Sample records for influence neuronal function
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Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian
2016-01-01
For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467
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Patel, Tapan P.; Ventre, Scott C.; Geddes-Klein, Donna; Singh, Pallab K.
2014-01-01
Alterations in the activity of neural circuits are a common consequence of traumatic brain injury (TBI), but the relationship between single-neuron properties and the aggregate network behavior is not well understood. We recently reported that the GluN2B-containing NMDA receptors (NMDARs) are key in mediating mechanical forces during TBI, and that TBI produces a complex change in the functional connectivity of neuronal networks. Here, we evaluated whether cell-to-cell heterogeneity in the connectivity and aggregate contribution of GluN2B receptors to [Ca2+]i before injury influenced the functional rewiring, spontaneous activity, and network plasticity following injury using primary rat cortical dissociated neurons. We found that the functional connectivity of a neuron to its neighbors, combined with the relative influx of calcium through distinct NMDAR subtypes, together contributed to the individual neuronal response to trauma. Specifically, individual neurons whose [Ca2+]i oscillations were largely due to GluN2B NMDAR activation lost many of their functional targets 1 h following injury. In comparison, neurons with large GluN2A contribution or neurons with high functional connectivity both independently protected against injury-induced loss in connectivity. Mechanistically, we found that traumatic injury resulted in increased uncorrelated network activity, an effect linked to reduction of the voltage-sensitive Mg2+ block of GluN2B-containing NMDARs. This uncorrelated activation of GluN2B subtypes after injury significantly limited the potential for network remodeling in response to a plasticity stimulus. Together, our data suggest that two single-cell characteristics, the aggregate contribution of NMDAR subtypes and the number of functional connections, influence network structure following traumatic injury. PMID:24647941
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Exposure to bisphenol A affects GABAergic neuron differentiation in neurosphere cultures.
Fukushima, Nobuyuki; Nagao, Tetsuji
2018-06-13
Endocrine-disrupting chemicals (EDCs) influence not only endocrine functions but also neuronal development and functions. In-vivo studies have suggested the relationship of EDC-induced neurobehavioral disorders with dysfunctions of neurotransmitter mechanisms including γ-aminobutyric acid (GABA)ergic mechanisms. However, whether EDCs affect GABAergic neuron differentiation remains unclear. In the present study, we show that a representative EDC, bisphenol A (BPA), affects GABAergic neuron differentiation. Cortical neurospheres prepared from embryonic mice were exposed to BPA for 7 days, and then neuronal differentiation was induced. We found that BPA exposure resulted in a decrease in the ratio of GABAergic neurons to total neurons. However, the same exposure stimulated the differentiation of neurons expressing calbindin, a calcium-binding protein observed in a subpopulation of GABAergic neurons. These findings suggested that BPA might influence the formation of an inhibitory neuronal network in developing cerebral cortex involved in the occurrence of neurobehavioral disorders.
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Theoretical Limitations on Functional Imaging Resolution in Auditory Cortex
Chen, Thomas L.; Watkins, Paul V.; Barbour, Dennis L.
2010-01-01
Functional imaging can reveal detailed organizational structure in cerebral cortical areas, but neuronal response features and local neural interconnectivity can influence the resulting images, possibly limiting the inferences that can be drawn about neural function. Discerning the fundamental principles of organizational structure in the auditory cortex of multiple species has been somewhat challenging historically both with functional imaging and with electrophysiology. A possible limitation affecting any methodology using pooled neuronal measures may be the relative distribution of response selectivity throughout the population of auditory cortex neurons. One neuronal response type inherited from the cochlea, for example, exhibits a receptive field that increases in size (i.e., decreases in selectivity) at higher stimulus intensities. Even though these neurons appear to represent a minority of auditory cortex neurons, they are likely to contribute disproportionately to the activity detected in functional images, especially if intense sounds are used for stimulation. To evaluate the potential influence of neuronal subpopulations upon functional images of primary auditory cortex, a model array representing cortical neurons was probed with virtual imaging experiments under various assumptions about the local circuit organization. As expected, different neuronal subpopulations were activated preferentially under different stimulus conditions. In fact, stimulus protocols that can preferentially excite selective neurons, resulting in a relatively sparse activation map, have the potential to improve the effective resolution of functional auditory cortical images. These experimental results also make predictions about auditory cortex organization that can be tested with refined functional imaging experiments. PMID:20079343
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Influence of movement parameters on area 18 neurones in the cat.
Orban, G A; Callens, M
1977-10-24
In cats, 107 area 18 neurones with identified FR type, 10-50 degrees from the visual axis, were tested for the influence of direction, velocity and amplitude of movement. These three parameters are believed to be the primary parameters of a movement analysing system. 94% of the neurones were influenced by the direction of movement, all of them by the angular velocity and 16% by the amplitude of movement. For each of the primary parameters, tuning curves were established. Angular velocity influenced not only the response magnitude but also the response latency and the direction bias. By preparing response amplitude functions at different velocities the influence of movement duration was ruled out. The association of functional properties and RF organization suggests a model of information processing in area 18 of the cat.
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Prolactin receptor in regulation of neuronal excitability and channels
Patil, Mayur J; Henry, Michael A; Akopian, Armen N
2014-01-01
Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency. PRL also influences neuronal functions via activation of certain neurons, resulting in Ca2+ influx and/or electrical firing with subsequent release of neurotransmitters. Although PRL was identified almost a century ago, very little specific information is known about how PRL regulates neuronal functions. Nevertheless, important initial steps have recently been made including the identification of PRL-induced transient signaling pathways in neurons and the modulation of neuronal transient receptor potential (TRP) and Ca2+-dependent K+ channels by PRL. In this review, we summarize current knowledge and recent progress in understanding the regulation of neuronal excitability and channels by PRL. PMID:24758841
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Influence of Pyrethroid Insecticides on Sodium and Calcium Influx in Neocortical Neurons
Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Using murine neocortical neurons in primary culture, we have compared the ability of 11 structurally diverse pyrethroid insecticides to evoke Na+ ...
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Scheff, N N; Yilmaz, E; Gold, M S
2014-01-01
The Na+–Ca2+ exchanger (NCX) appears to play an important role in the regulation of the high K+-evoked Ca2+ transient in putative nociceptive dorsal root ganglion (DRG) neurons. The purpose of the present study was to (1) characterize the properties of NCX activity in subpopulations of DRG neurons, (2) identify the isoform(s) underlying NCX activity, and (3) begin to assess the function of the isoform(s) in vivo. In retrogradely labelled neurons from the glabrous skin of adult male Sprague–Dawley rats, NCX activity, as assessed with fura-2-based microfluorimetry, was only detected in putative nociceptive IB4+ neurons. There were two modes of NCX activity: one was evoked in response to relatively large and long lasting (∼325 nm for >12 s) increases in the concentration of intracellular Ca2+ ([Ca2+]i), and a second was active at resting [Ca2+]i > ∼150 nm. There also were two modes of evoked activity: one that decayed relatively rapidly (<5 min) and a second that persisted (>10 min). Whereas mRNA encoding all three NCX isoforms (NCX1–3) was detected in putative nociceptive cutaneous neurons with single cell PCR, pharmacological analysis and small interfering RNA (siRNA) knockdown of each isoform in vivo suggested that NCX2 and 3 were responsible for NCX activity. Western blot analyses suggested that NCX isoforms were differentially distributed within sensory neurons. Functional assays of excitability, action potential propagation, and nociceptive behaviour suggest NCX activity has little influence on excitability per se, but instead influences axonal conduction velocity, resting membrane potential, and nociceptive threshold. Together these results indicate that the function of NCX in the regulation of [Ca2+]i in putative nociceptive neurons may be unique relative to other cells in which these exchanger isoforms have been characterized and it has the potential to influence sensory neuron properties at multiple levels. PMID:25239455
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2012-01-01
Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners. PMID:22852823
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Phenotypic Checkpoints Regulate Neuronal Development
Ben-Ari, Yehezkel; Spitzer, Nicholas C.
2010-01-01
Nervous system development proceeds by sequential gene expression mediated by cascades of transcription factors in parallel with sequences of patterned network activity driven by receptors and ion channels. These sequences are cell type- and developmental stage-dependent and modulated by paracrine actions of substances released by neurons and glia. How and to what extent these sequences interact to enable neuronal network development is not understood. Recent evidence demonstrates that CNS development requires intermediate stages of differentiation providing functional feedback that influences gene expression. We suggest that embryonic neuronal functions constitute a series of phenotypic checkpoint signatures; neurons failing to express these functions are delayed or developmentally arrested. Such checkpoints are likely to be a general feature of neuronal development and may constitute presymptomatic signatures of neurological disorders when they go awry. PMID:20864191
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Parker, J Alex; Metzler, Martina; Georgiou, John; Mage, Marilyne; Roder, John C; Rose, Ann M; Hayden, Michael R; Néri, Christian
2007-10-10
Huntingtin-interacting protein 1 (HIP1) was identified through its interaction with htt (huntingtin), the Huntington's disease (HD) protein. HIP1 is an endocytic protein that influences transport and function of AMPA and NMDA receptors in the brain. However, little is known about its contribution to neuronal dysfunction in HD. We report that the Caenorhabditis elegans HIP1 homolog hipr-1 modulates presynaptic activity and the abundance of synaptobrevin, a protein involved in synaptic vesicle fusion. Presynaptic function was also altered in hippocampal brain slices of HIP1-/- mice demonstrating delayed recovery from synaptic depression and a reduction in paired-pulse facilitation, a form of presynaptic plasticity. Interestingly, neuronal dysfunction in transgenic nematodes expressing mutant N-terminal huntingtin was specifically enhanced by hipr-1 loss of function. A similar effect was observed with several other mutant proteins that are expressed at the synapse and involved in endocytosis, such as unc-11/AP180, unc-26/synaptojanin, and unc-57/endophilin. Thus, HIP1 is involved in presynaptic nerve terminal activity and modulation of mutant polyglutamine-induced neuronal dysfunction. Moreover, synaptic proteins involved in endocytosis may protect neurons against amino acid homopolymer expansion.
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Memory formation orchestrates the wiring of adult-born hippocampal neurons into brain circuits.
Petsophonsakul, Petnoi; Richetin, Kevin; Andraini, Trinovita; Roybon, Laurent; Rampon, Claire
2017-08-01
During memory formation, structural rearrangements of dendritic spines provide a mean to durably modulate synaptic connectivity within neuronal networks. New neurons generated throughout the adult life in the dentate gyrus of the hippocampus contribute to learning and memory. As these neurons become incorporated into the network, they generate huge numbers of new connections that modify hippocampal circuitry and functioning. However, it is yet unclear as to how the dynamic process of memory formation influences their synaptic integration into neuronal circuits. New memories are established according to a multistep process during which new information is first acquired and then consolidated to form a stable memory trace. Upon recall, memory is transiently destabilized and vulnerable to modification. Using contextual fear conditioning, we found that learning was associated with an acceleration of dendritic spines formation of adult-born neurons, and that spine connectivity becomes strengthened after memory consolidation. Moreover, we observed that afferent connectivity onto adult-born neurons is enhanced after memory retrieval, while extinction training induces a change of spine shapes. Together, these findings reveal that the neuronal activity supporting memory processes strongly influences the structural dendritic integration of adult-born neurons into pre-existing neuronal circuits. Such change of afferent connectivity is likely to impact the overall wiring of hippocampal network, and consequently, to regulate hippocampal function.
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Aguilar-Arredondo, Andrea; Arias, Clorinda; Zepeda, Angélica
2015-01-01
Hippocampal neurogenesis occurs in the adult brain in various species, including humans. A compelling question that arose when neurogenesis was accepted to occur in the adult dentate gyrus (DG) is whether new neurons become functionally relevant over time, which is key for interpreting their potential contributions to synaptic circuitry. The functional state of adult-born neurons has been evaluated using various methodological approaches, which have, in turn, yielded seemingly conflicting results regarding the timing of maturation and functional integration. Here, we review the contributions of different methodological approaches to addressing the maturation process of adult-born neurons and their functional state, discussing the contributions and limitations of each method. We aim to provide a framework for interpreting results based on the approaches currently used in neuroscience for evaluating functional integration. As shown by the experimental evidence, adult-born neurons are prone to respond from early stages, even when they are not yet fully integrated into circuits. The ongoing integration process for the newborn neurons is characterised by different features. However, they may contribute differently to the network depending on their maturation stage. When combined, the strategies used to date convey a comprehensive view of the functional development of newly born neurons while providing a framework for approaching the critical time at which new neurons become functionally integrated and influence brain function.
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Gruss, Marco; Ettorre, Giovanni; Stehr, Annette Jana; Henrich, Michael; Hempelmann, Gunter; Scholz, Andreas
2006-01-01
Hypoxia alters neuronal function and can lead to neuronal injury or death especially in the central nervous system. But little is known about the effects of hypoxia in neurones of the peripheral nervous system (PNS), which survive longer hypoxic periods. Additionally, people have experienced unpleasant sensations during ischemia which are dedicated to changes in conduction properties or changes in excitability in the PNS. However, the underlying ionic conductances in dorsal root ganglion (DRG) neurones have not been investigated in detail. Therefore we investigated the influence of moderate hypoxia (27.0 ± 1.5 mmHg) on action potentials, excitability and ionic conductances of small neurones in a slice preparation of DRGs of young rats. The neurones responded within a few minutes non-uniformly to moderate hypoxia: changes of excitability could be assigned to decreased outward currents in most of the neurones (77%) whereas a smaller group (23%) displayed increased outward currents in Ringer solution. We were able to attribute most of the reduction in outward-current to a voltage-gated K+ current which activated at potentials positive to -50 mV and was sensitive to 50 nM α-dendrotoxin (DTX). Other toxins that inhibit subtypes of voltage gated K+ channels, such as margatoxin (MgTX), dendrotoxin-K (DTX-K), r-tityustoxin Kα (TsTX-K) and r-agitoxin (AgTX-2) failed to prevent the hypoxia induced reduction. Therefore we could not assign the hypoxia sensitive K+ current to one homomeric KV channel type in sensory neurones. Functionally this K+ current blockade might underlie the increased action potential (AP) duration in these neurones. Altogether these results, might explain the functional impairment of peripheral neurones under moderate hypoxia. PMID:16579848
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The timing and location of GDNF expression determines enteric nervous system structure and function
Wang, Hongtao; Hughes, Inna; Planer, William; Parsadanian, Alexander; Grider, John R.; Vohra, Bhupinder P.S.; Keller-Peck, Cynthia; Heuckeroth, Robert O.
2010-01-01
Ret signaling is critical for formation of the enteric nervous system (ENS) because Ret activation promotes ENS precursor survival, proliferation, and migration and provides trophic support for mature enteric neurons. While these roles are well established, we now provide evidence that increasing levels of the Ret ligand GDNF in mice causes alterations in ENS structure and function that are critically dependent on the time and location of increased GDNF availability. This is demonstrated using two different strains of transgenic mice and by injecting newborn mice with GDNF. Furthermore, because different subclasses of ENS precursors withdraw from the cell cycle at different times during development, increases in GDNF at specific times alter the ratio of neuronal subclasses in the mature ENS. In addition, we confirm that esophageal neurons are GDNF responsive and demonstrate that the location of GDNF production influences neuronal process projection for NADPH diaphorase expressing, but not acetylcholinesterase, choline acetyltransferase, or tryptophan hydroxylase expressing small bowel myenteric neurons. We further demonstrate that changes in GDNF availability influence intestinal function in vitro and in vivo. Thus, changes in GDNF expression can create a wide variety of alterations in ENS structure and function and may in part contribute to human motility disorders. PMID:20107080
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Wang, Hongtao; Hughes, Inna; Planer, William; Parsadanian, Alexander; Grider, John R; Vohra, Bhupinder P S; Keller-Peck, Cynthia; Heuckeroth, Robert O
2010-01-27
Ret signaling is critical for formation of the enteric nervous system (ENS) because Ret activation promotes ENS precursor survival, proliferation, and migration and provides trophic support for mature enteric neurons. Although these roles are well established, we now provide evidence that increasing levels of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) in mice causes alterations in ENS structure and function that are critically dependent on the time and location of increased GDNF availability. This is demonstrated using two different strains of transgenic mice and by injecting newborn mice with GDNF. Furthermore, because different subclasses of ENS precursors withdraw from the cell cycle at different times during development, increases in GDNF at specific times alter the ratio of neuronal subclasses in the mature ENS. In addition, we confirm that esophageal neurons are GDNF responsive and demonstrate that the location of GDNF production influences neuronal process projection for NADPH diaphorase-expressing, but not acetylcholinesterase-, choline acetyltransferase-, or tryptophan hydroxylase-expressing, small bowel myenteric neurons. We further demonstrate that changes in GDNF availability influence intestinal function in vitro and in vivo. Thus, changes in GDNF expression can create a wide variety of alterations in ENS structure and function and may in part contribute to human motility disorders.
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Ho, S Shaun; Macdonald, Adam; Swain, James E
2014-04-01
Mirror neuron-based associative learning may be understood according to associative learning theories, in addition to sensorimotor learning theories. This is important for a comprehensive understanding of the role of mirror neurons and related hormone modulators, such as oxytocin, in complex social interactions such as among parent-infant dyads and in examples of mirror neuron function that involve abnormal motor systems such as depression.
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Pharmacological Tools to Study the Role of Astrocytes in Neural Network Functions.
Peña-Ortega, Fernando; Rivera-Angulo, Ana Julia; Lorea-Hernández, Jonathan Julio
2016-01-01
Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.
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Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction.
Noda, Mami
2018-01-01
The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5-triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. © 2018 Elsevier Inc. All rights reserved.
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Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra
2013-01-01
It is known that cell density influences the maturation process of in vitro neuronal networks. Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity. Although many authors provided detailed information about the effects of cell density on neuronal culture activity, a dedicated report of density and age influence on neuronal hippocampal culture activity has not yet been reported. Therefore, this work aims at providing reference data to researchers that set up an experimental study on hippocampal neuronal cultures, helping in planning and decoding the experiments. In this work, we analysed the effects of both neuronal density and culture age on functional attributes of maturing hippocampal cultures. We characterized the electrophysiological activity of neuronal cultures seeded at three different cell densities, recording their spontaneous electrical activity over maturation by means of MicroElectrode Arrays (MEAs). We had gather data from 86 independent hippocampal cultures to achieve solid statistic results, considering the high culture-to-culture variability. Network activity was evaluated in terms of simple spiking, burst and network burst features. We observed that electrical descriptors were characterized by a functional peak during maturation, followed by a stable phase (for sparse and medium density cultures) or by a decrease phase (for high dense neuronal cultures). Moreover, 900 cells/mm2 cultures showed characteristics suitable for long lasting experiments (e.g. chronic effect of drug treatments) while 1800 cells/mm2 cultures should be preferred for experiments that require intense electrical activity (e.g. to evaluate the effect of inhibitory molecules). Finally, cell cultures at 3600 cells/mm2 are more appropriate for experiments in which time saving is relevant (e.g. drug screenings). These results are intended to be a reference for the planning of in vitro neurophysiological and neuropharmacological experiments with MEAs. PMID:24386305
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Biffi, Emilia; Regalia, Giulia; Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra
2013-01-01
It is known that cell density influences the maturation process of in vitro neuronal networks. Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity. Although many authors provided detailed information about the effects of cell density on neuronal culture activity, a dedicated report of density and age influence on neuronal hippocampal culture activity has not yet been reported. Therefore, this work aims at providing reference data to researchers that set up an experimental study on hippocampal neuronal cultures, helping in planning and decoding the experiments. In this work, we analysed the effects of both neuronal density and culture age on functional attributes of maturing hippocampal cultures. We characterized the electrophysiological activity of neuronal cultures seeded at three different cell densities, recording their spontaneous electrical activity over maturation by means of MicroElectrode Arrays (MEAs). We had gather data from 86 independent hippocampal cultures to achieve solid statistic results, considering the high culture-to-culture variability. Network activity was evaluated in terms of simple spiking, burst and network burst features. We observed that electrical descriptors were characterized by a functional peak during maturation, followed by a stable phase (for sparse and medium density cultures) or by a decrease phase (for high dense neuronal cultures). Moreover, 900 cells/mm(2) cultures showed characteristics suitable for long lasting experiments (e.g. chronic effect of drug treatments) while 1800 cells/mm(2) cultures should be preferred for experiments that require intense electrical activity (e.g. to evaluate the effect of inhibitory molecules). Finally, cell cultures at 3600 cells/mm(2) are more appropriate for experiments in which time saving is relevant (e.g. drug screenings). These results are intended to be a reference for the planning of in vitro neurophysiological and neuropharmacological experiments with MEAs.
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Ribeiro, Luís F; de Wit, Joris
2017-04-19
Accurate control of polarized cargo trafficking is essential for neuronal function. In this issue of Neuron, Gumy et al. (2017) show that MAP2 defines a pre-axonal filtering zone and controls axonal cargo transport by influencing the activities of distinct kinesin motors. Copyright © 2017 Elsevier Inc. All rights reserved.
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McClelland, Shawn; Brennan, Gary P; Dubé, Celine; Rajpara, Seeta; Iyer, Shruti; Richichi, Cristina; Bernard, Christophe; Baram, Tallie Z
2014-01-01
The mechanisms generating epileptic neuronal networks following insults such as severe seizures are unknown. We have previously shown that interfering with the function of the neuron-restrictive silencer factor (NRSF/REST), an important transcription factor that influences neuronal phenotype, attenuated development of this disorder. In this study, we found that epilepsy-provoking seizures increased the low NRSF levels in mature hippocampus several fold yet surprisingly, provoked repression of only a subset (∼10%) of potential NRSF target genes. Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked. Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels. Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function. Thus, dynamic, selective regulation of NRSF target genes may play a role in influencing neuronal properties in pathological and physiological contexts. DOI: http://dx.doi.org/10.7554/eLife.01267.001 PMID:25117540
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Spike-Timing of Orbitofrontal Neurons Is Synchronized With Breathing.
Kőszeghy, Áron; Lasztóczi, Bálint; Forro, Thomas; Klausberger, Thomas
2018-01-01
The orbitofrontal cortex (OFC) has been implicated in a multiplicity of complex brain functions, including representations of expected outcome properties, post-decision confidence, momentary food-reward values, complex flavors and odors. As breathing rhythm has an influence on odor processing at primary olfactory areas, we tested the hypothesis that it may also influence neuronal activity in the OFC, a prefrontal area involved also in higher order processing of odors. We recorded spike timing of orbitofrontal neurons as well as local field potentials (LFPs) in awake, head-fixed mice, together with the breathing rhythm. We observed that a large majority of orbitofrontal neurons showed robust phase-coupling to breathing during immobility and running. The phase coupling of action potentials to breathing was significantly stronger in orbitofrontal neurons compared to cells in the medial prefrontal cortex. The characteristic synchronization of orbitofrontal neurons with breathing might provide a temporal framework for multi-variable processing of olfactory, gustatory and reward-value relationships.
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Computational exploration of neuron and neural network models in neurobiology.
Prinz, Astrid A
2007-01-01
The electrical activity of individual neurons and neuronal networks is shaped by the complex interplay of a large number of non-linear processes, including the voltage-dependent gating of ion channels and the activation of synaptic receptors. These complex dynamics make it difficult to understand how individual neuron or network parameters-such as the number of ion channels of a given type in a neuron's membrane or the strength of a particular synapse-influence neural system function. Systematic exploration of cellular or network model parameter spaces by computational brute force can overcome this difficulty and generate comprehensive data sets that contain information about neuron or network behavior for many different combinations of parameters. Searching such data sets for parameter combinations that produce functional neuron or network output provides insights into how narrowly different neural system parameters have to be tuned to produce a desired behavior. This chapter describes the construction and analysis of databases of neuron or neuronal network models and describes some of the advantages and downsides of such exploration methods.
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Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan
2016-08-01
Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.
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Li, Fangxu; Yang, Zhilai; Lu, Yang; Wei, Yan; Wang, Jinhui; Yin, Dazhong; He, Rongqiao
2010-01-01
The levels of malondialdehyde (MDA) are high in the brain during carbonyl stress, such as following daily activities and sleep deprivation. To examine our hypothesis that MDA is one of the major substances in the brain leading to fatigue, the influences of MDA on brain functions and neuronal encodings in red-eared turtle (Trachemys scripta) were studied. The intrathecal injections of MDA brought about sleep-like EEG and fatigue-like behaviors in a dose-dependent manner. These changes were found associated with the deterioration of encoding action potentials in cortical neurons. In addition, MDA increased the ratio of γ-aminobutyric acid to glutamate in turtle's brain, as well as the sensitivity of GABAergic neurons to inputs compared to excitatory neurons. Therefore, MDA, as a metabolic product in the brain, may weaken cerebral function during carbonyl stress through breaking the homeostasis between excitatory and inhibitory neurons. PMID:21203547
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Häring, Martin; Enk, Vanessa; Aparisi Rey, Alejandro; Loch, Sebastian; Ruiz de Azua, Inigo; Weber, Tillmann; Bartsch, Dusan; Monory, Krisztina; Lutz, Beat
2015-01-01
The endocannabinoid (eCB) system possesses neuromodulatory functions by influencing the release of various neurotransmitters, including γ-aminobutyric acid (GABA) and glutamate. A functional interaction between eCBs and the serotonergic system has already been suggested. Previously, we showed that cannabinoid type-1 (CB1) receptor mRNA and protein are localized in serotonergic neurons of the raphe nuclei, implying that the eCB system can modulate serotonergic functions. In order to substantiate the physiological role of the CB1 receptor in serotonergic neurons of the raphe nuclei, we generated serotonergic 5-hydroxytryptamine (5-HT) neuron-specific CB1 receptor-deficient mice, using the Cre/loxP system with a tamoxifen-inducible Cre recombinase under the control of the regulatory sequences of the tryptophan hydroxylase 2 gene (TPH2-CreERT2), thus, restricting the recombination to 5-HT neurons of the central nervous system (CNS). Applying several different behavioral paradigms, we revealed that mice lacking the CB1 receptor in serotonergic neurons are more anxious and less sociable than control littermates. Thus, we were able to show that functional CB1 receptor signaling in central serotonergic neurons modulates distinct behaviors in mice. PMID:26388750
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Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function
Spencer, William C.; Deneris, Evan S.
2017-01-01
The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling these processes may result in long-lasting changes in brain function in adulthood. Further study of 5-HT neuron gene regulatory networks is likely to provide additional insight into how neurons acquire their mature identities and how terminal selector-type TFs function in postmitotic vertebrate neurons. PMID:28769770
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Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function.
Spencer, William C; Deneris, Evan S
2017-01-01
The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling these processes may result in long-lasting changes in brain function in adulthood. Further study of 5-HT neuron gene regulatory networks is likely to provide additional insight into how neurons acquire their mature identities and how terminal selector-type TFs function in postmitotic vertebrate neurons.
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Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study.
Fabiani, Monica; Gordon, Brian A; Maclin, Edward L; Pearson, Melanie A; Brumback-Peltz, Carrie R; Low, Kathy A; McAuley, Edward; Sutton, Bradley P; Kramer, Arthur F; Gratton, Gabriele
2014-01-15
Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function. Copyright © 2013 Elsevier Inc. All rights reserved.
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Pattern separation: a common function for new neurons in hippocampus and olfactory bulb.
Sahay, Amar; Wilson, Donald A; Hen, René
2011-05-26
While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, "Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron. Copyright © 2011 Elsevier Inc. All rights reserved.
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Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment.
Vizi, E S; Fekete, A; Karoly, R; Mike, A
2010-06-01
Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic-extrasynaptic receptor trafficking, neuron-glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.
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Brain foods: the effects of nutrients on brain function
Gómez-Pinilla, Fernando
2009-01-01
It has long been suspected that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that are responsible for the action of diet on brain health and mental function. Several gut hormones that can enter the brain, or that are produced in the brain itself, influence cognitive ability. In addition, well-established regulators of synaptic plasticity, such as brain-derived neurotrophic factor, can function as metabolic modulators, responding to peripheral signals such as food intake. Understanding the molecular basis of the effects of food on cognition will help us to determine how best to manipulate diet in order to increase the resistance of neurons to insults and promote mental fitness. PMID:18568016
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Yang, Zhilai; Wang, Jin-Hui
2013-12-01
The spike propagation on nerve axons, like synaptic transmission, is essential to ensure neuronal communication. The secure propagation of sequential spikes toward axonal terminals has been challenged in the neurons with a high firing rate, such as cerebellar Purkinje cells. The shortfall of spike propagation makes some digital spikes disappearing at axonal terminals, such that the elucidation of the mechanisms underlying spike propagation reliability is crucial to find the strategy of preventing loss of neuronal codes. As the spike propagation failure is influenced by the membrane potentials, this process is likely caused by altering the functional status of voltage-gated sodium channels (VGSC). We examined this hypothesis in Purkinje cells by using pair-recordings at their somata and axonal blebs in cerebellar slices. The reliability of spike propagation was deteriorated by elevating spike frequency. The frequency-dependent reliability of spike propagation was attenuated by inactivating VGSCs and improved by removing their inactivation. Thus, the functional status of axonal VGSCs influences the reliability of spike propagation.
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Reliability, synchrony and noise
Ermentrout, G. Bard; Galán, Roberto F.; Urban, Nathaniel N.
2008-01-01
The brain is noisy. Neurons receive tens of thousands of highly fluctuating inputs and generate spike trains that appear highly irregular. Much of this activity is spontaneous—uncoupled to overt stimuli or motor outputs—leading to questions about the functional impact of this noise. Although noise is most often thought of as disrupting patterned activity and interfering with the encoding of stimuli, recent theoretical and experimental work has shown that noise can play a constructive role—leading to increased reliability or regularity of neuronal firing in single neurons and across populations. These results raise fundamental questions about how noise can influence neural function and computation. PMID:18603311
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Myocardial ischaemia and the cardiac nervous system.
Armour, J A
1999-01-01
The intrinsic cardiac nervous system has been classically considered to contain only parasympathetic efferent postganglionic neurones which receive inputs from medullary parasympathetic efferent preganglionic neurones. In such a view, intrinsic cardiac ganglia act as simple relay stations of parasympathetic efferent neuronal input to the heart, the major autonomic control of the heart purported to reside solely in the brainstem and spinal cord. Data collected over the past two decades indicate that processing occurs within the mammalian intrinsic cardiac nervous system which involves afferent neurones, local circuit neurones (interconnecting neurones) as well as both sympathetic and parasympathetic efferent postganglionic neurones. As such, intrinsic cardiac ganglionic interactions represent the organ component of the hierarchy of intrathoracic nested feedback control loops which provide rapid and appropriate reflex coordination of efferent autonomic neuronal outflow to the heart. In such a concept, the intrinsic cardiac nervous system acts as a distributive processor, integrating parasympathetic and sympathetic efferent centrifugal information to the heart in addition to centripetal information arising from cardiac sensory neurites. A number of neurochemicals have been shown to influence the interneuronal interactions which occur within the intrathoracic cardiac nervous system. For instance, pharmacological interventions that modify beta-adrenergic or angiotensin II receptors affect cardiomyocyte function not only directly, but indirectly by influencing the capacity of intrathoracic neurones to regulate cardiomyocytes. Thus, current pharmacological management of heart disease may influence cardiomyocyte function directly as well as indirectly secondary to modifying the cardiac nervous system. This review presents a brief summary of developing concepts about the role of the cardiac nervous system in regulating the normal heart. In addition, it provides some tentative ideas concerning the importance of this nervous system in cardiac disease states with a view to stimulating further interest in neural control of the heart so that appropriate neurocardiological strategies can be devised for the management of heart disease.
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Cotel, Florence; Fletcher, Lee N; Kalita-de Croft, Simon; Apergis-Schoute, John; Williams, Stephen R
2018-07-01
Neocortical information processing is powerfully influenced by the activity of layer 6 projection neurons through control of local intracortical and subcortical circuitry. Morphologically distinct classes of layer 6 projection neuron have been identified in the mammalian visual cortex, which exhibit contrasting receptive field properties, but little information is available on their functional specificity. To address this we combined anatomical tracing techniques with high-resolution patch-clamp recording to identify morphological and functional distinct classes of layer 6 projection neurons in the rat primary visual cortex, which innervated separable subcortical territories. Multisite whole-cell recordings in brain slices revealed that corticoclaustral and corticothalamic layer 6 projection neurons exhibited similar somatically recorded electrophysiological properties. These classes of layer 6 projection neurons were sparsely and reciprocally synaptically interconnected, but could be differentiated by cell-class, but not target-cell-dependent rules of use-dependent depression and facilitation of unitary excitatory synaptic output. Corticoclaustral and corticothalamic layer 6 projection neurons were differentially innervated by columnar excitatory circuitry, with corticoclaustral, but not corticothalamic, neurons powerfully driven by layer 4 pyramidal neurons, and long-range pathways conveyed in neocortical layer 1. Our results therefore reveal projection target-specific, functionally distinct, streams of layer 6 output in the rodent neocortex.
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Baslow, Morris H
2011-01-01
The human brain is a complex organ made up of neurons and several other cell types, and whose role is processing information for use in eliciting behaviors. However, the composition of its repeating cellular units for both structure and function are unresolved. Based on recent descriptions of the brain's physiological "operating system", a function of the tri-cellular metabolism of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) for supply of energy, and on the nature of "neuronal words and languages" for intercellular communication, insights into the brain's modular structural and functional units have been gained. In this article, it is proposed that the basic structural unit in brain is defined by its physiological operating system, and that it consists of a single neuron, and one or more astrocytes, oligodendrocytes, and vascular system endothelial cells. It is also proposed that the basic functional unit in the brain is defined by how neurons communicate, and consists of two neurons and their interconnecting dendritic-synaptic-dendritic field. Since a functional unit is composed of two neurons, it requires two structural units to form a functional unit. Thus, the brain can be envisioned as being made up of the three-dimensional stacking and intertwining of myriad structural units which results not only in its gross structure, but also in producing a uniform distribution of binary functional units. Since the physiological NAA-NAAG operating system for supply of energy is repeated in every structural unit, it is positioned to control global brain function.
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Mechanisms and use of neural transplants for brain repair.
Dunnett, Stephen B; Björklund, Anders
2017-01-01
Under appropriate conditions, neural tissues transplanted into the adult mammalian brain can survive, integrate, and function so as to influence the behavior of the host, opening the prospect of repairing neuronal damage, and alleviating symptoms associated with neuronal injury or neurodegenerative disease. Alternative mechanisms of action have been postulated: nonspecific effects of surgery; neurotrophic and neuroprotective influences on disease progression and host plasticity; diffuse or locally regulated pharmacological delivery of deficient neurochemicals, neurotransmitters, or neurohormones; restitution of the neuronal and glial environment necessary for proper host neuronal support and processing; promoting local and long-distance host and graft axon growth; formation of reciprocal connections and reconstruction of local circuits within the host brain; and up to full integration and reconstruction of fully functional host neuronal networks. Analysis of neural transplants in a broad range of anatomical systems and disease models, on simple and complex classes of behavioral function and information processing, have indicated that all of these alternative mechanisms are likely to contribute in different circumstances. Thus, there is not a single or typical mode of graft function; rather grafts can and do function in multiple ways, specific to each particular context. Consequently, to develop an effective cell-based therapy, multiple dimensions must be considered: the target disease pathogenesis; the neurodegenerative basis of each type of physiological dysfunction or behavioral symptom; the nature of the repair required to alleviate or remediate the functional impairments of particular clinical relevance; and identification of a suitable cell source or delivery system, along with the site and method of implantation, that can achieve the sought for repair and recovery. © 2017 Elsevier B.V. All rights reserved.
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Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes
Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.
2012-01-01
Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363
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Lymperopoulos, Ilias N
2017-10-01
The interaction of social networks with the external environment gives rise to non-stationary activity patterns reflecting the temporal structure and strength of exogenous influences that drive social dynamical processes far from an equilibrium state. Following a neuro-inspired approach, based on the dynamics of a passive neuronal membrane, and the firing rate dynamics of single neurons and neuronal populations, we build a state-of-the-art model of the collective social response to exogenous interventions. In this regard, we analyze online activity patterns with a view to determining the transfer function of social systems, that is, the dynamic relationship between external influences and the resulting activity. To this end, first we estimate the impulse response (Green's function) of collective activity, and then we show that the convolution of the impulse response with a time-varying external influence field accurately reproduces empirical activity patterns. To capture the dynamics of collective activity when the generating process is in a state of statistical equilibrium, we incorporate into the model a noisy input convolved with the impulse response function, thus precisely reproducing the fluctuations of stationary collective activity around a resting value. The outstanding goodness-of-fit of the model results to empirical observations, indicates that the model explains human activity patterns generated by time-dependent external influences in various socio-economic contexts. The proposed model can be used for inferring the temporal structure and strength of external influences, as well as the inertia of collective social activity. Furthermore, it can potentially predict social activity patterns. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Bekdash, Rola; Zhang, Changqing; Sarkar, Dipak
2014-09-01
Hypothalamic proopiomelanocortin (POMC) neurons, one of the major regulators of the hypothalamic-pituitary-adrenal (HPA) axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE). These effects are manifested in POMC neurons by a decrease in Pomc gene expression, a decrement in the levels of its derived peptide β-endorphin and a dysregulation of the stress response in the adult offspring. The HPA axis is a major neuroendocrine system with pivotal physiological functions and mode of regulation. This system has been shown to be perturbed by prenatal alcohol exposure. It has been demonstrated that the perturbation of the HPA axis by FAE is long-lasting and is linked to molecular, neurophysiological, and behavioral changes in exposed individuals. Recently, we showed that the dysregulation of the POMC system function by FAE is induced by epigenetic mechanisms such as hypermethylation of Pomc gene promoter and an alteration in histone marks in POMC neurons. This developmental programming of the POMC system by FAE altered the transcriptome in POMC neurons and induced a hyperresponse to stress in adulthood. These long-lasting epigenetic changes influenced subsequent generations via the male germline. We also demonstrated that the epigenetic programming of the POMC system by FAE was reversed in adulthood with the application of the inhibitors of DNA methylation or histone modifications. Thus, prenatal environmental influences, such as alcohol exposure, could epigenetically modulate POMC neuronal circuits and function to shape adult behavioral patterns. Identifying specific epigenetic factors in hypothalamic POMC neurons that are modulated by fetal alcohol and target Pomc gene could be potentially useful for the development of new therapeutic approaches to treat stress-related diseases in patients with fetal alcohol spectrum disorders. Copyright © 2014 by the Research Society on Alcoholism.
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Bekdash, Rola; Zhang, Changqing; Sarkar, Dipak
2014-01-01
Hypothalamic proopiomelanocortin (POMC) neurons, one of the major regulators of the HPA axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE). These effects are manifested in POMC neurons by a decrease in Pomc gene expression, a decrement in the levels of its derived peptide β-endorphin (β-EP) and a dysregulation of the stress response in the adult offspring. The HPA axis is a major neuroendocrine system with pivotal physiological functions and mode of regulation. This system has been shown to be perturbed by prenatal alcohol exposure. It has been demonstrated that the perturbation of the HPA axis by FAE is long-lasting and is linked to molecular, neurophysiological and behavioral changes in exposed individuals. Recently, we showed that the dysregulation of the POMC system function by FAE is induced by epigenetic mechanisms such as hypermethylation of POMC gene promoter and an alteration in histone marks in POMC neurons. This developmental programming of the POMC system by FAE altered the transcriptome in POMC neurons and induced a hyperresponse to stress in adulthood. These long-lasting epigenetic changes influenced subsequent generations via the male germline. We also demonstrated that the epigenetic programming of the POMC system by FAE was reversed in adulthood with the application of the inhibitors of DNA methylation or histone modifications. Thus, prenatal environmental influences such as alcohol exposure could epigenetically modulate POMC neuronal circuits and function to shape adult behavioral patterns. Identifying specific epigenetic factors in hypothalamic POMC neurons that are modulated by fetal alcohol and target Pomc gene could be potentially useful for the development of new therapeutic approaches to treat stress-related diseases in patients with Fetal Alcohol Spectrum Disorders. PMID:25069392
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Large-scale imaging in small brains.
Ahrens, Misha B; Engert, Florian
2015-06-01
The dense connectivity in the brain means that one neuron's activity can influence many others. To observe this interconnected system comprehensively, an aspiration within neuroscience is to record from as many neurons as possible at the same time. There are two useful routes toward this goal: one is to expand the spatial extent of functional imaging techniques, and the second is to use animals with small brains. Here we review recent progress toward imaging many neurons and complete populations of identified neurons in small vertebrates and invertebrates. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Sartini, S; Lattanzi, D; Ambrogini, P; Di Palma, M; Galati, C; Savelli, D; Polidori, E; Calcabrini, C; Rocchi, M B L; Sestili, P; Cuppini, R
2016-01-15
Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Shumilov, V. N., E-mail: vnshumilov@rambler.ru; Syryamkin, V. I., E-mail: maximus70sir@gmail.com; Syryamkin, M. V., E-mail: maximus70sir@gmail.com
The paper puts forward principles of action of devices operating similarly to the nervous system and the brain of biological systems. We propose an alternative method of studying diseases of the nervous system, which may significantly influence prevention, medical treatment, or at least retardation of development of these diseases. This alternative is to use computational and electronic models of the nervous system. Within this approach, we represent the brain in the form of a huge electrical circuit composed of active units, namely, neuron-like units and connections between them. As a result, we created computational and electronic models of elementary nervousmore » systems, which are based on the principles of functioning of biological nervous systems that we have put forward. Our models demonstrate reactions to external stimuli and their change similarly to the behavior of simplest biological organisms. The models possess the ability of self-training and retraining in real time without human intervention and switching operation/training modes. In our models, training and memorization take place constantly under the influence of stimuli on the organism. Training is without any interruption and switching operation modes. Training and formation of new reflexes occur by means of formation of new connections between excited neurons, between which formation of connections is physically possible. Connections are formed without external influence. They are formed under the influence of local causes. Connections are formed between outputs and inputs of two neurons, when the difference between output and input potentials of excited neurons exceeds a value sufficient to form a new connection. On these grounds, we suggest that the proposed principles truly reflect mechanisms of functioning of biological nervous systems and the brain. In order to confirm the correspondence of the proposed principles to biological nature, we carry out experiments for the study of processes of formation of connections between neurons in simplest biological objects. Based on the correspondence of function of the created models to function of biological nervous systems we suggest the use of computational and electronic models of the brain for the study of its function under normal and pathological conditions, because operating principles of the models are built on principles imitating the function of biological nervous systems and the brain.« less
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NASA Astrophysics Data System (ADS)
Shumilov, V. N.; Syryamkin, V. I.; Syryamkin, M. V.
2015-11-01
The paper puts forward principles of action of devices operating similarly to the nervous system and the brain of biological systems. We propose an alternative method of studying diseases of the nervous system, which may significantly influence prevention, medical treatment, or at least retardation of development of these diseases. This alternative is to use computational and electronic models of the nervous system. Within this approach, we represent the brain in the form of a huge electrical circuit composed of active units, namely, neuron-like units and connections between them. As a result, we created computational and electronic models of elementary nervous systems, which are based on the principles of functioning of biological nervous systems that we have put forward. Our models demonstrate reactions to external stimuli and their change similarly to the behavior of simplest biological organisms. The models possess the ability of self-training and retraining in real time without human intervention and switching operation/training modes. In our models, training and memorization take place constantly under the influence of stimuli on the organism. Training is without any interruption and switching operation modes. Training and formation of new reflexes occur by means of formation of new connections between excited neurons, between which formation of connections is physically possible. Connections are formed without external influence. They are formed under the influence of local causes. Connections are formed between outputs and inputs of two neurons, when the difference between output and input potentials of excited neurons exceeds a value sufficient to form a new connection. On these grounds, we suggest that the proposed principles truly reflect mechanisms of functioning of biological nervous systems and the brain. In order to confirm the correspondence of the proposed principles to biological nature, we carry out experiments for the study of processes of formation of connections between neurons in simplest biological objects. Based on the correspondence of function of the created models to function of biological nervous systems we suggest the use of computational and electronic models of the brain for the study of its function under normal and pathological conditions, because operating principles of the models are built on principles imitating the function of biological nervous systems and the brain.
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Statistical technique for analysing functional connectivity of multiple spike trains.
Masud, Mohammad Shahed; Borisyuk, Roman
2011-03-15
A new statistical technique, the Cox method, used for analysing functional connectivity of simultaneously recorded multiple spike trains is presented. This method is based on the theory of modulated renewal processes and it estimates a vector of influence strengths from multiple spike trains (called reference trains) to the selected (target) spike train. Selecting another target spike train and repeating the calculation of the influence strengths from the reference spike trains enables researchers to find all functional connections among multiple spike trains. In order to study functional connectivity an "influence function" is identified. This function recognises the specificity of neuronal interactions and reflects the dynamics of postsynaptic potential. In comparison to existing techniques, the Cox method has the following advantages: it does not use bins (binless method); it is applicable to cases where the sample size is small; it is sufficiently sensitive such that it estimates weak influences; it supports the simultaneous analysis of multiple influences; it is able to identify a correct connectivity scheme in difficult cases of "common source" or "indirect" connectivity. The Cox method has been thoroughly tested using multiple sets of data generated by the neural network model of the leaky integrate and fire neurons with a prescribed architecture of connections. The results suggest that this method is highly successful for analysing functional connectivity of simultaneously recorded multiple spike trains. Copyright © 2011 Elsevier B.V. All rights reserved.
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Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons.
Fernandes, Maria Fernanda A; Matthys, Dominique; Hryhorczuk, Cécile; Sharma, Sandeep; Mogra, Shabana; Alquier, Thierry; Fulton, Stephanie
2015-10-06
The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food. Copyright © 2015 Elsevier Inc. All rights reserved.
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Akins, Victoria T; Weragalaarachchi, Krishanthi; Picardo, Maria Cristina D; Revill, Ann L; Del Negro, Christopher A
2017-08-01
The relationship between neuron morphology and function is a perennial issue in neuroscience. Information about synaptic integration, network connectivity, and the specific roles of neuronal subpopulations can be obtained through morphological analysis of key neurons within a microcircuit. Here we present morphologies of two classes of brainstem respiratory neurons. First, interneurons derived from Dbx1-expressing precursors (Dbx1 neurons) in the preBötzinger complex (preBötC) of the ventral medulla that generate the rhythm for inspiratory breathing movements. Second, Dbx1 neurons of the intermediate reticular formation that influence the motor pattern of pharyngeal and lingual movements during the inspiratory phase of the breathing cycle. We describe the image acquisition and subsequent digitization of morphologies of respiratory Dbx1 neurons from the preBötC and the intermediate reticular formation that were first recorded in vitro. These data can be analyzed comparatively to examine how morphology influences the roles of Dbx1 preBötC and Dbx1 reticular interneurons in respiration and can also be utilized to create morphologically accurate compartmental models for simulation and modeling of respiratory circuits.
