi, S. - Nakamura, Y. - Inamura, K. - Matsumoto, S. - Mochizuki, S. - Katou, M.
Journal: J Neurosci
The K+ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K+ channel genes are expressed in the CNS. The therapeutic potential of K+ channel blockers for cognitive enhancement has been discussed, but the contribution each K+ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K+ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K+ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K+ channel that contributes preferentially and bidirectionally to cognitive function.
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Authors: Miyake, A. - Takahashi, S. - Nakamura, Y. - Inamura, K. - Matsumoto, S. - Mochizuki, S. - Katou, M.
Journal: J Neurosci
The K+ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K+ channel genes are expressed in the CNS. The therapeutic potential of K+ channel blockers for cognitive enhancement has been discussed, but the contribution each K+ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K+ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K+ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K+ channel that contributes preferentially and bidirectionally to cognitive function.
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Regaining motor control in musician's dystonia by restoring sensorimotor organization.
Publication Date: 2009 Nov 18 PMID: 19923295
Authors: Rosenkranz, K. - Butler, K. - Williamon, A. - Rothwell, J. C.
Journal: J Neurosci
Professional musicians are an excellent model of long-term motor learning effects on structure and function of the sensorimotor system. However, intensive motor skill training has been associated with task-specific deficiency in hand motor control, which has a higher prevalence among musicians (musician's dystonia) than in the general population. Using a transcranial magnetic stimulation paradigm, we previously found an expanded spatial integration of proprioceptive input into the hand motor cortex [sensorimotor organization (SMO)] in healthy musicians. In musician's dystonia, however, this expansion was even larger. Whereas motor skills of musicians are likely to be supported by a spatially expanded SMO, we hypothesized that in musician's dystonia this might have developed too far and now disrupts rather than assists task-specific motor control. If so, motor control should be regained by reversing the excessive reorganization in musician's dystonia. Here, we test this hypothesis and show that a 15 min intervention with proprioceptive input (proprioceptive training) restored SMO in pianists with musician's dystonia to the pattern seen in healthy pianists. Crucially, task-specific motor control improved significantly and objectively as measured with a MIDI (musical instrument digital interface) piano, and the amount of behavioral improvement was significantly correlated to the degree of sensorimotor reorganization. In healthy pianists and nonmusicians, the SMO and motor performance remained essentially unchanged. These findings suggest that the differentiation of SMO in the hand motor cortex and the degree of motor control of intensively practiced tasks are significantly linked and finely balanced. Proprioceptive training restored this balance in musician's dystonia to the behaviorally beneficial level of healthy musicians.
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Authors: Rosenkranz, K. - Butler, K. - Williamon, A. - Rothwell, J. C.
Journal: J Neurosci
Professional musicians are an excellent model of long-term motor learning effects on structure and function of the sensorimotor system. However, intensive motor skill training has been associated with task-specific deficiency in hand motor control, which has a higher prevalence among musicians (musician's dystonia) than in the general population. Using a transcranial magnetic stimulation paradigm, we previously found an expanded spatial integration of proprioceptive input into the hand motor cortex [sensorimotor organization (SMO)] in healthy musicians. In musician's dystonia, however, this expansion was even larger. Whereas motor skills of musicians are likely to be supported by a spatially expanded SMO, we hypothesized that in musician's dystonia this might have developed too far and now disrupts rather than assists task-specific motor control. If so, motor control should be regained by reversing the excessive reorganization in musician's dystonia. Here, we test this hypothesis and show that a 15 min intervention with proprioceptive input (proprioceptive training) restored SMO in pianists with musician's dystonia to the pattern seen in healthy pianists. Crucially, task-specific motor control improved significantly and objectively as measured with a MIDI (musical instrument digital interface) piano, and the amount of behavioral improvement was significantly correlated to the degree of sensorimotor reorganization. In healthy pianists and nonmusicians, the SMO and motor performance remained essentially unchanged. These findings suggest that the differentiation of SMO in the hand motor cortex and the degree of motor control of intensively practiced tasks are significantly linked and finely balanced. Proprioceptive training restored this balance in musician's dystonia to the behaviorally beneficial level of healthy musicians.