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De Cicco, Vincenzo; Tramonti Fantozzi, Maria P.; Cataldo, Enrico; Barresi, Massimo; Bruschini, Luca; Faraguna, Ugo; Manzoni, Diego
2018-01-01
It is known that sensory signals sustain the background discharge of the ascending reticular activating system (ARAS) which includes the noradrenergic locus coeruleus (LC) neurons and controls the level of attention and alertness. Moreover, LC neurons influence brain metabolic activity, gene expression and brain inflammatory processes. As a consequence of the sensory control of ARAS/LC, stimulation of a sensory channel may potential influence neuronal activity and trophic state all over the brain, supporting cognitive functions and exerting a neuroprotective action. On the other hand, an imbalance of the same input on the two sides may lead to an asymmetric hemispheric excitability, leading to an impairment in cognitive functions. Among the inputs that may drive LC neurons and ARAS, those arising from the trigeminal region, from visceral organs and, possibly, from the vestibular system seem to be particularly relevant in regulating their activity. The trigeminal, visceral and vestibular control of ARAS/LC activity may explain why these input signals: (1) affect sensorimotor and cognitive functions which are not directly related to their specific informational content; and (2) are effective in relieving the symptoms of some brain pathologies, thus prompting peripheral activation of these input systems as a complementary approach for the treatment of cognitive impairments and neurodegenerative disorders. PMID:29358907
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Genetic Approaches to Reveal the Connectivity of Adult-Born Neurons
Arenkiel, Benjamin R.
2011-01-01
Much has been learned about the environmental and molecular factors that influence the division, migration, and programmed cell death of adult-born neurons in the mammalian brain. However, detailed knowledge of the mechanisms that govern the formation and maintenance of functional circuit connectivity via adult neurogenesis remains elusive. Recent advances in genetic technologies now afford the ability to precisely target discrete brain tissues, neuronal subtypes, and even single neurons for vital reporter expression and controlled activity manipulations. Here, I review current viral tracing methods, heterologous receptor expression systems, and optogenetic technologies that hold promise toward elucidating the wiring diagrams and circuit properties of adult-born neurons. PMID:21519388
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Baslow, Morris H.
2011-01-01
The human brain is a complex organ made up of neurons and several other cell types, and whose role is processing information for use in eliciting behaviors. However, the composition of its repeating cellular units for both structure and function are unresolved. Based on recent descriptions of the brain's physiological “operating system”, a function of the tri-cellular metabolism of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) for supply of energy, and on the nature of “neuronal words and languages” for intercellular communication, insights into the brain's modular structural and functional units have been gained. In this article, it is proposed that the basic structural unit in brain is defined by its physiological operating system, and that it consists of a single neuron, and one or more astrocytes, oligodendrocytes, and vascular system endothelial cells. It is also proposed that the basic functional unit in the brain is defined by how neurons communicate, and consists of two neurons and their interconnecting dendritic–synaptic–dendritic field. Since a functional unit is composed of two neurons, it requires two structural units to form a functional unit. Thus, the brain can be envisioned as being made up of the three-dimensional stacking and intertwining of myriad structural units which results not only in its gross structure, but also in producing a uniform distribution of binary functional units. Since the physiological NAA–NAAG operating system for supply of energy is repeated in every structural unit, it is positioned to control global brain function. PMID:21720525
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The formation and distribution of hippocampal synapses on patterned neuronal networks
NASA Astrophysics Data System (ADS)
Dowell-Mesfin, Natalie M.
Communication within the central nervous system is highly orchestrated with neurons forming trillions of specialized junctions called synapses. In vivo, biochemical and topographical cues can regulate neuronal growth. Biochemical cues also influence synaptogenesis and synaptic plasticity. The effects of topography on the development of synapses have been less studied. In vitro, neuronal growth is unorganized and complex making it difficult to study the development of networks. Patterned topographical cues guide and control the growth of neuronal processes (axons and dendrites) into organized networks. The aim of this dissertation was to determine if patterned topographical cues can influence synapse formation and distribution. Standard fabrication and compression molding procedures were used to produce silicon masters and polystyrene replicas with topographical cues presented as 1 mum high pillars with diameters of 0.5 and 2.0 mum and gaps of 1.0 to 5.0 mum. Embryonic rat hippocampal neurons grown unto patterned surfaces. A developmental analysis with immunocytochemistry was used to assess the distribution of pre- and post-synaptic proteins. Activity-dependent pre-synaptic vesicle uptake using functional imaging dyes was also performed. Adaptive filtering computer algorithms identified synapses by segmenting juxtaposed pairs of pre- and post-synaptic labels. Synapse number and area were automatically extracted from each deconvolved data set. In addition, neuronal processes were traced automatically to assess changes in synapse distribution. The results of these experiments demonstrated that patterned topographic cues can induce organized and functional neuronal networks that can serve as models for the study of synapse formation and plasticity as well as for the development of neuroprosthetic devices.
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Child, Nicholas D; Benarroch, Eduardo E
2014-03-18
Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.
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[Physical activity: positive impact on brain plasticity].
Achiron, Anat; Kalron, Alon
2008-03-01
The central nervous system has a unique capability of plasticity that enables a single neuron or a group of neurons to undergo functional and constructional changes that are important to learning processes and for compensation of brain damage. The current review aims to summarize recent data related to the effects of physical activity on brain plasticity. In the last decade it was reported that physical activity can affect and manipulate neuronal connections, synaptic activity and adaptation to new neuronal environment following brain injury. One of the most significant neurotrophic factors that is critical for synaptic re-organization and is influenced by physical activity is brain-derived neurotrophic factor (BDNF). The frequency of physical activity and the intensity of exercises are of importance to brain remodeling, support neuronal survival and positively affect rehabilitation therapy. Physical activity should be employed as a tool to improve neural function in healthy subjects and in patients suffering from neurological damage.
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Gliotransmitters travel in time and space.
Araque, Alfonso; Carmignoto, Giorgio; Haydon, Philip G; Oliet, Stéphane H R; Robitaille, Richard; Volterra, Andrea
2014-02-19
The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons. Copyright © 2014 Elsevier Inc. All rights reserved.
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Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons
Ripamonti, Silvia; Ambrozkiewicz, Mateusz C; Guzzi, Francesca; Gravati, Marta; Biella, Gerardo; Bormuth, Ingo; Hammer, Matthieu; Tuffy, Liam P; Sigler, Albrecht; Kawabe, Hiroshi; Nishimori, Katsuhiko; Toselli, Mauro; Brose, Nils; Parenti, Marco; Rhee, JeongSeop
2017-01-01
Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances. DOI: http://dx.doi.org/10.7554/eLife.22466.001 PMID:28231043
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Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons.
Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David
2016-12-17
Orexin neurons are known to augment the sympathetic control of cardiovascular function, however the role of orexin neurons in parasympathetic cardiac regulation remains unclear. To test the hypothesis that orexin neurons contribute to parasympathetic control we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in orexin-Cre transgenic rats and examined postsynaptic currents in cardiac vagal neurons (CVNs) in the dorsal motor nucleus of the vagus (DMV). Simultaneous photostimulation and recording in ChR2-expressing orexin neurons in the lateral hypothalamus resulted in reliable action potential firing as well as large whole-cell currents suggesting a strong expression of ChR2 and reliable optogenetic excitation. Photostimulation of ChR2-expressing fibers in the DMV elicited short-latency (ranging from 3.2ms to 8.5ms) postsynaptic currents in 16 out of 44 CVNs tested. These responses were heterogeneous and included excitatory glutamatergic (63%) and inhibitory GABAergic (37%) postsynaptic currents. The results from this study suggest different sub-population of orexin neurons may exert diverse influences on brainstem CVNs and therefore may play distinct functional roles in parasympathetic control of the heart. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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Shah, Niyathi Hegde; Aizenman, Elias
2013-01-01
Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system, and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death of neurons. Injury-mediated increased K+ efflux through Kv2.1 channels promotes neuronal apoptosis, contributing to widespread neuronal loss in neurodegenerative disorders such as Alzheimer’s disease and stroke. In contrast, some forms of neuronal activity can dramatically alter Kv2.1 channel phosphorylation levels and influence their localization. These changes are normally accompanied by modifications in channel voltage-dependence, which may be neuroprotective within the context of ischemic injury. Kv1 and Kv7 channel dysfunction leads to neuronal hyperexcitability that critically contributes to the pathophysiology of human clinical disorders such as episodic ataxia and epilepsy. This review summarizes the neurotoxic, neuroprotective, and neuroregulatory roles of Kv channels, and highlights the consequences of Kv channel dysfunction on neuronal physiology. The studies described in this review thus underscore the importance of normal Kv channel function in neurons, and emphasize the therapeutic potential of targeting Kv channels in the treatment of a wide range of neurological diseases. PMID:24323720
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The Effects of Motor Neurone Disease on Language: Further Evidence
ERIC Educational Resources Information Center
Bak, Thomas H.; Hodges, John R.
2004-01-01
It might sound surprising that Motor Neurone Disease (MND), regarded still by many as the very example of a neurodegenerative disease affecting selectively the motor system and sparing the sensory functions as well as cognition, can have a significant influence on language. In this article we hope to demonstrate that language dysfunction is not…
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Allison, J D; Bonds, A B
1994-01-01
Intracortical inhibition is believed to enhance the orientation tuning of striate cortical neurons, but the origin of this inhibition is unclear. To examine the possible influence of ascending inhibitory projections from the infragranular layers of striate cortex on the orientation selectivity of neurons in the supragranular layers, we measured the spatiotemporal response properties of 32 supragranular neurons in the cat before, during, and after neural activity in the infragranular layers beneath the recorded cells was inactivated by iontophoretic administration of GABA. During GABA iontophoresis, the orientation tuning bandwidth of 15 (46.9%) supragranular neurons broadened as a result of increases in response amplitude to stimuli oriented about +/- 20 degrees away from the preferred stimulus angle. The mean (+/- SD) baseline orientation tuning bandwidth (half width at half height) of these neurons was 13.08 +/- 2.3 degrees. Their mean tuning bandwidth during inactivation of the infragranular layers increased to 19.59 +/- 2.54 degrees, an increase of 49.7%. The mean percentage increase in orientation tuning bandwidth of the individual neurons was 47.4%. Four neurons exhibited symmetrical changes in their orientation tuning functions, while 11 neurons displayed asymmetrical changes. The change in form of the orientation tuning functions appeared to depend on the relative vertical alignment of the recorded neuron and the infragranular region of inactivation. Neurons located in close vertical register with the inactivated infragranular tissue exhibited symmetric changes in their orientation tuning functions. The neurons exhibiting asymmetric changes in their orientation tuning functions were located just outside the vertical register. Eight of these 11 neurons also demonstrated a mean shift of 6.67 +/- 5.77 degrees in their preferred stimulus orientation. The magnitude of change in the orientation tuning functions increased as the delivery of GABA was prolonged. Responses returned to normal approximately 30 min after the delivery of GABA was discontinued. We conclude that inhibitory projections from neurons within the infragranular layers of striate cortex in cats can enhance the orientation selectivity of supragranular striate cortical neurons.
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Diet and cognition: interplay between cell metabolism and neuronal plasticity.
Gomez-Pinilla, Fernando; Tyagi, Ethika
2013-11-01
To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long-term neuronal plasticity. The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid docosahexenoic acid, disrupting neuronal signaling. Thus, dietary docosahexenoic acid seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation.
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From structure to function, via dynamics
NASA Astrophysics Data System (ADS)
Stetter, O.; Soriano, J.; Geisel, T.; Battaglia, D.
2013-01-01
Neurons in the brain are wired into a synaptic network that spans multiple scales, from local circuits within cortical columns to fiber tracts interconnecting distant areas. However, brain function require the dynamic control of inter-circuit interactions on time-scales faster than synaptic changes. In particular, strength and direction of causal influences between neural populations (described by the so-called directed functional connectivity) must be reconfigurable even when the underlying structural connectivity is fixed. Such directed functional influences can be quantified resorting to causal analysis of time-series based on tools like Granger Causality or Transfer Entropy. The ability to quickly reorganize inter-areal interactions is a chief requirement for performance in a changing natural environment. But how can manifold functional networks stem "on demand" from an essentially fixed structure? We explore the hypothesis that the self-organization of neuronal synchronous activity underlies the control of brain functional connectivity. Based on simulated and real recordings of critical neuronal cultures in vitro, as well as on mean-field and spiking network models of interacting brain areas, we have found that "function follows dynamics", rather than structure. Different dynamic states of a same structural network, characterized by different synchronization properties, are indeed associated to different functional digraphs (functional multiplicity). We also highlight the crucial role of dynamics in establishing a structure-to-function link, by showing that whenever different structural topologies lead to similar dynamical states, than the associated functional connectivities are also very similar (structural degeneracy).
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BAD and KATP channels regulate neuron excitability and epileptiform activity
Fernández-Agüera, María Carmen; Nathwani, Nidhi; Lahmann, Carolina; Burnham, Veronica L
2018-01-01
Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity. PMID:29368690
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Dmitrieva, E V; Moshkov, D A; Gakhova, E N
2006-01-01
Investigation of a possibility of long-term storage of frozen (-196 degrees C) viable neurons and nervous tissue is one of the central present day problems. In this study ultrastructural changes in neurons of frozen-thawed snail brain were examined as a function of time. We studied the influence of cryopreservation, cryoprotectant (Me2SO), cooling to 4-6 degrees C, and a prolonged incubation in physiological solution at 4-6 degrees C on dictyosomes of Golgi apparatus, endoplasmic reticulum (ER) cisternae and mitochondria. It has been found that responses of these intracellular structures of cryopreserved neurons to the above influences are similar: dissociation of Golgi dictyosomes, swelling of endoplasmic reticulum cisternae and mitochondrial cristae. Both freezing-thawing and cryoprotectant were seen to cause an increase in the number of lysosomes, liposomes, myelin-like structures, and to form large vacuoles. The structural changes in molluscan neurons caused by cryopreservation with Me2SO (2 M) were reversible.
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Bacterial Signaling to the Nervous System through Toxins and Metabolites.
Yang, Nicole J; Chiu, Isaac M
2017-03-10
Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons-olfactory chemosensory neurons and nociceptor sensory neurons-detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the "gut-brain axis" to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Functionalized anatomical models for EM-neuron Interaction modeling
NASA Astrophysics Data System (ADS)
Neufeld, Esra; Cassará, Antonino Mario; Montanaro, Hazael; Kuster, Niels; Kainz, Wolfgang
2016-06-01
The understanding of interactions between electromagnetic (EM) fields and nerves are crucial in contexts ranging from therapeutic neurostimulation to low frequency EM exposure safety. To properly consider the impact of in vivo induced field inhomogeneity on non-linear neuronal dynamics, coupled EM-neuronal dynamics modeling is required. For that purpose, novel functionalized computable human phantoms have been developed. Their implementation and the systematic verification of the integrated anisotropic quasi-static EM solver and neuronal dynamics modeling functionality, based on the method of manufactured solutions and numerical reference data, is described. Electric and magnetic stimulation of the ulnar and sciatic nerve were modeled to help understanding a range of controversial issues related to the magnitude and optimal determination of strength-duration (SD) time constants. The results indicate the importance of considering the stimulation-specific inhomogeneous field distributions (especially at tissue interfaces), realistic models of non-linear neuronal dynamics, very short pulses, and suitable SD extrapolation models. These results and the functionalized computable phantom will influence and support the development of safe and effective neuroprosthetic devices and novel electroceuticals. Furthermore they will assist the evaluation of existing low frequency exposure standards for the entire population under all exposure conditions.
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Gray, Elizabeth; Ginty, Mark; Kemp, Kevin; Scolding, Neil; Wilkins, Alastair
2011-04-01
Inflammation is known to cause significant neuronal damage and axonal injury in many neurological disorders. Among the range of inflammatory mediators, nitric oxide is a potent neurotoxic agent. Recent evidence has suggested that cellular peroxisomes may be important in protecting neurons from inflammatory damage. To assess the influence of peroxisomal activation on nitric oxide-mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator-activated receptor (PPAR)-α agonist fenofibrate on cortical neurons exposed to a nitric oxide donor or co-cultured with activated microglia. Fenofibrate protected neurons and axons against both nitric oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in gene expression of ABCD3 (the gene encoding for peroxisomal membrane protein-70), with a concomitant increase in protein levels of PPAR-α and catalase, which was associated with a functional increase in the activity of this enzyme. Collectively, these observations provide evidence that modulation of PPAR-α activity and peroxisomal function by fenofibrate attenuates nitric oxide-mediated neuronal and axonal damage, suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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Bi, Zedong; Zhou, Changsong
2016-01-01
In neural systems, synaptic plasticity is usually driven by spike trains. Due to the inherent noises of neurons and synapses as well as the randomness of connection details, spike trains typically exhibit variability such as spatial randomness and temporal stochasticity, resulting in variability of synaptic changes under plasticity, which we call efficacy variability. How the variability of spike trains influences the efficacy variability of synapses remains unclear. In this paper, we try to understand this influence under pair-wise additive spike-timing dependent plasticity (STDP) when the mean strength of plastic synapses into a neuron is bounded (synaptic homeostasis). Specifically, we systematically study, analytically and numerically, how four aspects of statistical features, i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations, as well as their interactions influence the efficacy variability in converging motifs (simple networks in which one neuron receives from many other neurons). Neurons (including the post-synaptic neuron) in a converging motif generate spikes according to statistical models with tunable parameters. In this way, we can explicitly control the statistics of the spike patterns, and investigate their influence onto the efficacy variability, without worrying about the feedback from synaptic changes onto the dynamics of the post-synaptic neuron. We separate efficacy variability into two parts: the drift part (DriftV) induced by the heterogeneity of change rates of different synapses, and the diffusion part (DiffV) induced by weight diffusion caused by stochasticity of spike trains. Our main findings are: (1) synchronous firing and burstiness tend to increase DiffV, (2) heterogeneity of rates induces DriftV when potentiation and depression in STDP are not balanced, and (3) heterogeneity of cross-correlations induces DriftV together with heterogeneity of rates. We anticipate our work important for understanding functional processes of neuronal networks (such as memory) and neural development. PMID:26941634
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Microglia in CNS development: Shaping the brain for the future.
Mosser, Coralie-Anne; Baptista, Sofia; Arnoux, Isabelle; Audinat, Etienne
Microglial cells are the resident macrophages of the central nervous system (CNS) and are mainly known for their roles in neuropathologies. However, major recent developments have revealed that these immune cells actively interact with neurons in physiological conditions and can modulate the fate and functions of synapses. Originating from myeloid precursors born in the yolk sac, microglial cells invade the CNS during early embryonic development. As a consequence they can potentially influence neuronal proliferation, migration and differentiation as well as the formation and maturation of neuronal networks, thereby contributing to the entire shaping of the CNS. We review here recent evidence indicating that microglial cells are indeed involved in crucial steps of the CNS development, including neuronal survival and apoptosis, axonal growth, migration of neurons, pruning of supernumerary synapses and functional maturation of developing synapses. We also discuss current hypotheses proposing that diverting microglial cells of their physiological functions, by promoting the expression of an immune phenotype during development, may be central to neurodevelopmental disorders such as autism, schizophrenia and epilepsy. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Depolarizing Actions of Hydrogen Sulfide on Hypothalamic Paraventricular Nucleus Neurons
Khademullah, C. Sahara; Ferguson, Alastair V.
2013-01-01
Hydrogen sulfide (H2S) is a novel neurotransmitter that has been shown to influence cardiovascular functions as well and corticotrophin hormone (CRH) secretion. Since the paraventricular nucleus of the hypothalamus (PVN) is a central relay center for autonomic and endocrine functions, we sought to investigate the effects of H2S on the neuronal population of the PVN. Whole cell current clamp recordings were acquired from the PVN neurons and sodium hydrosulfide hydrate (NaHS) was bath applied at various concentrations (0.1, 1, 10, and 50 mM). NaHS (1, 10, and 50 mM) elicited a concentration-response relationship from the majority of recorded neurons, with almost exclusively depolarizing effects following administration. Cells responded and recovered from NaHS administration quickly and the effects were repeatable. Input differences from baseline and during the NaHS-induced depolarization uncovered a biphasic response, implicating both a potassium and non-selective cation conductance. The results from the neuronal population of the PVN shed light on the possible physiological role that H2S has in autonomic and endocrine function. PMID:23691233
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Cellular changes in the enteric nervous system during ageing.
Saffrey, M Jill
2013-10-01
The intrinsic neurons of the gut, enteric neurons, have an essential role in gastrointestinal functions. The enteric nervous system is plastic and continues to undergo changes throughout life, as the gut grows and responds to dietary and other environmental changes. Detailed analysis of changes in the ENS during ageing suggests that enteric neurons are more vulnerable to age-related degeneration and cell death than neurons in other parts of the nervous system, although there is considerable variation in the extent and time course of age-related enteric neuronal loss reported in different studies. Specific neuronal subpopulations, particularly cholinergic myenteric neurons, may be more vulnerable than others to age-associated loss or damage. Enteric degeneration and other age-related neuronal changes may contribute to gastrointestinal dysfunction that is common in the elderly population. Evidence suggests that caloric restriction protects against age-associated loss of enteric neurons, but recent advances in the understanding of the effects of the microbiota and the complex interactions between enteric ganglion cells, mucosal immune system and intestinal epithelium indicate that other factors may well influence ageing of enteric neurons. Much remains to be understood about the mechanisms of neuronal loss and damage in the gut, although there is evidence that reactive oxygen species, neurotrophic factor dysregulation and/or activation of a senescence associated phenotype may be involved. To date, there is no evidence for ongoing neurogenesis that might replace dying neurons in the ageing gut, although small local sites of neurogenesis would be difficult to detect. Finally, despite the considerable evidence for enteric neurodegeneration during ageing, and evidence for some physiological changes in animal models, the ageing gut appears to maintain its function remarkably well in animals that exhibit major neuronal loss, indicating that the ENS has considerable functional reserve. © 2013 Elsevier Inc. All rights reserved.
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Lord, Anton R.; Li, Meng; Demenescu, Liliana R.; van den Meer, Johan; Borchardt, Viola; Krause, Anna Linda; Heinze, Hans-Jochen; Breakspear, Michael; Walter, Martin
2017-01-01
The brain's connectivity skeleton—a rich club of strongly interconnected members—was initially shown to exist in human structural networks, but recent evidence suggests a functional counterpart. This rich club typically includes key regions (or hubs) from multiple canonical networks, reducing the cost of inter-network communication. The posterior cingulate cortex (PCC), a hub node embedded within the default mode network, is known to facilitate communication between brain networks and is a key member of the “rich club.” Here, we assessed how metabolic signatures of neuronal integrity and cortical thickness influence the global extent of a functional rich club as measured using the functional rich club coefficient (fRCC). Rich club estimation was performed on functional connectivity of resting state brain signals acquired at 3T in 48 healthy adult subjects. Magnetic resonance spectroscopy was measured in the same session using a point resolved spectroscopy sequence. We confirmed convergence of functional rich club with a previously established structural rich club. N-acetyl aspartate (NAA) in the PCC is significantly correlated with age (p = 0.001), while the rich club coefficient showed no effect of age (p = 0.106). In addition, we found a significant quadratic relationship between fRCC and NAA concentration in PCC (p = 0.009). Furthermore, cortical thinning in the PCC was correlated with a reduced rich club coefficient after accounting for age and NAA. In conclusion, we found that the fRCC is related to a marker of neuronal integrity in a key region of the cingulate cortex. Furthermore, cortical thinning in the same area was observed, suggesting that both cortical thinning and neuronal integrity in the hub regions influence functional integration of at a whole brain level. PMID:28439224
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Lord, Anton R; Li, Meng; Demenescu, Liliana R; van den Meer, Johan; Borchardt, Viola; Krause, Anna Linda; Heinze, Hans-Jochen; Breakspear, Michael; Walter, Martin
2017-01-01
The brain's connectivity skeleton-a rich club of strongly interconnected members-was initially shown to exist in human structural networks, but recent evidence suggests a functional counterpart. This rich club typically includes key regions (or hubs) from multiple canonical networks, reducing the cost of inter-network communication. The posterior cingulate cortex (PCC), a hub node embedded within the default mode network, is known to facilitate communication between brain networks and is a key member of the "rich club." Here, we assessed how metabolic signatures of neuronal integrity and cortical thickness influence the global extent of a functional rich club as measured using the functional rich club coefficient (fRCC). Rich club estimation was performed on functional connectivity of resting state brain signals acquired at 3T in 48 healthy adult subjects. Magnetic resonance spectroscopy was measured in the same session using a point resolved spectroscopy sequence. We confirmed convergence of functional rich club with a previously established structural rich club. N-acetyl aspartate (NAA) in the PCC is significantly correlated with age ( p = 0.001), while the rich club coefficient showed no effect of age (p = 0.106). In addition, we found a significant quadratic relationship between fRCC and NAA concentration in PCC ( p = 0.009). Furthermore, cortical thinning in the PCC was correlated with a reduced rich club coefficient after accounting for age and NAA. In conclusion, we found that the fRCC is related to a marker of neuronal integrity in a key region of the cingulate cortex. Furthermore, cortical thinning in the same area was observed, suggesting that both cortical thinning and neuronal integrity in the hub regions influence functional integration of at a whole brain level.
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Mamczur, Piotr; Borsuk, Borys; Paszko, Jadwiga; Sas, Zuzanna; Mozrzymas, Jerzy; Wiśniewski, Jacek R; Gizak, Agnieszka; Rakus, Dariusz
2015-02-01
Astrocytes releasing glucose- and/or glycogen-derived lactate and glutamine play a crucial role in shaping neuronal function and plasticity. Little is known, however, how metabolic functions of astrocytes, e.g., their ability to degrade glucosyl units, are affected by the presence of neurons. To address this issue we carried out experiments which demonstrated that co-culturing of rat hippocampal astrocytes with neurons significantly elevates the level of mRNA and protein for crucial enzymes of glycolysis (phosphofructokinase, aldolase, and pyruvate kinase), glycogen metabolism (glycogen synthase and glycogen phosphorylase), and glutamine synthetase in astrocytes. Simultaneously, the decrease of the capability of neurons to metabolize glucose and glutamine is observed. We provide evidence that neurons alter the expression of astrocytic enzymes by secretion of as yet unknown molecule(s) into the extracellular fluid. Moreover, our data demonstrate that almost all studied enzymes may localize in astrocytic nuclei and this localization is affected by the co-culturing with neurons which also reduces proliferative activity of astrocytes. Our results provide the first experimental evidence that the astrocyte-neuron crosstalk substantially affects the expression of basal metabolic enzymes in the both types of cells and influences their subcellular localization in astrocytes. © 2014 Wiley Periodicals, Inc.
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Neuronal Reward and Decision Signals: From Theories to Data
Schultz, Wolfram
2015-01-01
Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations. The approach and choice functions involve subjective value, which is objectively assessed by behavioral choices eliciting internal, subjective reward preferences. Utility is the formal mathematical characterization of subjective value and a prime decision variable in economic choice theory. It is coded as utility prediction error by phasic dopamine responses. Utility can incorporate various influences, including risk, delay, effort, and social interaction. Appropriate for formal decision mechanisms, rewards are coded as object value, action value, difference value, and chosen value by specific neurons. Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts. The neuronal reward signals provide guidance for behavior while constraining the free will to act. PMID:26109341
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GSK3 temporally regulates neurogenin 2 proneural activity in the neocortex.
Li, Saiqun; Mattar, Pierre; Zinyk, Dawn; Singh, Kulwant; Chaturvedi, Chandra-Prakash; Kovach, Christopher; Dixit, Rajiv; Kurrasch, Deborah M; Ma, Yong-Chao; Chan, Jennifer A; Wallace, Valerie; Dilworth, F Jeffrey; Brand, Marjorie; Schuurmans, Carol
2012-06-06
The neocortex is comprised of six neuronal layers that are generated in a defined temporal sequence. While extrinsic and intrinsic cues are known to regulate the sequential production of neocortical neurons, how these factors interact and function in a coordinated manner is poorly understood. The proneural gene Neurog2 is expressed in progenitors throughout corticogenesis, but is only required to specify early-born, deep-layer neuronal identities. Here, we examined how neuronal differentiation in general and Neurog2 function in particular are temporally controlled during murine neocortical development. We found that Neurog2 proneural activity declines in late corticogenesis, correlating with its phosphorylation by GSK3 kinase. Accordingly, GSK3 activity, which is negatively regulated by canonical Wnt signaling, increases over developmental time, while Wnt signaling correspondingly decreases. When ectopically activated, GSK3 inhibits Neurog2-mediated transcription in cultured cells and Neurog2 proneural activities in vivo. Conversely, a reduction in GSK3 activity promotes the precocious differentiation of later stage cortical progenitors without influencing laminar fate specification. Mechanistically, we show that GSK3 suppresses Neurog2 activity by influencing its choice of dimerization partner, promoting heterodimeric interactions with E47 (Tcfe2a), as opposed to Neurog2-Neurog2 homodimer formation, which occurs when GSK3 activity levels are low. At the functional level, Neurog2-E47 heterodimers have a reduced ability to transactivate neuronal differentiation genes compared with Neurog2-Neurog2 homodimers, both in vitro and in vivo. We thus conclude that the temporal regulation of Neurog2-E47 heterodimerization by GSK3 is a central component of the neuronal differentiation "clock" that coordinates the timing and tempo of neocortical neurogenesis in mouse.
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Emerging roles for neurosteroids in sexual behavior and function.
King, Steven R
2008-01-01
Although gonadal and adrenal steroids heavily impact sexual function at the level of the brain, the nervous system also produces its own steroids de novo that may regulate sexual behavior and reproduction. Current evidence points to important roles for neurosteroids in sexual and gender-typical behaviors, control of ovulation, and behaviors that strongly influence sexual interest and motivation like aggression, anxiety and depression. At the cellular level, neurosteroids act through stimulating rapid changes in excitability and direct activation of membrane receptors in neurons. Thus, unlike peripheral steroids, neurosteroids can have immediate and specific effects on select neuronal pathways to regulate sexual function.
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Species-specific diversity in the anatomical and physiological organisation of the BNST-VTA pathway.
Kaufling, Jennifer; Girard, Delphine; Maitre, Marlène; Leste-Lasserre, Thierry; Georges, François
2017-05-01
The anteromedial part of the bed nucleus of the stria terminalis (amBNST) is a limbic structure innervating the ventral tegmental area (VTA) that is remarkably constant across species. The amBNST modulates fear and anxiety, and activation of VTA dopamine (DA) neurons by amBNST afferents seems to be the way by which stress controls motivational states associated with reward or aversion. Because fear learning and anxiety states can be expressed differently between rats and mice, we compared the functional connectivity between amBNST and the VTA-DA neurons in both species using consistent methodological approaches. Using a combination of in vivo electrophysiological, neuroanatomical tracing and laser capture approaches we explored the BNST influences on VTA-DA neuron activity. First, we characterised in rats the molecular phenotype of the amBNST neurons projecting to the VTA. We found that this projection is complex, including both GABAergic and glutamatergic neurons. Then, VTA injections of a conventional retrograde tracer, the β-sub-unit of the cholera toxin (CTB), revealed a stronger BNST-VTA projection in mice than in rats. Finally, electrical stimulations of the BNST during VTA-DA neuron recording demonstrated a more potent excitatory influence of the amBNST on VTA-DA neuron activity in rats than in mice. These data illustrate anatomically, but also functionally, a significant difference between rats and mice in the amBNST-VTA pathway. More generally, together with previous findings, our research highlights the importance of species differences for the interpretation and the generalisation of research data. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse.
Lacagnina, Michael J; Rivera, Phillip D; Bilbo, Staci D
2017-01-01
Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.
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Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells.
Maldonado, Paloma P; Angulo, María Cecilia
2015-06-01
The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron-OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders. © The Author(s) 2014.
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Shpin'kova, V N; Nikol'skaia, K A; Gershteĭn, L M
2000-01-01
The influence of weak disturbances (up to 300 microT) of natural magnetic field on the protein metabolism in neurons of sensomotor cortex (layers III and V) in Wistar rats upon learning in a complex maze was studied. It was found that sensomotor neurons were very sensitive to weak disturbances of magnetic field. The protein content increased, while the nucleus-cytoplasm ratio and osmotic state of neurons remained unchanged. The specificity of neuron's reaction manifested itself in a sharp increase of nucleus and cytoplasm dimensions. In associative neurons (layer III), both the nucleus and cytoplasm were involved in the response; in efferent neurons (layer V), only nuclear parameters changed. The variance coefficients of all parameters of protein metabolism in sensomotor neurons, independently of their functional properties, were much higher than in control, which resulted in a wide diversity of cytochemical response.
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Than, Minh T; Kudlow, Brian A; Han, Min
2013-06-01
Identifying the physiological functions of microRNAs (miRNAs) is often challenging because miRNAs commonly impact gene expression under specific physiological conditions through complex miRNA::mRNA interaction networks and in coordination with other means of gene regulation, such as transcriptional regulation and protein degradation. Such complexity creates difficulties in dissecting miRNA functions through traditional genetic methods using individual miRNA mutations. To investigate the physiological functions of miRNAs in neurons, we combined a genetic "enhancer" approach complemented by biochemical analysis of neuronal miRNA-induced silencing complexes (miRISCs) in C. elegans. Total miRNA function can be compromised by mutating one of the two GW182 proteins (AIN-1), an important component of miRISC. We found that combining an ain-1 mutation with a mutation in unc-3, a neuronal transcription factor, resulted in an inappropriate entrance into the stress-induced, alternative larval stage known as dauer, indicating a role of miRNAs in preventing aberrant dauer formation. Analysis of this genetic interaction suggests that neuronal miRNAs perform such a role partly by regulating endogenous cyclic guanosine monophosphate (cGMP) signaling, potentially influencing two other dauer-regulating pathways. Through tissue-specific immunoprecipitations of miRISC, we identified miRNAs and their likely target mRNAs within neuronal tissue. We verified the biological relevance of several of these miRNAs and found that many miRNAs likely regulate dauer formation through multiple dauer-related targets. Further analysis of target mRNAs suggests potential miRNA involvement in various neuronal processes, but the importance of these miRNA::mRNA interactions remains unclear. Finally, we found that neuronal genes may be more highly regulated by miRNAs than intestinal genes. Overall, our study identifies miRNAs and their targets, and a physiological function of these miRNAs in neurons. It also suggests that compromising other aspects of gene expression, along with miRISC, can be an effective approach to reveal miRNA functions in specific tissues under specific physiological conditions.
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Supervised learning with decision margins in pools of spiking neurons.
Le Mouel, Charlotte; Harris, Kenneth D; Yger, Pierre
2014-10-01
Learning to categorise sensory inputs by generalising from a few examples whose category is precisely known is a crucial step for the brain to produce appropriate behavioural responses. At the neuronal level, this may be performed by adaptation of synaptic weights under the influence of a training signal, in order to group spiking patterns impinging on the neuron. Here we describe a framework that allows spiking neurons to perform such "supervised learning", using principles similar to the Support Vector Machine, a well-established and robust classifier. Using a hinge-loss error function, we show that requesting a margin similar to that of the SVM improves performance on linearly non-separable problems. Moreover, we show that using pools of neurons to discriminate categories can also increase the performance by sharing the load among neurons.
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Convergent neuromodulation onto a network neuron can have divergent effects at the network level.
Kintos, Nickolas; Nusbaum, Michael P; Nadim, Farzan
2016-04-01
Different neuromodulators often target the same ion channel. When such modulators act on different neuron types, this convergent action can enable a rhythmic network to produce distinct outputs. Less clear are the functional consequences when two neuromodulators influence the same ion channel in the same neuron. We examine the consequences of this seeming redundancy using a mathematical model of the crab gastric mill (chewing) network. This network is activated in vitro by the projection neuron MCN1, which elicits a half-center bursting oscillation between the reciprocally-inhibitory neurons LG and Int1. We focus on two neuropeptides which modulate this network, including a MCN1 neurotransmitter and the hormone crustacean cardioactive peptide (CCAP). Both activate the same voltage-gated current (I MI ) in the LG neuron. However, I MI-MCN1 , resulting from MCN1 released neuropeptide, has phasic dynamics in its maximal conductance due to LG presynaptic inhibition of MCN1, while I MI-CCAP retains the same maximal conductance in both phases of the gastric mill rhythm. Separation of time scales allows us to produce a 2D model from which phase plane analysis shows that, as in the biological system, I MI-MCN1 and I MI-CCAP primarily influence the durations of opposing phases of this rhythm. Furthermore, I MI-MCN1 influences the rhythmic output in a manner similar to the Int1-to-LG synapse, whereas I MI-CCAP has an influence similar to the LG-to-Int1 synapse. These results show that distinct neuromodulators which target the same voltage-gated ion channel in the same network neuron can nevertheless produce distinct effects at the network level, providing divergent neuromodulator actions on network activity.
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Convergent neuromodulation onto a network neuron can have divergent effects at the network level
Kintos, Nickolas; Nusbaum, Michael P.; Nadim, Farzan
2016-01-01
Different neuromodulators often target the same ion channel. When such modulators act on different neuron types, this convergent action can enable a rhythmic network to produce distinct outputs. Less clear are the functional consequences when two neuromodulators influence the same ion channel in the same neuron. We examine the consequences of this seeming redundancy using a mathematical model of the crab gastric mill (chewing) network. This network is activated in vitro by the projection neuron MCN1, which elicits a half-center bursting oscillation between the reciprocally-inhibitory neurons LG and Int1. We focus on two neuropeptides which modulate this network, including a MCN1 neurotransmitter and the hormone crustacean cardioactive peptide (CCAP). Both activate the same voltage-gated current (IMI) in the LG neuron. However, IMI-MCN1, resulting from MCN1 released neuropeptide, has phasic dynamics in its maximal conductance due to LG presynaptic inhibition of MCN1, while IMI-CCAP retains the same maximal conductance in both phases of the gastric mill rhythm. Separation of time scales allows us to produce a 2D model from which phase plane analysis shows that, as in the biological system, IMI-MCN1 and IMI-CCAP primarily influence the durations of opposing phases of this rhythm. Furthermore, IMI-MCN1 influences the rhythmic output in a manner similar to the Int1-to-LG synapse, whereas IMI-CCAP has an influence similar to the LG-to-Int1 synapse. These results show that distinct neuromodulators which target the same voltage-gated ion channel in the same network neuron can nevertheless produce distinct effects at the network level, providing divergent neuromodulator actions on network activity. PMID:26798029
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Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy.
Genabai, Naresh K; Kannan, Annapoorna; Ahmad, Saif; Jiang, Xiaoting; Bhatia, Kanchan; Gangwani, Laxman
2017-08-15
Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA.
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Shibasaki, Koji; Suzuki, Makoto; Mizuno, Atsuko; Tominaga, Makoto
2007-02-14
Physiological body temperature is an important determinant for neural functions, and it is well established that changes in temperature have dynamic influences on hippocampal neural activities. However, the detailed molecular mechanisms have never been clarified. Here, we show that hippocampal neurons express functional transient receptor potential vanilloid 4 (TRPV4), one of the thermosensitive TRP (transient receptor potential) channels, and that TRPV4 is constitutively active at physiological temperature. Activation of TRPV4 at 37 degrees C depolarized the resting membrane potential in hippocampal neurons by allowing cation influx, which was observed in wild-type (WT) neurons, but not in TRPV4-deficient (TRPV4KO) cells, although dendritic morphology, synaptic marker clustering, and synaptic currents were indistinguishable between the two genotypes. Furthermore, current injection studies revealed that TRPV4KO neurons required larger depolarization to evoke firing, equivalent to WT neurons, indicating that TRPV4 is a key regulator for hippocampal neural excitabilities. We conclude that TRPV4 is activated by physiological temperature in hippocampal neurons and thereby controls their excitability.
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Large-scale imaging in small brains
Ahrens, Misha B.; Engert, Florian
2016-01-01
The dense connectivity in the brain and arrangements of cells into circuits means that one neuron’s activity can influence many others. To observe this interconnected system comprehensively, an aspiration within neuroscience is to record from as many neurons as possible at the same time. There are two useful routes toward this goal: one is to expand the spatial extent of functional imaging techniques, and the second is to use animals with small brains. Here we review recent progress toward imaging many neurons and complete populations of identified neurons in small vertebrates and invertebrates. PMID:25636154
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The hippocampal formation: morphological changes induced by thyroid, gonadal and adrenal hormones.
Gould, E; Woolley, C S; McEwen, B S
1991-01-01
The hippocampal formation is of considerable interest due to its proposed role in a number of important functions, including learning and memory processes. Manipulations of thyroid, gonadal and adrenal hormones have been shown to influence hippocampal physiology as well as learning and memory. The cellular events which underlie these hormone-induced functional changes are largely unexplored. However, studies suggest that hormonal manipulations during development and in adulthood result in dramatic morphological changes within the hippocampal formation. Because neuronal physiology has been suggested to depend upon neuronal morphology, we have been determining the morphologic sensitivity of hippocampal neurons to thyroid and steroid hormones in an effort to elucidate possible structural mechanisms to account for differences in hippocampal function. In this review, hormone-induced structural changes in the developing and adult hippocampal formation are discussed, with particular emphasis on their functional relevance. Sex differences, as well as the developmental effects of thyroid hormone and glucocorticoids, are described. Moreover, the effects of ovarian steroids, thyroid hormone and glucocorticoids on neuronal morphology in the hippocampal formation of the adult rat are reviewed. These hormone-induced structural changes may account, at least in part, for previously reported hormone-induced changes in hippocampal function.
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Mitterauer, Bernhard J.; Kofler-Westergren, Birgitta
2011-01-01
A model of glial–neuronal interactions is proposed that could be explanatory for the demyelination identified in brains with schizophrenia. It is based on two hypotheses: (1) that glia–neuron systems are functionally viable and important for normal brain function, and (2) that disruption of this postulated function disturbs the glial categorization function, as shown by formal analysis. According to this model, in schizophrenia receptors on astrocytes in glial–neuronal synaptic units are not functional, loosing their modulatory influence on synaptic neurotransmission. Hence, an unconstrained neurotransmission flux occurs that hyperactivates the axon and floods the cognate receptors of neurotransmitters on oligodendrocytes. The excess of neurotransmitters may have a toxic effect on oligodendrocytes and myelin, causing demyelination. In parallel, an increasing impairment of axons may disconnect neuronal networks. It is formally shown how oligodendrocytes normally categorize axonic information processing via their processes. Demyelination decomposes the oligodendrocyte–axonic system making it incapable to generate categories of information. This incoherence may be responsible for symptoms of disorganization in schizophrenia, such as thought disorder, inappropriate affect and incommunicable motor behavior. In parallel, the loss of oligodendrocytes affects gap junctions in the panglial syncytium, presumably responsible for memory impairment in schizophrenia. PMID:21647404
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Diet and cognition: interplay between cell metabolism and neuronal plasticity
Gomez-Pinilla, Fernando; Tyagi, Ethika
2014-01-01
Purpose of Study To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Recent Findings Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long term neuronal plasticity. Summary The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid DHA, disrupting neuronal signaling. Thus, dietary DHA seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor (BDNF) in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation. PMID:24071781
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Neurotrophin signaling endosomes; biogenesis, regulation, and functions
Yamashita, Naoya; Kuruvilla, Rejji
2016-01-01
In the nervous system, communication between neurons and their post-synaptic target cells is critical for the formation, refinement and maintenance of functional neuronal connections. Diffusible signals secreted by target tissues, exemplified by the family of neurotrophins, impinge on nerve terminals to influence diverse developmental events including neuronal survival and axonal growth. Key mechanisms of action of target-derived neurotrophins include the cell biological processes of endocytosis and retrograde trafficking of their Trk receptors from growth cones to cell bodies. In this review, we summarize the molecular mechanisms underlying this endosome-mediated signaling, focusing on the instructive role of neurotrophin signaling itself in directing its own trafficking. Recent studies have linked impaired neurotrophin trafficking to neurodevelopmental disorders, highlighting the relevance of neurotrophin endosomes in human health. PMID:27327126
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Transsynaptic trophic effects of steroid hormones in an avian model of adult brain plasticity
Brenowitz, Eliot A.
2014-01-01
The avian song control system provides an excellent model for studying transsynaptic trophic effects of steroid sex hormones. Seasonal changes in systemic testosterone (T) and its metabolites regulate plasticity of this system. Steroids interact with the neurotrophin brain-derived neurotrophic factor (BDNF) to influence cellular processes of plasticity in nucleus HVC of adult birds, including the addition of newborn neurons. This interaction may also occur transsynpatically; T increases the synthesis of BDNF in HVC, and BDNF protein is then released by HVC neurons on to postsynaptic cells in nucleus RA where it has trophic effects on activity and morphology. Androgen action on RA neurons increases their activity and this has a retrograde trophic effect on the addition of new neurons to HVC. The functional linkage of sex steroids to BDNF may be of adaptive value in regulating the trophic effects of the neurotrophin and coordinating circuit function in reproductively relevant contexts. PMID:25285401
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Face-selective neurons maintain consistent visual responses across months
McMahon, David B. T.; Jones, Adam P.; Bondar, Igor V.; Leopold, David A.
2014-01-01
Face perception in both humans and monkeys is thought to depend on neurons clustered in discrete, specialized brain regions. Because primates are frequently called upon to recognize and remember new individuals, the neuronal representation of faces in the brain might be expected to change over time. The functional properties of neurons in behaving animals are typically assessed over time periods ranging from minutes to hours, which amounts to a snapshot compared to a lifespan of a neuron. It therefore remains unclear how neuronal properties observed on a given day predict that same neuron's activity months or years later. Here we show that the macaque inferotemporal cortex contains face-selective cells that show virtually no change in their patterns of visual responses over time periods as long as one year. Using chronically implanted microwire electrodes guided by functional MRI targeting, we obtained distinct profiles of selectivity for face and nonface stimuli that served as fingerprints for individual neurons in the anterior fundus (AF) face patch within the superior temporal sulcus. Longitudinal tracking over a series of daily recording sessions revealed that face-selective neurons maintain consistent visual response profiles across months-long time spans despite the influence of ongoing daily experience. We propose that neurons in the AF face patch are specialized for aspects of face perception that demand stability as opposed to plasticity. PMID:24799679
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Face-selective neurons maintain consistent visual responses across months.
McMahon, David B T; Jones, Adam P; Bondar, Igor V; Leopold, David A
2014-06-03
Face perception in both humans and monkeys is thought to depend on neurons clustered in discrete, specialized brain regions. Because primates are frequently called upon to recognize and remember new individuals, the neuronal representation of faces in the brain might be expected to change over time. The functional properties of neurons in behaving animals are typically assessed over time periods ranging from minutes to hours, which amounts to a snapshot compared to a lifespan of a neuron. It therefore remains unclear how neuronal properties observed on a given day predict that same neuron's activity months or years later. Here we show that the macaque inferotemporal cortex contains face-selective cells that show virtually no change in their patterns of visual responses over time periods as long as one year. Using chronically implanted microwire electrodes guided by functional MRI targeting, we obtained distinct profiles of selectivity for face and nonface stimuli that served as fingerprints for individual neurons in the anterior fundus (AF) face patch within the superior temporal sulcus. Longitudinal tracking over a series of daily recording sessions revealed that face-selective neurons maintain consistent visual response profiles across months-long time spans despite the influence of ongoing daily experience. We propose that neurons in the AF face patch are specialized for aspects of face perception that demand stability as opposed to plasticity.
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Rehabilitation in practice: management of lower motor neuron weakness.
Ramdharry, Gita M
2010-05-01
This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'The trainee consistently demonstrates a knowledge of the pathophysiology of various specific impairments including lower motor neuron weakness' and 'management approaches for specific impairments including lower motor neuron weakness'.This article explores weakness as a lower motor symptom. Weakness as a primary impairment of neuromuscular diseases is addressed, with recognition of the phenomenon of disuse atrophy, and how weakness impacts on the functional abilities of people with myopathy and neuropathy. Interventions to reduce weakness or address the functional consequences of weakness are evaluated with consideration of safety and clinical application. This paper will allow readers to: (1) appraise the contribution of research in rehabilitation of lower motor neuron weakness to clinical decision making and (2) engage with the issues that arise when researching rehabilitation interventions for lower motor neuron weakness. Impairments associated with neuromuscular conditions can lead to significant functional difficulties that can impact on a person's daily participation. This article focuses on the primary impairment of weakness and explores the research evidence for rehabilitation interventions that directly influence weakness or address the impact of weakness on function.
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NASA Astrophysics Data System (ADS)
Nam, Ki-Hwan; Jamilpour, Nima; Mfoumou, Etienne; Wang, Fei-Yue; Zhang, Donna D.; Wong, Pak Kin
2014-11-01
Cells sense and interpret mechanical cues, including cell-cell and cell-substrate interactions, in the microenvironment to collectively regulate various physiological functions. Understanding the influences of these mechanical factors on cell behavior is critical for fundamental cell biology and for the development of novel strategies in regenerative medicine. Here, we demonstrate plasma lithography patterning on elastomeric substrates for elucidating the influences of mechanical cues on neuronal differentiation and neuritogenesis. The neuroblastoma cells form neuronal spheres on plasma-treated regions, which geometrically confine the cells over two weeks. The elastic modulus of the elastomer is controlled simultaneously by the crosslinker concentration. The cell-substrate mechanical interactions are also investigated by controlling the size of neuronal spheres with different cell seeding densities. These physical cues are shown to modulate with the formation of focal adhesions, neurite outgrowth, and the morphology of neuroblastoma. By systematic adjustment of these cues, along with computational biomechanical analysis, we demonstrate the interrelated mechanoregulatory effects of substrate elasticity and cell size. Taken together, our results reveal that the neuronal differentiation and neuritogenesis of neuroblastoma cells are collectively regulated via the cell-substrate mechanical interactions.
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BAD and KATP channels regulate neuron excitability and epileptiform activity.
Martínez-François, Juan Ramón; Fernández-Agüera, María Carmen; Nathwani, Nidhi; Lahmann, Carolina; Burnham, Veronica L; Danial, Nika N; Yellen, Gary
2018-01-25
Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad ( B CL-2 a gonist of cell d eath) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (K ATP ) channels. Here we investigated the effect of BAD manipulation on K ATP channel activity and excitability in acute brain slices. We found that BAD's influence on neuronal K ATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal K ATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of K ATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a 'dentate gate' function that is reinforced by increased K ATP channel activity. © 2018, Martínez-François et al.
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Witham, Emily; Comunian, Claudio; Ratanpal, Harkaranveer; Skora, Susanne; Zimmer, Manuel; Srinivasan, Supriya
2016-02-23
It is known that internal physiological state, or interoception, influences CNS function and behavior. However, the neurons and mechanisms that integrate sensory information with internal physiological state remain largely unknown. Here, we identify C. elegans body cavity neurons called URX(L/R) as central homeostatic sensors that integrate fluctuations in oxygen availability with internal metabolic state. We show that depletion of internal body fat reserves increases the tonic activity of URX neurons, which influences the magnitude of the evoked sensory response to oxygen. These responses are integrated via intracellular cGMP and Ca(2+). The extent of neuronal activity thus reflects the balance between the perception of oxygen and available fat reserves. The URX homeostatic sensor ensures that neural signals that stimulate fat loss are only deployed when there are sufficient fat reserves to do so. Our results uncover an interoceptive neuroendocrine axis that relays internal state information to the nervous system. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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Nucleus Ambiguus Cholinergic Neurons Activated by Acupuncture: Relation to Enkephalin
Guo, Zhi-Ling; Li, Min; Longhurst, John C.
2012-01-01
Acupuncture regulates autonomic function. Our previous studies have shown that electroacupuncture (EA) at the Jianshi–Neiguan acupoints (P5–P6, underlying the median nerve) inhibits central sympathetic outflow and attenuates excitatory cardiovascular reflexes, in part, through an opioid mechanism. It is unknown if EA at these acupoints influences the parasympathetic system. Thus, using c-Fos expression, we examined activation of nucleus ambiguus (NAmb) neurons by EA, their relation to cholinergic (preganglionic parasympathetic) neurons and those containing enkephalin. To enhance detection of cell bodies containing enkephalin, colchicine (90–100 μg/kg) was administered into the subarachnoid space of cats 30 hr prior to EA or sham-operated controls for EA. Following bilateral barodenervation and cervical vagotomy, either EA for 30 min at P5–P6 acupoints or control stimulation (needle placement at P5–P6 without stimulation) was applied. While perikarya containing enkephalin were observed in some medullary nuclei (e.g., râphe), only enkephalin-containing neuronal processes were found in the NAmb. Compared to controls (n=4), more c-Fos immunoreactivity, located principally in close proximity to fibers containing enkephalin was noted in the NAmb of EA-treated cats (n=5; P<0.01). Moreover, neurons double-labeled with c-Fos and choline acetyltransferase in the NAmb were identified in EA-treated, but not the control animals. These data demonstrate for the first time that EA activates preganglionic parasympathetic neurons in the NAmb. Because of their close proximity, these EA-activated neurons likely interact with nerve fibers containing enkephalin. These results suggest that EA at the P5–P6 acupoints has the potential to influence parasympathetic outflow and cardiovascular function, likely through an enkephalinergic mechanism. PMID:22306033
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McDougal, David H.; Gamlin, Paul D.
2016-01-01
The autonomic nervous system influences numerous ocular functions. It does this by way of parasympathetic innervation from postganglionic fibers that originate from neurons in the ciliary and pterygopalatine ganglia, and by way of sympathetic innervation from postganglionic fibers that originate from neurons in the superior cervical ganglion. Ciliary ganglion neurons project to the ciliary body and the sphincter pupillae muscle of the iris to control ocular accommodation and pupil constriction, respectively. Superior cervical ganglion neurons project to the dilator pupillae muscle of the iris to control pupil dilation. Ocular blood flow is controlled both via direct autonomic influences on the vasculature of the optic nerve, choroid, ciliary body, and iris, as well as via indirect influences on retinal blood flow. In mammals, this vasculature is innervated by vasodilatory fibers from the pterygopalatine ganglion, and by vasoconstrictive fibers from the superior cervical ganglion. Intraocular pressure is regulated primarily through the balance of aqueous humor formation and outflow. Autonomic regulation of ciliary body blood vessels and the ciliary epithelium is an important determinant of aqueous humor formation; autonomic regulation of the trabecular meshwork and episcleral blood vessels is an important determinant of aqueous humor outflow. These tissues are all innervated by fibers from the pterygopalatine and superior cervical ganglia. In addition to these classical autonomic pathways, trigeminal sensory fibers exert local, intrinsic influences on many of these regions of the eye, as well as on some neurons within the ciliary and pterygopalatine ganglia. PMID:25589275
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Auditory and visual modulation of temporal lobe neurons in voice-sensitive and association cortices.
Perrodin, Catherine; Kayser, Christoph; Logothetis, Nikos K; Petkov, Christopher I
2014-02-12
Effective interactions between conspecific individuals can depend upon the receiver forming a coherent multisensory representation of communication signals, such as merging voice and face content. Neuroimaging studies have identified face- or voice-sensitive areas (Belin et al., 2000; Petkov et al., 2008; Tsao et al., 2008), some of which have been proposed as candidate regions for face and voice integration (von Kriegstein et al., 2005). However, it was unclear how multisensory influences occur at the neuronal level within voice- or face-sensitive regions, especially compared with classically defined multisensory regions in temporal association cortex (Stein and Stanford, 2008). Here, we characterize auditory (voice) and visual (face) influences on neuronal responses in a right-hemisphere voice-sensitive region in the anterior supratemporal plane (STP) of Rhesus macaques. These results were compared with those in the neighboring superior temporal sulcus (STS). Within the STP, our results show auditory sensitivity to several vocal features, which was not evident in STS units. We also newly identify a functionally distinct neuronal subpopulation in the STP that appears to carry the area's sensitivity to voice identity related features. Audiovisual interactions were prominent in both the STP and STS. However, visual influences modulated the responses of STS neurons with greater specificity and were more often associated with congruent voice-face stimulus pairings than STP neurons. Together, the results reveal the neuronal processes subserving voice-sensitive fMRI activity patterns in primates, generate hypotheses for testing in the visual modality, and clarify the position of voice-sensitive areas within the unisensory and multisensory processing hierarchies.
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Auditory and Visual Modulation of Temporal Lobe Neurons in Voice-Sensitive and Association Cortices
Perrodin, Catherine; Kayser, Christoph; Logothetis, Nikos K.
2014-01-01
Effective interactions between conspecific individuals can depend upon the receiver forming a coherent multisensory representation of communication signals, such as merging voice and face content. Neuroimaging studies have identified face- or voice-sensitive areas (Belin et al., 2000; Petkov et al., 2008; Tsao et al., 2008), some of which have been proposed as candidate regions for face and voice integration (von Kriegstein et al., 2005). However, it was unclear how multisensory influences occur at the neuronal level within voice- or face-sensitive regions, especially compared with classically defined multisensory regions in temporal association cortex (Stein and Stanford, 2008). Here, we characterize auditory (voice) and visual (face) influences on neuronal responses in a right-hemisphere voice-sensitive region in the anterior supratemporal plane (STP) of Rhesus macaques. These results were compared with those in the neighboring superior temporal sulcus (STS). Within the STP, our results show auditory sensitivity to several vocal features, which was not evident in STS units. We also newly identify a functionally distinct neuronal subpopulation in the STP that appears to carry the area's sensitivity to voice identity related features. Audiovisual interactions were prominent in both the STP and STS. However, visual influences modulated the responses of STS neurons with greater specificity and were more often associated with congruent voice-face stimulus pairings than STP neurons. Together, the results reveal the neuronal processes subserving voice-sensitive fMRI activity patterns in primates, generate hypotheses for testing in the visual modality, and clarify the position of voice-sensitive areas within the unisensory and multisensory processing hierarchies. PMID:24523543
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Local and global influences on protein turnover in neurons and glia
Dörrbaum, Aline R; Kochen, Lisa
2018-01-01
Regulation of protein turnover allows cells to react to their environment and maintain homeostasis. Proteins can show different turnover rates in different tissue, but little is known about protein turnover in different brain cell types. We used dynamic SILAC to determine half-lives of over 5100 proteins in rat primary hippocampal cultures as well as in neuron-enriched and glia-enriched cultures ranging from <1 to >20 days. In contrast to synaptic proteins, membrane proteins were relatively shorter-lived and mitochondrial proteins were longer-lived compared to the population. Half-lives also correlate with protein functions and the dynamics of the complexes they are incorporated in. Proteins in glia possessed shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the turnover of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover. PMID:29914620
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Chipman, Peter H; Zhang, Ying; Rafuse, Victor F
2014-01-01
Pluripotent stem cells can be directed to differentiate into motor neurons and assessed for functionality in vitro. An emerging application of this technique is to model genetically inherited diseases in differentiated motor neurons and to screen for new therapeutic targets. The neuromuscular junction (NMJ) is essential to the functionality of motor neurons and its dysfunction is a primary hallmark of motor neuron disease. However, mature NMJs that possess the functional and morphological characteristics of those formed in vivo have so far not been obtained in vitro. Here we describe the generation and analysis of mature NMJs formed between embryonic stem cell-derived motor neurons (ESCMNs) and primary myotubes. We compared the formation and maturation of NMJs generated by wild-type (NCAM+/+) ESCMNs to those generated by neural cell adhesion molecule null (NCAM-/-) ESCMNs in order to definitively test the sensitivity of this assay to identify synaptic pathology. We find that co-cultures using NCAM-/- ESCMNs replicate key in vivo NCAM-/- phenotypes and reveal that NCAM influences neuromuscular synaptogenesis by controlling the mode of synaptic vesicle endocytosis. Further, we could improve synapse formation and function in NCAM-/- co-cultures by chronic treatment with nifedipine, which blocks an immature synaptic vesicle recycling pathway. Together, our results demonstrate that this ESCMN/myofiber co-culture system is a highly sensitive bioassay for examining molecules postulated to regulate synaptic function and for screening therapeutics that will improve the function of compromised NMJs.
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Amatrudo, Joseph M.; Weaver, Christina M.; Crimins, Johanna L.; Hof, Patrick R.; Rosene, Douglas L.; Luebke, Jennifer I.
2012-01-01
Whole-cell patch-clamp recordings and high-resolution 3D morphometric analyses of layer 3 pyramidal neurons in in vitro slices of monkey primary visual cortex (V1) and dorsolateral granular prefrontal cortex (dlPFC) revealed that neurons in these two brain areas possess highly distinctive structural and functional properties. Area V1 pyramidal neurons are much smaller than dlPFC neurons, with significantly less extensive dendritic arbors and far fewer dendritic spines. Relative to dlPFC neurons, V1 neurons have a significantly higher input resistance, depolarized resting membrane potential and higher action potential (AP) firing rates. Most V1 neurons exhibit both phasic and regular-spiking tonic AP firing patterns, while dlPFC neurons exhibit only tonic firing. Spontaneous postsynaptic currents are lower in amplitude and have faster kinetics in V1 than in dlPFC neurons, but are no different in frequency. Three-dimensional reconstructions of V1 and dlPFC neurons were incorporated into computational models containing Hodgkin-Huxley and AMPA- and GABAA-receptor gated channels. Morphology alone largely accounted for observed passive physiological properties, but led to AP firing rates that differed more than observed empirically, and to synaptic responses that opposed empirical results. Accordingly, modeling predicts that active channel conductances differ between V1 and dlPFC neurons. The unique features of V1 and dlPFC neurons are likely fundamental determinants of area-specific network behavior. The compact electrotonic arbor and increased excitability of V1 neurons support the rapid signal integration required for early processing of visual information. The greater connectivity and dendritic complexity of dlPFC neurons likely support higher level cognitive functions including working memory and planning. PMID:23035077
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Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons
NASA Astrophysics Data System (ADS)
Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas
2016-04-01
There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven’t been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries.
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Phosphatidylserine in the Brain: Metabolism and Function
Kim, Hee-Yong; Huang, Bill X.; Spector, Arthur A.
2014-01-01
Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine in reactions are catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear. PMID:24992464
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Modeling the Blood-Brain Barrier in a 3D triple co-culture microfluidic system.
Adriani, G; Ma, D; Pavesi, A; Goh, E L K; Kamm, R D
2015-01-01
The need for a blood-brain barrier (BBB) model that accurately mimics the physiological characteristics of the in-vivo situation is well-recognized by researchers in academia and industry. However, there is currently no in-vitro model allowing studies of neuronal growth and/or function influenced by factors from the blood that cross through the BBB. Therefore, we established a 3D triple co-culture microfluidic system using human umbilical vein endothelial cells (HUVEC) together with primary rat astrocytes and neurons. Immunostaining confirmed the successful triple co-culture system consisting of an intact BBB with tight intercellular junctions in the endothelial monolayer. The BBB selective permeability was determined by a fluorescent-based assay using dextrans of different molecular weights. Finally, neuron functionality was demonstrated by calcium imaging.
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Synchrony dynamics underlying effective connectivity reconstruction of neuronal circuits
NASA Astrophysics Data System (ADS)
Yu, Haitao; Guo, Xinmeng; Qin, Qing; Deng, Yun; Wang, Jiang; Liu, Jing; Cao, Yibin
2017-04-01
Reconstruction of effective connectivity between neurons is essential for neural systems with function-related significance, characterizing directionally causal influences among neurons. In this work, causal interactions between neurons in spinal dorsal root ganglion, activated by manual acupuncture at Zusanli acupoint of experimental rats, are estimated using Granger causality (GC) method. Different patterns of effective connectivity are obtained for different frequencies and types of acupuncture. Combined with synchrony analysis between neurons, we show a dependence of effective connection on the synchronization dynamics. Based on the experimental findings, a neuronal circuit model with synaptic connections is constructed. The variation of neuronal effective connectivity with respect to its structural connectivity and synchronization dynamics is further explored. Simulation results show that reciprocally causal interactions with statistically significant are formed between well-synchronized neurons. The effective connectivity may be not necessarily equivalent to synaptic connections, but rather depend on the synchrony relationship. Furthermore, transitions of effective interaction between neurons are observed following the synchronization transitions induced by conduction delay and synaptic conductance. These findings are helpful to further investigate the dynamical mechanisms underlying the reconstruction of effective connectivity of neuronal population.
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Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals.
Freire-Regatillo, Alejandra; Argente-Arizón, Pilar; Argente, Jesús; García-Segura, Luis Miguel; Chowen, Julie A
2017-01-01
Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding "non-neuronal" cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed.
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Eberwine, James; Bartfai, Tamas
2011-01-01
We report on an ‘unbiased’ molecular characterization of individual, adult neurons, active in a central, anterior hypothalamic neuronal circuit, by establishing cDNA libraries from each individual, electrophysiologically identified warm sensitive neuron (WSN). The cDNA libraries were analyzed by Affymetrix microarray. The presence and frequency of cDNAs was confirmed and enhanced with Illumina sequencing of each single cell cDNA library. cDNAs encoding the GABA biosynthetic enzyme. GAD1 and of adrenomedullin, galanin, prodynorphin, somatostatin, and tachykinin were found in the WSNs. The functional cellular and in vivo studies on dozens of the more than 500 neurotransmitter -, hormone- receptors and ion channels, whose cDNA was identified and sequence confirmed, suggest little or no discrepancy between the transcriptional and functional data in WSNs; whenever agonists were available for a receptor whose cDNA was identified, a functional response was found.. Sequencing single neuron libraries permitted identification of rarely expressed receptors like the insulin receptor, adiponectin receptor2 and of receptor heterodimers; information that is lost when pooling cells leads to dilution of signals and mixing signals. Despite the common electrophysiological phenotype and uniform GAD1 expression, WSN- transcriptomes show heterogenity, suggesting strong epigenetic influence on the transcriptome. Our study suggests that it is well-worth interrogating the cDNA libraries of single neurons by sequencing and chipping. PMID:20970451
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Yao, Ning; Wu, Yanhong; Zhou, Yan; Ju, Lili; Liu, Yujun; Ju, Rongkai; Duan, Deyi; Xu, Qunyuan
2015-11-02
The degeneration of noradrenergic neurons in the locus coeruleus (LC) commonly occurs in patients with Parkinson's disease (PD), which is characterized by a selective injury of dopaminergic neurons in the substantia nigra (SN). The pathological impact of the LC on the SN in the disease is unknown. In the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), to deplete noradrenaline (NA) derived from the LC to explore its influence on degeneration or injury of dopaminergic neurons in the SN in mouse model produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide (LPS). Our results demonstrated that lesion of the LC could change microglial function in the brain, which led to enhanced or prolonged expression of pro-inflammatory cytokines, diminished neurotrophic factors, and weakened ability of anti-oxidation in the SN. The in vitro experiments further confirmed that NA could reduce the inflammatory reaction of microglia. The selective injury of dopaminergic neurons by inflammation, however, was due to the inflammation in different brain regions rather than the depletion of NA. Our results indicate that the lesion in the LC is an important factor in promoting dopaminergic neuron degeneration by impacting the function of microglia in the midbrain. Copyright © 2015 Elsevier B.V. All rights reserved.
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Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment
Vizi, ES; Fekete, A; Karoly, R; Mike, A
2010-01-01
Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the ‘what’ of brain function, the ‘how’ of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the ‘how’ that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic–extrasynaptic receptor trafficking, neuron–glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them. PMID:20136842
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Kast, Ryan J; Wu, Hsiao-Huei; Levitt, Pat
2017-11-28
The complex circuitry and cell-type diversity of the cerebral cortex are required for its high-level functions. The mechanisms underlying the diversification of cortical neurons during prenatal development have received substantial attention, but understanding of neuronal heterogeneity is more limited during later periods of cortical circuit maturation. To address this knowledge gap, connectivity analysis and molecular phenotyping of cortical neuron subtypes that express the developing synapse-enriched MET receptor tyrosine kinase were performed. Experiments used a MetGFP transgenic mouse line, combined with coexpression analysis of class-specific molecular markers and retrograde connectivity mapping. The results reveal that MET is expressed by a minor subset of subcerebral and a larger number of intratelencephalic projection neurons. Remarkably, MET is excluded from most layer 6 corticothalamic neurons. These findings are particularly relevant for understanding the maturation of discrete cortical circuits, given converging evidence that MET influences dendritic elaboration and glutamatergic synapse maturation. The data suggest that classically defined cortical projection classes can be further subdivided based on molecular characteristics that likely influence synaptic maturation and circuit wiring. Additionally, given that MET is classified as a high confidence autism risk gene, the data suggest that projection neuron subpopulations may be differentially vulnerable to disorder-associated genetic variation. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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The Role of Rab Proteins in Neuronal Cells and in the Trafficking of Neurotrophin Receptors
Bucci, Cecilia; Alifano, Pietro; Cogli, Laura
2014-01-01
Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways. PMID:25295627
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Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals
Freire-Regatillo, Alejandra; Argente-Arizón, Pilar; Argente, Jesús; García-Segura, Luis Miguel; Chowen, Julie A.
2017-01-01
Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding “non-neuronal” cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed. PMID:28377744
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Neuronal effects of nicotine during auditory selective attention.
Smucny, Jason; Olincy, Ann; Eichman, Lindsay S; Tregellas, Jason R
2015-06-01
Although the attention-enhancing effects of nicotine have been behaviorally and neurophysiologically well-documented, its localized functional effects during selective attention are poorly understood. In this study, we examined the neuronal effects of nicotine during auditory selective attention in healthy human nonsmokers. We hypothesized to observe significant effects of nicotine in attention-associated brain areas, driven by nicotine-induced increases in activity as a function of increasing task demands. A single-blind, prospective, randomized crossover design was used to examine neuronal response associated with a go/no-go task after 7 mg nicotine or placebo patch administration in 20 individuals who underwent functional magnetic resonance imaging at 3T. The task design included two levels of difficulty (ordered vs. random stimuli) and two levels of auditory distraction (silence vs. noise). Significant treatment × difficulty × distraction interaction effects on neuronal response were observed in the hippocampus, ventral parietal cortex, and anterior cingulate. In contrast to our hypothesis, U and inverted U-shaped dependencies were observed between the effects of nicotine on response and task demands, depending on the brain area. These results suggest that nicotine may differentially affect neuronal response depending on task conditions. These results have important theoretical implications for understanding how cholinergic tone may influence the neurobiology of selective attention.
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Mathur, Deepali; María-Lafuente, Eva; Ureña-Peralta, Juan R.; Sorribes, Lucas; Hernández, Alberto; Casanova, Bonaventura; López-Rodas, Gerardo; Coret-Ferrer, Francisco; Burgal-Marti, Maria
2017-01-01
Axonal damage is widely accepted as a major cause of permanent functional disability in Multiple Sclerosis (MS). In relapsing-remitting MS, there is a possibility of remyelination by myelin producing cells and restoration of neurological function. The purpose of this study was to delineate the pathophysiological mechanisms underpinning axonal injury through hitherto unknown factors present in cerebrospinal fluid (CSF) that may regulate axonal damage, remyelinate the axon and make functional recovery possible. We employed primary cultures of rat unmyelinated cerebellar granule neurons and treated them with CSF obtained from MS and Neuromyelitis optica (NMO) patients. We performed microarray gene expression profiling to study changes in gene expression in treated neurons as compared to controls. Additionally, we determined the influence of gene-gene interaction upon the whole metabolic network in our experimental conditions using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) program. Our findings revealed the downregulated expression of genes involved in glucose metabolism in MS-derived CSF-treated neurons and upregulated expression of genes in NMO-derived CSF-treated neurons. We conclude that factors in the CSF of these patients caused a perturbation in metabolic gene(s) expression and suggest that MS appears to be linked with metabolic deformity. PMID:29267205
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Gupte, Raeesa P; Kadunganattil, Suraj; Shepherd, Andrew J; Merrill, Ronald; Planer, William; Bruchas, Michael R; Strack, Stefan; Mohapatra, Durga P
2016-02-01
The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K(+) channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children
Dufault, Renee; Schnoll, Roseanne; Lukiw, Walter J; LeBlanc, Blaise; Cornett, Charles; Patrick, Lyn; Wallinga, David; Gilbert, Steven G; Crider, Raquel
2009-01-01
Among dietary factors, learning and behavior are influenced not only by nutrients, but also by exposure to toxic food contaminants such as mercury that can disrupt metabolic processes and alter neuronal plasticity. Neurons lacking in plasticity are a factor in neurodevelopmental disorders such as autism and mental retardation. Essential nutrients help maintain normal neuronal plasticity. Nutritional deficiencies, including deficiencies in the long chain polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, the amino acid methionine, and the trace minerals zinc and selenium, have been shown to influence neuronal function and produce defects in neuronal plasticity, as well as impact behavior in children with attention deficit hyperactivity disorder. Nutritional deficiencies and mercury exposure have been shown to alter neuronal function and increase oxidative stress among children with autism. These dietary factors may be directly related to the development of behavior disorders and learning disabilities. Mercury, either individually or in concert with other factors, may be harmful if ingested in above average amounts or by sensitive individuals. High fructose corn syrup has been shown to contain trace amounts of mercury as a result of some manufacturing processes, and its consumption can also lead to zinc loss. Consumption of certain artificial food color additives has also been shown to lead to zinc deficiency. Dietary zinc is essential for maintaining the metabolic processes required for mercury elimination. Since high fructose corn syrup and artificial food color additives are common ingredients in many foodstuffs, their consumption should be considered in those individuals with nutritional deficits such as zinc deficiency or who are allergic or sensitive to the effects of mercury or unable to effectively metabolize and eliminate it from the body. PMID:19860886
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Niwa, Minae; Kamiya, Atsushi; Murai, Rina; Kubo, Ken-ichiro; Gruber, Aaron J; Tomita, Kenji; Lu, Lingling; Tomisato, Shuta; Jaaro-Peled, Hanna; Seshadri, Saurav; Hiyama, Hideki; Huang, Beverly; Kohda, Kazuhisa; Noda, Yukihiro; O’Donnell, Patricio; Nakajima, Kazunori; Sawa, Akira; Nabeshima, Toshitaka
2011-01-01
SUMMARY Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming “pathways” or “signalosomes.” Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses, such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and peri-natal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty. PMID:20188653
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Inagaki, Hidehiko K; Jung, Yonil; Hoopfer, Eric D; Wong, Allan M; Mishra, Neeli; Lin, John Y; Tsien, Roger Y; Anderson, David J
2014-03-01
Optogenetics allows the manipulation of neural activity in freely moving animals with millisecond precision, but its application in Drosophila melanogaster has been limited. Here we show that a recently described red activatable channelrhodopsin (ReaChR) permits control of complex behavior in freely moving adult flies, at wavelengths that are not thought to interfere with normal visual function. This tool affords the opportunity to control neural activity over a broad dynamic range of stimulation intensities. Using time-resolved activation, we show that the neural control of male courtship song can be separated into (i) probabilistic, persistent and (ii) deterministic, command-like components. The former, but not the latter, neurons are subject to functional modulation by social experience, which supports the idea that they constitute a locus of state-dependent influence. This separation is not evident using thermogenetic tools, a result underscoring the importance of temporally precise control of neuronal activation in the functional dissection of neural circuits in Drosophila.
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The influence of hubs in the structure of a neuronal network during an epileptic seizure
NASA Astrophysics Data System (ADS)
Rodrigues, Abner Cardoso; Cerdeira, Hilda A.; Machado, Birajara Soares
2016-02-01
In this work, we propose changes in the structure of a neuronal network with the intention to provoke strong synchronization to simulate episodes of epileptic seizure. Starting with a network of Izhikevich neurons we slowly increase the number of connections in selected nodes in a controlled way, to produce (or not) hubs. We study how these structures alter the synchronization on the spike firings interval, on individual neurons as well as on mean values, as a function of the concentration of connections for random and non-random (hubs) distribution. We also analyze how the post-ictal signal varies for the different distributions. We conclude that a network with hubs is more appropriate to represent an epileptic state.
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Moreno, Andrea; Jego, Pierrick; de la Cruz, Feliberto; Canals, Santiago
2013-01-01
Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals. PMID:23543907
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Bonnet, Udo; Scherbaum, Norbert; Wiemann, Martin
2008-02-15
The endogenous alkaloid harmane is enriched in plasma of patients with neurodegenerative or addictive disorders. As harmane affects neuronal activity and viability and because both parameters are strongly influenced by intracellular pH (pH(i)), we tested whether effects of harmane are correlated with altered pH(i) regulation. Pyramidal neurons in the CA3 field of hippocampal slices were investigated under bicarbonate-buffered conditions. Harmane (50 and 100 microM) reversibly decreased spontaneous firing of action potentials and caffeine-induced bursting of CA3 neurons. In parallel experiments, 50 and 100 microM harmane evoked a neuronal acidification of 0.12+/-0.08 and 0.18+/-0.07 pH units, respectively. Recovery from intracellular acidification subsequent to an ammonium prepulse was also impaired, suggesting an inhibition of transmembrane acid extrusion by harmane. Harmane may modulate neuronal functions via altered pH(i)-regulation. Implications of these findings for neuronal survival are discussed.
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Central neural pathways for thermoregulation.
Morrison, Shaun F; Nakamura, Kazuhiro
2011-01-01
Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction.
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2012-01-01
Background In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Results Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. Conclusions These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit. PMID:22413901
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Dus, Monica; Ai, Minrong; Suh, Greg S. B.
2013-01-01
Animals can determine the nutritional value of sugar without the influence of taste. Here, we describe a Drosophila mutant that is insensitive to the nutritional value of sugars, but responds only to the concentration (i.e. sweetness). The affected gene encodes a sodium/solute cotransporter-like protein, designated dSLC5A11 (or cupcake), which is structurally similar to mammalian sodium/glucose cotransporters (SGLTs) that transport sugar across the intestinal and renal lumen. However, dSLC5A11 is prominently expressed in 10-13 pairs of R4 neurons of the ellipsoid body (EB) in the brain and functions in these neurons for selecting appropriate foods. We propose that dSLC5A11 and EB R4 neurons carry out a critical signaling function in responding to internal glycemic levels. PMID:23542692
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Neural electrical activity and neural network growth.
Gafarov, F M
2018-05-01
The development of central and peripheral neural system depends in part on the emergence of the correct functional connectivity in its input and output pathways. Now it is generally accepted that molecular factors guide neurons to establish a primary scaffold that undergoes activity-dependent refinement for building a fully functional circuit. However, a number of experimental results obtained recently shows that the neuronal electrical activity plays an important role in the establishing of initial interneuronal connections. Nevertheless, these processes are rather difficult to study experimentally, due to the absence of theoretical description and quantitative parameters for estimation of the neuronal activity influence on growth in neural networks. In this work we propose a general framework for a theoretical description of the activity-dependent neural network growth. The theoretical description incorporates a closed-loop growth model in which the neural activity can affect neurite outgrowth, which in turn can affect neural activity. We carried out the detailed quantitative analysis of spatiotemporal activity patterns and studied the relationship between individual cells and the network as a whole to explore the relationship between developing connectivity and activity patterns. The model, developed in this work will allow us to develop new experimental techniques for studying and quantifying the influence of the neuronal activity on growth processes in neural networks and may lead to a novel techniques for constructing large-scale neural networks by self-organization. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Diversity of layer 5 projection neurons in the mouse motor cortex
Oswald, Manfred J.; Tantirigama, Malinda L. S.; Sonntag, Ivo; Hughes, Stephanie M.; Empson, Ruth M.
2013-01-01
In the primary motor cortex (M1), layer 5 projection neurons signal directly to distant motor structures to drive movement. Despite their pivotal position and acknowledged diversity these neurons are traditionally separated into broad commissural and corticofugal types, and until now no attempt has been made at resolving the basis for their diversity. We therefore probed the electrophysiological and morphological properties of retrogradely labeled M1 corticospinal (CSp), corticothalamic (CTh), and commissural projecting corticostriatal (CStr) and corticocortical (CC) neurons. An unsupervised cluster analysis established at least four phenotypes with additional differences between lumbar and cervical projecting CSp neurons. Distinguishing parameters included the action potential (AP) waveform, firing behavior, the hyperpolarisation-activated sag potential, sublayer position, and soma and dendrite size. CTh neurons differed from CSp neurons in showing spike frequency acceleration and a greater sag potential. CStr neurons had the lowest AP amplitude and maximum rise rate of all neurons. Temperature influenced spike train behavior in corticofugal neurons. At 26°C CTh neurons fired bursts of APs more often than CSp neurons, but at 36°C both groups fired regular APs. Our findings provide reliable phenotypic fingerprints to identify distinct M1 projection neuron classes as a tool to understand their unique contributions to motor function. PMID:24137110
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Intrinsic cardiac nervous system in tachycardia induced heart failure.
Arora, Rakesh C; Cardinal, Rene; Smith, Frank M; Ardell, Jeffrey L; Dell'Italia, Louis J; Armour, J Andrew
2003-11-01
The purpose of this study was to test the hypothesis that early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiac function. After 2 wk of rapid ventricular pacing in nine anesthetized canines, cardiac and right atrial neuronal function were evaluated in situ in response to enhanced cardiac sensory inputs, stimulation of extracardiac autonomic efferent neuronal inputs, and close coronary arterial administration of neurochemicals that included nicotine. Right atrial neuronal intracellular electrophysiological properties were then evaluated in vitro in response to synaptic activation and nicotine. Intrinsic cardiac nicotine-sensitive, neuronally induced cardiac responses were also evaluated in eight sham-operated, unpaced animals. Two weeks of rapid ventricular pacing reduced the cardiac index by 54%. Intrinsic cardiac neurons of paced hearts maintained their cardiac mechano- and chemosensory transduction properties in vivo. They also responded normally to sympathetic and parasympathetic preganglionic efferent neuronal inputs, as well as to locally administered alpha-or beta-adrenergic agonists or angiotensin II. The dose of nicotine needed to modify intrinsic cardiac neurons was 50 times greater in failure compared with normal preparations. That dose failed to alter monitored cardiovascular indexes in failing preparations. Phasic and accommodating neurons identified in vitro displayed altered intracellular membrane properties compared with control, including decreased membrane resistance, indicative of reduced excitability. Early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiodynamics. While maintaining its capacity to transduce cardiac mechano- and chemosensory inputs, as well as inputs from extracardiac autonomic efferent neurons, intrinsic cardiac nicotine-sensitive, local-circuit neurons differentially remodel such that their capacity to influence cardiodynamics becomes obtunded.
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Nistor, Paul A; May, Paul W; Tamagnini, Francesco; Randall, Andrew D; Caldwell, Maeve A
2015-08-01
Brain Computer Interfaces (BCI) currently represent a field of intense research aimed both at understanding neural circuit physiology and at providing functional therapy for traumatic or degenerative neurological conditions. Due to its chemical inertness, biocompatibility and stability, diamond is currently being actively investigated as a potential substrate material for culturing cells and for use as the electrically active component of a neural sensor. Here we provide a protocol for the differentiation of mature, electrically active neurons on microcrystalline synthetic thin-film diamond substrates starting from undifferentiated pluripotent stem cells. Furthermore, we investigate the optimal characteristics of the diamond microstructure for long-term neuronal sustainability. We also analyze the effect of boron as a dopant for such a culture. We found that the diamond crystalline structure has a significant influence on the neuronal culture unlike the boron doping. Specifically, small diamond microcrystals promote higher neurite density formation. We find that boron incorporated into the diamond does not influence the neurite density and has no deleterious effect on cell survival. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Xiong, Ying-Zi; Zhang, Jun-Yun; Yu, Cong
2016-01-01
Perceptual learning is often orientation and location specific, which may indicate neuronal plasticity in early visual areas. However, learning specificity diminishes with additional exposure of the transfer orientation or location via irrelevant tasks, suggesting that the specificity is related to untrained conditions, likely because neurons representing untrained conditions are neither bottom-up stimulated nor top-down attended during training. To demonstrate these top-down and bottom-up contributions, we applied a “continuous flash suppression” technique to suppress the exposure stimulus into sub-consciousness, and with additional manipulations to achieve pure bottom-up stimulation or top-down attention with the transfer condition. We found that either bottom-up or top-down influences enabled significant transfer of orientation and Vernier discrimination learning. These results suggest that learning specificity may result from under-activations of untrained visual neurons due to insufficient bottom-up stimulation and/or top-down attention during training. High-level perceptual learning thus may not functionally connect to these neurons for learning transfer. DOI: http://dx.doi.org/10.7554/eLife.14614.001 PMID:27377357
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The influence of passband limitation on the waveform of extracellular action potential.
Mizuhiki, Takashi; Inaba, Kiyonori; Setogawa, Tsuyoshi; Toda, Koji; Ozaki, Shigeru; Shidara, Muneteka
2012-03-01
The duration of the extracellular action potential (EAP) in single neuronal recording has often been used as a clue to infer biochemical, physiological or functional substrate of the recorded neurons, e.g. neurochemical type. However, when recording a neuronal activity, the high-pass filter is routinely used to achieve higher signal-to-noise ratio. Signal processing theory predicts that passband limitation stretches the waveform of discrete brief impulse. To examine whether the duration of filtered EAP could be the reliable measure, we investigated the influence of high-pass filter both by simulation and unfiltered unit recording data from monkey dorsal raphe. Consistent with the findings in recent theoretical study, the unfiltered EAPs displayed the sharp wave without following bumps. The duration of unfiltered EAP was not correlated with that of filtered EAP. Thus the duration of original EAP cannot be estimated from filtered EAP. It is needed to reexamine the EAP duration measured for classifying the neurons whose activities were recorded under the passband limitation in the related studies. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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MicroRNAs in neuronal function and dysfunction
Im, Heh-In; Kenny, Paul J.
2012-01-01
MicroRNAs (miRNAs) are small noncoding RNA transcripts expressed throughout the brain that can regulate neuronal gene expression at the post-transcriptional level. Here, we provide an overview of the role for miRNAs in brain development and function, and review evidence suggesting that dysfunction in miRNA signaling contributes to neurodevelopment disorders such as Rett and fragile X syndromes, as well as complex behavioral disorders including schizophrenia, depression and drug addiction. A better understanding of how miRNAs influence the development of neuropsychiatric disorders may reveal fundamental insights into the causes of these devastating illnesses and offer novel targets for therapeutic development. PMID:22436491
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Kim, Seongkyun; Kim, Hyoungkyu; Kralik, Jerald D.; Jeong, Jaeseung
2016-01-01
Determining the fundamental architectural design of complex nervous systems will lead to significant medical and technological advances. Yet it remains unclear how nervous systems evolved highly efficient networks with near optimal sharing of pathways that yet produce multiple distinct behaviors to reach the organism’s goals. To determine this, the nematode roundworm Caenorhabditis elegans is an attractive model system. Progress has been made in delineating the behavioral circuits of the C. elegans, however, many details are unclear, including the specific functions of every neuron and synapse, as well as the extent the behavioral circuits are separate and parallel versus integrative and serial. Network analysis provides a normative approach to help specify the network design. We investigated the vulnerability of the Caenorhabditis elegans connectome by performing computational experiments that (a) “attacked” 279 individual neurons and 2,990 weighted synaptic connections (composed of 6,393 chemical synapses and 890 electrical junctions) and (b) quantified the effects of each removal on global network properties that influence information processing. The analysis identified 12 critical neurons and 29 critical synapses for establishing fundamental network properties. These critical constituents were found to be control elements—i.e., those with the most influence over multiple underlying pathways. Additionally, the critical synapses formed into circuit-level pathways. These emergent pathways provide evidence for (a) the importance of backward locomotion, avoidance behavior, and social feeding behavior to the organism; (b) the potential roles of specific neurons whose functions have been unclear; and (c) both parallel and serial design elements in the connectome—i.e., specific evidence for a mixed architectural design. PMID:27540747
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Neuroregulatory and neuroendocrine GnRH pathways in the hypothalamus and forebrain of the baboon.
Marshall, P E; Goldsmith, P C
1980-07-14
The distribution of neurons containing gonadotropin-releasing hormone (GnRH) in the baboon hypothalamus and forebrain was studied immunocytochemically by light and electron microscopy. GnRH was present in the perikarya, axonal and dendritic processes of immunoreactive neurons. Three populations of GnRH neurons could be distinguished. Most of the GnRH neurons which are assumed to directly influence the anterior pituitary were in the medial basal hypothalamus. Other cells that projected to the median eminence were found scattered throughout the hypothalamus. A second, larger population of neurons apparently was not involved with control of the anterior pituitary. These neurons were generally found within afferent and efferent pathways of the hypothalamus and forebrain, and may receive external information affecting reproduction. A few neurons projecting to the median eminence were also observed sending collaterals to other brain areas. Thus, in addition to their neuroendocrine role, these cells possibly have neuroregulatory functions. The inference is made that these bifunctional neurons, together with the widely observed GnRH-GnRH cellular interactions may help to synchronize ovulation and sexual behavior.
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Callaghan, Brid; Furness, John B; Pustovit, Ruslan V
2018-03-01
Narrative review. The purpose is to review the organisation of the nerve pathways that control defecation and to relate this knowledge to the deficits in colorectal function after SCI. A literature review was conducted to identify salient features of defecation control pathways and the functional consequences of damage to these pathways in SCI. The control pathways for defecation have separate pontine centres under cortical control that influence defecation. The pontine centres connect, separately, with autonomic preganglionic neurons of the spinal defecation centres and somatic motor neurons of Onuf's nucleus in the sacral spinal cord. Organised propulsive motor patterns can be generated by stimulation of the spinal defecation centres. Activation of the somatic neurons contracts the external sphincter. The analysis aids in interpreting the consequences of SCI and predicts therapeutic strategies. Analysis of the bowel control circuits identifies sites at which bowel function may be modulated after SCI. Colokinetic drugs that elicit propulsive contractions of the colorectum may provide valuable augmentation of non-pharmacological bowel management procedures.
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The neurogenetic frontier--lessons from misbehaving zebrafish.
Burgess, Harold A; Granato, Michael
2008-11-01
One of the central questions in neuroscience is how refined patterns of connectivity in the brain generate and monitor behavior. Genetic mutations can influence neural circuits by disrupting differentiation or maintenance of component neuronal cells or by altering functional patterns of nervous system connectivity. Mutagenesis screens therefore have the potential to reveal not only the molecular underpinnings of brain development and function, but to illuminate the cellular basis of behavior. Practical considerations make the zebrafish an organism of choice for undertaking forward genetic analysis of behavior. The powerful array of experimental tools at the disposal of the zebrafish researcher makes it possible to link molecular function to neuronal properties that underlie behavior. This review focuses on specific challenges to isolating and analyzing behavioral mutants in zebrafish.
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The neurogenetic frontier—lessons from misbehaving zebrafish
Granato, Michael
2008-01-01
One of the central questions in neuroscience is how refined patterns of connectivity in the brain generate and monitor behavior. Genetic mutations can influence neural circuits by disrupting differentiation or maintenance of component neuronal cells or by altering functional patterns of nervous system connectivity. Mutagenesis screens therefore have the potential to reveal not only the molecular underpinnings of brain development and function, but to illuminate the cellular basis of behavior. Practical considerations make the zebrafish an organism of choice for undertaking forward genetic analysis of behavior. The powerful array of experimental tools at the disposal of the zebrafish researcher makes it possible to link molecular function to neuronal properties that underlie behavior. This review focuses on specific challenges to isolating and analyzing behavioral mutants in zebrafish. PMID:18836206
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Lin, Chia-Wen; Chen, Chiung-Ya; Cheng, Sin-Jhong; Hu, Hsiao-Tang; Hsueh, Yi-Ping
2014-01-01
Innate immune responses have been shown to influence brain development and function. Dysregulation of innate immunity is significantly associated with psychiatric disorders such as autism spectrum disorders and schizophrenia, which are well-known neurodevelopmental disorders. Recent studies have revealed that critical players of the innate immune response are expressed in neuronal tissues and regulate neuronal function and activity. For example, Sarm1, a negative regulator that acts downstream of Toll-like receptor (TLR) 3 and 4, is predominantly expressed in neurons. We have previously shown that Sarm1 regulates neuronal morphogenesis and the expression of inflammatory cytokines in the brain, which then affects learning ability, cognitive flexibility, and social interaction. Because impaired neuronal morphogenesis and dysregulation of cytokine expression may disrupt neuronal activity, we investigated whether Sarm1 knockdown affects the synaptic responses of neurons. We here show that reduced Sarm1 expression impairs metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) formation but enhances N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation production in hippocampal CA1 neurons. The expression levels of post-synaptic proteins, including NR2a, NR1, Shank1 and Shank3, are also altered in Sarm1 knockdown mice, suggesting a role for Sarm1 in the maintenance of synaptic homeostasis. The addition of a positive allosteric modulator of mGluR5, CDPPB, ameliorates the LTD defects in slice recording and the behavioral deficits in social interaction and associative memory. These results suggest an important role for mGluR5 signaling in the function of Sarm1. In conclusion, our study demonstrates a role for Sarm1 in the regulation of synaptic plasticity. Through these mechanisms, Sarm1 knockdown results in the impairment of associative memory and social interactions in mice.