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How humans integrate the prospects of pain and reward during choice.
Publication Date: 2009 Nov 18 PMID: 19923294
Authors: Talmi, D. - Dayan, P. - Kiebel, S. J. - Frith, C. D. - Dolan, R. J.
Journal: J Neurosci
The maxim "no pain, no gain" summarizes scenarios in which an action leading to reward also entails a cost. Although we know a substantial amount about how the brain represents pain and reward separately, we know little about how they are integrated during goal-directed behavior. Two theoretical models might account for the integration of reward and pain. An additive model specifies that the disutility of costs is summed linearly with the utility of benefits, whereas an interactive model suggests that cost and benefit utilities interact so that the sensitivity to benefits is attenuated as costs become increasingly aversive. Using a novel task that required integration of physical pain and monetary reward, we examined the mechanism underlying cost-benefit integration in humans. We provide evidence in support of an interactive model in behavioral choice. Using functional neuroimaging, we identify a neural signature for this interaction such that, when the consequences of actions embody a mixture of reward and pain, there is an attenuation of a predictive reward signal in both ventral anterior cingulate cortex and ventral striatum. We conclude that these regions subserve integration of action costs and benefits in humans, a finding that suggests a cross-species similarity in neural substrates that implement this function and illuminates mechanisms that underlie altered decision making under aversive conditions.
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Authors: Talmi, D. - Dayan, P. - Kiebel, S. J. - Frith, C. D. - Dolan, R. J.
Journal: J Neurosci
The maxim "no pain, no gain" summarizes scenarios in which an action leading to reward also entails a cost. Although we know a substantial amount about how the brain represents pain and reward separately, we know little about how they are integrated during goal-directed behavior. Two theoretical models might account for the integration of reward and pain. An additive model specifies that the disutility of costs is summed linearly with the utility of benefits, whereas an interactive model suggests that cost and benefit utilities interact so that the sensitivity to benefits is attenuated as costs become increasingly aversive. Using a novel task that required integration of physical pain and monetary reward, we examined the mechanism underlying cost-benefit integration in humans. We provide evidence in support of an interactive model in behavioral choice. Using functional neuroimaging, we identify a neural signature for this interaction such that, when the consequences of actions embody a mixture of reward and pain, there is an attenuation of a predictive reward signal in both ventral anterior cingulate cortex and ventral striatum. We conclude that these regions subserve integration of action costs and benefits in humans, a finding that suggests a cross-species similarity in neural substrates that implement this function and illuminates mechanisms that underlie altered decision making under aversive conditions.
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A comparative magnetic resonance imaging study of the anatomy, variability, and asymmetry of broca's area in the human and chimpanzee brain.
Publication Date: 2009 Nov 18 PMID: 19923293
Authors: Keller, S. S. - Roberts, N. - Hopkins, W.
Journal: J Neurosci
The frontal operculum-classically considered to be Broca's area-has special significance and interest in clinical, cognitive, and comparative neuroscience given its role in spoken language and the long-held assumption that structural asymmetry of this region of cortex may be related to functional lateralization of human language. We performed a detailed morphological and morphometric analysis of this area of the brain in humans and chimpanzees using identical image acquisition parameters, image analysis techniques, and consistent anatomical boundaries in both species. We report great inter-individual variability of the sulcal contours defining the operculum in both species, particularly discontinuity of the inferior frontal sulcus in humans and bifurcation of the inferior precentral sulcus in chimpanzees. There was no evidence of population-based asymmetry of the frontal opercular gray matter in humans or chimpanzees. The diagonal sulcus was only identified in humans, and its presence was significantly (F = 12.782, p < 0.001) associated with total volume of the ipsilateral operculum. The findings presented here suggest that there is no population-based interhemispheric macroscopic asymmetry of Broca's area in humans or Broca's area homolog in chimpanzees. However, given that previous studies have reported asymmetry in the cytoarchitectonic fields considered to represent Broca's area-which is important given that cytoarchitectonic boundaries are more closely related to the regional functional properties of cortex relative to sulcal landmarks-it may be that the gross morphology of the frontal operculum is not a reliable indicator of Broca's area per se.