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An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep.
Bjorness, Theresa E; Dale, Nicholas; Mettlach, Gabriel; Sonneborn, Alex; Sahin, Bogachan; Fienberg, Allen A; Yanagisawa, Masashi; Bibb, James A; Greene, Robert W
2016-03-30
Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis. The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to sleep function. Copyright © 2016 the authors 0270-6474/16/363709-13$15.00/0.
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Eberwine, James; Bartfai, Tamas
2011-03-01
We report on an 'unbiased' molecular characterization of individual, adult neurons, active in a central, anterior hypothalamic neuronal circuit, by establishing cDNA libraries from each individual, electrophysiologically identified warm sensitive neuron (WSN). The cDNA libraries were analyzed by Affymetrix microarray. The presence and frequency of cDNAs were confirmed and enhanced with Illumina sequencing of each single cell cDNA library. cDNAs encoding the GABA biosynthetic enzyme Gad1 and of adrenomedullin, galanin, prodynorphin, somatostatin, and tachykinin were found in the WSNs. The functional cellular and in vivo studies on dozens of the more than 500 neurotransmitters, hormone receptors and ion channels, whose cDNA was identified and sequence confirmed, suggest little or no discrepancy between the transcriptional and functional data in WSNs; whenever agonists were available for a receptor whose cDNA was identified, a functional response was found. Sequencing single neuron libraries permitted identification of rarely expressed receptors like the insulin receptor, adiponectin receptor 2 and of receptor heterodimers; information that is lost when pooling cells leads to dilution of signals and mixing signals. Despite the common electrophysiological phenotype and uniform Gad1 expression, WSN transcriptomes show heterogeneity, suggesting strong epigenetic influence on the transcriptome. Our study suggests that it is well-worth interrogating the cDNA libraries of single neurons by sequencing and chipping. Copyright © 2010 Elsevier Inc. All rights reserved.
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Somatostatin-Expressing Inhibitory Interneurons in Cortical Circuits
Yavorska, Iryna; Wehr, Michael
2016-01-01
Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM) inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons. PMID:27746722
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Al-Nedawi, Khalid; Mian, M Firoz; Hossain, Nazia; Karimi, Khalil; Mao, Yu-Kang; Forsythe, Paul; Min, Kevin K; Stanisz, Andrew M; Kunze, Wolfgang A; Bienenstock, John
2015-02-01
Ingestion of a commensal bacteria, Lactobacillus rhamnosus JB-1, has potent immunoregulatory effects, and changes nerve-dependent colon migrating motor complexes (MMCs), enteric nerve function, and behavior. How these alterations occur is unknown. JB-1 microvesicles (MVs) are enriched for heat shock protein components such as chaperonin 60 heat-shock protein isolated from Escherichia coli (GroEL) and reproduce regulatory and neuronal effects in vitro and in vivo. Ingested labeled MVs were detected in murine Peyer's patch (PP) dendritic cells (DCs) within 18 h. After 3 d, PP and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4(+)25(+)Foxp3+ T cells. JB-1, MVs, and GroEL similarly induced phenotypic change in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 and Dectin-1, as well as TLR-2 and -9. JB-1 and MVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial, but not direct neuronal application of, MVs, replicated functional effects of JB-1 on in situ patch-clamped enteric neurons. GroEL and anti-TLR-2 were without effect in this system, suggesting the importance of epithelium neuron signaling and discrimination between pathways for bacteria-neuron and -immune communication. Together these results offer a mechanistic explanation of how Gram-positive commensals and probiotics may influence the host's immune and nervous systems. © FASEB.
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Astrocytes influence the severity of spinal muscular atrophy
Rindt, Hansjörg; Feng, Zhihua; Mazzasette, Chiara; Glascock, Jacqueline J.; Valdivia, David; Pyles, Noah; Crawford, Thomas O.; Swoboda, Kathryn J.; Patitucci, Teresa N.; Ebert, Allison D.; Sumner, Charlotte J.; Ko, Chien-Ping; Lorson, Christian L.
2015-01-01
Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). α-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron-autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA. PMID:25911676
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Diversity of vestibular nuclei neurons targeted by cerebellar nodulus inhibition
Meng, Hui; Blázquez, Pablo M; Dickman, J David; Angelaki, Dora E
2014-01-01
Abstract A functional role of the cerebellar nodulus and ventral uvula (lobules X and IXc,d of the vermis) for vestibular processing has been strongly suggested by direct reciprocal connections with the vestibular nuclei, as well as direct vestibular afferent inputs as mossy fibres. Here we have explored the types of neurons in the macaque vestibular nuclei targeted by nodulus/ventral uvula inhibition using orthodromic identification from the caudal vermis. We found that all nodulus-target neurons are tuned to vestibular stimuli, and most are insensitive to eye movements. Such non-eye-movement neurons are thought to project to vestibulo-spinal and/or thalamo-cortical pathways. Less than 20% of nodulus-target neurons were sensitive to eye movements, suggesting that the caudal vermis can also directly influence vestibulo-ocular pathways. In general, response properties of nodulus-target neurons were diverse, spanning the whole continuum previously described in the vestibular nuclei. Most nodulus-target cells responded to both rotation and translation stimuli and only a few were selectively tuned to translation motion only. Other neurons were sensitive to net linear acceleration, similar to otolith afferents. These results demonstrate that, unlike the flocculus and ventral paraflocculus which target a particular cell group, nodulus/ventral uvula inhibition targets a large diversity of cell types in the vestibular nuclei, consistent with a broad functional significance contributing to vestibulo-ocular, vestibulo-thalamic and vestibulo-spinal pathways. PMID:24127616
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A neuronal pathway that controls sperm ejection and storage in female Drosophila.
Lee, Kang-Min; Daubnerová, Ivana; Isaac, R Elwyn; Zhang, Chen; Choi, Sekyu; Chung, Jongkyeong; Kim, Young-Joon
2015-03-16
In polyandrous females, sperm storage permits competition between sperm of different mates, and in some species females influence the relative fertilization success of competing sperm in favor of a preferred mate [1, 2]. In female Drosophila melanogaster, sperm competition is strongly influenced by the timing of sperm ejection from the uterus [3, 4]. Understanding how female behavior influences sperm competition requires knowledge of the neuronal mechanisms controlling sperm retention and storage, which is currently lacking. Here, we show that D. melanogaster females eject male ejaculates from the uterus 1-6 hr after mating with a stereotypic behavior regulated by a brain signaling pathway composed of diuretic hormone 44 (Dh44), a neuropeptide related to vertebrate corticotropin-releasing factor (CRF), and its receptor, Dh44R1. Suppression of Dh44 signals in the brain expedites sperm ejection from the uterus, resulting in marked reduction of sperm in the storage organs and decreased fecundity, whereas enhancement of Dh44 signals delays sperm expulsion. The Dh44 function was mapped to six neurons located in the pars intercerebralis of the brain together with a small subset of Dh44R1 neurons that express the sex-specific transcription factor doublesex. This study identifies a neuronal pathway by which females can control sperm retention and storage and provides new insight into how the female might exercise post-copulatory sexual selection. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology
Ballas, Nurit; Lioy, Daniel T.; Grunseich, Christopher; Mandel, Gail
2011-01-01
The neurodevelopmental disorder Rett Syndrome (RTT) is caused by sporadic mutations in the transcriptional factor methyl-CpG binding protein 2 (MeCP2). Although it is thought that the primary cause of RTT is cell autonomous due to lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease, is unknown. Here, we show that loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brain. Using an in vitro co-culture system, we find that mutant astrocytes from a RTT mouse model, and their conditioned medium, fail to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that in RTT brain, astrocytes carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, likely due to aberrant secretion of soluble factor(s). PMID:19234456
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Tupone, Domenico; Madden, Christopher J; Cano, Georgina; Morrison, Shaun F
2011-11-02
Orexin (hypocretin) neurons, located exclusively in the PeF-LH, which includes the perifornical area (PeF), the lateral hypothalamus (LH), and lateral portions of the medial hypothalamus, have widespread projections and influence many physiological functions, including the autonomic regulation of body temperature and energy metabolism. Narcolepsy is characterized by the loss of orexin neurons and by disrupted sleep, but also by dysregulation of body temperature and by a strong tendency for obesity. Heat production (thermogenesis) in brown adipose tissue (BAT) contributes to the maintenance of body temperature and, through energy consumption, to body weight regulation. We identified a neural substrate for the influence of orexin neurons on BAT thermogenesis in rat. Nanoinjection of orexin-A (12 pmol) into the rostral raphe pallidus (rRPa), the site of BAT sympathetic premotor neurons, produced large, sustained increases in BAT sympathetic outflow and in BAT thermogenesis. Activation of neurons in the PeF-LH also enhanced BAT thermogenesis over a long time course. Combining viral retrograde tracing from BAT, or cholera toxin subunit b tracing from rRPa, with orexin immunohistochemistry revealed synaptic connections to BAT from orexin neurons in PeF-LH and from rRPa neurons with closely apposed, varicose orexin fibers, as well as a direct, orexinergic projection from PeF-LH to rRPa. These results indicate a potent modulation of BAT thermogenesis by orexin released from the terminals of orexin neurons in PeF-LH directly into the rRPa and provide a potential mechanism contributing to the disrupted regulation of body temperature and energy metabolism in the absence of orexin.
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Sadeghi, Soroush G.; Minor, Lloyd B.
2011-01-01
Plasticity in neuronal responses is necessary for compensation following brain lesions and adaptation to new conditions and motor learning. In a previous study, we showed that compensatory changes in the vestibuloocular reflex (VOR) following unilateral vestibular loss were characterized by dynamic reweighting of inputs from vestibular and extravestibular modalities at the level of single neurons that constitute the first central stage of VOR signal processing. Here, we studied another class of neurons, i.e., the vestibular-only neurons, in the vestibular nuclei that mediate vestibulospinal reflexes and provide information for higher brain areas. We investigated changes in the relative contribution of vestibular, neck proprioceptive, and efference copy signals in the response of these neurons during compensation after contralateral vestibular loss in Macaca mulata monkeys. We show that the time course of recovery of vestibular sensitivity of neurons corresponds with that of lower extremity muscle and tendon reflexes reported in previous studies. More important, we found that information from neck proprioceptors, which did not influence neuronal responses before the lesion, were unmasked after lesion. Such inputs influenced the early stages of the compensation process evidenced by faster and more substantial recovery of the resting discharge in proprioceptive-sensitive neurons. Interestingly, unlike our previous study of VOR interneurons, the improvement in the sensitivity of the two groups of neurons did not show any difference in the early or late stages after lesion. Finally, neuronal responses during active head movements were not different before and after lesion and were attenuated relative to passive movements over the course of recovery, similar to that observed in control conditions. Comparison of compensatory changes observed in the vestibuloocular and vestibulospinal pathways provides evidence for similarities and differences between the two classes of neurons that mediate these pathways at the functional and cellular levels. PMID:21148096
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Sadeghi, Soroush G; Minor, Lloyd B; Cullen, Kathleen E
2011-02-01
Plasticity in neuronal responses is necessary for compensation following brain lesions and adaptation to new conditions and motor learning. In a previous study, we showed that compensatory changes in the vestibuloocular reflex (VOR) following unilateral vestibular loss were characterized by dynamic reweighting of inputs from vestibular and extravestibular modalities at the level of single neurons that constitute the first central stage of VOR signal processing. Here, we studied another class of neurons, i.e., the vestibular-only neurons, in the vestibular nuclei that mediate vestibulospinal reflexes and provide information for higher brain areas. We investigated changes in the relative contribution of vestibular, neck proprioceptive, and efference copy signals in the response of these neurons during compensation after contralateral vestibular loss in Macaca mulata monkeys. We show that the time course of recovery of vestibular sensitivity of neurons corresponds with that of lower extremity muscle and tendon reflexes reported in previous studies. More important, we found that information from neck proprioceptors, which did not influence neuronal responses before the lesion, were unmasked after lesion. Such inputs influenced the early stages of the compensation process evidenced by faster and more substantial recovery of the resting discharge in proprioceptive-sensitive neurons. Interestingly, unlike our previous study of VOR interneurons, the improvement in the sensitivity of the two groups of neurons did not show any difference in the early or late stages after lesion. Finally, neuronal responses during active head movements were not different before and after lesion and were attenuated relative to passive movements over the course of recovery, similar to that observed in control conditions. Comparison of compensatory changes observed in the vestibuloocular and vestibulospinal pathways provides evidence for similarities and differences between the two classes of neurons that mediate these pathways at the functional and cellular levels.
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Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior
Picciotto, Marina R.; Higley, Michael J.; Mineur, Yann S.
2012-01-01
Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss the consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on the site of release, the receptor subtypes, and the target neuronal population, however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. PMID:23040810
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Ng, KY; Yeung, BHS; Wong, YH; Wise, H
2013-01-01
Background and Purpose Hyper-nociceptive PGE2 EP4 receptors and prostacyclin (IP) receptors are present in adult rat dorsal root ganglion (DRG) neurones and glial cells in culture. The present study has investigated the cell-specific expression of two other Gs-protein coupled hyper-nociceptive receptor systems: β-adrenoceptors and calcitonin gene-related peptide (CGRP) receptors in isolated DRG cells and has examined the influence of neurone–glial cell interactions in regulating adenylyl cyclase (AC) activity. Experimental Approach Agonist-stimulated AC activity was determined in mixed DRG cell cultures from adult rats and compared with activity in DRG neurone-enriched cell cultures and pure DRG glial cell cultures. Key Results Pharmacological analysis showed the presence of Gs-coupled β2-adrenoceptors and CGRP receptors, but not β1-adrenoceptors, in all three DRG cell preparations. Agonist-stimulated AC activity was weakest in DRG neurone-enriched cell cultures. DRG neurones inhibited IP receptor-stimulated glial cell AC activity by a process dependent on both cell–cell contact and neurone-derived soluble factors, but this is unlikely to involve purine or glutamine receptor activation. Conclusions and Implications Gs-coupled hyper-nociceptive receptors are readily expressed on DRG glial cells in isolated cell cultures and the activity of CGRP, EP4 and IP receptors, but not β2-adrenoceptors, in glial cells is inhibited by DRG neurones. Studies using isolated DRG cells should be aware that hyper-nociceptive ligands may stimulate receptors on glial cells in addition to neurones, and that variable numbers of neurones and glial cells will influence absolute measures of AC activity and affect downstream functional responses. PMID:22924655
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Coherent control of an opsin in living brain tissue
NASA Astrophysics Data System (ADS)
Paul, Kush; Sengupta, Parijat; Ark, Eugene D.; Tu, Haohua; Zhao, Youbo; Boppart, Stephen A.
2017-11-01
Retinal-based opsins are light-sensitive proteins. The photoisomerization reaction of these proteins has been studied outside cellular environments using ultrashort tailored light pulses. However, how living cell functions can be modulated via opsins by modifying fundamental nonlinear optical properties of light interacting with the retinal chromophore has remained largely unexplored. We report the use of chirped ultrashort near-infrared pulses to modulate light-evoked ionic current from Channelrhodopsin-2 (ChR2) in brain tissue, and consequently the firing pattern of neurons, by manipulating the phase of the spectral components of the light. These results confirm that quantum coherence of the retinal-based protein system, even in a living neuron, can influence its current output, and open up the possibilities of using designer-tailored pulses for controlling molecular dynamics of opsins in living tissue to selectively enhance or suppress neuronal function for adaptive feedback-loop applications in the future.
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Neuronal growth on L- and D-cysteine self-assembled monolayers reveals neuronal chiral sensitivity.
Baranes, Koby; Moshe, Hagay; Alon, Noa; Schwartz, Shmulik; Shefi, Orit
2014-05-21
Studying the interaction between neuronal cells and chiral molecules is fundamental for the design of novel biomaterials and drugs. Chirality influences all biological processes that involve intermolecular interaction. One common method used to study cellular interactions with different enantiomeric targets is the use of chiral surfaces. Based on previous studies that demonstrated the importance of cysteine in the nervous system, we studied the effect of L- and D-cysteine on single neuronal growth. L-Cysteine, which normally functions as a neuromodulator or a neuroprotective antioxidant, causes damage at elevated levels, which may occur post trauma. In this study, we grew adult neurons in culture enriched with L- and D-cysteine as free compounds or as self-assembled monolayers of chiral surfaces and examined the effect on the neuronal morphology and adhesion. Notably, we have found that exposure to the L-cysteine enantiomer inhibited, and even prevented, neuronal attachment more severely than exposure to the D-cysteine enantiomer. Atop the L-cysteine surfaces, neuronal growth was reduced and degenerated. Since the cysteine molecules were attached to the surface via the thiol groups, the neuronal membrane was exposed to the molecular chiral site. Thus, our results have demonstrated high neuronal chiral sensitivity, revealing chiral surfaces as indirect regulators of neuronal cells and providing a reference for studying chiral drugs.
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Schapansky, Jason; Khasnavis, Saurabh; DeAndrade, Mark P; Nardozzi, Jonathan D; Falkson, Samuel R; Boyd, Justin D; Sanderson, John B; Bartels, Tim; Melrose, Heather L; LaVoie, Matthew J
2018-03-01
Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD. Copyright © 2017 Elsevier Inc. All rights reserved.
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Creation of defined single cell resolution neuronal circuits on microelectrode arrays
NASA Astrophysics Data System (ADS)
Pirlo, Russell Kirk
2009-12-01
The way cell-cell organization of neuronal networks influences activity and facilitates function is not well understood. Microelectrode arrays (MEAs) and advancing cell patterning technologies have enabled access to and control of in vitro neuronal networks spawning much new research in neuroscience and neuroengineering. We propose that small, simple networks of neurons with defined circuitry may serve as valuable research models where every connection can be analyzed, controlled and manipulated. Towards the goal of creating such neuronal networks we have applied microfabricated elastomeric membranes, surface modification and our unique laser cell patterning system to create defined neuronal circuits with single-cell precision on MEAs. Definition of synaptic connectivity was imposed by the 3D physical constraints of polydimethylsiloxane elastomeric membranes. The membranes had 20mum clear-through holes and 2-3mum deep channels which when applied to the surface of the MEA formed microwells to confine neurons to electrodes connected via shallow tunnels to direct neurite outgrowth. Tapering and turning of channels was used to influence neurite polarity. Biocompatibility of the membranes was increased by vacuum baking, oligomer extraction, and autoclaving. Membranes were bound to the MEA by oxygen plasma treatment and heated pressure. The MEA/membrane surface was treated with oxygen plasma, poly-D-lysine and laminin to improve neuron attachment, survival and neurite outgrowth. Prior to cell patterning the outer edge of culture area was seeded with 5x10 5 cells per cm and incubated for 2 days. Single embryonic day 7 chick forebrain neurons were then patterned into the microwells and onto the electrodes using our laser cell patterning system. Patterned neurons successfully attached to and were confined to the electrodes. Neurites extended through the interconnecting channels and connected with adjacent neurons. These results demonstrate that neuronal circuits can be created with clearly defined circuitry and a one-to-one neuron-electrode ratio. The techniques and processes described here may be used in future research to create defined neuronal circuits to model in vivo circuits and study neuronal network processing.
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Central neural pathways for thermoregulation
Morrison, Shaun F.; Nakamura, Kazuhiro
2010-01-01
Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction. PMID:21196160
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Neuroelectric Tuning of Cortical Oscillations by Apical Dendrites in Loop Circuits
LaBerge, David; Kasevich, Ray S.
2017-01-01
Bundles of relatively long apical dendrites dominate the neurons that make up the thickness of the cerebral cortex. It is proposed that a major function of the apical dendrite is to produce sustained oscillations at a specific frequency that can serve as a common timing unit for the processing of information in circuits connected to that apical dendrite. Many layer 5 and 6 pyramidal neurons are connected to thalamic neurons in loop circuits. A model of the apical dendrites of these pyramidal neurons has been used to simulate the electric activity of the apical dendrite. The results of that simulation demonstrated that subthreshold electric pulses in these apical dendrites can be tuned to specific frequencies and also can be fine-tuned to narrow bandwidths of less than one Hertz (1 Hz). Synchronous pulse outputs from the circuit loops containing apical dendrites can tune subthreshold membrane oscillations of neurons they contact. When the pulse outputs are finely tuned, they function as a local “clock,” which enables the contacted neurons to synchronously communicate with each other. Thus, a shared tuning frequency can select neurons for membership in a circuit. Unlike layer 6 apical dendrites, layer 5 apical dendrites can produce burst firing in many of their neurons, which increases the amplitude of signals in the neurons they contact. This difference in amplitude of signals serves as basis of selecting a sub-circuit for specialized processing (e.g., sustained attention) within the typically larger layer 6-based circuit. After examining the sustaining of oscillations in loop circuits and the processing of spikes in network circuits, we propose that cortical functioning can be globally viewed as two systems: a loop system and a network system. The loop system oscillations influence the network system’s timing and amplitude of pulse signals, both of which can select circuits that are momentarily dominant in cortical activity. PMID:28659768
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Neuroelectric Tuning of Cortical Oscillations by Apical Dendrites in Loop Circuits.
LaBerge, David; Kasevich, Ray S
2017-01-01
Bundles of relatively long apical dendrites dominate the neurons that make up the thickness of the cerebral cortex. It is proposed that a major function of the apical dendrite is to produce sustained oscillations at a specific frequency that can serve as a common timing unit for the processing of information in circuits connected to that apical dendrite. Many layer 5 and 6 pyramidal neurons are connected to thalamic neurons in loop circuits. A model of the apical dendrites of these pyramidal neurons has been used to simulate the electric activity of the apical dendrite. The results of that simulation demonstrated that subthreshold electric pulses in these apical dendrites can be tuned to specific frequencies and also can be fine-tuned to narrow bandwidths of less than one Hertz (1 Hz). Synchronous pulse outputs from the circuit loops containing apical dendrites can tune subthreshold membrane oscillations of neurons they contact. When the pulse outputs are finely tuned, they function as a local "clock," which enables the contacted neurons to synchronously communicate with each other. Thus, a shared tuning frequency can select neurons for membership in a circuit. Unlike layer 6 apical dendrites, layer 5 apical dendrites can produce burst firing in many of their neurons, which increases the amplitude of signals in the neurons they contact. This difference in amplitude of signals serves as basis of selecting a sub-circuit for specialized processing (e.g., sustained attention) within the typically larger layer 6-based circuit. After examining the sustaining of oscillations in loop circuits and the processing of spikes in network circuits, we propose that cortical functioning can be globally viewed as two systems: a loop system and a network system. The loop system oscillations influence the network system's timing and amplitude of pulse signals, both of which can select circuits that are momentarily dominant in cortical activity.
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The Ketogenic Diet and Potassium Channel Function
2015-11-01
1 AWARD NUMBER: W81XWH-13-1-0463 TITLE: The Ketogenic Diet and Potassium Channel Function PRINCIPAL INVESTIGATOR: Dr. Geoffrey Murphy...NUMBER The Ketogenic Diet and Potassium Channel Function 5b. GRANT NUMBER W81XWH-13-1-0463 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Geoffrey Murphy...The overall objective of this Discovery Award was to explore the hypothesis the ketogenic diet (KD) regulates neuronal excitability by influencing
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Cubelos, Beatriz; Sebastián-Serrano, Alvaro; Beccari, Leonardo; Calcagnotto, Maria Elisa; Cisneros, Elsa; Kim, Seonhee; Dopazo, Ana; Alvarez-Dolado, Manuel; Redondo, Juan Miguel; Bovolenta, Paola; Walsh, Christopher A.; Nieto, Marta
2010-01-01
Summary Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular and electrophysiological analysis we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development and synapse formation in layer II–III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits. PMID:20510857
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Joachimsthaler, Bettina; Uhlmann, Michaela; Miller, Frank; Ehret, Günter; Kurt, Simone
2014-01-01
Because of its great genetic potential, the mouse (Mus musculus) has become a popular model species for studies on hearing and sound processing along the auditory pathways. Here, we present the first comparative study on the representation of neuronal response parameters to tones in primary and higher-order auditory cortical fields of awake mice. We quantified 12 neuronal properties of tone processing in order to estimate similarities and differences of function between the fields, and to discuss how far auditory cortex (AC) function in the mouse is comparable to that in awake monkeys and cats. Extracellular recordings were made from 1400 small clusters of neurons from cortical layers III/IV in the primary fields AI (primary auditory field) and AAF (anterior auditory field), and the higher-order fields AII (second auditory field) and DP (dorsoposterior field). Field specificity was shown with regard to spontaneous activity, correlation between spontaneous and evoked activity, tone response latency, sharpness of frequency tuning, temporal response patterns (occurrence of phasic responses, phasic-tonic responses, tonic responses, and off-responses), and degree of variation between the characteristic frequency (CF) and the best frequency (BF) (CF–BF relationship). Field similarities were noted as significant correlations between CFs and BFs, V-shaped frequency tuning curves, similar minimum response thresholds and non-monotonic rate-level functions in approximately two-thirds of the neurons. Comparative and quantitative analyses showed that the measured response characteristics were, to various degrees, susceptible to influences of anesthetics. Therefore, studies of neuronal responses in the awake AC are important in order to establish adequate relationships between neuronal data and auditory perception and acoustic response behavior. PMID:24506843
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From functional architecture to functional connectomics.
Reid, R Clay
2012-07-26
"Receptive Fields, Binocular Interaction and Functional Architecture in the Cat's Visual Cortex" by Hubel and Wiesel (1962) reported several important discoveries: orientation columns, the distinct structures of simple and complex receptive fields, and binocular integration. But perhaps the paper's greatest influence came from the concept of functional architecture (the complex relationship between in vivo physiology and the spatial arrangement of neurons) and several models of functionally specific connectivity. They thus identified two distinct concepts, topographic specificity and functional specificity, which together with cell-type specificity constitute the major determinants of nonrandom cortical connectivity. Orientation columns are iconic examples of topographic specificity, whereby axons within a column connect with cells of a single orientation preference. Hubel and Wiesel also saw the need for functional specificity at a finer scale in their model of thalamic inputs to simple cells, verified in the 1990s. The difficult but potentially more important question of functional specificity between cortical neurons is only now becoming tractable with new experimental techniques. Copyright © 2012 Elsevier Inc. All rights reserved.
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NASA Technical Reports Server (NTRS)
Schmidt, M. A.; Goodwin, T. J.
2014-01-01
Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth
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Li, Yiping; Li, Yinxia; Wu, Qiuli; Ye, Huayue; Sun, Lingmei; Ye, Boping; Wang, Dayong
2013-01-01
α-tocopherol is a powerful liposoluble antioxidant and the most abundant isoform of vitamin E in the body. Under normal physiological conditions, adverse effects of relatively high concentration of vitamin E on organisms and the underlying mechanisms are still largely unclear. In the present study, we used the nematode Caenorhabditis elegans as an in vivo assay system to investigate the possible adverse effects of high concentration of vitamin E on thermosensation and thermotaxis learning and the underlying mechanisms. Our data show that treatment with 100-200 µg/mL of vitamin E did not noticeably influence both thermosensation and thermotaxis learning; however, treatment with 400 µg/mL of vitamin E altered both thermosensation and thermotaxis learning. The observed decrease in thermotaxis learning in 400 µg/mL of vitamin E treated nematodes might be partially due to the moderate but significant deficits in thermosensation, but not due to deficits in locomotion behavior or perception to food and starvation. Treatment with 400 µg/mL of vitamin E did not noticeably influence the morphology of GABAergic neurons, but significantly decreased fluorescent intensities of the cell bodies in AFD sensory neurons and AIY interneurons, required for thermosensation and thermotaxis learning control. Treatment with 400 µg/mL of vitamin E affected presynaptic function of neurons, but had no remarkable effects on postsynaptic function. Moreover, promotion of synaptic transmission by activating PKC-1 effectively retrieved deficits in both thermosensation and thermotaxis learning induced by 400 µg/mL of vitamin E. Therefore, relatively high concentrations of vitamin E administration may cause adverse effects on thermosensation and thermotaxis learning by inducing damage on the development of specific neurons and presynaptic function under normal physiological conditions in C. elegans.
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Acute Hippocampal Slice Preparation and Hippocampal Slice Cultures
Lein, Pamela J.; Barnhart, Christopher D.; Pessah, Isaac N.
2012-01-01
A major advantage of hippocampal slice preparations is that the cytoarchitecture and synaptic circuits of the hippocampus are largely retained. In neurotoxicology research, organotypic hippocampal slices have mostly been used as acute ex vivo preparations for investigating the effects of neurotoxic chemicals on synaptic function. More recently, hippocampal slice cultures, which can be maintained for several weeks to several months in vitro, have been employed to study how neurotoxic chemicals influence the structural and functional plasticity in hippocampal neurons. This chapter provides protocols for preparing hippocampal slices to be used acutely for electrophysiological measurements using glass microelectrodes or microelectrode arrays or to be cultured for morphometric assessments of individual neurons labeled using biolistics. PMID:21815062
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Leptin regulates dopamine responses to sustained stress in humans.
Burghardt, Paul R; Love, Tiffany M; Stohler, Christian S; Hodgkinson, Colin; Shen, Pei-Hong; Enoch, Mary-Anne; Goldman, David; Zubieta, Jon-Kar
2012-10-31
Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity.
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Neuronal survival in the brain: neuron type-specific mechanisms.
Pfisterer, Ulrich; Khodosevich, Konstantin
2017-03-02
Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.
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Glucose, Lactate, and Shuttling of Metabolites in Vertebrate Retinas
Hurley, James B.; Lindsay, Kenneth J.; Du, Jianhai
2016-01-01
The vertebrate retina has specific functions and structures that give it a unique set of constraints on the way in which it can produce and use metabolic energy. The retina’s response to illumination influences its energy requirements, and the retina’s laminated structure influences the extent to which neurons and glia can access metabolic fuels. There are fundamental differences between energy metabolism in retina and that in brain. The retina relies on aerobic glycolysis much more than the brain does, and morphological differences between retina and brain limit the types of metabolic relationships that are possible between neurons and glia. This Mini-Review summarizes the unique metabolic features of the retina with a focus on the role of lactate shuttling. PMID:25801286
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USDA-ARS?s Scientific Manuscript database
Concord grape juice contains flavonoid polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signaling. Concord grape juice supplementation has been shown to reduce inflammation, blood pressure, and vascular pathology in individuals with cardiovascular...
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From CNS stem cells to neurons and glia: Sox for everyone.
Reiprich, Simone; Wegner, Michael
2015-01-01
Neuroepithelial precursor cells of the vertebrate central nervous system either self-renew or differentiate into neurons, oligodendrocytes or astrocytes under the influence of a gene regulatory network that consists in transcription factors, epigenetic modifiers and microRNAs. Sox transcription factors are central to this regulatory network, especially members of the SoxB, SoxC, SoxD, SoxE and SoxF groups. These Sox proteins are widely expressed in neuroepithelial precursor cells and in newly specified, differentiating and mature neurons, oligodendrocytes and astrocytes and influence their identity, survival and development. They exert their effect predominantly at the transcriptional level but also have substantial impact on expression at the epigenetic and posttranscriptional levels with some Sox proteins acting as pioneer factors, recruiting chromatin-modifying and -remodelling complexes or influencing microRNA expression. They interact with a large variety of other transcription factors and influence the expression of regulatory molecules and effector genes in a cell-type-specific and temporally controlled manner. As versatile regulators with context-dependent functions, they are not only indispensable for central nervous system development but might also be instrumental for the development of reprogramming and cell conversion strategies for replacement therapies and for assisted regeneration after injury or degeneration-induced cell loss in the central nervous system.
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Schink, Martin; Leipolcf, Enrico; Schirmeyer, Jana; Schönherr, Roland; Hoshi, Toshinori; Heinemann, Stefan H.
2016-01-01
Dorsal root ganglia (DRG) neurons are important relay stations between the periphery and the central nervous system and are essential for somatosensory signaling. Reactive species are produced in a variety of physiological and pathophysiological conditions and are known to alter electric signaling. Here we studied the influence of reactive species on the electrical properties of DRG neurons from mice with the whole-cell patch-clamp method. Even mild stress induced by either low concentrations of chloramine-T (10 µM) or low-intensity blue-light irradiation profoundly diminished action potential frequency but prolonged single action potentials in wild-type neurons. The impact on evoked action potentials was much smaller in neurons deficient of the tetrodotoxin (TTX)-resistant voltage-gated sodium channel NaV1.8 (NaV1.8−/−), the channel most important for the action potential upstroke in DRG neurons. Low concentrations of chloramine-T caused a significant reduction of NaV1.8 peak current and at higher concentrations progressively slowed down inactivation. Blue light had a smaller effect on amplitude but slowed down NaV1.8 channel inactivation. The observed effects were less apparent for TTX-sensitive NaV channels. NaV1.8 is an important reactive-species-sensitive component in the electrical signaling of DRG neurons, potentially giving rise to loss-of-function and gain-of-function phenomena depending on the type of reactive species and their effective concentration and time of exposure. PMID:26383867
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Schink, Martin; Leipold, Enrico; Schirmeyer, Jana; Schönherr, Roland; Hoshi, Toshinori; Heinemann, Stefan H
2016-01-01
Dorsal root ganglion (DRG) neurons are important relay stations between the periphery and the central nervous system and are essential for somatosensory signaling. Reactive species are produced in a variety of physiological and pathophysiological conditions and are known to alter electric signaling. Here we studied the influence of reactive species on the electrical properties of DRG neurons from mice with the whole-cell patch-clamp method. Even mild stress induced by either low concentrations of chloramine-T (10 μM) or low-intensity blue light irradiation profoundly diminished action potential frequency but prolonged single action potentials in wild-type neurons. The impact on evoked action potentials was much smaller in neurons deficient of the tetrodotoxin (TTX)-resistant voltage-gated sodium channel NaV1.8 (NaV1.8(-/-)), the channel most important for the action potential upstroke in DRG neurons. Low concentrations of chloramine-T caused a significant reduction of NaV1.8 peak current and, at higher concentrations, progressively slowed down inactivation. Blue light had a smaller effect on amplitude but slowed down NaV1.8 channel inactivation. The observed effects were less apparent for TTX-sensitive NaV channels. NaV1.8 is an important reactive-species-sensitive component in the electrical signaling of DRG neurons, potentially giving rise to loss-of-function and gain-of-function phenomena depending on the type of reactive species and their effective concentration and time of exposure.
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Individual differences and vulnerability to drug addiction: a focus on the endocannabinoid system.
Sagheddu, Claudia; Melis, Miriam
2015-01-01
Vulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed.
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Bardoni, Barbara; Abekhoukh, Sabiha; Zongaro, Samantha; Melko, Mireille
2012-01-01
Intellectual disability (ID) is the most frequent cause of serious handicap in children and young adults and interests 2-3% of worldwide population, representing a serious problem from the medical, social, and economic points of view. The causes are very heterogeneous. Genes involved in ID have various functions altering different pathways important in neuronal function. Regulation of mRNA metabolism is particularly important in neurons for synaptic structure and function. Here, we review ID due to alteration of mRNA metabolism. Functional absence of some RNA-binding proteins--namely, FMRP, FMR2P, PQBP1, UFP3B, VCX-A--causes different forms of ID. These proteins are involved in different steps of RNA metabolism and, even if a detailed analysis of their RNA targets has been performed so far only for FMRP, it appears clear that they modulate some aspects (translation, stability, transport, and sublocalization) of a subset of RNAs coding for proteins, whose function must be relevant for neurons. Two other proteins, DYRK1A and CDKL5, involved in Down syndrome and Rett syndrome, respectively, have been shown to have an impact on splicing efficiency of specific mRNAs. Both proteins are kinases and their effect is indirect. Interestingly, both are localized in nuclear speckles, the nuclear domains where splicing factors are assembled, stocked, and recycled and influence their biogenesis and/or their organization. Copyright © 2012 Elsevier B.V. All rights reserved.
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Microglia in the developing brain: a potential target with lifetime effects
Harry, G. Jean; Kraft, Andrew D.
2012-01-01
Microglia are a heterogeneous group of monocyte-derived cells serving multiple roles within the brain, many of which are associated with immune and macrophage like properties. These cells are known to serve a critical role during brain injury and to maintain homeostasis; yet, their defined roles during development have yet to be elucidated. Microglial actions appear to influence events associated with neuronal proliferation and differentiation during development, as well as, contribute to processes associated with the removal of dying neurons or cellular debris and management of synaptic connections. These long-lived cells display changes during injury and with aging that are critical to the maintenance of the neuronal environment over the lifespan of the organism. These processes may be altered by changes in the colonization of the brain or by inflammatory events during development. This review addresses the role of microglia during brain development, both structurally and functionally, as well as the inherent vulnerability of the developing nervous system. A framework is presented considering microglia as a critical nervous system-specific cell that can influence multiple aspects of brain development (e.g., vascularization, synaptogenesis, and myelination) and have a long term impact on the functional vulnerability of the nervous system to a subsequent insult, whether environmental, physical, age-related, or disease-related. PMID:22322212
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Jarriault, David; Grosmaitre, Xavier
2015-01-01
Analyzing the physiological responses of olfactory sensory neurons (OSN) when stimulated with specific ligands is critical to understand the basis of olfactory-driven behaviors and their modulation. These coding properties depend heavily on the initial interaction between odor molecules and the olfactory receptor (OR) expressed in the OSNs. The identity, specificity and ligand spectrum of the expressed OR are critical. The probability to find the ligand of the OR expressed in an OSN chosen randomly within the epithelium is very low. To address this challenge, this protocol uses genetically tagged mice expressing the fluorescent protein GFP under the control of the promoter of defined ORs. OSNs are located in a tight and organized epithelium lining the nasal cavity, with neighboring cells influencing their maturation and function. Here we describe a method to isolate an intact olfactory epithelium and record through patch-clamp recordings the properties of OSNs expressing defined odorant receptors. The protocol allows one to characterize OSN membrane properties while keeping the influence of the neighboring tissue. Analysis of patch-clamp results yields a precise quantification of ligand/OR interactions, transduction pathways and pharmacology, OSNs' coding properties and their modulation at the membrane level. PMID:26275097
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Gambino, Giuditta; Allegra, Mario; Sardo, Pierangelo; Attanzio, Alessandro; Tesoriere, Luisa; Livrea, Maria A.; Ferraro, Giuseppe; Carletti, Fabio
2018-01-01
Several studies have recently investigated the role of nutraceuticals in complex pathophysiological processes such as oxidative damages, inflammatory conditions and excitotoxicity. In this regard, the effects of nutraceuticals on basic functions of neuronal cells, such as excitability, are still poorly investigated. For this reason, the possible modulation of neuronal excitability by phytochemicals (PhC) could represent an interesting field of research given that excitotoxicity phenomena are involved in neurodegenerative alterations leading, for example, to Alzheimer’s disease. The present study was focused on indicaxanthin from Opuntia ficus indica, a bioactive betalain pigment, with a proven antioxidant and anti-inflammatory potential, previously found to cross blood-brain barrier (BBB) and to modulate the bioelectric activity of hippocampal neurons. On this basis, we aimed at detecting the specific brain areas where indicaxanthin localizes after oral administration at dietary-achievable amounts and highlighting eventual local effects on the excitability of single neuronal units. HPLC analysis of brain tissue 1 h after ingestion of 2 μmol/kg indicaxanthin indicated that the phytochemical accumulates in cortex, hippocampus, diencephalon, brainstem and cerebellum, but not in the striato-pallidal complex. Then, electrophysiological recordings, applying the microiontophoretic technique, were carried out with different amounts of indicaxanthin (0.34, 0.17, 0.085 ng/neuron) to assess whether indicaxanthin influenced the neuronal firing rate. The data showed that the bioelectric activity of neurons belonging to different brain areas was modulated after local injection of indicaxanthin, mainly with dose-related responses. A predominating inhibitory effect was observed, suggesting a possible novel beneficial effect of indicaxanthin in reducing cell excitability. These findings can constitute a new rationale for exploring biological mechanisms through which PhC could modulate neuronal function with a relapse on complex cognitive brain process and related neurodegenerative conditions. PMID:29867444
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Miller, D. M.; Cotter, L. A.; Gandhi, N. J.; Schor, R. H.; Cass, S. P.; Huff, N. O.; Raj, S. G.; Shulman, J. A; Yates, B. J.
2008-01-01
Although many previous experiments have considered the responses of vestibular nucleus neurons to rotations and translations of the head, little data are available regarding cells in the caudalmost portions of the vestibular nuclei (CVN), which mediate vestibulo-autonomic responses among other functions. This study examined the responses of CVN neurons of conscious cats to rotations in vertical planes, both before and after a bilateral vestibular neurectomy. None of the units included in the data sample had eye movement-related activity. In labyrinth-intact animals, some CVN neurons (22%) exhibited graviceptive responses consistent with inputs from otolith organs, but most (55%) had dynamic responses with phases synchronized with stimulus velocity. Furthermore, the large majority of CVN neurons had response vector orientations that were aligned either near the roll or vertical canal planes, and only 18% of cells were preferentially activated by pitch rotations. Sustained head-up rotations of the body provide challenges to the cardiovascular system and breathing, and thus the response dynamics of the large majority of CVN neurons were dissimilar to those of posturally-related autonomic reflexes. These data suggest that vestibular influences on autonomic control mediated by the CVN are more complex than previously envisioned, and likely involve considerable processing and integration of signals by brainstem regions involved in cardiovascular and respiratory regulation. Following a bilateral vestibular neurectomy, CVN neurons regained spontaneous activity within 24 h, and a very few neurons (<10%) responded to vertical tilts <15° in amplitude. These findings indicate that nonlabyrinthine inputs are likely important in sustaining the activity of CVN neurons; thus, these inputs may play a role in functional recovery following peripheral vestibular lesions. PMID:18368395
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Saito, Shigeru; Nakatsuka, Kazumasa; Takahashi, Kenji; Fukuta, Naomi; Imagawa, Toshiaki; Ohta, Toshio; Tominaga, Makoto
2012-08-31
Transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (V1) perceive noxious temperatures and chemical stimuli and are involved in pain sensation in mammals. Thus, these two channels provide a model for understanding how different genes with similar biological roles may influence the function of one another during the course of evolution. However, the temperature sensitivity of TRPA1 in ancestral vertebrates and its evolutionary path are unknown as its temperature sensitivities vary among different vertebrate species. To elucidate the functional evolution of TRPA1, TRPA1s of the western clawed (WC) frogs and green anole lizards were characterized. WC frog TRPA1 was activated by heat and noxious chemicals that activate mammalian TRPA1. These stimuli also activated native sensory neurons and elicited nocifensive behaviors in WC frogs. Similar to mammals, TRPA1 was functionally co-expressed with TRPV1, another heat- and chemical-sensitive nociceptive receptor, in native sensory neurons of the WC frog. Green anole TRPA1 was also activated by heat and noxious chemical stimulation. These results suggest that TRPA1 was likely a noxious heat and chemical receptor and co-expressed with TRPV1 in the nociceptive sensory neurons of ancestral vertebrates. Conservation of TRPV1 heat sensitivity throughout vertebrate evolution could have changed functional constraints on TRPA1 and influenced the functional evolution of TRPA1 regarding temperature sensitivity, whereas conserving its noxious chemical sensitivity. In addition, our results also demonstrated that two mammalian TRPA1 inhibitors elicited different effect on the TRPA1s of WC frogs and green anoles, which can be utilized to clarify the structural bases for inhibition of TRPA1.
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Saito, Shigeru; Nakatsuka, Kazumasa; Takahashi, Kenji; Fukuta, Naomi; Imagawa, Toshiaki; Ohta, Toshio; Tominaga, Makoto
2012-01-01
Transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (V1) perceive noxious temperatures and chemical stimuli and are involved in pain sensation in mammals. Thus, these two channels provide a model for understanding how different genes with similar biological roles may influence the function of one another during the course of evolution. However, the temperature sensitivity of TRPA1 in ancestral vertebrates and its evolutionary path are unknown as its temperature sensitivities vary among different vertebrate species. To elucidate the functional evolution of TRPA1, TRPA1s of the western clawed (WC) frogs and green anole lizards were characterized. WC frog TRPA1 was activated by heat and noxious chemicals that activate mammalian TRPA1. These stimuli also activated native sensory neurons and elicited nocifensive behaviors in WC frogs. Similar to mammals, TRPA1 was functionally co-expressed with TRPV1, another heat- and chemical-sensitive nociceptive receptor, in native sensory neurons of the WC frog. Green anole TRPA1 was also activated by heat and noxious chemical stimulation. These results suggest that TRPA1 was likely a noxious heat and chemical receptor and co-expressed with TRPV1 in the nociceptive sensory neurons of ancestral vertebrates. Conservation of TRPV1 heat sensitivity throughout vertebrate evolution could have changed functional constraints on TRPA1 and influenced the functional evolution of TRPA1 regarding temperature sensitivity, whereas conserving its noxious chemical sensitivity. In addition, our results also demonstrated that two mammalian TRPA1 inhibitors elicited different effect on the TRPA1s of WC frogs and green anoles, which can be utilized to clarify the structural bases for inhibition of TRPA1. PMID:22791718
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Shi, Mingjian; Majumdar, Devi; Gao, Yandong; Brewer, Bryson M; Goodwin, Cody R; McLean, John A; Li, Deyu; Webb, Donna J
2013-08-07
Two novel microfluidic cell culture schemes, a vertically-layered set-up and a four chamber set-up, were developed for co-culturing central nervous system (CNS) neurons and glia. The cell chambers in these devices were separated by pressure-enabled valve barriers, which permitted us to control communication between the two cell types. The unique design of these devices facilitated the co-culture of glia with neurons in close proximity (∼50-100 μm), differential transfection of neuronal populations, and dynamic visualization of neuronal interactions, such as the development of synapses. With these co-culture devices, initial synaptic contact between neurons transfected with different fluorescent markers, such as green fluorescent protein (GFP) and mCherry-synaptophysin, was imaged using high-resolution fluorescence microscopy. The presence of glial cells had a profound influence on synapses by increasing the number and stability of synaptic contacts. Interestingly, as determined by liquid chromatography-ion mobility-mass spectrometry, neuron-glia co-cultures produced elevated levels of soluble factors compared to that secreted by individual neuron or glia cultures, suggesting a potential mechanism by which neuron-glia interactions could modulate synaptic function. Collectively, these results show that communication between neurons and glia is critical for the formation and stability of synapses and point to the importance of developing neuron-glia co-culture systems such as the microfluidic platforms described in this study.
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Three-dimensional micro-electrode array for recording dissociated neuronal cultures.
Musick, Katherine; Khatami, David; Wheeler, Bruce C
2009-07-21
This work demonstrates the design, fabrication, packaging, characterization, and functionality of an electrically and fluidically active three-dimensional micro-electrode array (3D MEA) for use with neuronal cell cultures. The successful function of the device implies that this basic concept-construction of a 3D array with a layered approach-can be utilized as the basis for a new family of neural electrode arrays. The 3D MEA prototype consists of a stack of individually patterned thin films that form a cell chamber conducive to maintaining and recording the electrical activity of a long-term three-dimensional network of rat cortical neurons. Silicon electrode layers contain a polymer grid for neural branching, growth, and network formation. Along the walls of these electrode layers lie exposed gold electrodes which permit recording and stimulation of the neuronal electrical activity. Silicone elastomer micro-fluidic layers provide a means for loading dissociated neurons into the structure and serve as the artificial vasculature for nutrient supply and aeration. The fluidic layers also serve as insulation for the micro-electrodes. Cells have been shown to survive in the 3D MEA for up to 28 days, with spontaneous and evoked electrical recordings performed in that time. The micro-fluidic capability was demonstrated by flowing in the drug tetrotodoxin to influence the activity of the culture.
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Yanagihara, Shin; Yazaki-Sugiyama, Yoko
2018-04-12
Behavioral states of animals, such as observing the behavior of a conspecific, modify signal perception and/or sensations that influence state-dependent higher cognitive behavior, such as learning. Recent studies have shown that neuronal responsiveness to sensory signals is modified when animals are engaged in social interactions with others or in locomotor activities. However, how these changes produce state-dependent differences in higher cognitive function is still largely unknown. Zebra finches, which have served as the premier songbird model, learn to sing from early auditory experiences with tutors. They also learn from playback of recorded songs however, learning can be greatly improved when song models are provided through social communication with tutors (Eales, 1989; Chen et al., 2016). Recently we found a subset of neurons in the higher-level auditory cortex of juvenile zebra finches that exhibit highly selective auditory responses to the tutor song after song learning, suggesting an auditory memory trace of the tutor song (Yanagihara and Yazaki-Sugiyama, 2016). Here we show that auditory responses of these selective neurons became greater when juveniles were paired with their tutors, while responses of non-selective neurons did not change. These results suggest that social interaction modulates cortical activity and might function in state-dependent song learning. Copyright © 2018 Elsevier B.V. All rights reserved.
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Estimating Temporal Causal Interaction between Spike Trains with Permutation and Transfer Entropy
Li, Zhaohui; Li, Xiaoli
2013-01-01
Estimating the causal interaction between neurons is very important for better understanding the functional connectivity in neuronal networks. We propose a method called normalized permutation transfer entropy (NPTE) to evaluate the temporal causal interaction between spike trains, which quantifies the fraction of ordinal information in a neuron that has presented in another one. The performance of this method is evaluated with the spike trains generated by an Izhikevich’s neuronal model. Results show that the NPTE method can effectively estimate the causal interaction between two neurons without influence of data length. Considering both the precision of time delay estimated and the robustness of information flow estimated against neuronal firing rate, the NPTE method is superior to other information theoretic method including normalized transfer entropy, symbolic transfer entropy and permutation conditional mutual information. To test the performance of NPTE on analyzing simulated biophysically realistic synapses, an Izhikevich’s cortical network that based on the neuronal model is employed. It is found that the NPTE method is able to characterize mutual interactions and identify spurious causality in a network of three neurons exactly. We conclude that the proposed method can obtain more reliable comparison of interactions between different pairs of neurons and is a promising tool to uncover more details on the neural coding. PMID:23940662
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Canolty, Ryan T.; Ganguly, Karunesh; Carmena, Jose M.
2012-01-01
Understanding the principles governing the dynamic coordination of functional brain networks remains an important unmet goal within neuroscience. How do distributed ensembles of neurons transiently coordinate their activity across a variety of spatial and temporal scales? While a complete mechanistic account of this process remains elusive, evidence suggests that neuronal oscillations may play a key role in this process, with different rhythms influencing both local computation and long-range communication. To investigate this question, we recorded multiple single unit and local field potential (LFP) activity from microelectrode arrays implanted bilaterally in macaque motor areas. Monkeys performed a delayed center-out reach task either manually using their natural arm (Manual Control, MC) or under direct neural control through a brain-machine interface (Brain Control, BC). In accord with prior work, we found that the spiking activity of individual neurons is coupled to multiple aspects of the ongoing motor beta rhythm (10–45 Hz) during both MC and BC, with neurons exhibiting a diversity of coupling preferences. However, here we show that for identified single neurons, this beta-to-rate mapping can change in a reversible and task-dependent way. For example, as beta power increases, a given neuron may increase spiking during MC but decrease spiking during BC, or exhibit a reversible shift in the preferred phase of firing. The within-task stability of coupling, combined with the reversible cross-task changes in coupling, suggest that task-dependent changes in the beta-to-rate mapping play a role in the transient functional reorganization of neural ensembles. We characterize the range of task-dependent changes in the mapping from beta amplitude, phase, and inter-hemispheric phase differences to the spike rates of an ensemble of simultaneously-recorded neurons, and discuss the potential implications that dynamic remapping from oscillatory activity to spike rate and timing may hold for models of computation and communication in distributed functional brain networks. PMID:23284276
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Organizational and activational effects of sex steroids on kisspeptin neuron development
Poling, Matthew C.; Kauffman, Alexander S.
2012-01-01
Kisspeptin, encoded by the Kiss1 gene, is a neuropeptide required for puberty and adult reproductive function. Understanding the regulation and development of the kisspeptin system provides valuable knowledge about the physiology of puberty and adult fertility, and may provide insights into human pubertal or reproductive disorders. Recent studies, particularly in rodent models, have assessed how kisspeptin neurons develop and how hormonal and non-hormonal factors regulate this developmental process. Exposure to sex steroids (testosterone and estradiol) during critical periods of development can induce organizational (permanent) effects on kisspeptin neuron development, with respect to both sexually dimorphic and non-sexually dimorphic aspects of kisspeptin biology. In addition, sex steroids can also impart activational (temporary) effects on kisspeptin neurons and Kiss1 gene expression at various times during neonatal and peripubertal development, as they do in adulthood. Here, we discuss the current knowledge—and in some cases, lack thereof—of the influence of hormones and other factors on kisspeptin neuronal development. PMID:22728025
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Depopulation of the ventromedial hypothalamic nucleus in the diabetic Chinese hamster.
Garris, D R; Diani, A R; Smith, C; Gerritsen, G C
1982-01-01
The relationship between diabetes and the size, density and area of the ventromedial hypothalamic nucleus (VMH) was studied in the genetically diabetic Chinese hamster. Matched diabetic and non-diabetic control chinese hamsters were perfused, the hypothalamus collected, sectioned and stained for light microscopy. The mid-point of each VMH nucleus was located, photographed and enlarged for morphometric analysis. Each neuron that possessed a nucleolus and was located within the confines of a VMH was counted, and subsequently the area of each nucleus and the density of neurons per area of VMH were calculated. The results indicated that both the area and absolute number of neurons within the VMH of diabetic hamsters were significantly reduced compared to control values (P less than 0.01) The density of neurons per unit area of VMH was similar in both groups. These data suggest that the VMH experiences a neuronal depopulation in diabetic hamsters which may have a functional influence on the hypothalamic-pancreatic axis in this species.
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Billard, J-M
2008-10-01
Rather different from their initial image as passive supportive cells of the CNS, the astrocytes are now considered as active partners at synapses, able to release a set of gliotransmitter-like substances to modulate synaptic communication within neuronal networks. Whereas glutamate and ATP were first regarded as main determinants of gliotransmission, growing evidence indicates now that the amino acid D-serine is another important player in the neuronal-glial dialogue. Through the regulation of glutamatergic neurotransmission through both N-methyl-D-aspartate (NMDA-R) and non-NMDA-R, D-serine is helping in modelling the appropriate connections in the developing brain and influencing the functional plasticity within neuronal networks throughout lifespan. The understanding of D-serine signalling, which has increased linearly in the last few years, gives new insights into the critical role of impaired neuronal-glial communication in the diseased brain, and offers new opportunities for developing relevant strategies to treat cognitive deficits associated to brain disorders.
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Strong G-Protein-Mediated Inhibition of Sodium Channels.
Mattheisen, Glynis B; Tsintsadze, Timur; Smith, Stephen M
2018-05-29
Voltage-gated sodium channels (VGSCs) are strategically positioned to mediate neuronal plasticity because of their influence on action potential waveform. VGSC function may be strongly inhibited by local anesthetic and antiepileptic drugs and modestly modulated via second messenger pathways. Here, we report that the allosteric modulators of the calcium-sensing receptor (CaSR) cinacalcet, calindol, calhex, and NPS 2143 completely inhibit VGSC current in the vast majority of cultured mouse neocortical neurons. This form of VGSC current block persisted in CaSR-deficient neurons, indicating a CaSR-independent mechanism. Cinacalcet-mediated blockade of VGSCs was prevented by the guanosine diphosphate (GDP) analog GDPβs, indicating that G-proteins mediated this effect. Cinacalcet inhibited VGSCs by increasing channel inactivation, and block was reversed by prolonged hyperpolarization. Strong cinacalcet inhibition of VGSC currents was also present in acutely isolated mouse cortical neurons. These data identify a dynamic signaling pathway by which G-proteins regulate VGSC current to indirectly modulate central neuronal excitability. Published by Elsevier Inc.
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Billard, J-M
2008-01-01
Rather different from their initial image as passive supportive cells of the CNS, the astrocytes are now considered as active partners at synapses, able to release a set of gliotransmitter-like substances to modulate synaptic communication within neuronal networks. Whereas glutamate and ATP were first regarded as main determinants of gliotransmission, growing evidence indicates now that the amino acid D-serine is another important player in the neuronal-glial dialogue. Through the regulation of glutamatergic neurotransmission through both N-methyl-D-aspartate (NMDA-R) and non-NMDA-R, D-serine is helping in modelling the appropriate connections in the developing brain and influencing the functional plasticity within neuronal networks throughout lifespan. The understanding of D-serine signalling, which has increased linearly in the last few years, gives new insights into the critical role of impaired neuronal-glial communication in the diseased brain, and offers new opportunities for developing relevant strategies to treat cognitive deficits associated to brain disorders. PMID:18363840
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Wright, Nathaniel C; Wessel, Ralf
2017-10-01
A primary goal of systems neuroscience is to understand cortical function, typically by studying spontaneous and stimulus-modulated cortical activity. Mounting evidence suggests a strong and complex relationship exists between the ongoing and stimulus-modulated cortical state. To date, most work in this area has been based on spiking in populations of neurons. While advantageous in many respects, this approach is limited in scope: it records the activity of a minority of neurons and gives no direct indication of the underlying subthreshold dynamics. Membrane potential recordings can fill these gaps in our understanding, but stable recordings are difficult to obtain in vivo. Here, we recorded subthreshold cortical visual responses in the ex vivo turtle eye-attached whole brain preparation, which is ideally suited for such a study. We found that, in the absence of visual stimulation, the network was "synchronous"; neurons displayed network-mediated transitions between hyperpolarized (Down) and depolarized (Up) membrane potential states. The prevalence of these slow-wave transitions varied across turtles and recording sessions. Visual stimulation evoked similar Up states, which were on average larger and less reliable when the ongoing state was more synchronous. Responses were muted when immediately preceded by large, spontaneous Up states. Evoked spiking was sparse, highly variable across trials, and mediated by concerted synaptic inputs that were, in general, only very weakly correlated with inputs to nearby neurons. Together, these results highlight the multiplexed influence of the cortical network on the spontaneous and sensory-evoked activity of individual cortical neurons. NEW & NOTEWORTHY Most studies of cortical activity focus on spikes. Subthreshold membrane potential recordings can provide complementary insight, but stable recordings are difficult to obtain in vivo. Here, we recorded the membrane potentials of cortical neurons during ongoing and visually evoked activity. We observed a strong relationship between network and single-neuron evoked activity spanning multiple temporal scales. The membrane potential perspective of cortical dynamics thus highlights the influence of intrinsic network properties on visual processing. Copyright © 2017 the American Physiological Society.
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Current disease modifying approaches to treat Parkinson's disease.
Lindholm, Dan; Mäkelä, Johanna; Di Liberto, Valentina; Mudò, Giuseppa; Belluardo, Natale; Eriksson, Ove; Saarma, Mart
2016-04-01
Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.
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NASA Technical Reports Server (NTRS)
Hof, P. R.; Nimchinsky, E. A.; Morrison, J. H.; Bloom, F. E. (Principal Investigator)
1995-01-01
The neurochemical characteristics of the neuronal subsets that furnish different types of corticocortical connections have been only partially determined. In recent years, several cytoskeletal proteins have emerged as reliable markers to distinguish subsets of pyramidal neurons in the cerebral cortex of primates. In particular, previous studies using an antibody to nonphosphorylated neurofilament protein (SMI-32) have revealed a consistent degree of regional and laminar specificity in the distribution of a subpopulation of pyramidal cells in the primate cerebral cortex. The density of neurofilament protein-immunoreactive neurons was shown to vary across corticocortical pathways in macaque monkeys. In the present study, we have used the antibody SMI-32 to examine further and to quantify the distribution of a subset of corticocortically projecting neurons in a series of long ipsilateral corticocortical pathways in comparison to short corticocortical, commissural, and limbic connections. The results demonstrate that the long association pathways interconnecting the frontal, parietal, and temporal neocortex have a high representation of neurofilament protein-enriched pyramidal neurons (45-90%), whereas short corticocortical, callosal, and limbic pathways are characterized by much lower numbers of such neurons (4-35%). These data suggest that different types of corticocortical connections have differential representation of highly specific neuronal subsets that share common neurochemical characteristics, thereby determining regional and laminar cortical patterns of morphological and molecular heterogeneity. These differences in neuronal neurochemical phenotype among corticocortical circuits may have considerable influence on cortical processing and may be directly related to the type of integrative function subserved by each cortical pathway. Finally, it is worth noting that neurofilament protein-immunoreactive neurons are dramatically affected in the course of Alzheimer's disease. The present results support the hypothesis that neurofilament protein may be crucially linked to the development of selective neuronal vulnerability and subsequent disruption of corticocortical pathways that lead to the severe impairment of cognitive function commonly observed in age-related dementing disorders.
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Bonnavion, Patricia; Jackson, Alexander C; Carter, Matthew E; de Lecea, Luis
2015-02-19
The hypothalamic-pituitary-adrenal (HPA) axis functions to coordinate behavioural and physiological responses to stress in a manner that depends on the behavioural state of the organism. However, the mechanisms through which arousal and metabolic states influence the HPA axis are poorly understood. Here using optogenetic approaches in mice, we show that neurons that produce hypocretin (Hcrt)/orexin in the lateral hypothalamic area (LHA) regulate corticosterone release and a variety of behaviours and physiological hallmarks of the stress response. Interestingly, we found that Hcrt neuronal activity and Hcrt-mediated stress responses were inhibited by the satiety hormone leptin, which acts, in part, through a network of leptin-sensitive neurons in the LHA. These data demonstrate how peripheral metabolic signals interact with hypothalamic neurons to coordinate stress and arousal and suggest one mechanism through which hyperarousal or altered metabolic states may be linked with abnormal stress responses.
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Micro- and nano-technologies to probe the mechano-biology of the brain.
Tay, Andy; Schweizer, Felix E; Di Carlo, Dino
2016-05-24
Biomechanical forces have been demonstrated to influence a plethora of neuronal functions across scales including gene expression, mechano-sensitive ion channels, neurite outgrowth and folding of the cortices in the brain. However, the detailed roles biomechanical forces may play in brain development and disorders has seen limited study, partly due to a lack of effective methods to probe the mechano-biology of the brain. Current techniques to apply biomechanical forces on neurons often suffer from low throughput and poor spatiotemporal resolution. On the other hand, newly developed micro- and nano-technologies can overcome these aforementioned limitations and offer advantages such as lower cost and possibility of non-invasive control of neuronal circuits. This review compares the range of conventional, micro- and nano-technological techniques that have been developed and how they have been or can be used to understand the effect of biomechanical forces on neuronal development and homeostasis.
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Cadherin-2 Is Required Cell Autonomously for Collective Migration of Facial Branchiomotor Neurons.
Rebman, Jane K; Kirchoff, Kathryn E; Walsh, Gregory S
2016-01-01
Collective migration depends on cell-cell interactions between neighbors that contribute to their overall directionality, yet the mechanisms that control the coordinated migration of neurons remains to be elucidated. During hindbrain development, facial branchiomotor neurons (FBMNs) undergo a stereotypic tangential caudal migration from their place of birth in rhombomere (r)4 to their final location in r6/7. FBMNs engage in collective cell migration that depends on neuron-to-neuron interactions to facilitate caudal directionality. Here, we demonstrate that Cadherin-2-mediated neuron-to-neuron adhesion is necessary for directional and collective migration of FBMNs. We generated stable transgenic zebrafish expressing dominant-negative Cadherin-2 (Cdh2ΔEC) driven by the islet1 promoter. Cell-autonomous inactivation of Cadherin-2 function led to non-directional migration of FBMNs and a defect in caudal tangential migration. Additionally, mosaic analysis revealed that Cdh2ΔEC-expressing FBMNs are not influenced to migrate caudally by neighboring wild-type FBMNs due to a defect in collective cell migration. Taken together, our data suggest that Cadherin-2 plays an essential cell-autonomous role in mediating the collective migration of FBMNs.
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Marchetti, B
1996-01-01
Neurons and astrocytes have a close anatomic and functional relationship that plays a crucial role during development and in the adult brain. Astrocytes in the central nervous system (CNS) express receptors for a variety of growth factors (GFs), neurotransmitters and/or neuromodulators; in turn, neuronal cells can respond to astrocyte-derived GFs and control astrocyte function via a common set of signaling molecules and intracellular transducing pathways. There is also increasing evidence that soluble factors from lymphoid/mononuclear cells are able to modulate the growth and function of cells found in the CNS, specifically macroglial and microglial cells. Furthermore, glial cells can secrete immunoregulatory molecules that influence immune cells as well as the glial cells themselves. As neuronal and immune cells share common signaling systems, the potential exists for bidirectional communication not only between lymphoid and glial cells, but also between neuronal cells and immune and glial cells. In the present work, interactions of luteinizing-hormone-releasing hormone (LHRH) and the astroglial cell are proposed as a prototype for the study of neuroimmune communication within the CNS in the light of (1) the commonality of signal molecules (hormones, neurotransmitters and cytokines) and transduction mechanisms shared by glia LHRH neurons and lymphoid cells; (2) the central role of glia in the developmental organization and pattern of LHRH neuronal migration during embryogenesis, and (3) the strong modulatory role played by sex steroids in mechanisms involved in synaptic and interneuronal organization, as well as in the sexual dimorphisms of neuroendocrine-immune functions. During their maturation and differentiation in vitro, astroglial cells release factors able to accelerate markedly the LHRH neuronal phenotypic differentiation as well as the acquisition of mature LHRH secretory potential, with a potency depending on both the 'age' and the specific brain localization of the astroglia, as well as the degree of LHRH neuronal differentiation in vitro. Regional differences in astroglial sensitivity to estrogens were also measured. Different experimental paradigms such as coculture and mixed-culture models between the immortalized LHRH (GT1-1) neuronal cell line and astroglial cells in primary culture, disclosed the presence of a bidirectional flow of informational molecules regulating both proliferative and secretory capacities of each cell type. The importance of adhesive mechanisms in such cross-talk is underscored by the complete abolition of GT1-1 LHRH production and cell proliferation following the counteraction of neuronal-neuronal/neuronal-glial interactions through addition of neural-cell adhesion molecule antiserum. Other information came from pharmacological experiments manipulating the astroglia-derived cytokines and/or nitric oxide, which revealed cross-talk between the neuronal and astroglial compartments. From the bulk of this information, it seems likely that interactions between astroglia and LHRH neurons play a major role in the integration of the multiplicity of brain signals converging on the LHRH neurons that govern reproduction. Another important facet of neuronal-glial interactions is that concerning neuron-guided migration, and unraveling astroglial/LHRH-neuronal networks might then constitute an additional effort in the comprehension of defective LHRH-neuronal migration in Kallman's syndrome.
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Chen, Xiaoming; Liu, Xinqin; Li, Bin; Zhang, Qian; Wang, Jiye; Zhang, Wenbin; Luo, Wenjing; Chen, Jingyuan
2017-01-01
Background: Neuron apoptosis mediated by hypoxia inducible factor 1α (HIF-1α) in hippocampus is one of the most important factors accounting for the chronic hypobaric hypoxia induced cognitive impairment. As a neuroprotective molecule that is up-regulated in response to various environmental stress, CIRBP was reported to crosstalk with HIF-1α under cellular stress. However, its function under chronic hypobaric hypoxia remains unknown. Objective: In this study, we tried to identify the role of CIRBP in HIF-1α mediated neuron apoptosis under chronic hypobaric hypoxia and find a possible method to maintain its potential neuroprotective in long-term high altitude environmental exposure. Methods: We established a chronic hypobaric hypoxia rat model as well as a tissue culture model where SH-SY5Y cells were exposed to 1% hypoxia. Based on these models, we measured the expressions of HIF-1α and CIRBP under hypoxia exposure and examined the apoptosis of neurons by TUNEL immunofluorescence staining and western blot analysis of apoptosis related proteins. In addition, by establishing HIF-1α shRNA and pEGFP-CIRBP plasmid transfected cells, we confirmed the role of HIF-1α in chronic hypoxia induced neuron apoptosis and identified the influence of CIRBP over-expression upon HIF-1α and neuron apoptosis in the process of exposure. Furthermore, we measured the expression of the reported hypoxia related miRNAs in both models and the influence of miRNAs' over-expression/knock-down upon CIRBP in the process of HIF-1α mediated neuron apoptosis. Results: HIF-1α expression as well as neuron apoptosis was significantly elevated by chronic hypobaric hypoxia both in vivo and in vitro . CIRBP was induced in the early stage of exposure (3d/7d); however as the exposure was prolonged (21d), CIRBP level of the hypoxia group became significantly lower than that of control. In addition, HIF-1α knockdown significantly decreased neuron apoptosis under hypoxia, suggesting HIF-1α may be pro-apoptotic in the process of exposure. CIRBP over-expression significantly suppressed HIF-1α up-regulation in hypoxia and inhibited HIF-1α mediated neuron apoptosis. Interestingly, miR-23a was also induced by hypoxia exposure and showed the same changing tendency with CIRBP (increasing in 3d/7d, decreasing in 21d). In addition, over-expressing miR-23a up-regulated CIRBP, down-regulated HIF-1α and attenuated neuron apoptosis. Conclusion: Cold inducible RNA binding protein is involved in chronic hypoxia induced neuron apoptosis by down-regulating HIF-1α expression, and MiR-23a may be an important tool to maintain CIRBP level and function.
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Serotonin targets inhibitory synapses to induce modulation of network functions
Manzke, Till; Dutschmann, Mathias; Schlaf, Gerald; Mörschel, Michael; Koch, Uwe R.; Ponimaskin, Evgeni; Bidon, Olivier; Lalley, Peter M.; Richter, Diethelm W.
2009-01-01
The cellular effects of serotonin (5-HT), a neuromodulator with widespread influences in the central nervous system, have been investigated. Despite detailed knowledge about the molecular biology of cellular signalling, it is not possible to anticipate the responses of neuronal networks to a global action of 5-HT. Heterogeneous expression of various subtypes of serotonin receptors (5-HTR) in a variety of neurons differently equipped with cell-specific transmitter receptors and ion channel assemblies can provoke diverse cellular reactions resulting in various forms of network adjustment and, hence, motor behaviour. Using the respiratory network as a model for reciprocal synaptic inhibition, we demonstrate that 5-HT1AR modulation primarily affects inhibition through glycinergic synapses. Potentiation of glycinergic inhibition of both excitatory and inhibitory neurons induces a functional reorganization of the network leading to a characteristic change of motor output. The changes in network operation are robust and help to overcome opiate-induced respiratory depression. Hence, 5-HT1AR activation stabilizes the rhythmicity of breathing during opiate medication of pain. PMID:19651659
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Disruption in the autophagic process underlies the sensory neuropathy in dystonia musculorum mice.
Ferrier, Andrew; De Repentigny, Yves; Lynch-Godrei, Anisha; Gibeault, Sabrina; Eid, Walaa; Kuo, Daniel; Zha, Xiaohui; Kothary, Rashmi
2015-01-01
A homozygous mutation in the DST (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in dystonia musculorum (Dst(dt)) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the Dst(dt-Tg4) mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, Dst(dt-Tg4) sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described Dst(dt-Tg4) mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to Dst(dt-Tg4) mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in Dst(dt-Tg4) dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies Dst(dt) pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis.
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Thibault, Dominic; Giguère, Nicolas; Loustalot, Fabien; Bourque, Marie-Josée; Ducrot, Charles; El Mestikawy, Salah; Trudeau, Louis-Éric
2016-05-01
Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.
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Disruption in the autophagic process underlies the sensory neuropathy in dystonia musculorum mice
Ferrier, Andrew; De Repentigny, Yves; Lynch-Godrei, Anisha; Gibeault, Sabrina; Eid, Walaa; Kuo, Daniel; Zha, Xiaohui; Kothary, Rashmi
2015-01-01
A homozygous mutation in the DST (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in dystonia musculorum (Dstdt) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the Dstdt-Tg4 mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, Dstdt-Tg4 sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described Dstdt-Tg4 mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to Dstdt-Tg4 mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in Dstdt-Tg4 dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies Dstdt pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis. PMID:26043942
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Engram formation in psychiatric disorders.
Gebicke-Haerter, Peter J
2014-01-01
Environmental factors substantially influence beginning and progression of mental illness, reinforcing or reducing the consequences of genetic vulnerability. Often initiated by early traumatic events, "engrams" or memories are formed that may give rise to a slow and subtle progression of psychiatric disorders. The large delay between beginning and time of onset (diagnosis) may be explained by efficient compensatory mechanisms observed in brain metabolism that use optional pathways in highly redundant molecular interactions. To this end, research has to deal with mechanisms of learning and long-term memory formation, which involves (a) epigenetic changes, (b) altered neuronal activities, and (c) changes in neuron-glia communication. On the epigenetic level, apparently DNA-methylations are more stable than histone modifications, although both closely interact. Neuronal activities basically deliver digital information, which clearly can serve as basis for memory formation (LTP). However, research in this respect has long time neglected the importance of glia. They are more actively involved in the control of neuronal activities than thought before. They can both reinforce and inhibit neuronal activities by transducing neuronal information from frequency-encoded to amplitude and frequency-modulated calcium wave patterns spreading in the glial syncytium by use of gap junctions. In this way, they serve integrative functions. In conclusion, we are dealing with two concepts of encoding information that mutually control each other and synergize: a digital (neuronal) and a wave-like (glial) computing, forming neuron-glia functional units with inbuilt feedback loops to maintain balance of excitation and inhibition. To better understand mental illness, we have to gain more insight into the dynamics of adverse environmental impact on those cellular and molecular systems. This report summarizes existing knowledge and draws some outline about further research in molecular psychiatry.
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Engram formation in psychiatric disorders
Gebicke-Haerter, Peter J.
2014-01-01
Environmental factors substantially influence beginning and progression of mental illness, reinforcing or reducing the consequences of genetic vulnerability. Often initiated by early traumatic events, “engrams” or memories are formed that may give rise to a slow and subtle progression of psychiatric disorders. The large delay between beginning and time of onset (diagnosis) may be explained by efficient compensatory mechanisms observed in brain metabolism that use optional pathways in highly redundant molecular interactions. To this end, research has to deal with mechanisms of learning and long-term memory formation, which involves (a) epigenetic changes, (b) altered neuronal activities, and (c) changes in neuron-glia communication. On the epigenetic level, apparently DNA-methylations are more stable than histone modifications, although both closely interact. Neuronal activities basically deliver digital information, which clearly can serve as basis for memory formation (LTP). However, research in this respect has long time neglected the importance of glia. They are more actively involved in the control of neuronal activities than thought before. They can both reinforce and inhibit neuronal activities by transducing neuronal information from frequency-encoded to amplitude and frequency-modulated calcium wave patterns spreading in the glial syncytium by use of gap junctions. In this way, they serve integrative functions. In conclusion, we are dealing with two concepts of encoding information that mutually control each other and synergize: a digital (neuronal) and a wave-like (glial) computing, forming neuron-glia functional units with inbuilt feedback loops to maintain balance of excitation and inhibition. To better understand mental illness, we have to gain more insight into the dynamics of adverse environmental impact on those cellular and molecular systems. This report summarizes existing knowledge and draws some outline about further research in molecular psychiatry. PMID:24904262
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Edgerton, Jeremy R.; Jaeger, Dieter
2011-01-01
Correlated firing among populations of neurons is present throughout the brain and is often rhythmic in nature, observable as an oscillatory fluctuation in the local field potential. Although rhythmic population activity is believed to be critical for normal function in many brain areas, synchronized neural oscillations are associated with disease states in other cases. In the globus pallidus (GP in rodents, homolog of the primate GPe), pairs of neurons generally have uncorrelated firing in normal animals despite an anatomical organization suggesting that they should receive substantial common input. By contrast, correlated and rhythmic GP firing is observed in animal models of Parkinson's disease (PD). Based in part on these findings it has been proposed that an important part of basal ganglia function is active decorrelation, whereby redundant information is compressed. Mechanisms that implement active decorrelation, and changes that cause it to fail in PD, are subjects of great interest. Rat GP neurons express fast, transient voltage-dependent sodium channels (NaF channels) in their dendrites, with the expression level being highest near asymmetric synapses. We recently showed that the dendritic NaF density strongly influences the responsiveness of model GP neurons to synchronous excitatory inputs. In the present study we use rat GP neuron models to show that dendritic NaF channel expression is a potential cellular mechanism of active decorrelation. We further show that model neurons with lower dendritic NaF channel expression have a greater tendency to phase lock with oscillatory synaptic input patterns like those observed in PD. PMID:21795543
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Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate
Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian
2017-01-01
The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning. PMID:28220796
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Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.
Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian
2017-07-01
The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.
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Badowska-Szalewska, Ewa; Ludkiewicz, Beata; Krawczyk, Rafał; Melka, Natalia; Moryś, Janusz
2017-01-01
The way hippocampal neurons function during stress in old age (critical times of life) is dependent on brain derived neurotrophin factor (BDNF). This study examined the influence of acute and chronic forced swim (FS) or high-light open field (HL‑OF) stimulation on the density of BDNF immunoreactive (ir) neurons in the hippocampal pyramidal layers of CA1, CA2, CA3 regions and the granular layer of dentate gyrus (DG) in old (postnatal day 720; P720) Wistar Han rats. Our data showed that in comparison with non-stressed rats, acute FS caused a significant increase in the density of BDNF-ir neurons in CA2 and CA3, while acute HL-OF led to an increase in this factor in all hippocampal subfields with the exception of DG. However, the density of BDNF-ir cells remained unchanged after exposure to chronic FS or HL‑OF in the hippocampal regions in relation to the control rats. These results indicate that acute FS or HL-OF proved to be a stressor that induces an increase in the density of BDNF-ir pyramidal neurons, which was probably connected with up-regulation of HPA axis activity and short‑time memory processing of the stressful situation. Moreover, as far as the influence on BDNF-ir cells in hippocampus is concerned, chronic FS or HL-OF was not an aggravating factor for rats in the ontogenetic periods studied.
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Effects of the diet on brain function
NASA Technical Reports Server (NTRS)
Fernstrom, J. D.
1981-01-01
The rates of synthesis by brain neurons of the neurotransmitters serotonin, acetylcholine, and the catecholamines depend on the brain levels of the respective precursor molecules. Brain levels of each precursor are influenced by their blood concentration, and for the amino acid precursors, by the blood levels of other amino acids as well. Since diet readily alters blood concentrations of each of these precursors, it thereby also influences the brain formation of their neutrotransmitter products.
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Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer's disease
Kar, Satyabrata; Slowikowski, Stephen P.M.; Westaway, David; Mount, Howard T.J.
2004-01-01
Alzheimer's disease is an age-related neurodegenerative disorder that is characterized by a progressive loss of memory and deterioration of higher cognitive functions. The brain of an individual with Alzheimer's disease exhibits extracellular plaques of aggregated β-amyloid protein (Aβ), intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Aβ accumulation may trigger or contribute to the process of neurodegeneration. However, the mechanisms whereby Aβ induces basal forebrain cholinergic cell loss and cognitive impairment remain obscure. Physiologically relevant concentrations of Aβ-related peptides have acute, negative effects on multiple aspects of acetylcholine (ACh) synthesis and release, without inducing toxicity. These data suggest a neuromodulatory influence of the peptides on central cholinergic functions. Long-term exposure to micromolar Aβ induces cholinergic cell toxicity, possibly via hyperphosphorylation of tau protein. Conversely, activation of selected cholinergic receptors has been shown to alter the processing of the amyloid precursor protein as well as phosphorylation of tau protein. A direct interaction between Aβ and nicotinic ACh receptors has also been demonstrated. This review addresses the role of Aβ-related peptides in regulating the function and survival of central cholinergic neurons and the relevance of these effects to cholinergic deficits in Alzheimer's disease. Understanding the functional interrelations between Aβ peptides, cholinergic neurons and tau phosphorylation will unravel the biologic events that precede neurodegeneration and may lead to the development of more effective pharmacotherapies for Alzheimer's disease. PMID:15644984
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Terekhova, S F; Grechenko, T N
2003-01-01
The role of biologically active substances in ultra-low doses (10(-15)-10(-27) mol/l) is discussed from the different points of view. The most detailed analysis of neurobiological effects produced by these doses can be studied on the preparate of completely isolated molluscan neurones. In this case the possibility arises to control the first modifications of action at the electrophysiological characteristics of neuronal activity. These changes of electrical activity can be regarded as a reaction to biologically active substance. The following characteristics were controlled: the level of membrane resting potential (MP), the electroexcitable membrane and pacemaker mechanism, chemical sensitivity of somatic membrane loci to neurotransmitter acetylcholine (Ach). Several substances were used in these experiments: two kinds of synthetic antioxidant, GABA, ethanol, serotonine, DSIP (delta-sleep inducing peptide), antibiotic ruboxil, nootrop GVS-111. The isolated neurones were placed into the special chamber. All these substances (0.35 ml) were added single dosing into this chamber with living physiological solution in concentration 10(-15)-10(-27) mol/l. The results demonstrated that all substances had initiated the development of prolonged neurophysiological responses. The intensities of neuronal reactions didn't depend in contact period on the concentration and on the type of substance. It is suggested that these data reveal the existence of unknown modes of regulation of neuronal functional states and presence of hidden channel for information transfer and receiving. This different way of regulation is extremely important influence living organisms.
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Potential clinical relevance of the 'little brain' on the mammalian heart.
Armour, J A
2008-02-01
It is hypothesized that the heart possesses a nervous system intrinsic to it that represents the final relay station for the co-ordination of regional cardiac indices. This 'little brain' on the heart is comprised of spatially distributed sensory (afferent), interconnecting (local circuit) and motor (adrenergic and cholinergic efferent) neurones that communicate with others in intrathoracic extracardiac ganglia, all under the tonic influence of central neuronal command and circulating catecholamines. Neurones residing from the level of the heart to the insular cortex form temporally dependent reflexes that control overlapping, spatially determined cardiac indices. The emergent properties that most of its components display depend primarily on sensory transduction of the cardiovascular milieu. It is further hypothesized that the stochastic nature of such neuronal interactions represents a stabilizing feature that matches cardiac output to normal corporal blood flow demands. Thus, with regard to cardiac disease states, one must consider not only cardiac myocyte dysfunction but also the fact that components within this neuroaxis may interact abnormally to alter myocyte function. This review emphasizes the stochastic behaviour displayed by most peripheral cardiac neurones, which appears to be a consequence of their predominant cardiac chemosensory inputs, as well as their complex functional interconnectivity. Despite our limited understanding of the whole, current data indicate that the emergent properties displayed by most neurones comprising the cardiac neuroaxis will have to be taken into consideration when contemplating the targeting of its individual components if predictable, long-term therapeutic benefits are to accrue.
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Self-referential forces are sufficient to explain different dendritic morphologies
Memelli, Heraldo; Torben-Nielsen, Benjamin; Kozloski, James
2013-01-01
Dendritic morphology constrains brain activity, as it determines first which neuronal circuits are possible and second which dendritic computations can be performed over a neuron's inputs. It is known that a range of chemical cues can influence the final shape of dendrites during development. Here, we investigate the extent to which self-referential influences, cues generated by the neuron itself, might influence morphology. To this end, we developed a phenomenological model and algorithm to generate virtual morphologies, which are then compared to experimentally reconstructed morphologies. In the model, branching probability follows a Galton–Watson process, while the geometry is determined by “homotypic forces” exerting influence on the direction of random growth in a constrained space. We model three such homotypic forces, namely an inertial force based on membrane stiffness, a soma-oriented tropism, and a force of self-avoidance, as directional biases in the growth algorithm. With computer simulations we explored how each bias shapes neuronal morphologies. We show that based on these principles, we can generate realistic morphologies of several distinct neuronal types. We discuss the extent to which homotypic forces might influence real dendritic morphologies, and speculate about the influence of other environmental cues on neuronal shape and circuitry. PMID:23386828
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Approach towards an integrative drug treatment of Alzheimer's disease.
Windisch, M
2000-01-01
At present pharmacotherapy of Alzheimer's disease (AD) is limited to acetylcholinesterase inhibitors. These drugs produce small, but consistent improvements of memory and global function, some are also positively influencing activities of daily living. This therapeutic approach neglects the complexity of AD and the fact that most of the degenerating neurons are not cholinergic. Acetylcholinesterase inhibitors are symptomatic drugs, with no influence on disease progression. There is a need for disease modifying compounds, or preventive drugs. Data are indicating that vitamin E has some ability to influence the disease progression. The potency of non-steroidal anti-inflammatory drugs (NSAIDs) or estrogen as preventive agents has to be explored further in prospective clinical studies. The initial hope in the use of naturally occurring neurotrophic factors, like nerve growth factor, to rescue cholinergic neurons from degeneration and to restore cognitive function has been disappointed in first, small clinical studies. The peptidergic drug Cerebrolysin exhibiting neurotrophic stimulation, neuroimmunotrophic regulation and induction of BBB glucose transporter expression, might be able to address the pathological changes of AD at different levels simultaneously. In addition to an impressive preclinical database, results from 3 placebo-controlled, double-blind studies demonstrate significant improvements of cognitive performance, global function and activities of daily living in AD patients. In all studies persisting improvements, up to 6 months after drug withdrawal, indicate a powerful disease modifying activity.
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Frédéric, Melissa Y; Lundin, Victor F; Whiteside, Matthew D; Cueva, Juan G; Tu, Domena K; Kang, S Y Catherine; Singh, Hansmeet; Baillie, David L; Hutter, Harald; Goodman, Miriam B; Brinkman, Fiona S L; Leroux, Michel R
2013-01-01
The evolution of metazoans from their choanoflagellate-like unicellular ancestor coincided with the acquisition of novel biological functions to support a multicellular lifestyle, and eventually, the unique cellular and physiological demands of differentiated cell types such as those forming the nervous, muscle and immune systems. In an effort to understand the molecular underpinnings of such metazoan innovations, we carried out a comparative genomics analysis for genes found exclusively in, and widely conserved across, metazoans. Using this approach, we identified a set of 526 core metazoan-specific genes (the 'metazoanome'), approximately 10% of which are largely uncharacterized, 16% of which are associated with known human disease, and 66% of which are conserved in Trichoplax adhaerens, a basal metazoan lacking neurons and other specialized cell types. Global analyses of previously-characterized core metazoan genes suggest a prevalent property, namely that they act as partially redundant modifiers of ancient eukaryotic pathways. Our data also highlights the importance of exaptation of pre-existing genetic tools during metazoan evolution. Expression studies in C. elegans revealed that many metazoan-specific genes, including tubulin folding cofactor E-like (TBCEL/coel-1), are expressed in neurons. We used C. elegans COEL-1 as a representative to experimentally validate the metazoan-specific character of our dataset. We show that coel-1 disruption results in developmental hypersensitivity to the microtubule drug paclitaxel/taxol, and that overexpression of coel-1 has broad effects during embryonic development and perturbs specialized microtubules in the touch receptor neurons (TRNs). In addition, coel-1 influences the migration, neurite outgrowth and mechanosensory function of the TRNs, and functionally interacts with components of the tubulin acetylation/deacetylation pathway. Together, our findings unveil a conserved molecular toolbox fundamental to metazoan biology that contains a number of neuronally expressed and disease-related genes, and reveal a key role for TBCEL/coel-1 in regulating microtubule function during metazoan development and neuronal differentiation.
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Builee, T L; Hatherill, J R
2004-11-01
Thyroid hormones (TH) are essential to normal brain development, influencing behavior and cognitive function in both adult and children. It is suggested that conditions found in TH abnormalities such as hypothyroidism, hyperthyroidism and generalized resistance to thyroid hormone (GRTH) share symptomatic behavioral impulses found in cases of attention deficit hyperactivity disorder (ADHD) and other cognitive disorders. Disrupters of TH are various and prevalent in the environment. This paper reviews the mechanisms of TH disruption caused by the general class of polyhalogenated aromatic hydrocarbons (PHAH)'s acting as thyroid disrupters (TD). PHAHs influence the hypothalamus-pituitary-thyroid (HPT) axis, as mimicry agents affecting synthesis and secretion of TH. Exposure to PHAH induces liver microsomal enzymes UDP-glucuronosyltransferase (UGT) resulting in accelerated clearance of TH. PHAHs can compromise function of transport and receptor binding proteins such as transthyretin and aryl hydrocarbon receptors (Ahr). Glucose metabolism and catecholamine synthesis are disrupted in the brain by the presence of PHAH. Further, PHAH can alter brain growth and development by perturbing cytoskeletal formation, thereby affecting neuronal migration, elongation and branching. The complex relationships between PHAH and cognitive function are examined in regard to the disruption of T4 regulation in the hypothalamus-pituitary-thyroid axis, blood, brain, neurons, liver and pre and postnatal development.
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Song, Mi-Ryoung; Sun, Yunfu; Bryson, Ami; Gill, Gordon N.; Evans, Sylvia M.; Pfaff, Samuel L.
2009-01-01
Summary LIM transcription factors bind to nuclear LIM interactor (Ldb/NLI/Clim) in specific ratios to form higher-order complexes that regulate gene expression. Here we examined how the dosage of LIM homeodomain proteins Isl1 and Isl2 and LIM-only protein Lmo4 influences the assembly and function of complexes involved in the generation of spinal motor neurons (MNs) and V2a interneurons (INs). Reducing the levels of Islet proteins using a graded series of mutations favored V2a IN differentiation at the expense of MN formation. Although LIM-only proteins (LMOs) are predicted to antagonize the function of Islet proteins, we found that the presence or absence of Lmo4 had little influence on MN or V2a IN specification. We did find, however, that the loss of MNs resulting from reduced Islet levels was rescued by eliminating Lmo4, unmasking a functional interaction between these proteins. Our findings demonstrate that MN and V2a IN fates are specified by distinct complexes that are sensitive to the relative stoichiometries of the constituent factors and we present a model to explain how LIM domain proteins modulate these complexes and, thereby, this binary-cell-fate decision. PMID:19666821
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Phase synchronization motion and neural coding in dynamic transmission of neural information.
Wang, Rubin; Zhang, Zhikang; Qu, Jingyi; Cao, Jianting
2011-07-01
In order to explore the dynamic characteristics of neural coding in the transmission of neural information in the brain, a model of neural network consisting of three neuronal populations is proposed in this paper using the theory of stochastic phase dynamics. Based on the model established, the neural phase synchronization motion and neural coding under spontaneous activity and stimulation are examined, for the case of varying network structure. Our analysis shows that, under the condition of spontaneous activity, the characteristics of phase neural coding are unrelated to the number of neurons participated in neural firing within the neuronal populations. The result of numerical simulation supports the existence of sparse coding within the brain, and verifies the crucial importance of the magnitudes of the coupling coefficients in neural information processing as well as the completely different information processing capability of neural information transmission in both serial and parallel couplings. The result also testifies that under external stimulation, the bigger the number of neurons in a neuronal population, the more the stimulation influences the phase synchronization motion and neural coding evolution in other neuronal populations. We verify numerically the experimental result in neurobiology that the reduction of the coupling coefficient between neuronal populations implies the enhancement of lateral inhibition function in neural networks, with the enhancement equivalent to depressing neuronal excitability threshold. Thus, the neuronal populations tend to have a stronger reaction under the same stimulation, and more neurons get excited, leading to more neurons participating in neural coding and phase synchronization motion.
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NASA Technical Reports Server (NTRS)
Stegenga, S. L.; Kalb, R. G.
2001-01-01
Spinal motor neurons undergo experience-dependent development during a critical period in early postnatal life. It has been suggested that the repertoire of glutamate receptor subunits differs between young and mature motor neurons and contributes to this activity-dependent development. In the present study we examined the expression patterns of N-methyl-D-aspartate- and kainate-type glutamate receptor subunits during the postnatal maturation of the spinal cord. Young motor neurons express much higher levels of the N-methyl-D-aspartate receptor subunit NR1 than do adult motor neurons. Although there are eight potential splice variants of NR1, only a subgroup is expressed by motor neurons. With respect to NR2 receptor subunits, young motor neurons express NR2A and C, while adult motor neurons express only NR2A. Young motor neurons express kainate receptor subunits GluR5, 6 and KA2 but we are unable to detect these or any other kainate receptor subunits in the adult spinal cord. Other spinal cord regions display a distinct pattern of developmental regulation of N-methyl-D-aspartate and kainate receptor subunit expression in comparison to motor neurons. Our findings indicate a precise spatio-temporal regulation of individual subunit expression in the developing spinal cord. Specific combinations of subunits in developing neurons influence their excitable properties and could participate in the emergence of adult neuronal form and function.
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Laurent, Vincent; Bertran-Gonzalez, Jesus; Chieng, Billy C.