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Authors: Keller, S. S. - Roberts, N. - Hopkins, W.
Journal: J Neurosci
The frontal operculum-classically considered to be Broca's area-has special significance and interest in clinical, cognitive, and comparative neuroscience given its role in spoken language and the long-held assumption that structural asymmetry of this region of cortex may be related to functional lateralization of human language. We performed a detailed morphological and morphometric analysis of this area of the brain in humans and chimpanzees using identical image acquisition parameters, image analysis techniques, and consistent anatomical boundaries in both species. We report great inter-individual variability of the sulcal contours defining the operculum in both species, particularly discontinuity of the inferior frontal sulcus in humans and bifurcation of the inferior precentral sulcus in chimpanzees. There was no evidence of population-based asymmetry of the frontal opercular gray matter in humans or chimpanzees. The diagonal sulcus was only identified in humans, and its presence was significantly (F = 12.782, p < 0.001) associated with total volume of the ipsilateral operculum. The findings presented here suggest that there is no population-based interhemispheric macroscopic asymmetry of Broca's area in humans or Broca's area homolog in chimpanzees. However, given that previous studies have reported asymmetry in the cytoarchitectonic fields considered to represent Broca's area-which is important given that cytoarchitectonic boundaries are more closely related to the regional functional properties of cortex relative to sulcal landmarks-it may be that the gross morphology of the frontal operculum is not a reliable indicator of Broca's area per se.
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Reliable recall of spontaneous activity patterns in cortical networks.
Publication Date: 2009 Nov 18 PMID: 19923292
Authors: Marre, O. - Yger, P. - Davison, A. P. - Fregnac, Y.
Journal: J Neurosci
Irregular ongoing activity in cortical networks is often modeled as arising from recurrent connectivity. Yet it remains unclear to what extent its presence corrupts sensory signal transmission and network computational capabilities. In a recurrent cortical-like network, we have determined the activity patterns that are better transmitted and self-sustained by the network. We show that reproducible spiking and subthreshold dynamics can be triggered if the statistics of the imposed external drive are consistent with patterns previously seen in the ongoing activity. A subset of neurons in the network, constrained to replay temporal pattern segments extracted from the recorded ongoing activity of the same network, reliably drives the remaining, free-running neurons to call the rest of the pattern. Comparison with surrogate Poisson patterns indicates that the efficiency of the recall and completion process depends on the similarity between the statistical properties of the input with previous ongoing activity The reliability of evoked dynamics in recurrent networks is thus dependent on the stimulus used, and we propose that the similarity between spontaneous and evoked activity in sensory cortical areas could be a signature of efficient transmission and propagation across cortical networks.
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Authors: Marre, O. - Yger, P. - Davison, A. P. - Fregnac, Y.
Journal: J Neurosci
Irregular ongoing activity in cortical networks is often modeled as arising from recurrent connectivity. Yet it remains unclear to what extent its presence corrupts sensory signal transmission and network computational capabilities. In a recurrent cortical-like network, we have determined the activity patterns that are better transmitted and self-sustained by the network. We show that reproducible spiking and subthreshold dynamics can be triggered if the statistics of the imposed external drive are consistent with patterns previously seen in the ongoing activity. A subset of neurons in the network, constrained to replay temporal pattern segments extracted from the recorded ongoing activity of the same network, reliably drives the remaining, free-running neurons to call the rest of the pattern. Comparison with surrogate Poisson patterns indicates that the efficiency of the recall and completion process depends on the similarity between the statistical properties of the input with previous ongoing activity The reliability of evoked dynamics in recurrent networks is thus dependent on the stimulus used, and we propose that the similarity between spontaneous and evoked activity in sensory cortical areas could be a signature of efficient transmission and propagation across cortical networks.
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