2014-01-01
Decision-making depends on the ability to extract predictive information from the environment to guide future actions. Outcome-specific Pavlovian-instrumental transfer (PIT) provides an animal model of this process in which a stimulus predicting a particular outcome biases choice toward actions earning that outcome. Recent evidence suggests that cellular adaptations of δ-opioid receptors (DORs) on cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) are necessary for PIT. Here we found that modulation of DORs in CINs critically influences D1-receptor (D1R)-expressing projection neurons in the NAc-S to promote PIT. First, we assessed PIT-induced changes in signaling processes in dopamine D1- and D2-receptor-expressing neurons using drd2-eGFP mice, and found that PIT-related signaling was restricted to non-D2R-eGFP-expressing neurons, suggesting major involvement of D1R-neurons. Next we confirmed the role of D1Rs pharmacologically: the D1R antagonist SCH-23390, but not the D2R antagonist raclopride, infused into the NAc-S abolished PIT in rats, an effect that depended on DOR activity. Moreover, asymmetrical infusion of SCH-23390 and the DOR antagonist naltrindole into the NAc-S also abolished PIT. DOR agonists were found to sensitize the firing responses of CINs in brain slices prepared immediately after the PIT test. We confirmed the opioid-acetylcholinergic influence over D1R-neurons by selectively blocking muscarinic M4 receptors in the NAc-S, which tightly regulate the activity of D1Rs, a treatment that rescued the deficit in PIT induced by naltrindole. We describe a model of NAc-S function in which DORs modulate CINs to influence both D1R-neurons and stimulus-guided choice between goal-directed actions. PMID:24453326
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Ortner, Marion; Kurz, Alexander; Alexopoulos, Panagiotis; Auer, Florian; Diehl-Schmid, Janine; Drzezga, Alexander; Förster, Stefan; Förstl, Hans; Perneczky, Robert; Sorg, Christian; Yousefi, Behrooz H; Grimmer, Timo
2015-04-15
There is controversy concerning whether Alzheimer's disease (AD) with early onset is distinct from AD with late onset with regard to amyloid pathology and neuronal metabolic deficit. We hypothesized that compared with patients with early-onset AD, patients with late-onset AD have more comorbid small vessel disease (SVD) contributing to clinical severity, whereas there are no differences in amyloid pathology and neuronal metabolic deficit. The study included two groups of patients with probable AD dementia with evidence of the AD pathophysiologic process: 24 patients with age at onset <60 years old and 36 patients with age at onset >70 years old. Amyloid deposition was assessed using carbon-11-labeled Pittsburgh compound B positron emission tomography, comorbid SVD was assessed using magnetic resonance imaging, and neuronal metabolic deficit was assessed using fluorodeoxyglucose positron emission tomography. Group differences of global and regional distribution of pathology were explored using region of interest and voxel-based analyses, respectively, carefully controlling for the influence of dementia severity, apolipoprotein E genotype, and in particular SVD. The pattern of cognitive impairment was determined using z scores of the subtests of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery. Patients with late-onset AD showed a significantly greater amount of SVD. No statistically significant differences in global or regional amyloid deposition or neuronal metabolic deficit between the two groups were revealed. However, when not controlling for SVD, subtle differences in fluorodeoxyglucose uptake between early-onset AD and late-onset AD groups were detectable. There were no significant differences regarding cognitive functioning. Age at onset does not influence amyloid deposition or neuronal metabolic deficit in AD. The greater extent of SVD in late-onset AD influences the association between neuronal metabolic deficit and clinical symptoms. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Hippocampal “Time Cells”: Time versus Path Integration
Kraus, Benjamin J.; Robinson, Robert J.; White, John A.; Eichenbaum, Howard; Hasselmo, Michael E.
2014-01-01
SUMMARY Recent studies have reported the existence of hippocampal “time cells,” neurons that fire at particular moments during periods when behavior and location are relatively constant. However, an alternative explanation of apparent time coding is that hippocampal neurons “path integrate” to encode the distance an animal has traveled. Here, we examined hippocampal neuronal firing patterns as rats ran in place on a treadmill, thus “clamping” behavior and location, while we varied the treadmill speed to distinguish time elapsed from distance traveled. Hippocampal neurons were strongly influenced by time and distance, and less so by minor variations in location. Furthermore, the activity of different neurons reflected integration over time and distance to varying extents, with most neurons strongly influenced by both factors and some significantly influenced by only time or distance. Thus, hippocampal neuronal networks captured both the organization of time and distance in a situation where these dimensions dominated an ongoing experience. PMID:23707613
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Ogawa, Fumiaki; Murphy, Laura C; Malavasi, Elise L V; O'Sullivan, Shane T; Torrance, Helen S; Porteous, David J; Millar, J Kirsty
2016-05-18
Mitochondria are essential for neuronal function, providing the energy required to power neurotransmission, and fulfilling many important additional roles. In neurons, mitochondria must be efficiently transported to sites, including synapses, where their functions are required. Neurons, with their highly elongated morphology, are consequently extremely sensitive to defective mitochondrial trafficking which can lead to neuronal ill-health/death. We recently demonstrated that DISC1 associates with mitochondrial trafficking complexes where it associates with the core kinesin and dynein adaptor molecule TRAK1. We now show that the DISC1 interactors NDE1 and GSK3β also associate robustly with TRAK1 and demonstrate that NDE1 promotes retrograde axonal mitochondrial movement. GSK3β is known to modulate axonal mitochondrial motility, although reports of its actual effect are conflicting. We show that, in our system, GSK3β promotes anterograde mitochondrial transport. Finally, we investigated the influence of cAMP elevation upon mitochondrial motility, and found a striking increase in mitochondrial motility and retrograde movement. DISC1, NDE1, and GSK3β are implicated as risk factors for major mental illness. Our demonstration that they function together within mitochondrial trafficking complexes suggests that defective mitochondrial transport may be a contributory disease mechanism in some cases of psychiatric disorder.
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Pigment-Dispersing Factor-expressing neurons convey circadian information in the honey bee brain
Beer, Katharina; Kolbe, Esther; Kahana, Noa B.; Yayon, Nadav; Weiss, Ron; Menegazzi, Pamela; Bloch, Guy
2018-01-01
Pigment-Dispersing Factor (PDF) is an important neuropeptide in the brain circadian network of Drosophila and other insects, but its role in bees in which the circadian clock influences complex behaviour is not well understood. We combined high-resolution neuroanatomical characterizations, quantification of PDF levels over the day and brain injections of synthetic PDF peptide to study the role of PDF in the honey bee Apis mellifera. We show that PDF co-localizes with the clock protein Period (PER) in a cluster of laterally located neurons and that the widespread arborizations of these PER/PDF neurons are in close vicinity to other PER-positive cells (neurons and glia). PDF-immunostaining intensity oscillates in a diurnal and circadian manner with possible influences for age or worker task on synchrony of oscillations in different brain areas. Finally, PDF injection into the area between optic lobes and the central brain at the end of the subjective day produced a consistent trend of phase-delayed circadian rhythms in locomotor activity. Altogether, these results are consistent with the hypothesis that PDF is a neuromodulator that conveys circadian information from pacemaker cells to brain centres involved in diverse functions including locomotion, time memory and sun-compass orientation. PMID:29321240
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Trujillo-Paredes, Niurka; Valencia, Concepción; Guerrero-Flores, Gilda; Arzate, Dulce-María; Baizabal, José-Manuel; Guerra-Crespo, Magdalena; Fuentes-Hernández, Ayari; Zea-Armenta, Iván; Covarrubias, Luis
2016-01-01
ABSTRACT Notch signalling is a well-established pathway that regulates neurogenesis. However, little is known about the role of Notch signalling in specific neuronal differentiation. Using Dll1 null mice, we found that Notch signalling has no function in the specification of mesencephalic dopaminergic neural precursor cells (NPCs), but plays an important role in regulating their expansion and differentiation into neurons. Premature neuronal differentiation was observed in mesencephalons of Dll1-deficient mice or after treatment with a Notch signalling inhibitor. Coupling between neurogenesis and dopaminergic differentiation was indicated from the coincident emergence of neuronal and dopaminergic markers. Early in differentiation, decreasing Notch signalling caused a reduction in NPCs and an increase in dopaminergic neurons in association with dynamic changes in the proportion of sequentially-linked dopaminergic NPCs (Msx1/2+, Ngn2+, Nurr1+). These effects in differentiation caused a significant reduction in the number of dopaminergic neurons produced. Accordingly, Dll1 haploinsufficient adult mice, in comparison with their wild-type littermates, have a consistent reduction in neuronal density that was particularly evident in the substantia nigra pars compacta. Our results are in agreement with a mathematical model based on a Dll1-mediated regulatory feedback loop between early progenitors and their dividing precursors that controls the emergence and number of dopaminergic neurons. PMID:26912775
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Trujillo-Paredes, Niurka; Valencia, Concepción; Guerrero-Flores, Gilda; Arzate, Dulce-María; Baizabal, José-Manuel; Guerra-Crespo, Magdalena; Fuentes-Hernández, Ayari; Zea-Armenta, Iván; Covarrubias, Luis
2016-02-24
Notch signalling is a well-established pathway that regulates neurogenesis. However, little is known about the role of Notch signalling in specific neuronal differentiation. Using Dll1 null mice, we found that Notch signalling has no function in the specification of mesencephalic dopaminergic neural precursor cells (NPCs), but plays an important role in regulating their expansion and differentiation into neurons. Premature neuronal differentiation was observed in mesencephalons of Dll1-deficient mice or after treatment with a Notch signalling inhibitor. Coupling between neurogenesis and dopaminergic differentiation was indicated from the coincident emergence of neuronal and dopaminergic markers. Early in differentiation, decreasing Notch signalling caused a reduction in NPCs and an increase in dopaminergic neurons in association with dynamic changes in the proportion of sequentially-linked dopaminergic NPCs (Msx1/2+, Ngn2+, Nurr1+). These effects in differentiation caused a significant reduction in the number of dopaminergic neurons produced. Accordingly, Dll1 haploinsufficient adult mice, in comparison with their wild-type littermates, have a consistent reduction in neuronal density that was particularly evident in the substantia nigra pars compacta. Our results are in agreement with a mathematical model based on a Dll1-mediated regulatory feedback loop between early progenitors and their dividing precursors that controls the emergence and number of dopaminergic neurons. © 2016. Published by The Company of Biologists Ltd.
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Zagrebelsky, Marta; Lonnemann, Niklas; Fricke, Steffen; Kellner, Yves; Preuß, Eike; Michaelsen-Preusse, Kristin; Korte, Martin
2017-02-01
Behavioral learning has been shown to involve changes in the function and structure of synaptic connections of the central nervous system (CNS). On the other hand, the neuronal circuitry in the mature brain is characterized by a high degree of stability possibly providing a correlate for long-term storage of information. This observation indicates the requirement for a set of molecules inhibiting plasticity and promoting stability thereby providing temporal and spatial specificity to plastic processes. Indeed, signaling of Nogo-A via its receptors has been shown to play a crucial role in restricting activity-dependent functional and structural plasticity in the adult CNS. However, whether Nogo-A controls learning and memory formation and what are the cellular and molecular mechanisms underlying this function is still unclear. Here we show that Nogo-A signaling controls spatial learning and reference memory formation upon training in the Morris water maze and negatively modulates structural changes at spines in the mouse hippocampus. Learning processes and the correlated structural plasticity have been shown to involve changes in excitatory as well as in inhibitory neuronal connections. We show here that Nogo-A is highly expressed not only in excitatory, but also in inhibitory, Parvalbumin positive neurons in the adult hippocampus. By this means our current and previous data indicate that Nogo-A loss-of-function positively influences spatial learning by priming the neuronal structure to a higher plasticity level. Taken together our results link the role of Nogo-A in negatively regulating plastic processes to a physiological function in controlling learning and memory processes in the mature hippocampus and open the interesting possibility that it might mainly act by controlling the function of the hippocampal inhibitory circuitry. Copyright © 2016 Elsevier Inc. All rights reserved.
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Klawonn, Anna M; Wilhelms, Daniel B; Lindström, Sarah H; Singh, Anand Kumar; Jaarola, Maarit; Wess, Jürgen; Fritz, Michael; Engblom, David
2018-01-01
The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression ( cFos and FosB ) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.
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Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice.
Mabe, Abigail M; Hoover, Donald B
2009-04-01
Previous work provided indirect evidence that the neurotrophic factor neurturin (NRTN) is required for normal cholinergic innervation of the heart. This study used nrtn knockout (KO) and wild-type (WT) mice to determine the effect of nrtn deletion on cardiac cholinergic innervation and function in the adult heart. Immunohistochemistry, confocal microscopy, and quantitative image analysis were used to directly evaluate intrinsic cardiac neuronal development. Atrial acetylcholine (ACh) levels were determined as an indirect index of cholinergic innervation. Cholinergic function was evaluated by measuring negative chronotropic responses to right vagal nerve stimulation in anaesthetized mice and responses of isolated atria to muscarinic agonists. KO hearts contained only 35% the normal number of cholinergic neurons, and the residual cholinergic neurons were 15% smaller than in WT. Cholinergic nerve density at the sinoatrial node was reduced by 87% in KOs, but noradrenergic nerve density was unaffected. Atrial ACh levels were substantially lower in KO mice (0.013 +/- 0.004 vs. 0.050 +/- 0.011 pmol/microg protein; P < 0.02) as expected from cholinergic neuron and nerve fibre deficits. Maximum bradycardia evoked by vagal stimulation was reduced in KO mice (38 +/- 6% vs. 69 +/- 3% decrease at 20 Hz; P < 0.001), and chronotropic responses took longer to develop and fade. In contrast to these deficits, isolated atria from KO mice had normal post-junctional sensitivity to carbachol and bethanechol. These findings demonstrate that NRTN is essential for normal cardiac cholinergic innervation and cholinergic control of heart rate. The presence of residual cardiac cholinergic neurons and vagal bradycardia in KO mice suggests that additional neurotrophic factors may influence this system.
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Sharma, Jitendra; Sugihara, Hiroki; Katz, Yarden; Schummers, James; Tenenbaum, Joshua; Sur, Mriganka
2015-01-01
The brain uses attention and expectation as flexible devices for optimizing behavioral responses associated with expected but unpredictably timed events. The neural bases of attention and expectation are thought to engage higher cognitive loci; however, their influence at the level of primary visual cortex (V1) remains unknown. Here, we asked whether single-neuron responses in monkey V1 were influenced by an attention task of unpredictable duration. Monkeys covertly attended to a spot that remained unchanged for a fixed period and then abruptly disappeared at variable times, prompting a lever release for reward. We show that monkeys responded progressively faster and performed better as the trial duration increased. Neural responses also followed monkey's task engagement—there was an early, but short duration, response facilitation, followed by a late but sustained increase during the time monkeys expected the attention spot to disappear. This late attentional modulation was significantly and negatively correlated with the reaction time and was well explained by a modified hazard function. Such bimodal, time-dependent changes were, however, absent in a task that did not require explicit attentional engagement. Thus, V1 neurons carry reliable signals of attention and temporal expectation that correlate with predictable influences on monkeys' behavioral responses. PMID:24836689
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Influence of Inflammation on Poststroke Plasticity
Kossut, Malgorzata
2013-01-01
Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke. PMID:23533818
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Lanni, C; Stanga, S; Racchi, M; Govoni, S
2010-01-01
Multiple molecular, cellular, structural and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively by employing multiple mechanisms in order to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands. Otherwise, they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. An important role in this balancement is played by neurotrophic factors, which are central to many aspects of nervous system function since they regulate the development, maintenance and survival of neurons and neuron-supporting cells such as glia and oligodendrocytes. A vast amount of evidence indicates that alterations in levels of neurotrophic factors or their receptors can lead to neuronal death and contribute to aging as well as to the pathogenesis of diseases of abnormal trophic support (such as neurodegenerative diseases and depression) and diseases of abnormal excitability (such as epilepsy and central pain sensitization). Cellular and molecular mechanisms by which neurotrophic factors may influence cell survival and excitability are also critically examined to provide novel concepts and targets for the treatment of physiological changes bearing detrimental functional alterations and of different diseases affecting the central nervous system during aging.
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Microglia During Development and Aging
Harry, G. Jean
2013-01-01
Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, andaxonal degeneration. Changes inmicroglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microgliapotentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. PMID:23644076
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Fujita, Akie; Bonnavion, Patricia; Wilson, Miryam H; Mickelsen, Laura E; Bloit, Julien; de Lecea, Luis; Jackson, Alexander C
2017-09-27
Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons ( Hdc -Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal. Copyright © 2017 the authors 0270-6474/17/379575-19$15.00/0.
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Fujita, Akie; Mickelsen, Laura E.; Bloit, Julien
2017-01-01
Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (Hdc-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep–wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo. We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal. PMID:28874450
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NASA Astrophysics Data System (ADS)
Bukoski, Alex; Steyn-Ross, D. A.; Pickett, Ashley F.; Steyn-Ross, Moira L.
2018-06-01
The dynamics of a stochastic type-I Hodgkin-Huxley-like point neuron model exposed to inhibitory synaptic noise are investigated as a function of distance from spiking threshold and the inhibitory influence of the general anesthetic agent propofol. The model is biologically motivated and includes the effects of intrinsic ion-channel noise via a stochastic differential equation description as well as inhibitory synaptic noise modeled as multiple Poisson-distributed impulse trains with saturating response functions. The effect of propofol on these synapses is incorporated through this drug's principal influence on fast inhibitory neurotransmission mediated by γ -aminobutyric acid (GABA) type-A receptors via reduction of the synaptic response decay rate. As the neuron model approaches spiking threshold from below, we track membrane voltage fluctuation statistics of numerically simulated stochastic trajectories. We find that for a given distance from spiking threshold, increasing the magnitude of anesthetic-induced inhibition is associated with augmented signatures of critical slowing: fluctuation amplitudes and correlation times grow as spectral power is increasingly focused at 0 Hz. Furthermore, as a function of distance from threshold, anesthesia significantly modifies the power-law exponents for variance and correlation time divergences observable in stochastic trajectories. Compared to the inverse square root power-law scaling of these quantities anticipated for the saddle-node bifurcation of type-I neurons in the absence of anesthesia, increasing anesthetic-induced inhibition results in an observable exponent <-0.5 for variance and >-0.5 for correlation time divergences. However, these behaviors eventually break down as distance from threshold goes to zero with both the variance and correlation time converging to common values independent of anesthesia. Compared to the case of no synaptic input, linearization of an approximating multivariate Ornstein-Uhlenbeck model reveals these effects to be the consequence of an additional slow eigenvalue associated with synaptic activity that competes with those of the underlying point neuron in a manner that depends on distance from spiking threshold.
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Zhang, Xueguo; Cui, Jinjuan; Tan, Zhenjun; Jiang, Chunhui; Fogel, Ronald
2003-01-01
Using retrograde tract-tracing and electrophysiological methods, we characterized the anatomical and functional relationship between the central nucleus of the amygdala and the dorsal vagal complex. Retrograde tract-tracing techniques revealed that the central nucleus of the amygdala projects to the dorsal vagal complex with a topographic distribution. Following injection of retrograde tracer into the vagal complex, retrogradely labelled neurons in the central nucleus of the amygdala were clustered in the central portion at the rostral level and in the medial part at the middle level of the nucleus. Few labelled neurons were seen at the caudal level. Electrical stimulation of the central nucleus of the amygdala altered the basal firing rates of 65 % of gut-related neurons in the nucleus of the solitary tract and in the dorsal motor nucleus of the vagus. Eighty-one percent of the neurons in the nucleus of the solitary tract and 47 % of the neurons in the dorsal motor nucleus were inhibited. Electrical stimulation of the central nucleus of the amygdala also modulated the response of neurons in the dorsal vagal complex to gastrointestinal stimuli. The predominant effect on the neurons of the nucleus of the solitary tract was inhibition. These results suggest that the central nucleus of the amygdala influences gut-related neurons in the dorsal vagal complex and provides a neuronal circuitry that explains the regulation of gastrointestinal activity by the amygdala. PMID:14555729
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Szabo, Miruna; Deco, Gustavo; Fusi, Stefano; Del Giudice, Paolo; Mattia, Maurizio; Stetter, Martin
2006-05-01
Recent experiments on behaving monkeys have shown that learning a visual categorization task makes the neurons in infero-temporal cortex (ITC) more selective to the task-relevant features of the stimuli (Sigala and Logothetis in Nature 415 318-320, 2002). We hypothesize that such a selectivity modulation emerges from the interaction between ITC and other cortical area, presumably the prefrontal cortex (PFC), where the previously learned stimulus categories are encoded. We propose a biologically inspired model of excitatory and inhibitory spiking neurons with plastic synapses, modified according to a reward based Hebbian learning rule, to explain the experimental results and test the validity of our hypothesis. We assume that the ITC neurons, receiving feature selective inputs, form stronger connections with the category specific neurons to which they are consistently associated in rewarded trials. After learning, the top-down influence of PFC neurons enhances the selectivity of the ITC neurons encoding the behaviorally relevant features of the stimuli, as observed in the experiments. We conclude that the perceptual representation in visual areas like ITC can be strongly affected by the interaction with other areas which are devoted to higher cognitive functions.
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Microglia in the Retina: Roles in Development, Maturity, and Disease.
Silverman, Sean M; Wong, Wai T
2018-05-31
Microglia, the primary resident immune cell type, constitute a key population of glia in the retina. Recent evidence indicates that microglia play significant functional roles in the retina at different life stages. During development, retinal microglia regulate neuronal survival by exerting trophic influences and influencing programmed cell death. During adulthood, ramified microglia in the plexiform layers interact closely with synapses to maintain synaptic structure and function that underlie the retina's electrophysiological response to light. Under pathological conditions, retinal microglia participate in potentiating neurodegeneration in diseases such as glaucoma, retinitis pigmentosa, and age-related neurodegeneration by producing proinflammatory neurotoxic cytokines and removing living neurons via phagocytosis. Modulation of pathogenic microglial activation states and effector mechanisms has been linked to neuroprotection in animal models of retinal diseases. These findings have led to the design of early proof-of-concept clinical trials with microglial modulation as a therapeutic strategy. Expected final online publication date for the Annual Review of Vision Science Volume 4 is September 15, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Keohane, Aoife; Ryan, Sinead; Maloney, Eimer; Sullivan, Aideen M; Nolan, Yvonne M
2010-01-01
Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1. Copyright 2009 Elsevier Inc. All rights reserved.
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Sensory and motor properties of the cerebellar uvula and modulus
NASA Technical Reports Server (NTRS)
Robinson, F. R.
1985-01-01
The uvula and nodulus (vermal lobules 9 and 10) of the vestibulocerebellum are implicated by behavioral evidence in the control of eye and head movements and in the production of motion sickness. The uvula and nodulus could play a role in these functions through known output pathways. Purkinje cells in both structures project via the fastigial and vestibular nuceli to the ventral horn of the cervical spin cord, to oculomotor neurons, and to the emetic region of the reticular formation (ablation of which abolishes susceptability to motion sickness). Uvula and nodulus Purkinje cells will be analyzed in cats trained to make controlled head movements. The activity of these neurons is expected to modulate well during head and/or eye movements because the uvula and nodulus receive heavy projections from sources of visual, vestibular and neck proprioceptive information. How neuron activity contributes to movement and how different sensory inputs converge to influence this contribution may be determined by characterizing movement related properties of these neurons. A population of neurons that modulates powerfully to the conflict between different head movement signals that can cause motion sickness may be identified.
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Vallano, M L; Beaman-Hall, C M; Mathur, A; Chen, Q
2000-04-01
Multiple isoforms of type II Ca(2+)-calmodulin-dependent kinase (CaM KII) are composed of two major neuron-specific subunits, designated alpha and beta, and two less well-characterized subunits that are also expressed in non-neuronal tissues, designated delta and gamma. Regulated expression of these 4 gene products, and several variants produced by alternative splicing, shows temporal and regional specificity and influences intracellular targeting. We used immunoblotting and RT-PCR to analyze subunit and variant expression and distribution in cultured cerebellar astrocytes and neurons, and whole cerebellar cortex from rodent brain. The data indicate that: (i) astrocytes express a single splice variant of delta, namely delta(2); (ii) like neurons, astrocytes express two forms of CaM KII gamma; gamma(B) and gamma(A); (iii) these CaM KII variants are enriched in the supernate fraction in astrocytes, and the particulate fraction in neurons; (iv) unlike neurons, astrocytes do not express detectable levels of alpha or beta subunits or their respective splice variants. The results indicate that neurons and astrocytes express distinct CaM KII subunits and variants that localize to distinct subcellular compartments and, by inference, exert distinct cellular functions. Copyright 2000 Wiley-Liss, Inc.
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Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting.
Morozova, Ekaterina O; Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C; Kuznetsov, Alexey
2016-10-01
In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca 2+ ) concentration, thus reducing the Ca 2+ -dependent potassium (K + ) current. In this way, the GABA-mediated hyperpolarization replaces Ca 2+ -dependent K + current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally. Copyright © 2016 the American Physiological Society.
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Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting
Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C.; Kuznetsov, Alexey
2016-01-01
In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally. PMID:27440240
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Lien, Anthony D.; Scanziani, Massimo
2011-01-01
Relating the functional properties of neurons in an intact organism with their cellular and synaptic characteristics is necessary for a mechanistic understanding of brain function. However, while the functional properties of cortical neurons (e.g., tuning to sensory stimuli) are necessarily determined in vivo, detailed cellular and synaptic analysis relies on in vitro techniques. Here we describe an approach that combines in vivo calcium imaging (for functional characterization) with photo-activation of fluorescent proteins (for neuron labeling), thereby allowing targeted in vitro recording of multiple neurons with known functional properties. We expressed photo-activatable GFP rendered non-diffusible through fusion with a histone protein (H2B–PAGFP) in the mouse visual cortex to rapidly photo-label constellations of neurons in vivo at cellular and sub-cellular resolution using two-photon excitation. This photo-labeling method was compatible with two-photon calcium imaging of neuronal responses to visual stimuli, allowing us to label constellations of neurons with specific functional properties. Photo-labeled neurons were easily identified in vitro in acute brain slices and could be targeted for whole-cell recording. We also demonstrate that in vitro and in vivo image stacks of the same photo-labeled neurons could be registered to one another, allowing the exact in vivo response properties of individual neurons recorded in vitro to be known. The ability to perform in vitro recordings from neurons with known functional properties opens up exciting new possibilities for dissecting the cellular, synaptic, and circuit mechanisms that underlie neuronal function in vivo. PMID:22144948
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Firnhaber, Christopher; Hammarlund, Marc
2013-11-01
Forward genetic screens are important tools for exploring the genetic requirements for neuronal function. However, conventional forward screens often have difficulty identifying genes whose relevant functions are masked by pleiotropy. In particular, if loss of gene function results in sterility, lethality, or other severe pleiotropy, neuronal-specific functions cannot be readily analyzed. Here we describe a method in C. elegans for generating cell-specific knockdown in neurons using feeding RNAi and its application in a screen for the role of essential genes in GABAergic neurons. We combine manipulations that increase the sensitivity of select neurons to RNAi with manipulations that block RNAi in other cells. We produce animal strains in which feeding RNAi results in restricted gene knockdown in either GABA-, acetylcholine-, dopamine-, or glutamate-releasing neurons. In these strains, we observe neuron cell-type specific behavioral changes when we knock down genes required for these neurons to function, including genes encoding the basal neurotransmission machinery. These reagents enable high-throughput, cell-specific knockdown in the nervous system, facilitating rapid dissection of the site of gene action and screening for neuronal functions of essential genes. Using the GABA-specific RNAi strain, we screened 1,320 RNAi clones targeting essential genes on chromosomes I, II, and III for their effect on GABA neuron function. We identified 48 genes whose GABA cell-specific knockdown resulted in reduced GABA motor output. This screen extends our understanding of the genetic requirements for continued neuronal function in a mature organism.
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Various fates of neuronal progenitor cells observed on several different chemical functional groups
NASA Astrophysics Data System (ADS)
Liu, Xi; Wang, Ying; He, Jin; Wang, Xiu-Mei; Cui, Fu-Zhai; Xu, Quan-Yuan
2011-12-01
Neuronal progenitor cells cultured on gold-coated glass surfaces modified by different chemical functional groups, including hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), bromo (-Br), mercapto (-SH), - Phenyl and methyl (-CH3), were studied here to investigate the influence of surface chemistry on the cells' adhesion, morphology, proliferation and functional gene expression. Focal adhesion staining indicated in the initial culture stage cells exhibited morphological changes in response to different chemical functional groups. Cells cultured on -NH2 grafted surface displayed focal adhesion plaque and flattened morphology and had the largest contact area. However, their counter parts on -CH3 grafted surface displayed no focal adhesion and rounded morphology and had the smallest contact area. After 6 days culture, the proliferation trend was as follows: -NH2 > -SH> -COOH> - Phenyl > - Br > -OH> -CH3. To determine the neural functional properties of the cells affected by surface chemistry, the expression of glutamate decarboxylase (GAD67), nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) were characterized. An increase of GAD67 expression was observed on -NH2, -COOH and -SH grafted surfaces, while no increase in NGF and BDNF expression was observed on any chemical surfaces. These results highlight the importance of surface chemistry in the fate determination of neuronal progenitor cells, and suggest that surface chemistry must be considered in the design of biomaterials for neural tissue engineering.
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Allen, Emily; Coote, John H; Grubb, Blair D; Batten, Trevor Fc; Pauza, Dainius H; Ng, G André; Brack, Kieran E
2018-05-22
The intrinsic cardiac nervous system (ICNS) is a rich network of cardiac nerves that converge to form distinct ganglia and extend across the heart and is capable of influencing cardiac function. To provide a picture of the neurotransmitter/neuromodulator profile of the rabbit ICNS and determine the action of spatially divergent ganglia on cardiac electrophysiology. Nicotinic or electrical stimulation was applied at discrete sites of the intrinsic cardiac nerve plexus in the Langendorff perfused rabbit heart. Functional effects on sinus rate and atrioventricular conduction were measured. Immunohistochemistry for choline acetyltransferase (ChAT), tyrosine hydroxylase (TH) and/or neuronal nitric oxide synthase (nNOS) was performed on whole-mount preparations. Stimulation within all ganglia produced either bradycardia, tachycardia or a biphasic brady-tachycardia. Electrical stimulation of the right atrial (RA) and right neuronal cluster (RNC) regions produced the greatest chronotropic responses. Significant prolongation of atrioventricular conduction (AVC) was predominant at the pulmonary vein-caudal vein region (PVCV). Neurons immunoreactive (IR) only for ChAT, or TH or nNOS were consistently located within the limits of the hilum and at the roots of the right cranial and right pulmonary veins. ChAT-IR neurons were most abundant (1946±668 neurons). Neurons IR solely for nNOS were distributed within ganglia. Stimulation of intrinsic ganglia, shown to be of phenotypic complexity but predominantly of cholinergic nature, indicates that clusters of neurons are capable of independent selective effects on cardiac electrophysiology, therefore providing a potential therapeutic target for the prevention and treatment of cardiac disease. Copyright © 2018. Published by Elsevier Inc.
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Bukowska, Dorota; Mierzejewska-Krzyzowska, Barbara; Zguczyński, Leszek
2005-01-01
Projections of the nucleus reticularis tegmenti pontis (NRTP) to the cerebellar paramedian lobule were examined in the rabbit by means of the double fluorescent retrograde tract-tracing method. The rabbit NRTP is composed of a medial, large part comprising zones A (dorsomedial), B (central) and C (lateral), and of a lateral, small part (the processus tegmentosus lateralis; PTL). Following unilateral injections of Fast Blue (FB) into the rostral part of the paramedian lobule (rPML) and of Diamidino Yellow (DY) into the caudal part (cPML), known to receive spinal inputs from forelimb and hindlimb, respectively, substantial numbers of single labeled neurons were found in all bilateral NRTP divisions, apart from the zone C. Most projection neurons to the PML were located in the medial and medioventral regions of the zone B. Smaller numbers of projection neurons were located in the PTL, zone A and outside the zone B among fibers of the medial lemniscus. The pattern of FB and DY labeling suggested that neurons projecting to the rPML and cPML originated in common rather than separate regions within the NRTP. In addition, a small percentage (mean 1.3%) of double FB+DY labeled neurons were detected with a clear contralateral preponderance, among single labeled FB or DY cells. In spite of the rarity, all the NRTP neurons giving rise to intralobular collateral projections can be regarded as potential sources of simultaneous modulating influences upon two functional different forelimb (rPML) and hindlimb (cPML) regions. The findings have been discussed in relation to earlier studies in other species and commented on with respect to the possible functional meaning of these projections.
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Brun, Yohann; Karachi, Carine; Fernandez-Vidal, Sara; Jodoin, Nicolas; Grabli, David; Bardinet, Eric; Mallet, Luc; Agid, Yves; Yelnik, Jerome; Welter, Marie-Laure
2012-09-01
In humans, the control of voluntary movement, in which the corticobasal ganglia (BG) circuitry participates, is mainly lateralized. However, several studies have suggested that both the contralateral and ipsilateral BG systems are implicated during unilateral movement. Bilateral improvement of motor signs in patients with Parkinson's disease (PD) has been reported with unilateral lesion or high-frequency stimulation (HFS) of the internal part of the globus pallidus or the subthalamic nucleus (STN-HFS). To decipher the mechanisms of production of ipsilateral movements induced by the modulation of unilateral BG circuitry activity, we recorded left STN neuronal activity during right STN-HFS in PD patients operated for bilateral deep brain stimulation. Left STN single cells were recorded in the operating room during right STN-HFS while patients experienced, or did not experience, right stimulation-induced dyskinesias. Most of the left-side STN neurons (64%) associated with the presence of right dyskinesias were inhibited, with a significant decrease in burst and intraburst frequencies. In contrast, left STN neurons not associated with right dyskinesias were mainly activated (48%), with a predominant increase 4-5 ms after the stimulation pulse and a decrease in oscillatory activity. This suggests that unilateral neuronal STN modulation is associated with changes in the activity of the contralateral STN. The fact that one side of the BG system can influence the functioning of the other could explain the occurrence of bilateral dyskinesias and motor improvement observed in PD patients during unilateral STN-HFS, as a result of a bilateral disruption of the pathological activity in the corticosubcortical circuitry.
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Schreck, Mary; Petralia, Ronald S.; Wang, Ya-Xian; Zhang, Qiuxiang
2017-01-01
In sensory hair cells of auditory and vestibular organs, the ribbon synapse is required for the precise encoding of a wide range of complex stimuli. Hair cells have a unique presynaptic structure, the synaptic ribbon, which organizes both synaptic vesicles and calcium channels at the active zone. Previous work has shown that hair-cell ribbon size is correlated with differences in postsynaptic activity. However, additional variability in postsynapse size presents a challenge to determining the specific role of ribbon size in sensory encoding. To selectively assess the impact of ribbon size on synapse function, we examined hair cells in transgenic zebrafish that have enlarged ribbons, without postsynaptic alterations. Morphologically, we found that enlarged ribbons had more associated vesicles and reduced presynaptic calcium-channel clustering. Functionally, hair cells with enlarged ribbons had larger global and ribbon-localized calcium currents. Afferent neuron recordings revealed that hair cells with enlarged ribbons resulted in reduced spontaneous spike rates. Additionally, despite larger presynaptic calcium signals, we observed fewer evoked spikes with longer latencies from stimulus onset. Together, our work indicates that hair-cell ribbon size influences the spontaneous spiking and the precise encoding of stimulus onset in afferent neurons. SIGNIFICANCE STATEMENT Numerous studies support that hair-cell ribbon size corresponds with functional sensitivity differences in afferent neurons and, in the case of inner hair cells of the cochlea, vulnerability to damage from noise trauma. Yet it is unclear whether ribbon size directly influences sensory encoding. Our study reveals that ribbon enlargement results in increased ribbon-localized calcium signals, yet reduces afferent spontaneous activity and disrupts the timing of stimulus onset, a distinct aspect of auditory and vestibular encoding. These observations suggest that varying ribbon size alone can influence sensory encoding, and give further insight into how hair cells transduce signals that cover a wide dynamic range of stimuli. PMID:28546313
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Hoover, Donald B.; Shepherd, Angela V.; Southerland, E. Marie; Armour, J. Andrew; Ardell, Jeffrey L.
2008-01-01
While much is known about the influence of ventricular afferent neurons on cardiovascular function in the dog, identification of the neurochemicals transmitting cardiac afferent signals to central neurons is lacking. Accordingly, we identified ventricular afferent neurons in canine dorsal root ganglia (DRG) and nodose ganglia by retrograde labeling after injecting horseradish peroxidase (HRP) into the anterior right and left ventricles. Primary antibodies from three host species were used in immunohistochemical experiments to simultaneously evaluate afferent somata for the presence of HRP and markers for two neurotransmitters. Only a small percentage (2%) of afferent somata were labeled with HRP. About half of the HRP-identified ventricular afferent neurons in T3 DRG also stained for substance P (SP), calcitonin gene-related peptide (CGRP), or neuronal nitric oxide synthase (nNOS), either alone or with two markers colocalized. Ventricular afferent neurons and the general population of T3 DRG neurons showed the same labeling profiles; CGRP (alone or colocalized with SP) being the most common (30–40% of ventricular afferent somata in T3 DRG). About 30% of the ventricular afferent neurons in T2 DRG displayed CGRP immunoreactivity and binding of the putative nociceptive marker IB4. Ventricular afferent neurons of the nodose ganglia were distinct from those in the DRG by having smaller size and lacking immunoreactivity for SP, CGRP, and nNOS. These findings suggest that ventricular sensory information is transferred to the central nervous system by relatively small populations of vagal and spinal afferent neurons and that spinal afferents use a variety of neurotransmitters. PMID:18558516
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Hoover, Donald B; Shepherd, Angela V; Southerland, E Marie; Armour, J Andrew; Ardell, Jeffrey L
2008-08-18
While much is known about the influence of ventricular afferent neurons on cardiovascular function in the dog, identification of the neurochemicals transmitting cardiac afferent signals to central neurons is lacking. Accordingly, we identified ventricular afferent neurons in canine dorsal root ganglia (DRG) and nodose ganglia by retrograde labeling after injecting horseradish peroxidase (HRP) into the anterior right and left ventricles. Primary antibodies from three host species were used in immunohistochemical experiments to simultaneously evaluate afferent somata for the presence of HRP and markers for two neurotransmitters. Only a small percentage (2%) of afferent somata were labeled with HRP. About half of the HRP-identified ventricular afferent neurons in T(3) DRG also stained for substance P (SP), calcitonin gene-related peptide (CGRP), or neuronal nitric oxide synthase (nNOS), either alone or with two markers colocalized. Ventricular afferent neurons and the general population of T(3) DRG neurons showed the same labeling profiles; CGRP (alone or colocalized with SP) being the most common (30-40% of ventricular afferent somata in T(3) DRG). About 30% of the ventricular afferent neurons in T(2) DRG displayed CGRP immunoreactivity and binding of the putative nociceptive marker IB(4). Ventricular afferent neurons of the nodose ganglia were distinct from those in the DRG by having smaller size and lacking immunoreactivity for SP, CGRP, and nNOS. These findings suggest that ventricular sensory information is transferred to the central nervous system by relatively small populations of vagal and spinal afferent neurons and that spinal afferents use a variety of neurotransmitters.
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Yang, Xiao-Dun; Liao, Xue-Mei; Uribe-Mariño, Andrés; Liu, Rui; Xie, Xiao-Meng; Jia, Jiao; Su, Yun-Ai; Li, Ji-Tao; Schmidt, Mathias V; Wang, Xiao-Dong; Si, Tian-Mei
2015-01-01
During the early postnatal period, environmental influences play a pivotal role in shaping the development of the neocortex, including the prefrontal cortex (PFC) that is crucial for working memory and goal-directed actions. Exposure to stressful experiences during this critical period may disrupt the development of PFC pyramidal neurons and impair the wiring and function of related neural circuits. However, the molecular mechanisms of the impact of early-life stress on PFC development and function are not well understood. In this study, we found that repeated stress exposure during the first postnatal week hampered dendritic development in layers II/III and V pyramidal neurons in the dorsal agranular cingulate cortex (ACd) and prelimbic cortex (PL) of neonatal mice. The deleterious effects of early postnatal stress on structural plasticity persisted to adulthood only in ACd layer V pyramidal neurons. Most importantly, concurrent blockade of corticotropin-releasing factor receptor 1 (CRF1) by systemic antalarmin administration (20 μg/g of body weight) during early-life stress exposure prevented stress-induced apical dendritic retraction and spine loss in ACd layer V neurons and impairments in PFC-dependent cognitive tasks. Moreover, the magnitude of dendritic regression, especially the shrinkage of apical branches, of ACd layer V neurons predicted the degree of cognitive deficits in stressed mice. Our data highlight the region-specific effects of early postnatal stress on the structural plasticity of prefrontal pyramidal neurons, and suggest a critical role of CRF1 in modulating early-life stress-induced prefrontal abnormalities. PMID:25403725
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NASA Astrophysics Data System (ADS)
Yuan, Chang-Qing; Zhao, Tong-Jun; Zhan, Yong; Zhang, Su-Hua; Liu, Hui; Zhang, Yu-Hong
2009-11-01
Based on the well accepted Hodgkin-Huxley neuron model, the neuronal intrinsic excitability is studied when the neuron is subject to varying environmental temperatures, the typical impact for its regulating ways. With computer simulation, it is found that altering environmental temperature can improve or inhibit the neuronal intrinsic excitability so as to influence the neuronal spiking properties. The impacts from environmental factors can be understood that the neuronal spiking threshold is essentially influenced by the fluctuations in the environment. With the environmental temperature varying, burst spiking is realized for the neuronal membrane voltage because of the environment-dependent spiking threshold. This burst induced by changes in spiking threshold is different from that excited by input currents or other stimulus.
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Attention stabilizes the shared gain of V4 populations
Rabinowitz, Neil C; Goris, Robbe L; Cohen, Marlene; Simoncelli, Eero P
2015-01-01
Responses of sensory neurons represent stimulus information, but are also influenced by internal state. For example, when monkeys direct their attention to a visual stimulus, the response gain of specific subsets of neurons in visual cortex changes. Here, we develop a functional model of population activity to investigate the structure of this effect. We fit the model to the spiking activity of bilateral neural populations in area V4, recorded while the animal performed a stimulus discrimination task under spatial attention. The model reveals four separate time-varying shared modulatory signals, the dominant two of which each target task-relevant neurons in one hemisphere. In attention-directed conditions, the associated shared modulatory signal decreases in variance. This finding provides an interpretable and parsimonious explanation for previous observations that attention reduces variability and noise correlations of sensory neurons. Finally, the recovered modulatory signals reflect previous reward, and are predictive of subsequent choice behavior. DOI: http://dx.doi.org/10.7554/eLife.08998.001 PMID:26523390
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NASA Astrophysics Data System (ADS)
Kanagasabapathi, Thirukumaran T.; Massobrio, Paolo; Barone, Rocco Andrea; Tedesco, Mariateresa; Martinoia, Sergio; Wadman, Wytse J.; Decré, Michel M. J.
2012-06-01
Co-cultures containing dissociated cortical and thalamic cells may provide a unique model for understanding the pathophysiology in the respective neuronal sub-circuitry. In addition, developing an in vitro dissociated co-culture model offers the possibility of studying the system without influence from other neuronal sub-populations. Here we demonstrate a dual compartment system coupled to microelectrode arrays (MEAs) for co-culturing and recording spontaneous activities from neuronal sub-populations. Propagation of electrical activities between cortical and thalamic regions and their interdependence in connectivity is verified by means of a cross-correlation algorithm. We found that burst events originate in the cortical region and drive the entire cortical-thalamic network bursting behavior while mutually weak thalamic connections play a relevant role in sustaining longer burst events in cortical cells. To support these experimental findings, a neuronal network model was developed and used to investigate the interplay between network dynamics and connectivity in the cortical-thalamic system.
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Revisiting the Quantum Brain Hypothesis: Toward Quantum (Neuro)biology?
Jedlicka, Peter
2017-01-01
The nervous system is a non-linear dynamical complex system with many feedback loops. A conventional wisdom is that in the brain the quantum fluctuations are self-averaging and thus functionally negligible. However, this intuition might be misleading in the case of non-linear complex systems. Because of an extreme sensitivity to initial conditions, in complex systems the microscopic fluctuations may be amplified and thereby affect the system’s behavior. In this way quantum dynamics might influence neuronal computations. Accumulating evidence in non-neuronal systems indicates that biological evolution is able to exploit quantum stochasticity. The recent rise of quantum biology as an emerging field at the border between quantum physics and the life sciences suggests that quantum events could play a non-trivial role also in neuronal cells. Direct experimental evidence for this is still missing but future research should address the possibility that quantum events contribute to an extremely high complexity, variability and computational power of neuronal dynamics. PMID:29163041
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The Effect of Substrate Topography on Direct Reprogramming of Fibroblasts to Induced Neurons
Kulangara, Karina; Adler, Andrew F.; Wang, Hong; Chellappan, Malathi; Hammett, Ellen; Yasuda, Ryohei; Leong, Kam W.
2014-01-01
Cellular reprogramming holds tremendous potential for cell therapy and regenerative medicine. Recently, fibroblasts have been directly converted into induced neurons (iNs) by overexpression of the neuronal transcription factors Ascl1, Brn2 and Myt1L. Hypothesizing that cell-topography interactions could influence the fibroblast-to-neuron reprogramming process, we investigated the effects of various topographies on iNs produced by direct reprogramming. Final iN purity and conversion efficiency were increased on micrograting substrates. Neurite branching was increased on microposts and decreased on microgratings, with a simplified dendritic arbor characterized by the reduction of MAP2+ neurites. Neurite outgrowth increased significantly on various topographies. DNA microarray analysis detected 20 differentially expressed genes in iNs reprogrammed on smooth versus microgratings, and quantitative PCR (qPCR) confirmed the upregulation of Vip and downregulation of Thy1 and Bmp5 on microgratings. Electrophysiology and calcium imaging verified the functionality of these iNs. This study demonstrates the potential of applying topographical cues to optimize cellular reprogramming. PMID:24709523
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Park, Junchol
2017-01-01
Actions motivated by rewards are often associated with risk of punishment. Little is known about the neural representation of punishment risk during reward-seeking behavior. We modeled this circumstance in rats by designing a task where actions were consistently rewarded but probabilistically punished. Spike activity and local field potentials were recorded during task performance simultaneously from VTA and mPFC, two reciprocally connected regions implicated in reward-seeking and aversive behaviors. At the single unit level, we found that ensembles of putative dopamine and non-dopamine VTA neurons and mPFC neurons encode the relationship between action and punishment. At the network level, we found that coherent theta oscillations synchronize VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions. This synchrony declined as a function of punishment probability, suggesting that during reward-seeking actions, risk of punishment diminishes VTA-driven neural synchrony between the two regions. PMID:29058673
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A new mode of pancreatic islet innervation revealed by live imaging in zebrafish.
Yang, Yu Hsuan Carol; Kawakami, Koichi; Stainier, Didier Yr
2018-06-19
Pancreatic islets are innervated by autonomic and sensory nerves that influence their function. Analyzing the innervation process should provide insight into the nerve-endocrine interactions and their roles in development and disease. Here, using in vivo time-lapse imaging and genetic analyses in zebrafish, we determined the events leading to islet innervation. Comparable neural density in the absence of vasculature indicates that it is dispensable for early pancreatic innervation. Neural crest cells are in close contact with endocrine cells early in development. We find these cells give rise to neurons that extend axons towards the islet as they surprisingly migrate away. Specific ablation of these neurons partly prevents other neurons from migrating away from the islet resulting in diminished innervation. Thus, our studies establish the zebrafish as a model to interrogate mechanisms of organ innervation, and reveal a novel mode of innervation whereby neurons establish connections with their targets before migrating away. © 2018, Yang et al.
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Calcium signal communication in the central nervous system.
Braet, Katleen; Cabooter, Liesbet; Paemeleire, Koen; Leybaert, Luc
2004-02-01
The communication of calcium signals between cells is known to be operative between neurons where these signals integrate intimately with electrical and chemical signal communication at synapses. Recently, it has become clear that glial cells also exchange calcium signals between each other in cultures and in brain slices. This communication pathway has received utmost attention since it is known that astrocytic calcium signals can be induced by neuronal stimulation and can be communicated back to the neurons to modulate synaptic transmission. In addition to this, cells that are generally not considered as brain cells become progressively incorporated in the picture, as astrocytic calcium signals are reported to be communicated to endothelial cells of the vessel wall and can affect smooth muscle cell tone to influence the vessel diameter and thus blood flow. We review the available evidence for calcium signal communication in the central nervous system, taking into account a basic functional unit -the brain cell tripartite- consisting of neurons, glial cells and vascular cells and with emphasis on glial-vascular calcium signaling aspects.
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The Influence of Nicotinamide on Health and Disease in the Central Nervous System
Fricker, Rosemary A; Green, Emma L; Jenkins, Stuart I; Griffin, Síle M
2018-01-01
Nicotinamide, the amide form of vitamin B3 (niacin), has long been associated with neuronal development, survival, and function in the central nervous system (CNS), being implicated in both neuronal death and neuroprotection. Here, we summarise a body of research investigating the role of nicotinamide in neuronal health within the CNS, with a focus on studies that have shown a neuroprotective effect. Nicotinamide appears to play a role in protecting neurons from traumatic injury, ischaemia, and stroke, as well as being implicated in 3 key neurodegenerative conditions: Alzheimer’s, Parkinson’s, and Huntington’s diseases. A key factor is the bioavailability of nicotinamide, with low concentrations leading to neurological deficits and dementia and high levels potentially causing neurotoxicity. Finally, nicotinamide’s potential mechanisms of action are discussed, including the general maintenance of cellular energy levels and the more specific inhibition of molecules such as the nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin 1 (SIRT1). PMID:29844677
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Revisiting the Quantum Brain Hypothesis: Toward Quantum (Neuro)biology?
Jedlicka, Peter
2017-01-01
The nervous system is a non-linear dynamical complex system with many feedback loops. A conventional wisdom is that in the brain the quantum fluctuations are self-averaging and thus functionally negligible. However, this intuition might be misleading in the case of non-linear complex systems. Because of an extreme sensitivity to initial conditions, in complex systems the microscopic fluctuations may be amplified and thereby affect the system's behavior. In this way quantum dynamics might influence neuronal computations. Accumulating evidence in non-neuronal systems indicates that biological evolution is able to exploit quantum stochasticity. The recent rise of quantum biology as an emerging field at the border between quantum physics and the life sciences suggests that quantum events could play a non-trivial role also in neuronal cells. Direct experimental evidence for this is still missing but future research should address the possibility that quantum events contribute to an extremely high complexity, variability and computational power of neuronal dynamics.
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Respiratory Network Stability and Modulatory Response to Substance P Require Nalcn.
Yeh, Szu-Ying; Huang, Wei-Hsiang; Wang, Wei; Ward, Christopher S; Chao, Eugene S; Wu, Zhenyu; Tang, Bin; Tang, Jianrong; Sun, Jenny J; Esther van der Heijden, Meike; Gray, Paul A; Xue, Mingshan; Ray, Russell S; Ren, Dejian; Zoghbi, Huda Y
2017-04-19
Respiration is a rhythmic activity as well as one that requires responsiveness to internal and external circumstances; both the rhythm and neuromodulatory responses of breathing are controlled by brainstem neurons in the preBötzinger complex (preBötC) and the retrotrapezoid nucleus (RTN), but the specific ion channels essential to these activities remain to be identified. Because deficiency of sodium leak channel, non-selective (Nalcn) causes lethal apnea in humans and mice, we investigated Nalcn function in these neuronal groups. We found that one-third of mice lacking Nalcn in excitatory preBötC neurons died soon after birth; surviving mice developed apneas in adulthood. Interestingly, in both preBötC and RTN neurons, the Nalcn current influences the resting membrane potential, contributes to maintenance of stable network activity, and mediates modulatory responses to the neuropeptide substance P. These findings reveal Nalcn's specific role in both rhythmic stability and responsiveness to neuropeptides within the respiratory network. Copyright © 2017 Elsevier Inc. All rights reserved.
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Fukuda, H
1975-06-01
The following conclusions may be drawn from the results in this work. The respiratory cycles are formed by the neuronal machinery in the reticular formation under the posterior part of the vagal motor nucleus. The motor neurones or the neuronal networks composing the motor nucleus of the respiratory muscles tonically discharge the action potentials, when the neurones or the networks are released from the inhibitory influences of the interneurones connecting the neuronal machinery to the motor neurones. Furthermore, the interneurones probably generate the tonic discharges after removing the inhibitory influences of the other interneurones or the neuronal machinery on them. A reflex mouth closing is elicited by a mechanical stimulus applying on the upper lip. The motor neurones of the m. adductor mandibulae are activated via only one synapse in the reflex. The reflex action potentials recorded from the motor nerve reduce in amplitude at the resting phase of the nerve in the respiratory cycles. These results suggest that the respiratory motor neurones are by nature spontaneous generators of the tonic action potentials and, in the time of the normal breathing, the tonic activity is interrupted by an inhibitory influence of the neuronal machinery generating the respiratory cycles.
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Herculano-Houzel, Suzana; Watson, Charles; Paxinos, George
2013-01-01
How are neurons distributed along the cortical surface and across functional areas? Here we use the isotropic fractionator (Herculano-Houzel and Lent, 2005) to analyze the distribution of neurons across the entire isocortex of the mouse, divided into 18 functional areas defined anatomically. We find that the number of neurons underneath a surface area (the N/A ratio) varies 4.5-fold across functional areas and neuronal density varies 3.2-fold. The face area of S1 contains the most neurons, followed by motor cortex and the primary visual cortex. Remarkably, while the distribution of neurons across functional areas does not accompany the distribution of surface area, it mirrors closely the distribution of cortical volumes—with the exception of the visual areas, which hold more neurons than expected for their volume. Across the non-visual cortex, the volume of individual functional areas is a shared linear function of their number of neurons, while in the visual areas, neuronal densities are much higher than in all other areas. In contrast, the 18 functional areas cluster into three different zones according to the relationship between the N/A ratio and cortical thickness and neuronal density: these three clusters can be called visual, sensory, and, possibly, associative. These findings are remarkably similar to those in the human cerebral cortex (Ribeiro et al., 2013) and suggest that, like the human cerebral cortex, the mouse cerebral cortex comprises two zones that differ in how neurons form the cortical volume, and three zones that differ in how neurons are distributed underneath the cortical surface, possibly in relation to local differences in connectivity through the white matter. Our results suggest that beyond the developmental divide into visual and non-visual cortex, functional areas initially share a common distribution of neurons along the parenchyma that become delimited into functional areas according to the pattern of connectivity established later. PMID:24155697
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[Origin of cortical interneurons: basic concepts and clinical implications].
Marín, O
Introduction and development. GABAergic interneurons play a prominent role in the function of the cerebral cortex, since they allow the synchronization of pyramidal neurons and greatly influence their differentiation and maturation during development. Until recently it has been thought that cortical interneurons and pyramidal neurons originate from progenitor cells located in the dorsal region of the telencephalon, the pallium. Recent studies, however, have demonstrated that a large number of cortical GABAergic neurons arise from progenitors located in the subpallium the region of the telencephalon that gives rise to the basal ganglia, and that they arise in the cerebral cortex after a long tangential migration. Aims. In this review I have summarized our current knowledge of the factors that control the specification of cortical interneurons, as well as the mechanisms that direct their migration to the cortex.
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Cellular complexity in subcortical white matter: a distributed control circuit?
Colombo, Jorge A
2018-03-01
The subcortical white matter (SWM) has been traditionally considered as a site for passive-neutral-information transfer through cerebral cortex association and projection fibers. Yet, the presence of subcortical neuronal and glial "interstitial" cells expressing immunolabelled neurotransmitters/neuromodulators and synaptic vesicular proteins, and recent immunohistochemical and electrophysiological observations on the rat visual cortex as well as interactive regulation of myelinating processes support the possibility that SWM nests subcortical, regionally variable, distributed neuronal-glial circuits, that could influence information transfer. Their hypothetical involvement in regulating the timing and signal transfer probability at the SWM axonal components ought to be considered and experimentally analysed. Thus, the "interstitial" neuronal cells-associated with local glial cells-traditionally considered to be vestigial and functionally inert under normal conditions, they may well turn to be critical in regulating information transfer at the SWM.
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Hellmich, Helen L.; Eidson, Kristine; Cowart, Jeremy; Crookshanks, Jeanna; Boone, Deborah K.; Shah, Syed; Uchida, Tatsuo; DeWitt, Douglas S.; Prough, Donald S.
2008-01-01
Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically brain-injured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade- positive neurons in the rat hippocampus 24 hours after injury but does not improve neurobehavioral outcome (spatial memory deficits) two weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory. PMID:18556117
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Chen Bo; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Science, Beijing 100101; Xia Jing
Physiological and behavioral studies have demonstrated that a number of visual functions such as visual acuity, contrast sensitivity, and motion perception can be impaired by acute alcohol exposure. The orientation- and direction-selective responses of cells in primary visual cortex are thought to participate in the perception of form and motion. To investigate how orientation selectivity and direction selectivity of neurons are influenced by acute alcohol exposure in vivo, we used the extracellular single-unit recording technique to examine the response properties of neurons in primary visual cortex (A17) of adult cats. We found that alcohol reduces spontaneous activity, visual evoked unitmore » responses, the signal-to-noise ratio, and orientation selectivity of A17 cells. In addition, small but detectable changes in both the preferred orientation/direction and the bandwidth of the orientation tuning curve of strongly orientation-biased A17 cells were observed after acute alcohol administration. Our findings may provide physiological evidence for some alcohol-related deficits in visual function observed in behavioral studies.« less
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Morphological and functional aspects of progenitors perturbed in cortical malformations
Bizzotto, Sara; Francis, Fiona
2015-01-01
In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area. PMID:25729350
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Guerreiro, Serge; Florence, Clélia; Rousseau, Erwann; Hamadat, Sabah; Hirsch, Etienne C; Michel, Patrick P
2015-01-01
To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-protein-coupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype, N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala(11), d-Leu(15)]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of α-bungarotoxin-sensitive (presumably α7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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Periodic activation function and a modified learning algorithm for the multivalued neuron.
Aizenberg, Igor
2010-12-01
In this paper, we consider a new periodic activation function for the multivalued neuron (MVN). The MVN is a neuron with complex-valued weights and inputs/output, which are located on the unit circle. Although the MVN outperforms many other neurons and MVN-based neural networks have shown their high potential, the MVN still has a limited capability of learning highly nonlinear functions. A periodic activation function, which is introduced in this paper, makes it possible to learn nonlinearly separable problems and non-threshold multiple-valued functions using a single multivalued neuron. We call this neuron a multivalued neuron with a periodic activation function (MVN-P). The MVN-Ps functionality is much higher than that of the regular MVN. The MVN-P is more efficient in solving various classification problems. A learning algorithm based on the error-correction rule for the MVN-P is also presented. It is shown that a single MVN-P can easily learn and solve those benchmark classification problems that were considered unsolvable using a single neuron. It is also shown that a universal binary neuron, which can learn nonlinearly separable Boolean functions, and a regular MVN are particular cases of the MVN-P.
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Changes in Afferent Activity After Spinal Cord Injury
de Groat, William C.; Yoshimura, Naoki
2010-01-01
Aims To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury. Methods Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways. Results Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Aδ) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs. Conclusions Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord. PMID:20025033
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Metzler, Martina; Gan, Lu; Wong, Tak Pan; Liu, Lidong; Helm, Jeffrey; Liu, Lili; Georgiou, John; Wang, Yushan; Bissada, Nagat; Cheng, Kevin; Roder, John C; Wang, Yu Tian; Hayden, Michael R
2007-02-28
Huntingtin-interacting protein 1 (HIP1) is an endocytic adaptor protein that plays a role in clathrin-mediated endocytosis and the ligand-induced internalization of AMPA receptors (AMPARs) (Metzler et al., 2003). In the present study, we investigated the role of HIP1 in NMDA receptor (NMDAR) function by analyzing NMDA-dependent transport and NMDA-induced excitotoxicity in neurons from HIP1-/- mice. HIP1 colocalizes with NMDARs in hippocampal and cortical neurons and affinity purifies with NMDARs by GST (glutathione S-transferase) pull down and coimmunoprecipitation. A profound decrease in NMDA-induced AMPAR internalization of 75% occurs in neurons from HIP1-/- mice compared with wild type, using a quantitative single-cell-based internalization assay. This defect in NMDA-dependent removal of surface AMPARs is in agreement with the observed defect in long-term depression induction in hippocampal brain slices of HIP1-/- mice and supports a role of HIP1 in AMPAR internalization in vivo. HIP1-/- neurons are partially protected from NMDA-induced excitotoxicity as assessed by LDH (lactate dehydrogenase) release, TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling) and caspase-3 activation assays, which points to a role of HIP1 in NMDA-induced cell death. Interestingly, phosphorylation of Akt and its substrate huntingtin (htt) decreases during NMDA-induced excitotoxicity by 48 and 31%, respectively. This decrease is significantly modulated by HIP1, resulting in 94 and 48% changes in P-Akt and P-htt levels in HIP1-/- neurons, respectively. In summary, we have shown that HIP1 influences important NMDAR functions and that both HIP1 and htt participate in NMDA-induced cell death. These findings may provide novel insights into the cellular mechanisms underlying enhanced NMDA-induced excitotoxicity in Huntington's disease.
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HIPPOCAMPAL ADULT NEUROGENESIS: ITS REGULATION AND POTENTIAL ROLE IN SPATIAL LEARNING AND MEMORY
Lieberwirth, Claudia; Pan, Yongliang; Liu, Yan; Zhang, Zhibin; Wang, Zuoxin
2016-01-01
Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk). PMID:27174001
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Bartho, Lorand; Nordtveit, Elin; Szombati, Veronika; Benko, Rita
2013-08-01
Allyl isothiocyanate (AITC; 200 μM) caused atropine- and tetrodotoxin-sensitive longitudinal muscle contraction on the guinea-pig small intestine. The response was not influenced by hexamethonium, a functional blockade of capsaicin-sensitive neurons or by antagonists acting at TRPV1 or TRPA1, but was abolished by the P2 purinoceptor antagonist PPADS (50 μM). It is concluded that cholinergic motoneurons are activated by a purinergic mechanism in the course of the AITC response, independently of capsaicin-sensitive processes or even TRPA1. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.
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Coordinated neuronal activity enhances corticocortical communication
Zandvakili, Amin; Kohn, Adam
2015-01-01
Summary Relaying neural signals between cortical areas is central to cognition and sensory processing. The temporal coordination of activity in a source population has been suggested to determine corticocortical signaling efficacy, but others have argued that coordination is functionally irrelevant. We reasoned that if coordination significantly influenced signaling, spiking in downstream networks should be preceded by transiently elevated coordination in a source population. We developed a metric to quantify network coordination in brief epochs, and applied it to simultaneous recordings of neuronal populations in cortical areas V1 and V2 of the macaque monkey. Spiking in the input layers of V2 was preceded by brief epochs of elevated V1 coordination, but this was not the case in other layers of V2. Our results indicate that V1 coordination influences its signaling to direct downstream targets, but that coordinated V1 epochs do not propagate through multiple downstream networks as in some corticocortical signaling schemes. PMID:26291164
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Comparative functional expression of nAChR subtypes in rodent DRG neurons.
Smith, Nathan J; Hone, Arik J; Memon, Tosifa; Bossi, Simon; Smith, Thomas E; McIntosh, J Michael; Olivera, Baldomero M; Teichert, Russell W
2013-01-01
We investigated the functional expression of nicotinic acetylcholine receptors (nAChRs) in heterogeneous populations of dissociated rat and mouse lumbar dorsal root ganglion (DRG) neurons by calcium imaging. By this experimental approach, it is possible to investigate the functional expression of multiple receptor and ion-channel subtypes across more than 100 neuronal and glial cells simultaneously. Based on nAChR expression, DRG neurons could be divided into four subclasses: (1) neurons that express predominantly α3β4 and α6β4 nAChRs; (2) neurons that express predominantly α7 nAChRs; (3) neurons that express a combination of α3β4/α6β4 and α7 nAChRs; and (4) neurons that do not express nAChRs. In this comparative study, the same four neuronal subclasses were observed in mouse and rat DRG. However, the expression frequency differed between species: substantially more rat DRG neurons were in the first three subclasses than mouse DRG neurons, at all developmental time points tested in our study. Approximately 70-80% of rat DRG neurons expressed functional nAChRs, in contrast to only ~15-30% of mouse DRG neurons. Our study also demonstrated functional coupling between nAChRs, voltage-gated calcium channels, and mitochondrial Ca(2) (+) transport in discrete subsets of DRG neurons. In contrast to the expression of nAChRs in DRG neurons, we demonstrated that a subset of non-neuronal DRG cells expressed muscarinic acetylcholine receptors and not nAChRs. The general approach to comparative cellular neurobiology outlined in this paper has the potential to better integrate molecular and systems neuroscience by uncovering the spectrum of neuronal subclasses present in a given cell population and the functionally integrated signaling components expressed in each subclass.
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Neuromodulatory influence of norepinephrine during developmental experience-dependent plasticity.
Golovin, Randall M; Ward, Nicholas J
2016-07-01
Critical periods represent phases of development during which neuronal circuits and their responses can be readily shaped by stimuli. Experience-dependent plasticity that occurs within these critical periods can be influenced in many ways; however, Shepard et al. (J Neurosci 35: 2432-2437, 2015) recently singled out norepinephrine as an essential driver of this plasticity within the auditory cortex. This work provides novel insight into the mechanisms of critical period plasticity and challenges previous conceptions that a functional redundancy exists between noradrenergic and cholinergic influences on cortical plasticity. Copyright © 2016 the American Physiological Society.
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Städele, Carola; Heigele, Stefanie; Stein, Wolfgang
2015-01-01
Stable rhythmic neural activity depends on the well-coordinated interplay of synaptic and cell-intrinsic conductances. Since all biophysical processes are temperature dependent, this interplay is challenged during temperature fluctuations. How the nervous system remains functional during temperature perturbations remains mostly unknown. We present a hitherto unknown mechanism of how temperature-induced changes in neural networks are compensated by changing their neuromodulatory state: activation of neuromodulatory pathways establishes a dynamic coregulation of synaptic and intrinsic conductances with opposing effects on neuronal activity when temperature changes, hence rescuing neuronal activity. Using the well-studied gastric mill pattern generator of the crab, we show that modest temperature increase can abolish rhythmic activity in isolated neural circuits due to increased leak currents in rhythm-generating neurons. Dynamic clamp-mediated addition of leak currents was sufficient to stop neuronal oscillations at low temperatures, and subtraction of additional leak currents at elevated temperatures was sufficient to rescue the rhythm. Despite the apparent sensitivity of the isolated nervous system to temperature fluctuations, the rhythm could be stabilized by activating extrinsic neuromodulatory inputs from descending projection neurons, a strategy that we indeed found to be implemented in intact animals. In the isolated nervous system, temperature compensation was achieved by stronger extrinsic neuromodulatory input from projection neurons or by augmenting projection neuron influence via bath application of the peptide cotransmitter Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia activates the modulator-induced current IMI (a nonlinear voltage-gated inward current) that effectively acted as a negative leak current and counterbalanced the temperature-induced leak to rescue neuronal oscillations. Computational modelling revealed the ability of IMI to reduce detrimental leak-current influences on neuronal networks over a broad conductance range and indicated that leak and IMI are closely coregulated in the biological system to enable stable motor patterns. In conclusion, these results show that temperature compensation does not need to be implemented within the network itself but can be conditionally provided by extrinsic neuromodulatory input that counterbalances temperature-induced modifications of circuit-intrinsic properties. PMID:26417944
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Duration-dependent effects of the bite-raised condition on hippocampal function in SAMP8 mice.
Arakawa, Yoko; Ichihashi, Yukiko; Iinuma, Mitsuo; Tamura, Yasuo; Iwaku, Fumihiko; Kubo, Kin-Ya
2007-11-01
We evaluated the effect of the duration of occlusal disharmony induced chronic stress on hippocampal function by examining spatial memory in the Morris water maze and on the number of hippocampal neurons in aged senescence-accelerated prone (SAMP8) mice. The bite of SAMP8 mice was raised 0.1 mm using dental adhesive. Groups of mice were tested in the Morris water maze 8, 11, or 22 d after raising the bite. The results indicated that the longer the duration of the bite-raised condition, the greater the impairment in spatial learning ability and the greater the decrease in the number of neurons in the hippocampal CA3 subfield. Thus, behavioral and morphologic deficits induced by the bite-raised condition in aged SAMP8 mice are influenced by the duration of the occlusal disharmony.
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Regulatory processes of hunger motivated behavior.
Lénárd, L; Karádi, Z
2012-01-01
While food intake and body weight are under homeostatic regulation, eating is a highly motivated and reinforced behavior that induces feelings of gratification and pleasure. The chemical senses (taste and odor) and their evaluation are essential to these functions. Brainstem and limbic glucose-monitoring (GM) neurons receiving neurochemical information from the periphery and from the local brain milieu are important controlling hunger motivation, and brain gut peptides have a modulatory role on this function. The hypothalamic and limbic forebrain areas are responsible for evaluation of reward quality and related emotions. They are innervated by the mesolimbic dopaminergic system (MLDS) and majority of GM neurons are also influenced by dopamine. Via dopamine release, the MLDS plays an essential role in rewarding-reinforcing processes of feeding and addiction. The GM network and the MLDS in the limbic system represent essential elements in the neural substrate of motivation.
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Engel, Dominique; Seutin, Vincent
2015-11-15
The hyperpolarization-activated cation current Ih is expressed in dopamine neurons of the substantia nigra, but the subcellular distribution of the current and its role in synaptic integration remain unknown. We used cell-attached patch recordings to determine the localization profile of Ih along the somatodendritic axis of nigral dopamine neurons in slices from young rats. Ih density is higher in axon-bearing dendrites, in a membrane area close to the axon origin, than in the soma and axon-lacking dendrites. Dual current-clamp recordings revealed a similar contribution of Ih to the waveform of single excitatory postsynaptic potentials throughout the somatodendritic domain. The Ih blocker ZD 7288 increased the temporal summation in all dendrites with a comparable effect in axon- and non-axon dendrites. The strategic position of Ih in the proximity of the axon may influence importantly transitions between pacemaker and bursting activities and consequently the downstream release of dopamine. Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The hyperpolarization-activated cation current Ih present in the dendrites of some pyramidal neurons affects their membrane and integration properties, synaptic plasticity and higher functions such as memory. A gradient of increasing h-channel density towards distal dendrites has been found to be responsible for the location independence of excitatory postsynaptic potential (EPSP) waveform and temporal summation in cortical and hippocampal pyramidal cells. However, reports on other cell types revealed that smoother gradients or even linear distributions of Ih can achieve homogeneous temporal summation. Although the existence of a robust, slowly activating Ih current has been repeatedly demonstrated in nigral dopamine neurons, its subcellular distribution and precise role in synaptic integration are unknown. Using cell-attached patch-clamp recordings, we find a higher Ih current density in the axon-bearing dendrite than in the soma or in dendrites without axon in nigral dopamine neurons. Ih is mainly concentrated in the dendritic membrane area surrounding the axon origin and decreases with increasing distances from this site. Single EPSPs and temporal summation are similarly affected by blockade of Ih in axon- and non-axon-bearing dendrites. The presence of Ih close to the axon is pivotal to control the integrative functions and the output signal of dopamine neurons and may consequently influence the downstream coding of movement. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.
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Peripheral Sensory Neurons Expressing Melanopsin Respond to Light
Matynia, Anna; Nguyen, Eileen; Sun, Xiaoping; Blixt, Frank W.; Parikh, Sachin; Kessler, Jason; Pérez de Sevilla Müller, Luis; Habib, Samer; Kim, Paul; Wang, Zhe Z.; Rodriguez, Allen; Charles, Andrew; Nusinowitz, Steven; Edvinsson, Lars; Barnes, Steven; Brecha, Nicholas C.; Gorin, Michael B.
2016-01-01
The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior. PMID:27559310
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Linehan, Victoria; Trask, Robert B.; Briggs, Chantalle; Rowe, Todd M.; Hirasawa, Michiru
2017-01-01
Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups, where orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying DA action on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using whole cell patch clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration dependent, bidirectional manner. Low (1 μM) and high concentrations (100 μM) of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors, whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. PMID:26036709
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Rosenkranz, J. Amiel
2012-01-01
The amygdala has a fundamental role in driving affective behaviors in response to sensory cues. To accomplish this, neurons of the lateral nucleus (LAT) must integrate a large number of synaptic inputs. A wide range of factors influence synaptic integration, including membrane potential, voltage-gated ion channels and GABAergic inhibition. However, little is known about how these factors modulate integration of synaptic inputs in LAT neurons in vivo. The purpose of this study was to determine the voltage-dependent factors that modify in vivo integration of synaptic inputs in the soma of LAT neurons. In vivo intracellular recordings from anesthetized rats were used to measure post-synaptic potentials (PSPs) and clusters of PSPs across a range of membrane potentials. These studies found that the relationship between membrane potential and PSP clusters was sublinear, due to a reduction of cluster amplitude and area at depolarized membrane potentials. In combination with intracellular delivery of pharmacological agents, it was found that the voltage-dependent suppression of PSP clusters was sensitive to tetraethylammonium (TEA), but not cesium or a blocker of fast GABAergic inhibition. These findings indicate that integration of PSPs in LAT neurons in vivo is strongly modified by somatic membrane potential, likely through voltage-dependent TEA-sensitive potassium channels. Conditions that lead to a shift in membrane potential, or a modulation of the number or function of these ion channels will lead to a more uniform capacity for integration across voltages, and perhaps greatly facilitate amygdala-dependent behaviors. PMID:22989917
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Sharma, Jitendra; Sugihara, Hiroki; Katz, Yarden; Schummers, James; Tenenbaum, Joshua; Sur, Mriganka
2015-09-01
The brain uses attention and expectation as flexible devices for optimizing behavioral responses associated with expected but unpredictably timed events. The neural bases of attention and expectation are thought to engage higher cognitive loci; however, their influence at the level of primary visual cortex (V1) remains unknown. Here, we asked whether single-neuron responses in monkey V1 were influenced by an attention task of unpredictable duration. Monkeys covertly attended to a spot that remained unchanged for a fixed period and then abruptly disappeared at variable times, prompting a lever release for reward. We show that monkeys responded progressively faster and performed better as the trial duration increased. Neural responses also followed monkey's task engagement-there was an early, but short duration, response facilitation, followed by a late but sustained increase during the time monkeys expected the attention spot to disappear. This late attentional modulation was significantly and negatively correlated with the reaction time and was well explained by a modified hazard function. Such bimodal, time-dependent changes were, however, absent in a task that did not require explicit attentional engagement. Thus, V1 neurons carry reliable signals of attention and temporal expectation that correlate with predictable influences on monkeys' behavioral responses. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Baroni, Fabiano; Burkitt, Anthony N; Grayden, David B
2014-05-01
High-frequency oscillations (above 30 Hz) have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF) or Generalized Integrate-and-Fire (GIF) neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i) the firing rate response to the noisy background input, ii) the membrane potential distribution, and iii) the shape of Inhibitory Post-Synaptic Potentials (IPSPs). For hyperpolarizing inhibition, the GIF IPSP profile (factor iii)) exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i) and ii), respectively), which tend to decrease synchrony. If inhibition is shunting instead of hyperpolarizing, post-inhibitory rebound is not elicited and factors i) and ii) dominate, yielding lower synchrony in GIF networks than in IF networks.
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Baroni, Fabiano; Burkitt, Anthony N.; Grayden, David B.
2014-01-01
High-frequency oscillations (above 30 Hz) have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF) or Generalized Integrate-and-Fire (GIF) neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i) the firing rate response to the noisy background input, ii) the membrane potential distribution, and iii) the shape of Inhibitory Post-Synaptic Potentials (IPSPs). For hyperpolarizing inhibition, the GIF IPSP profile (factor iii)) exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i) and ii), respectively), which tend to decrease synchrony. If inhibition is shunting instead of hyperpolarizing, post-inhibitory rebound is not elicited and factors i) and ii) dominate, yielding lower synchrony in GIF networks than in IF networks. PMID:24784237
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Contextual modulation revealed by optical imaging exhibits figural asymmetry in macaque V1 and V2.
Zarella, Mark D; Ts'o, Daniel Y
2017-01-01
Neurons in early visual cortical areas are influenced by stimuli presented well beyond the confines of their classical receptive fields, endowing them with the ability to encode fine-scale features while also having access to the global context of the visual scene. This property can potentially define a role for the early visual cortex to contribute to a number of important visual functions, such as surface segmentation and figure-ground segregation. It is unknown how extraclassical response properties conform to the functional architecture of the visual cortex, given the high degree of functional specialization in areas V1 and V2. We examined the spatial relationships of contextual activations in macaque V1 and V2 with intrinsic signal optical imaging. Using figure-ground stimulus configurations defined by orientation or motion, we found that extraclassical modulation is restricted to the cortical representations of the figural component of the stimulus. These modulations were positive in sign, suggesting a relative enhancement in neuronal activity that may reflect an excitatory influence. Orientation and motion cues produced similar patterns of activation that traversed the functional subdivisions of V2. The asymmetrical nature of the enhancement demonstrated the capacity for visual cortical areas as early as V1 to contribute to figure-ground segregation, and the results suggest that this information can be extracted from the population activity constrained only by retinotopy, and not the underlying functional organization.
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Contextual modulation revealed by optical imaging exhibits figural asymmetry in macaque V1 and V2
Zarella, Mark D; Ts’o, Daniel Y
2017-01-01
Neurons in early visual cortical areas are influenced by stimuli presented well beyond the confines of their classical receptive fields, endowing them with the ability to encode fine-scale features while also having access to the global context of the visual scene. This property can potentially define a role for the early visual cortex to contribute to a number of important visual functions, such as surface segmentation and figure–ground segregation. It is unknown how extraclassical response properties conform to the functional architecture of the visual cortex, given the high degree of functional specialization in areas V1 and V2. We examined the spatial relationships of contextual activations in macaque V1 and V2 with intrinsic signal optical imaging. Using figure–ground stimulus configurations defined by orientation or motion, we found that extraclassical modulation is restricted to the cortical representations of the figural component of the stimulus. These modulations were positive in sign, suggesting a relative enhancement in neuronal activity that may reflect an excitatory influence. Orientation and motion cues produced similar patterns of activation that traversed the functional subdivisions of V2. The asymmetrical nature of the enhancement demonstrated the capacity for visual cortical areas as early as V1 to contribute to figure–ground segregation, and the results suggest that this information can be extracted from the population activity constrained only by retinotopy, and not the underlying functional organization. PMID:28761385
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Boulanger-Weill, Jonathan; Candat, Virginie; Jouary, Adrien; Romano, Sebastián A; Pérez-Schuster, Verónica; Sumbre, Germán
2017-06-19
From development up to adulthood, the vertebrate brain is continuously supplied with newborn neurons that integrate into established mature circuits. However, how this process is coordinated during development remains unclear. Using two-photon imaging, GCaMP5 transgenic zebrafish larvae, and sparse electroporation in the larva's optic tectum, we monitored spontaneous and induced activity of large neuronal populations containing newborn and functionally mature neurons. We observed that the maturation of newborn neurons is a 4-day process. Initially, newborn neurons showed undeveloped dendritic arbors, no neurotransmitter identity, and were unresponsive to visual stimulation, although they displayed spontaneous calcium transients. Later on, newborn-labeled neurons began to respond to visual stimuli but in a very variable manner. At the end of the maturation period, newborn-labeled neurons exhibited visual tuning curves (spatial receptive fields and direction selectivity) and spontaneous correlated activity with neighboring functionally mature neurons. At this developmental stage, newborn-labeled neurons presented complex dendritic arbors and neurotransmitter identity (excitatory or inhibitory). Removal of retinal inputs significantly perturbed the integration of newborn neurons into the functionally mature tectal network. Our results provide a comprehensive description of the maturation of newborn neurons during development and shed light on potential mechanisms underlying their integration into a functionally mature neuronal circuit. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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Collective behaviors of suprachiasm nucleus neurons under different light—dark cycles
NASA Astrophysics Data System (ADS)
Gu, Chang-Gui; Zhang, Xin-Hua; Liu, Zong-Hua
2014-07-01
The principal circadian clock in the suprachiasm nucleus (SCN) regulates the circadian rhythm of physiological and behavioral activities of mammals. Except for the normal function of the circadian rhythm, the ensemble of SCN neurons may show two collective behaviors, i.e., a free running period in the absence of a light—dark cycle and an entrainment ability to an external T cycle. Experiments show that both the free running periods and the entrainment ranges may vary from one species to another and can be seriously influenced by the coupling among the SCN neurons. We here review the recent progress on how the heterogeneous couplings influence these two collective behaviors. We will show that in the case of homogeneous coupling, the free running period increases monotonically while the entrainment range decreases monotonically with the increase of the coupling strength. While in the case of heterogenous coupling, the dispersion of the coupling strength plays a crucial role. It has been found that the free running period decreases with the increase of the dispersion while the entrainment ability is enhanced by the dispersion. These findings provide new insights into the mechanism of the circadian clock in the SCN.
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Exploring associations between gaze patterns and putative human mirror neuron system activity.
Donaldson, Peter H; Gurvich, Caroline; Fielding, Joanne; Enticott, Peter G
2015-01-01
The human mirror neuron system (MNS) is hypothesized to be crucial to social cognition. Given that key MNS-input regions such as the superior temporal sulcus are involved in biological motion processing, and mirror neuron activity in monkeys has been shown to vary with visual attention, aberrant MNS function may be partly attributable to atypical visual input. To examine the relationship between gaze pattern and interpersonal motor resonance (IMR; an index of putative MNS activity), healthy right-handed participants aged 18-40 (n = 26) viewed videos of transitive grasping actions or static hands, whilst the left primary motor cortex received transcranial magnetic stimulation. Motor-evoked potentials recorded in contralateral hand muscles were used to determine IMR. Participants also underwent eyetracking analysis to assess gaze patterns whilst viewing the same videos. No relationship was observed between predictive gaze and IMR. However, IMR was positively associated with fixation counts in areas of biological motion in the videos, and negatively associated with object areas. These findings are discussed with reference to visual influences on the MNS, and the possibility that MNS atypicalities might be influenced by visual processes such as aberrant gaze pattern.
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Translational neuropharmacology: the use of human isolated gastrointestinal tissues.
Sanger, G J; Broad, J; Kung, V; Knowles, C H
2013-01-01
Translational sciences increasingly emphasize the measurement of functions in native human tissues. However, such studies must confront variations in patient age, gender, genetic background and disease. Here, these are discussed with reference to neuromuscular and neurosecretory functions of the human gastrointestinal (GI) tract. Tissues are obtained after informed consent, in collaboration with surgeons (surgical techniques help minimize variables) and pathologists. Given the difficulties of directly recording from human myenteric neurones (embedded between muscle layers), enteric motor nerve functions are studied by measuring muscle contractions/relaxations evoked by electrical stimulation of intrinsic nerves; responses are regionally dependent, often involving cholinergic and nitrergic phenotypes. Enteric sensory functions can be studied by evoking the peristaltic reflex, involving enteric sensory and motor nerves, but this has rarely been achieved. As submucosal neurones are more accessible (after removing the mucosa), direct neuronal recordings are possible. Neurosecretory functions are studied by measuring changes in short-circuit current across the mucosa. For all experiments, basic questions must be addressed. Because tissues are from patients, what are the controls and the influence of disease? How long does it take before function fully recovers? What is the impact of age- and gender-related differences? What is the optimal sample size? Addressing these and other questions minimizes variability and raises the scientific credibility of human tissue research. Such studies also reduce animal use. Further, the many differences between animal and human GI functions also means that human tissue research must question the ethical validity of using strains of animals with unproved translational significance. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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Sagheddu, Claudia; Muntoni, Anna Lisa; Pistis, Marco; Melis, Miriam
2015-01-01
Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. © 2015 Elsevier Inc. All rights reserved.
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Sale, Martin V.; Rogasch, Nigel C.; Nordstrom, Michael A.
2016-01-01
The amplitude of motor-evoked potentials (MEPs) elicited with transcranial magnetic stimulation (TMS) varies from trial-to-trial. Synchronous oscillations in cortical neuronal excitability contribute to this variability, however it is not known how different frequencies of stimulation influence MEP variability, and whether these oscillations are rhythmic or aperiodic. We stimulated the motor cortex with TMS at different regular (i.e., rhythmic) rates, and compared this with pseudo-random (aperiodic) timing. In 18 subjects, TMS was applied at three regular frequencies (0.05 Hz, 0.2 Hz, 1 Hz) and one aperiodic frequency (mean 0.2 Hz). MEPs (n = 50) were recorded from three intrinsic hand muscles of the left hand with different functional and anatomical relations. MEP amplitude correlation was highest for the functionally related muscle pair, less for the anatomically related muscle pair and least for the functionally- and anatomically-unrelated muscle pair. MEP correlations were greatest with 1 Hz, and least for stimulation at 0.05 Hz. Corticospinal neuron synchrony is higher with shorter TMS intervals. Further, corticospinal neuron synchrony is similar irrespective of whether the stimulation is periodic or aperiodic. These findings suggest TMS frequency is a crucial consideration for studies using TMS to probe correlated activity between muscle pairs. PMID:27014031
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An internal thermal sensor controlling temperature preference in Drosophila.
Hamada, Fumika N; Rosenzweig, Mark; Kang, Kyeongjin; Pulver, Stefan R; Ghezzi, Alfredo; Jegla, Timothy J; Garrity, Paul A
2008-07-10
Animals from flies to humans are able to distinguish subtle gradations in temperature and show strong temperature preferences. Animals move to environments of optimal temperature and some manipulate the temperature of their surroundings, as humans do using clothing and shelter. Despite the ubiquitous influence of environmental temperature on animal behaviour, the neural circuits and strategies through which animals select a preferred temperature remain largely unknown. Here we identify a small set of warmth-activated anterior cell (AC) neurons located in the Drosophila brain, the function of which is critical for preferred temperature selection. AC neuron activation occurs just above the fly's preferred temperature and depends on dTrpA1, an ion channel that functions as a molecular sensor of warmth. Flies that selectively express dTrpA1 in the AC neurons select normal temperatures, whereas flies in which dTrpA1 function is reduced or eliminated choose warmer temperatures. This internal warmth-sensing pathway promotes avoidance of slightly elevated temperatures and acts together with a distinct pathway for cold avoidance to set the fly's preferred temperature. Thus, flies select a preferred temperature by using a thermal sensing pathway tuned to trigger avoidance of temperatures that deviate even slightly from the preferred temperature. This provides a potentially general strategy for robustly selecting a narrow temperature range optimal for survival.
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Schwieger, Jana; Esser, Karl-Heinz; Lenarz, Thomas; Scheper, Verena
2016-08-01
Sensorineural deafness is mainly caused by damage to hair cells and degeneration of the spiral ganglion neurons (SGN). Cochlear implants can functionally replace lost hair cells and stimulate the SGN electrically. The benefit from cochlear implantation depends on the number and excitability of these neurons. To identify potential therapies for SGN protection, in vitro tests are carried out on spiral ganglion cells (SGC). A glial cell-reduced and neuron-enhanced culture of neonatal rat SGC under mitotic inhibition (cytarabine (AraC)) for up to seven days is presented. Serum containing and neurotrophin-enriched cultures with and without AraC-addition were analyzed after 4 and 7 days. The total number of cells was significantly reduced, while the proportion of neurons was greatly increased by AraC-treatment. Cell type-specific labeling demonstrated that nearly all fibroblasts and most of the glial cells were removed. Neither the neuronal survival, nor the neurite outgrowth or soma diameter were negatively affected. Additionally neurites remain partly free of surrounding non-neuronal cells. Recent culture conditions allow only for short-term cultivation of neonatal SGC and lack information on the influence of non-neuronal cells on SGN and of direct contact of neurites with test-materials. AraC-addition reduces the number of non-neuronal cells and increases the ratio of SGN in culture, without negative impact on neuronal viability. This treatment allows longer-term cultivation of SGC and provides deeper insight into SGN-glial cell interaction and the attachment of neurites on test-material surfaces. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
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Differential Effects of RET and TRKB on Axonal Branching and Survival of Parasympathetic Neurons
Simpson, Julie; Keefe, Julie; Nishi, Rae
2014-01-01
Interactions between neurons and their targets of innervation influence many aspects of neural development. To examine how synaptic activity interacts with neurotrophic signaling, we determined the effects of blocking neuromuscular transmission on survival and axonal outgrowth of ciliary neurons from the embryonic chicken ciliary ganglion. Ciliary neurons undergo a period of cell loss due to programmed cell death between embryonic Days (E) 8 and 14 and they innervate the striated muscle of the iris. The nicotinic antagonist d-tubocurarine (dTC) induces an increase in branching measured by counting neurofilament-positive voxels (NF-VU) in the iris between E14–17 while reducing ciliary neuron survival. Blocking ganglionic transmission with dihyro-β-erythroidin and α-methyllycacontine does not mimic dTC. At E8, many trophic factors stimulate neurite outgrowth and branching of neurons placed in cell culture; however, at E13, only GDNF stimulates branching selectively in cultured ciliary neurons. The GDNF-induced branching at E13 could be inhibited by BDNF. Blocking ret signaling in vivo with a dominant negative (dn)ret decreases survival of ciliary and choroid neurons at E14 and prevents dTC induced increases in NF-VU in the iris at E17. Blocking TRKB signaling with dn TRKB increases NF-VU in the iris at E17 and decreases neuronal survival at E17, but not at E14. Thus, RET promotes survival during programmed cell death in the ciliary ganglion and contributes to promoting branching when synaptic transmission is blocked while TRKB inhibits branching and promotes maintenance of neuronal survival. These studies highlight the multifunctional nature of trophic molecule function during neuronal development. PMID:22648743
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[The ontogeny of the mirror neuron system].
Myowa-Yamakoshi, Masako
2014-06-01
Abstract Humans utilize the mirror neuron system to understand and predict others' actions. However, the ontogeny of the mirror neuron system remains unknown. Whether mirror neuron function is an innate trait or whether mirror neurons acquire their sensorimotor matching properties ontogenetically remains to be clarified. In this paper, I review the ontogenetic theory of the mirror neuron system. I then discuss the functioning of the mirror neuron system in the context of social cognitive abilities, which are unique to humans. Recently, some researchers argue that it is too early to interpret the function of mirror neurons as an understanding of the underlying psychological states of others. They imply that such functioning would require inferential cognitive processes that are known to involve areas outside the mirror neuron system. Filling in this missing link may be the key to elucidating the unique ability of humans to understand others' actions.
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FNDC5/irisin, a molecular target for boosting reward-related learning and motivation.
Zsuga, Judit; Tajti, Gabor; Papp, Csaba; Juhasz, Bela; Gesztelyi, Rudolf
2016-05-01
Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Lecca, Salvatore; Melis, Miriam; Luchicchi, Antonio; Ennas, Maria Grazia; Castelli, Maria Paola; Muntoni, Anna Lisa; Pistis, Marco
2011-02-01
Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.
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Physical Exercise Promotes Recovery of Neurological Function after Ischemic Stroke in Rats
Zheng, Hai-Qing; Zhang, Li-Ying; Luo, Jing; Li, Li-Li; Li, Menglin; Zhang, Qingjie; Hu, Xi-Quan
2014-01-01
Although physical exercise is an effective strategy for treatment of ischemic stroke, the underlying protective mechanisms are still not well understood. It has been recently demonstrated that neural progenitor cells play a vital role in the recovery of neurological function (NF) through differentiation into mature neurons. In the current study, we observed that physical exercise significantly reduced the infarct size and improved damaged neural functional recovery after an ischemic stroke. Furthermore, we found that the treatment not only exhibited a significant increase in the number of neural progenitor cells and neurons but also decreased the apoptotic cells in the peri-infarct region, compared to a control in the absence of exercise. Importantly, the insulin-like growth factor-1 (IGF-1)/Akt signaling pathway was dramatically activated in the peri-infarct region of rats after physical exercise training. Therefore, our findings suggest that physical exercise directly influences the NF recovery process by increasing neural progenitor cell count via activation of the IGF-1/Akt signaling pathway. PMID:24945308
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GW182 controls Drosophila circadian behavior and PDF-Receptor signaling
Zhang, Yong; Emery, Patrick
2013-01-01
The neuropeptide PDF is crucial for Drosophila circadian behavior: it keeps circadian neurons synchronized. Here, we identify GW182 as a key regulator of PDF signaling. Indeed, GW182 downregulation results in phenotypes similar to those of Pdf and Pdf-receptor (Pdfr) mutants. gw182 genetically interacts with Pdfr and cAMP signaling, which is essential for PDFR function. GW182 mediates miRNA-dependent gene silencing through its interaction with AGO1. Consistently, GW182's AGO1 interaction domain is required for GW182's circadian function. Moreover, our results indicate that GW182 modulates PDFR signaling by silencing the expression of the cAMP phosphodiesterase DUNCE. Importantly, this repression is under photic control, and GW182 activity level - which is limiting in circadian neurons - influences the responses of the circadian neural network to light. We propose that GW182's gene silencing activity functions as a rheostat for PDFR signaling, and thus profoundly impacts the circadian neural network and its response to environmental inputs. PMID:23583112
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Reduced Mastication Impairs Memory Function.
Fukushima-Nakayama, Y; Ono, Takehito; Hayashi, M; Inoue, M; Wake, H; Ono, Takashi; Nakashima, T
2017-08-01
Mastication is an indispensable oral function related to physical, mental, and social health throughout life. The elderly tend to have a masticatory dysfunction due to tooth loss and fragility in the masticatory muscles with aging, potentially resulting in impaired cognitive function. Masticatory stimulation has influence on the development of the central nervous system (CNS) as well as the growth of maxillofacial tissue in children. Although the relationship between mastication and cognitive function is potentially important in the growth period, the cellular and molecular mechanisms have not been sufficiently elucidated. Here, we show that the reduced mastication resulted in impaired spatial memory and learning function owing to the morphological change and decreased activity in the hippocampus. We used an in vivo model for reduced masticatory stimuli, in which juvenile mice were fed with powder diet and found that masticatory stimulation during the growth period positively regulated long-term spatial memory to promote cognitive function. The functional linkage between mastication and brain was validated by the decrease in neurons, neurogenesis, neuronal activity, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. These findings taken together provide in vivo evidence for a functional linkage between mastication and cognitive function in the growth period, suggesting a need for novel therapeutic strategies in masticatory function-related cognitive dysfunction.
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Estrogens of multiple classes and their role in mental health disease mechanisms.
Watson, Cheryl S; Alyea, Rebecca A; Cunningham, Kathryn A; Jeng, Yow-Jiun
2010-08-09
Gender and sex hormones can influence a variety of mental health states, including mood, cognitive development and function, and vulnerability to neurodegenerative diseases and brain damage. Functions of neuronal cells may be altered by estrogens depending upon the availability of different physiological estrogenic ligands; these ligands and their effects vary with life stages, the genetic or postgenetic regulation of receptor levels in specific tissues, or the intercession of competing nonphysiological ligands (either intentional or unintentional, beneficial to health or not). Here we review evidence for how different estrogens (physiological and environmental/dietary), acting via different estrogen receptor subtypes residing in alternative subcellular locations, influence brain functions and behavior. We also discuss the families of receptors and transporters for monoamine neurotransmitters and how they may interact with the estrogenic signaling pathways.
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Schmid, H A
1995-01-01
Recently published electrophysiological data investigated the effect of blood borne and brain intrinsic substances on the activity of neurons in the duck subfornical organ (SFO). This study defines histologically the region in the duck SFO, where blood borne substances can possibly influence neuronal activity. Intravenous injection of Evans blue, a dye which labels brain structures devoid of a blood brain barrier (BBB), resulted in diffuse labelling of the duck SFO from the anterior commissure to the end of the organ in rostrocaudal extension. In addition, specifically labelled neurons could be observed just rostral to the diffuse Evans blue labelling and in an area dorsomedial to the large central blood vessel. The majority of the somata of these heavily stained neurons were located inside the BBB, whereas in the areas with diffuse Evans blue labelling, thus being outside the BBB, labelled cells were rarely observed. Intravenous injection of Evans blue in rats resulted similarly in diffuse labelling of the parenchyma of the medial and caudal part of the SFO, with only a few, but heavily stained cells with fusiform somata. The rostral region of the rat SFO, which is known to have a functional BBB, shows hardly any diffuse labelling, but there the majority of neurons show strong Evans blue fluorescence. It is concluded that the heavily labelled somata inside the BBB have axonal or dendritic projections to BBB-free areas, where they can take up the dye. This study gives a functional description of the extension of the SFO areas without a BBB of rats and ducks. It is concluded that blood borne agents can affect those SFO neurons which have their somata located outside the BBB as well as those located inside the BBB which have terminals projecting to BBB free regions.
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Gonchar, Yuri; Burkhalter, Andreas
2003-11-26
Processing of visual information is performed in different cortical areas that are interconnected by feedforward (FF) and feedback (FB) pathways. Although FF and FB inputs are excitatory, their influences on pyramidal neurons also depend on the outputs of GABAergic neurons, which receive FF and FB inputs. Rat visual cortex contains at least three different families of GABAergic neurons that express parvalbumin (PV), calretinin (CR), and somatostatin (SOM) (Gonchar and Burkhalter, 1997). To examine whether pathway-specific inhibition (Shao and Burkhalter, 1996) is attributable to distinct connections with GABAergic neurons, we traced FF and FB inputs to PV, CR, and SOM neurons in layers 1-2/3 of area 17 and the secondary lateromedial area in rat visual cortex. We found that in layer 2/3 maximally 2% of FF and FB inputs go to CR and SOM neurons. This contrasts with 12-13% of FF and FB inputs onto layer 2/3 PV neurons. Unlike inputs to layer 2/3, connections to layer 1, which contains CR but lacks SOM and PV somata, are pathway-specific: 21% of FB inputs go to CR neurons, whereas FF inputs to layer 1 and its CR neurons are absent. These findings suggest that FF and FB influences on layer 2/3 pyramidal neurons mainly involve disynaptic connections via PV neurons that control the spike outputs to axons and proximal dendrites. Unlike FF input, FB input in addition makes a disynaptic link via CR neurons, which may influence the excitability of distal pyramidal cell dendrites in layer 1.
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Electrophysiology of Axonal Constrictions
NASA Astrophysics Data System (ADS)
Johnson, Christopher; Jung, Peter; Brown, Anthony
2013-03-01
Axons of myelinated neurons are constricted at the nodes of Ranvier, where they are directly exposed to the extracellular space and where the vast majority of the ion channels are located. These constrictions are generated by local regulation of the kinetics of neurofilaments the most important cytoskeletal elements of the axon. In this paper we discuss how this shape affects the electrophysiological function of the neuron. Specifically, although the nodes are short (about 1 μm) in comparison to the distance between nodes (hundreds of μm) they have a substantial influence on the conduction velocity of neurons. We show through computational modeling that nodal constrictions (all other features such as numbers of ion channels left constant) reduce the required fiber diameter for a given target conduction velocity by up to 50% in comparison to an unconstricted axon. We further show that the predicted optimal fiber morphologies closely match reported fiber morphologies. Supported by The National Science Foundation (IOS 1146789)
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Aptamer antagonists of myelin-derived inhibitors promote axon growth.
Wang, Yuxuan; Khaing, Zin Z; Li, Na; Hall, Brad; Schmidt, Christine E; Ellington, Andrew D
2010-03-16
Myelin of the adult central nervous system (CNS) is one of the major sources of inhibitors of axon regeneration following injury. The three known myelin-derived inhibitors (Nogo, MAG, and OMgp) bind with high affinity to the Nogo-66 receptor (NgR) on axons and limit neurite outgrowth. Here we show that RNA aptamers can be generated that bind with high affinity to NgR, compete with myelin-derived inhibitors for binding to NgR, and promote axon elongation of neurons in vitro even in the presence of these inhibitors. Aptamers may have key advantages over protein antagonists, including low immunogenicity and the possibility of ready modification during chemical synthesis for stability, signaling, or immobilization. This first demonstration that aptamers can directly influence neuronal function suggests that aptamers may prove useful for not only healing spinal cord and other neuronal damage, but may be more generally useful as neuromodulators.
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Aptamer Antagonists of Myelin-Derived Inhibitors Promote Axon Growth
Wang, Yuxuan; Khaing, Zin Z.; Li, Na; Hall, Brad; Schmidt, Christine E.; Ellington, Andrew D.
2010-01-01
Myelin of the adult central nervous system (CNS) is one of the major sources of inhibitors of axon regeneration following injury. The three known myelin-derived inhibitors (Nogo, MAG, and OMgp) bind with high affinity to the Nogo-66 receptor (NgR) on axons and limit neurite outgrowth. Here we show that RNA aptamers can be generated that bind with high affinity to NgR, compete with myelin-derived inhibitors for binding to NgR, and promote axon elongation of neurons in vitro even in the presence of these inhibitors. Aptamers may have key advantages over protein antagonists, including low immunogenicity and the possibility of ready modification during chemical synthesis for stability, signaling, or immobilization. This first demonstration that aptamers can directly influence neuronal function suggests that aptamers may prove useful for not only healing spinal cord and other neuronal damage, but may be more generally useful as neuromodulators. PMID:20300533
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Fukushima, Kazuyuki; Miura, Yuji; Sawada, Kohei; Yamazaki, Kazuto; Ito, Masashi
2016-01-01
Using human cell models mimicking the central nervous system (CNS) provides a better understanding of the human CNS, and it is a key strategy to improve success rates in CNS drug development. In the CNS, neurons function as networks in which astrocytes play important roles. Thus, an assessment system of neuronal network functions in a co-culture of human neurons and astrocytes has potential to accelerate CNS drug development. We previously demonstrated that human hippocampus-derived neural stem/progenitor cells (HIP-009 cells) were a novel tool to obtain human neurons and astrocytes in the same culture. In this study, we applied HIP-009 cells to a multielectrode array (MEA) system to detect neuronal signals as neuronal network functions. We observed spontaneous firings of HIP-009 neurons, and validated functional formation of neuronal networks pharmacologically. By using this assay system, we investigated effects of several reference compounds, including agonists and antagonists of glutamate and γ-aminobutyric acid receptors, and sodium, potassium, and calcium channels, on neuronal network functions using firing and burst numbers, and synchrony as readouts. These results indicate that the HIP-009/MEA assay system is applicable to the pharmacological assessment of drug candidates affecting synaptic functions for CNS drug development. © 2015 Society for Laboratory Automation and Screening.
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Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons.
Bello, Sanusi M; Millo, Hadas; Rajebhosale, Manisha; Price, Stephen R
2012-01-11
Motor neurons that control limb movements are organized as a neuronal nucleus in the developing ventral horn of the spinal cord called the lateral motor column. Neuronal migration segregates motor neurons into distinct lateral and medial divisions within the lateral motor column that project axons to dorsal or ventral limb targets, respectively. This migratory phase is followed by an aggregation phase whereby motor neurons within a division that project to the same muscle cluster together. These later phases of motor neuron organization depend on limb-regulated differential cadherin expression within motor neurons. Initially, all motor neurons display the same cadherin expression profile, which coincides with the migratory phase of motor neuron segregation. Here, we show that this early, pan-motor neuron cadherin function drives the divisional segregation of spinal motor neurons in the chicken embryo by controlling motor neuron migration. We manipulated pan-motor neuron cadherin function through dissociation of cadherin binding to their intracellular partners. We found that of the major intracellular transducers of cadherin signaling, γ-catenin and α-catenin predominate in the lateral motor column. In vivo manipulations that uncouple cadherin-catenin binding disrupt divisional segregation via deficits in motor neuron migration. Additionally, reduction of the expression of cadherin-7, a cadherin predominantly expressed in motor neurons only during their migration, also perturbs divisional segregation. Our results show that γ-catenin-dependent cadherin function is required for spinal motor neuron migration and divisional segregation and suggest a prolonged role for cadherin expression in all phases of motor neuron organization.
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Cheong, Rachel Y; Czieselsky, Katja; Porteous, Robert; Herbison, Allan E
2015-10-28
Circulating estradiol exerts a profound influence on the activity of the gonadotropin-releasing hormone (GnRH) neuronal network controlling fertility. Using genetic strategies enabling neuron-specific deletion of estrogen receptor α (Esr1), we examine here whether estradiol-modulated GABA and glutamate transmission are critical for the functioning of the GnRH neuron network in the female mouse. Using Vgat- and Vglut2-ires-Cre knock-in mice and ESR1 immunohistochemistry, we demonstrate that subpopulations of GABA and glutamate neurons throughout the limbic forebrain express ESR1, with ESR1-GABAergic neurons being more widespread and numerous than ESR1-glutamatergic neurons. We crossed Vgat- and Vglut2-ires-Cre mice with an Esr1(lox/lox) line to generate animals with GABA-neuron-specific or glutamate-neuron-specific deletion of Esr1. Vgat-ires-Cre;Esr1(lox/lox) mice were infertile, with abnormal estrous cycles, and exhibited a complete failure of the estrogen positive feedback mechanism responsible for the preovulatory GnRH surge. However, puberty onset and estrogen negative feedback were normal. Vglut2-ires-Cre;Esr1(lox/lox) mice were also infertile but displayed a wider range of deficits, including advanced puberty onset, abnormal negative feedback, and abolished positive feedback. Whereas <25% of preoptic kisspeptin neurons expressed Cre in Vgat- and Vglut2-ires-Cre lines, ∼70% of arcuate kisspeptin neurons were targeted in Vglut2-ires-Cre;Esr1(lox/lox) mice, possibly contributing to their advanced puberty phenotype. These observations show that, unexpectedly, ESR1-GABA neurons are only essential for the positive feedback mechanism. In contrast, we reveal the key importance of ESR1 in glutamatergic neurons for multiple estrogen feedback loops within the GnRH neuronal network required for fertility in the female mouse. Copyright © 2015 the authors 0270-6474/15/3514533-11$15.00/0.
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D'Angelo, Barbara; Astarita, Carlo; Boffo, Silvia; Massaro-Giordano, Mina; Antonella Ianuzzi, Carmelina; Caporaso, Antonella; Macaluso, Marcella; Giordano, Antonio
2017-01-01
Cell cycle reactivation in adult neurons is an early hallmark of neurodegeneration. The lipopolysaccharide (LPS) is a well-known pro-inflammatory factor that provokes neuronal cell death via glial cells activation. The retinoblastoma (RB) family includes RB1/p105, retinoblastoma-like 1 (RBL1/p107), and retinoblastoma-like 2 (Rb2/p130). Several studies have indicated that RB proteins exhibit tumor suppressor activities, and play a central role in cell cycle regulation. In this study, we assessed LPS-mediated inflammatory effect on cell cycle reactivation and apoptosis of neuronally differentiated cells. Also, we investigated whether the LPS-mediated inflammatory response can influence the function and expression of RB proteins. Our results showed that LPS challenges triggered cell cycle reactivation of differentiated neuronal cells, indicated by an accumulation of cells in S and G2/M phase. Furthermore, we found that LPS treatment also induced apoptotic death of neurons. Interestingly, we observed that LPS-mediated inflammatory effect on cell cycle re-entry and apoptosis was concomitant with the aberrant expression of RBL1/p107 and RB1/p105. To the best of our knowledge, our study is the first to indicate a role of LPS in inducing cell cycle re-entry and/or apoptosis of differentiated neuronal cells, perhaps through mechanisms altering the expression of specific members of RB family proteins. This study provides novel information on the biology of post-mitotic neurons and could help in identifying novel therapeutic targets to prevent de novo cell cycle reactivation and/or apoptosis of neurons undergoing neurodegenerative processes.
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Recording temperature affects the excitability of mouse superficial dorsal horn neurons, in vitro.
Graham, B A; Brichta, A M; Callister, R J
2008-05-01
Superficial dorsal horn (SDH) neurons in laminae I-II of the spinal cord play an important role in processing noxious stimuli. These neurons represent a heterogeneous population and are divided into various categories according to their action potential (AP) discharge during depolarizing current injection. We recently developed an in vivo mouse preparation to examine functional aspects of nociceptive processing and AP discharge in SDH neurons and to extend investigation of pain mechanisms to the genetic level of analysis. Not surprisingly, some in vivo data obtained at body temperature (37 degrees C) differed from those generated at room temperature (22 degrees C) in spinal cord slices. In the current study we examine how temperature influences SDH neuron properties by making recordings at 22 and 32 degrees C in transverse spinal cord slices prepared from L3-L5 segments of adult mice (C57Bl/6). Patch-clamp recordings (KCH(3)SO(4) internal) were made from visualized SDH neurons. At elevated temperature all SDH neurons had reduced input resistance and smaller, briefer APs. Resting membrane potential and AP afterhyperpolarization amplitude were temperature sensitive only in subsets of the SDH population. Notably, elevated temperature increased the prevalence of neurons that did not discharge APs during current injection. These reluctant firing neurons expressed a rapid A-type potassium current, which is enhanced at higher temperatures and thus restrains AP discharge. When compared with previously published whole cell recordings obtained in vivo (37 degrees C) our results suggest that, on balance, in vitro data collected at elevated temperature more closely resemble data collected under in vivo conditions.
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Fatigue of muscles weakened by death of motoneurons.
Thomas, Christine K; Zijdewind, Inge
2006-01-01
Weakness is a characteristic of muscles influenced by the postpolio syndrome (PPS), amyotrophic lateral sclerosis (ALS), and spinal cord injury (SCI). The strength deficits relate to changes in muscle use and to the chronic denervation that can follow the spinal motoneuron death common to these disorders. PPS, ALS, and SCI also involve variable amounts of supraspinal neuron death, the effects of which on muscle weakness remains unclear. Nevertheless, weakness of muscle itself defines the functional consequences of these disorders. A weaker muscle requires an individual to work that muscle at higher than usual intensities relative to its maximal capacity, inducing progressive fatigue and an increased sense of effort. Little evidence is available to suggest that the fatigue commonly experienced by individuals with these disorders relates to an increase in the intrinsic fatigability of the muscle fibers. The only exception is when SCI induces chronic muscle paralysis. To reduce long-term functional deficits in these disorders, studies must identify the signaling pathways that influence neuron survival and determine the factors that encourage and limit sprouting of motor axons. This may ensure that a greater proportion of the fibers in each muscle remain innervated and available for use.
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Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex
McGarry, Laura M.
2016-01-01
Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. PMID:27605614
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Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.
McGarry, Laura M; Carter, Adam G
2016-09-07
Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. Copyright © 2016 the authors 0270-6474/16/369391-16$15.00/0.
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Transcranial Alternating Current Stimulation (tACS) Mechanisms and Protocols
Tavakoli, Amir V.; Yun, Kyongsik
2017-01-01
Perception, cognition and consciousness can be modulated as a function of oscillating neural activity, while ongoing neuronal dynamics are influenced by synaptic activity and membrane potential. Consequently, transcranial alternating current stimulation (tACS) may be used for neurological intervention. The advantageous features of tACS include the biphasic and sinusoidal tACS currents, the ability to entrain large neuronal populations, and subtle control over somatic effects. Through neuromodulation of phasic, neural activity, tACS is a powerful tool to investigate the neural correlates of cognition. The rapid development in this area requires clarity about best practices. Here we briefly introduce tACS and review the most compelling findings in the literature to provide a starting point for using tACS. We suggest that tACS protocols be based on functional brain mechanisms and appropriate control experiments, including active sham and condition blinding. PMID:28928634
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Ultraweak photon emission in the brain.
Salari, V; Valian, H; Bassereh, H; Bókkon, I; Barkhordari, A
2015-09-01
Besides the low-frequency electromagnetic body-processes measurable through the electroencephalography (EEG), electrocardiography (ECG), etc. there are processes that do not need external excitation, emitting light within or close to the visible spectra. Such ultraweak photon emission (UPE), also named biophoton emission, reflects the cellular (and body) oxidative status. Recently, a growing body of evidence shows that UPE may play an important role in the basic functioning of living cells. Moreover, interesting evidences are beginning to emerge that UPE may well play an important role in neuronal functions. In fact, biophotons are byproducts in cellular metabolism and produce false signals (e.g., retinal discrete dark noise) but on the other side neurons contain many light sensitive molecules that makes it hard to imagine how they might not be influenced by UPE, and thus UPE may carry informational contents. Here, we investigate UPE in the brain from different points of view such as experimental evidences, theoretical modeling, and physiological significance.
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Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg
2016-08-15
The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks.
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Linehan, Victoria; Trask, Robert B; Briggs, Chantalle; Rowe, Todd M; Hirasawa, Michiru
2015-08-01
Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 μM) and high (100 μM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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The Mast Cell Degranulator Compound 48/80 Directly Activates Neurons
Schemann, Michael; Kugler, Eva Maria; Buhner, Sabine; Eastwood, Christopher; Donovan, Jemma; Jiang, Wen; Grundy, David
2012-01-01
Background Compound 48/80 is widely used in animal and tissue models as a “selective” mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. Methodology/Principal Findings We used in vivo recordings from extrinsic intestinal afferents together with Ca++ imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca++ and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca++ transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H1 and H2 antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca++ transients in mast cell-free enteric neuron cultures. Conclusions/Significance The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn. PMID:23272218
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Arbitrary nonlinearity is sufficient to represent all functions by neural networks - A theorem
NASA Technical Reports Server (NTRS)
Kreinovich, Vladik YA.
1991-01-01
It is proved that if we have neurons implementing arbitrary linear functions and a neuron implementing one (arbitrary but smooth) nonlinear function g(x), then for every continuous function f(x sub 1,..., x sub m) of arbitrarily many variables, and for arbitrary e above 0, we can construct a network that consists of g-neurons and linear neurons, and computes f with precision e.
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Multivesicular Bodies in Neurons: Distribution, Protein Content, and Trafficking Functions
VON BARTHELD, CHRISTOPHER S.; ALTICK, AMY L.
2011-01-01
Summary Multivesicular bodies (MVBs) are intracellular endosomal organelles characterized by multiple internal vesicles that are enclosed within a single outer membrane. MVBs were initially regarded as purely prelysosomal structures along the degradative endosomal pathway of internalized proteins. MVBs are now known to be involved in numerous endocytic and trafficking functions, including protein sorting, recycling, transport, storage, and release. This review of neuronal MVBs summarizes their research history, morphology, distribution, accumulation of cargo and constitutive proteins, transport, and theories of functions of MVBs in neurons and glia. Due to their complex morphologies, neurons have expanded trafficking and signaling needs, beyond those of “geometrically simpler” cells, but it is not known whether neuronal MVBs perform additional transport and signaling functions. This review examines the concept of compartment-specific MVB functions in endosomal protein trafficking and signaling within synapses, axons, dendrites and cell bodies. We critically evaluate reports of the accumulation of neuronal MVBs based on evidence of stress-induced MVB formation. Furthermore, we discuss potential functions of neuronal and glial MVBs in development, in dystrophic neuritic syndromes, injury, disease, and aging. MVBs may play a role in Alzheimer’s, Huntington’s, and Niemann-Pick diseases, some types of frontotemporal dementia, prion and virus trafficking, as well as in adaptive responses of neurons to trauma and toxin or drug exposure. Functions of MVBs in neurons have been much neglected, and major gaps in knowledge currently exist. Developing truly MVB-specific markers would help to elucidate the roles of neuronal MVBs in intra- and intercellular signaling of normal and diseased neurons. PMID:21216273
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Bidirectional control of postsynaptic density-95 (PSD-95) clustering by Huntingtin.
Parsons, Matthew P; Kang, Rujun; Buren, Caodu; Dau, Alejandro; Southwell, Amber L; Doty, Crystal N; Sanders, Shaun S; Hayden, Michael R; Raymond, Lynn A
2014-02-07
Huntington disease is associated with early alterations in corticostriatal synaptic function that precede cell death, and it is postulated that ameliorating such changes may delay clinical onset and/or prevent neurodegeneration. Although many of these synaptic alterations are thought to be attributable to a toxic gain of function of the mutant huntingtin protein, the role that nonpathogenic huntingtin (HTT) plays in synaptic function is relatively unexplored. Here, we compare the immunocytochemical localization of a major postsynaptic scaffolding protein, PSD-95, in striatal neurons from WT mice and mice overexpressing HTT with 18 glutamine repeats (YAC18, nonpathogenic). We found that HTT overexpression resulted in a palmitoylation- and BDNF-dependent increase in PSD-95 clustering at synaptic sites in striatal spiny projection neurons (SPNs) co-cultured with cortical neurons. Surprisingly, the latter effect was mediated presynaptically, as HTT overexpression in cortical neurons alone was sufficient to increase PSD-95 clustering in the postsynaptic SPNs. In contrast, antisense oligonucleotide knockdown of HTT in WT co-cultures resulted in a significant reduction of PSD-95 clustering in SPNs. Notably, despite these bidirectional changes in PSD-95 clustering, we did not observe an alteration in basal electrophysiological measures of AMPA and NMDA receptors. Thus, unlike in previous studies in the hippocampus, enhanced or decreased PSD-95 clustering alone was insufficient to drive AMPA or NMDA receptors into or out of SPN synapses. In all, our results demonstrate that nonpathogenic HTT can indeed influence synaptic protein localization and uncover a novel role of HTT in PSD-95 distribution.
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Bidirectional Control of Postsynaptic Density-95 (PSD-95) Clustering by Huntingtin*
Parsons, Matthew P.; Kang, Rujun; Buren, Caodu; Dau, Alejandro; Southwell, Amber L.; Doty, Crystal N.; Sanders, Shaun S.; Hayden, Michael R.; Raymond, Lynn A.
2014-01-01
Huntington disease is associated with early alterations in corticostriatal synaptic function that precede cell death, and it is postulated that ameliorating such changes may delay clinical onset and/or prevent neurodegeneration. Although many of these synaptic alterations are thought to be attributable to a toxic gain of function of the mutant huntingtin protein, the role that nonpathogenic huntingtin (HTT) plays in synaptic function is relatively unexplored. Here, we compare the immunocytochemical localization of a major postsynaptic scaffolding protein, PSD-95, in striatal neurons from WT mice and mice overexpressing HTT with 18 glutamine repeats (YAC18, nonpathogenic). We found that HTT overexpression resulted in a palmitoylation- and BDNF-dependent increase in PSD-95 clustering at synaptic sites in striatal spiny projection neurons (SPNs) co-cultured with cortical neurons. Surprisingly, the latter effect was mediated presynaptically, as HTT overexpression in cortical neurons alone was sufficient to increase PSD-95 clustering in the postsynaptic SPNs. In contrast, antisense oligonucleotide knockdown of HTT in WT co-cultures resulted in a significant reduction of PSD-95 clustering in SPNs. Notably, despite these bidirectional changes in PSD-95 clustering, we did not observe an alteration in basal electrophysiological measures of AMPA and NMDA receptors. Thus, unlike in previous studies in the hippocampus, enhanced or decreased PSD-95 clustering alone was insufficient to drive AMPA or NMDA receptors into or out of SPN synapses. In all, our results demonstrate that nonpathogenic HTT can indeed influence synaptic protein localization and uncover a novel role of HTT in PSD-95 distribution. PMID:24347167
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Integrative Mechanisms of Oriented Neuronal Migration in the Developing Brain
Evsyukova, Irina; Plestant, Charlotte; Anton, E.S.
2014-01-01
The emergence of functional neuronal connectivity in the developing cerebral cortex depends on neuronal migration. This process enables appropriate positioning of neurons and the emergence of neuronal identity so that the correct patterns of functional synaptic connectivity between the right types and numbers of neurons can emerge. Delineating the complexities of neuronal migration is critical to our understanding of normal cerebral cortical formation and neurodevelopmental disorders resulting from neuronal migration defects. For the most part, the integrated cell biological basis of the complex behavior of oriented neuronal migration within the developing mammalian cerebral cortex remains an enigma. This review aims to analyze the integrative mechanisms that enable neurons to sense environmental guidance cues and translate them into oriented patterns of migration toward defined areas of the cerebral cortex. We discuss how signals emanating from different domains of neurons get integrated to control distinct aspects of migratory behavior and how different types of cortical neurons coordinate their migratory activities within the developing cerebral cortex to produce functionally critical laminar organization. PMID:23937349
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The glycolipid GM1 reshapes asymmetric biomembranes and giant vesicles by curvature generation.
Dasgupta, Raktim; Miettinen, Markus S; Fricke, Nico; Lipowsky, Reinhard; Dimova, Rumiana
2018-05-29
The ganglioside GM1 is present in neuronal membranes at elevated concentrations with an asymmetric spatial distribution. It is known to generate curvature and can be expected to strongly influence the neuron morphology. To elucidate these effects, we prepared giant vesicles with GM1 predominantly present in one leaflet of the membrane, mimicking the asymmetric GM1 distribution in neuronal membranes. Based on pulling inward and outward tubes, we developed a technique that allowed the direct measurement of the membrane spontaneous curvature. Using vesicle electroporation and fluorescence intensity analysis, we were able to quantify the GM1 asymmetry across the membrane and to subsequently estimate the local curvature generated by the molecule in the bilayer. Molecular-dynamics simulations confirm the experimentally determined dependence of the membrane spontaneous curvature as a function of GM1 asymmetry. GM1 plays a crucial role in connection with receptor proteins. Our results on curvature generation of GM1 point to an additional important role of this ganglioside, namely in shaping neuronal membranes. Copyright © 2018 the Author(s). Published by PNAS.
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CNS Macrophages Control Neurovascular Development via CD95L.
Chen, Si; Tisch, Nathalie; Kegel, Marcel; Yerbes, Rosario; Hermann, Robert; Hudalla, Hannes; Zuliani, Cecilia; Gülcüler, Gülce Sila; Zwadlo, Klara; von Engelhardt, Jakob; Ruiz de Almodóvar, Carmen; Martin-Villalba, Ana
2017-05-16
The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific deletion thereof reduces both neurovascular complexity and synaptic activity in the brain. CD95L-induced neuronal and vascular growth is mediated through src-family kinase (SFK) and PI3K signaling. Together, our study highlights a coordinated neurovascular development instructed by CNS macrophage-derived CD95L, and it underlines the importance of macrophages for the establishment of the neurovascular network during CNS development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
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Simplified and Yet Turing Universal Spiking Neural P Systems with Communication on Request.
Wu, Tingfang; Bîlbîe, Florin-Daniel; Păun, Andrei; Pan, Linqiang; Neri, Ferrante
2018-04-02
Spiking neural P systems are a class of third generation neural networks belonging to the framework of membrane computing. Spiking neural P systems with communication on request (SNQ P systems) are a type of spiking neural P system where the spikes are requested from neighboring neurons. SNQ P systems have previously been proved to be universal (computationally equivalent to Turing machines) when two types of spikes are considered. This paper studies a simplified version of SNQ P systems, i.e. SNQ P systems with one type of spike. It is proved that one type of spike is enough to guarantee the Turing universality of SNQ P systems. Theoretical results are shown in the cases of the SNQ P system used in both generating and accepting modes. Furthermore, the influence of the number of unbounded neurons (the number of spikes in a neuron is not bounded) on the computation power of SNQ P systems with one type of spike is investigated. It is found that SNQ P systems functioning as number generating devices with one type of spike and four unbounded neurons are Turing universal.
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Farkas, Imre; Vastagh, Csaba; Sárvári, Miklós; Liposits, Zsolt
2013-01-01
The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R) in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+)-imaging revealed a ghrelin-triggered increase of the Ca(2+)-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM) suggesting direct action of ghrelin. Estradiol (1nM) eliminated the ghrelin-evoked rise of Ca(2+)-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM) administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1) antagonist AM251 (1µM) and the intracellularly applied DAG-lipase inhibitor THL (10 µM), indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.
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Wahab, Fazal; Shahab, Muhammad; Behr, Rüdiger
2016-10-01
A large body of data suggests that body weight influences puberty onset and adult reproduction. However, the underlying mechanism of how body weight influences puberty onset and fertility is not completely understood. The hypothalamic neuronal circuit regulating reproduction is restrained by inhibitory signals during childhood. At the time of puberty, these inhibitory signals are weakened and supplanted by stimulatory signals that, in turn, stimulate the release of gonadotropin-releasing hormone (GnRH) - a hypothalamic neuropeptide governing reproduction. A number of studies, however, suggest that puberty commencement occurs when body (fat) weight reaches a certain threshold, which is critical for the initiation of puberty and for support of the adult reproductive function. Previously, various signals have been studied which might link body (fat) weight-related information to the hypothalamic neuronal network regulating reproduction. However, the nature of the signal(s) that may link body fat and/or muscle mass with the hypothalamic neuronal network governing reproduction is still unclear. It has been intuitively speculated that augmentation of such signal(s) will cause a restriction of inhibitory input and activation of stimulatory input to GnRH secreting neurons at the time of puberty onset. Therefore, the unveiling of such signal(s) will greatly help in understanding the mechanism of puberty onset. Recently, it has been shown that expression of fibronectin type III domain containing-5 (FNDC5) mRNA in central and peripheral tissues upsurges during postnatal development, especially around the time of puberty onset. Moreover, the systemic level of irisin - one of the protein products of the FNDC5 gene that is secreted as myokine and adipokine - also rises during postnatal development and correlates with the timing of puberty onset. Therefore, we propose here that irisin might serve as a possible signal for linking body fat/muscle mass with the hypothalamic center governing reproductive function. We hypothesize that irisin acts as a trigger for the activation of the hypothalamic neuronal network monitoring the onset of puberty. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Mirror neurons: from origin to function.
Cook, Richard; Bird, Geoffrey; Catmur, Caroline; Press, Clare; Heyes, Cecilia
2014-04-01
This article argues that mirror neurons originate in sensorimotor associative learning and therefore a new approach is needed to investigate their functions. Mirror neurons were discovered about 20 years ago in the monkey brain, and there is now evidence that they are also present in the human brain. The intriguing feature of many mirror neurons is that they fire not only when the animal is performing an action, such as grasping an object using a power grip, but also when the animal passively observes a similar action performed by another agent. It is widely believed that mirror neurons are a genetic adaptation for action understanding; that they were designed by evolution to fulfill a specific socio-cognitive function. In contrast, we argue that mirror neurons are forged by domain-general processes of associative learning in the course of individual development, and, although they may have psychological functions, they do not necessarily have a specific evolutionary purpose or adaptive function. The evidence supporting this view shows that (1) mirror neurons do not consistently encode action "goals"; (2) the contingency- and context-sensitive nature of associative learning explains the full range of mirror neuron properties; (3) human infants receive enough sensorimotor experience to support associative learning of mirror neurons ("wealth of the stimulus"); and (4) mirror neurons can be changed in radical ways by sensorimotor training. The associative account implies that reliable information about the function of mirror neurons can be obtained only by research based on developmental history, system-level theory, and careful experimentation.
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Juárez-Morales, José L; Martinez-De Luna, Reyna I; Zuber, Michael E; Roberts, Alan; Lewis, Katharine E
2017-09-01
A correctly functioning spinal cord is crucial for locomotion and communication between body and brain but there are fundamental gaps in our knowledge of how spinal neuronal circuitry is established and functions. To understand the genetic program that regulates specification and functions of this circuitry, we need to connect neuronal molecular phenotypes with physiological analyses. Studies using Xenopus laevis tadpoles have increased our understanding of spinal cord neuronal physiology and function, particularly in locomotor circuitry. However, the X. laevis tetraploid genome and long generation time make it difficult to investigate how neurons are specified. The opacity of X. laevis embryos also makes it hard to connect functional classes of neurons and the genes that they express. We demonstrate here that Tol2 transgenic constructs using zebrafish enhancers that drive expression in specific zebrafish spinal neurons label equivalent neurons in X. laevis and that the incorporation of a Gal4:UAS amplification cassette enables cells to be observed in live X. laevis tadpoles. This technique should enable the molecular phenotypes, morphologies and physiologies of distinct X. laevis spinal neurons to be examined together in vivo. We have used an islet1 enhancer to label Rohon-Beard sensory neurons and evx enhancers to identify V0v neurons, for the first time, in X. laevis spinal cord. Our work demonstrates the homology of spinal cord circuitry in zebrafish and X. laevis, suggesting that future work could combine their relative strengths to elucidate a more complete picture of how vertebrate spinal cord neurons are specified, and function to generate behavior. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1007-1020, 2017. © 2017 Wiley Periodicals, Inc.
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Harnett, Mark T.; Magee, Jeffrey C.
2015-01-01
The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons. PMID:25609619
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Salbaum, J Michael; Cirelli, Chiara; Walcott, Elisabeth; Krushel, Les A; Edelman, Gerald M; Tononi, Giulio
2004-07-30
The noradrenergic locus coeruleus (LC) has been implicated in the promotion of arousal, in focused attention and learning, and in the regulation of the sleep/waking cycle. The complex biological functions of the central noradrenergic system have been investigated largely through electrophysiological recordings and neurotoxic lesions of LC neurons. Activation of LC neurons through electrical or chemical stimulation has also led to important insights, although these techniques have limited cellular specificity and short-term effects. Here, we describe a novel method aimed at stimulating the central noradrenergic system in a highly selective manner for prolonged periods of time. This was achieved through the conditional expression of a transgene for chlorotoxin (Cltx) in the LC of adult mice. Chlorotoxin is a component of scorpion venom that partially blocks small conductance chloride channels. In this manner, the influence of GABAergic and glycinergic inhibitory inputs on LC cells is greatly reduced, while their ability to respond to excitatory inputs is unaffected. We demonstrate that the unilateral induction of Cltx expression in the LC is associated with a concomitant ipsilateral increase in the expression of markers of noradrenergic activity in LC neurons. Moreover, LC disinhibition is associated with the ipsilateral induction of the immediate early gene NGFI-A in cortical and subcortical target areas. Unlike previous gain of function approaches, transgenic disinhibition of LC cells is highly selective and persists for at least several weeks. This method represents a powerful new tool to assess the long-term effects of LC activation and is potentially applicable to other neuronal systems.
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Goodson, James L; Kabelik, David; Kelly, Aubrey M; Rinaldi, Jacob; Klatt, James D
2009-05-26
Mesolimbic dopamine (DA) circuits mediate a wide range of goal-oriented behavioral processes, and DA strongly influences appetitive and consummatory aspects of male sexual behavior. In both birds and mammals, mesolimbic projections arise primarily from the ventral tegmental area (VTA), with a smaller contribution from the midbrain central gray (CG). Despite the well known importance of the VTA cell group for incentive motivation functions, relationships of VTA subpopulations to specific aspects of social phenotype remain wholly undescribed. We now show that in male zebra finches (Estrildidae: Taeniopygia guttata), Fos activity within a subpopulation of tyrosine hydroxylase-immunoreactive (TH-ir; presumably dopaminergic) neurons in the caudal VTA is significantly correlated with courtship singing and coupled to gonadal state. In addition, the number of TH-ir neurons in this caudal subpopulation dichotomously differentiates courting from non-courting male phenotypes, and evolves in relation to sociality (flocking vs. territorial) across several related finch species. Combined, these findings for the VTA suggest that divergent social phenotypes may arise due to the differential assignment of "incentive value" to conspecific stimuli. TH-ir neurons of the CG (a population of unknown function in mammals) exhibit properties that are even more selectively and tightly coupled to the expression of courtship phenotypes (and appetitive courtship singing), both in terms of TH-ir cell number, which correlates significantly with constitutive levels of courtship motivation, and with TH-Fos colocalization, which increases in direct proportion to the phasic expression of song. We propose that these neurons may be core components of social communication circuits across diverse vertebrate taxa.
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Hammond, Mark W; Xydas, Dimitris; Downes, Julia H; Bucci, Giovanna; Becerra, Victor; Warwick, Kevin; Constanti, Andrew; Nasuto, Slawomir J; Whalley, Benjamin J
2013-03-26
Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat ('artificial animal') applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown. Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion. We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.
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Activity of nigral dopaminergic neurons after lesion of the neostriatum in rats.
Doudet, D; Gross, C; Seal, J; Bioulac, B
1984-06-04
As shown by post-mortem analysis the major neuropathological trait of Huntington's chorea is a degeneration of the intrinsic neurons of the neostriatum (caudate nucleus and putamen). Such a situation can be reproduced by a destruction of the neostriatum by kainic acid. When injected into the caudate nucleus this excitatory amino acid destroys the intrinsic neurons of the neostriatum and spares fairly well the passing fibers. In the present work, we have chosen to examine the influence of neostriatal destruction on the activity of identified dopaminergic cells in the pars compacta of the substantia nigra. As a key element in the nigro-neostriato-nigral loop, this structure is a relevant site for observing the functional effects of neostriatal lesion. Our research hypothesis was based on the generally accepted view that the suppression of the important neostriato-nigral pathway and in particular the inhibitory GABAergic contingent, could generate a hyperactivity of nigral dopaminergic cells. One may therefore consider that the dopaminergic hyperactivity produces abnormal messages which can influence via several pathways the motoneurons, and which participates in the genesis of the hyperkinetic movements characteristic of chorea. After destruction of the neostriatum, we have shown that the pattern of discharge of most identified nigral dopaminergic neurons becomes greatly disorganized. This drastic change in the pattern of activity cannot be interpreted as the simple 'lift of a brake' on these cells by the suppression of the inhibitory GABAergic striato-nigral tract.
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Evans, I M; Pickard, M R; Sinha, A K; Leonard, A J; Sampson, D C; Ekins, R P
2002-12-01
Maternal hypothyroidism during pregnancy impairs brain function in human and rat offspring, but little is known regarding the influence of maternal hyperthyroidism on neurodevelopment. We have previously shown that the expression of neuronal and glial differentiation markers in fetal brain is compromised in hypothyroid rat dam pregnancies and have now therefore extended this investigation to hyperthyroid rat dams. Study groups comprised partially thyroidectomised dams, implanted with osmotic pumps infusing either vehicle (TX dams) or a supraphysiological dose of thyroxine (T4) (HYPER dams), and euthyroid dams infused with vehicle (N dams). Cytoskeletal protein abundance was determined in fetal brain at 21 days of gestation by immunoblot analysis. Relative to N dams, circulating total T4 levels were reduced to around one-third in TX dams but were doubled in HYPER dams. Fetal brain weight was increased in HYPER dams, whereas litter size and fetal body weight were reduced in TX dams. Glial fibrillary acidic protein expression was similar in HYPER and TX dams, being reduced in both cases relative to N dams. alpha-Internexin (INX) abundance was reduced in HYPER dams and increased in TX dams, whereas neurofilament 68 (NF68) exhibited increased abundance in HYPER dams. Furthermore, INX was inversely related to - and NF68 directly related to - maternal serum total T4 levels, independently of fetal brain weight. In conclusion, maternal hyperthyroidism compromises the expression of neuronal cytoskeletal proteins in late fetal brain, suggestive of a pattern of accelerated neuronal differentiation.
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Besser, Limor; Chorin, Ehud; Sekler, Israel; Silverman, William F; Atkin, Stan; Russell, James T; Hershfinkel, Michal
2009-03-04
Zn(2+) is coreleased with glutamate from mossy fiber terminals and can influence synaptic function. Here, we demonstrate that synaptically released Zn(2+) activates a selective postsynaptic Zn(2+)-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca(2+), as well as phosphorylation of extracellular-regulated kinase and Ca(2+)/calmodulin kinase II. Blockade of synaptic transmission by tetrodotoxin or CdCl inhibited the ZnR-mediated Ca(2+) rises. The responses mediated by ZnR were largely attenuated by the extracellular Zn(2+) chelator, CaEDTA, and in slices from mice lacking vesicular Zn(2+), suggesting that synaptically released Zn(2+) triggers the metabotropic activity. Knockdown of the expression of the orphan G-protein-coupled receptor 39 (GPR39) attenuated ZnR activity in a neuronal cell line. Importantly, we observed widespread GPR39 labeling in CA3 neurons, suggesting a role for this receptor in mediating ZnR signaling in the hippocampus. Our results describe a unique role for synaptic Zn(2+) acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic Zn(2+) can regulate neuronal function.
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Chai, Sunghee; Cambronne, Xiaolu A; Eichhorn, Stephen W; Goodman, Richard H
2013-10-29
MicroRNA-134 (miR-134) serves as a widely accepted model for microRNA function in synaptic plasticity. In this model, synaptic activity stimulates miR-134 expression, which then regulates dendrite growth and spine formation. By using a ratiometric microRNA sensor, we found, unexpectedly, that miR-134 activity in cortical neurons was restricted to interneurons. Using an assay designed to trap microRNA-mRNA complexes, we determined that miR-134 interacted directly with the mRNA encoding the palmitoylation enzyme, DHHC9. This enzyme is known to palmitoylate H-Ras, a modification required for proper membrane trafficking. Treatment with bicuculline, a GABAA receptor antagonist, decreased DHHC9 expression in somatostatin-positive interneurons and membrane localization of an H-Ras reporter in a manner that depended on miR-134. Thus, although miR-134 has been proposed to affect all types of neurons, we showed that functionally active miR-134 is produced in only a selected population of neurons where it influences the expression of targets, such as DHHC9, that regulate membrane targeting of critical signaling molecules.
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Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease.
Parker, Krystal L; Kim, Youngcho; Alberico, Stephanie L; Emmons, Eric B; Narayanan, Nandakumar S
2016-03-01
Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.
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Metabolic influences on neuroendocrine regulation of reproduction.
Navarro, Víctor M; Kaiser, Ursula B
2013-08-01
Reproduction is a tightly regulated function in which many mechanisms contribute to ensure the survival of the species. Among those, due to the elevated energy requirements of reproduction, metabolic factors exert a pivotal role in the control of hypothalamic-pituitary-gonadal axis. Although this control may occur at multiple levels of the axis, the majority of interactions between metabolic and reproductive systems take place in the hypothalamus. In this article, we present an overview of the state-of-the-art knowledge regarding the metabolic regulation of reproduction at the central level. We aim to identify the neuroanatomical location where both functions interconnect by discussing the likelihood of each component of the neuronal hierarchical network controlling gonadotropin-releasing hormone (GnRH) release to be first-order responders to metabolic cues, especially the peripheral metabolic signals leptin, insulin, and ghrelin. Latest evidence suggests that the primary action of leptin, insulin, and ghrelin to regulate reproduction is located upstream of the main central elicitors of gonadotropin release, Kiss1 and GnRH neurons, and neuroanatomically separated from their metabolic action. The study of the neuronal interactions between the mechanisms governing metabolism and reproduction offers the platform to overcome or treat a number of prevailing metabolic and/or reproductive conditions.
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Volume transmission-mediated encephalopathies: a possible new concept?
Hartung, Hans-Peter; Dihné, Marcel
2012-03-01
There is strong evidence that the composition of cerebrospinal fluid (CSF) influences brain development, neurogenesis, and behavior. The bidirectional exchange of CSF and interstitial fluid (ISF) across the ependymal and pia-glial membranes is required for these phenomena to occur. Because ISF surrounds the parenchymal compartment, neuroactive substances in the CSF and ISF can influence neuronal activity. Functionally important neuroactive substances are distributed to distant sites of the central nervous system by the convection and diffusion of CSF and ISF, a process known as volume transmission. It has recently been shown that pathologically altered CSF from patients with acute traumatic brain injury suppresses in vitro neuronal network activity (ivNNA) recorded by multielectrode arrays measuring synchronously bursting neural populations. Functionally relevant substances in pathologically altered CSF have been biochemically identified, and ivNNA has been partially recovered by pharmacologic intervention. It remains unclear whether the in vivo parenchymal compartment remains unaffected by pathologically altered CSF that significantly impairs ivNNA. We hypothesize that pathologic CSF alterations are not just passive indicators of brain diseases but that they actively and directly evoke functional disturbances in global brain activity through the distribution of neuroactive substances, for instance, secondary to focal neurologic disease. For this mechanism, we propose the new term volume transmission-mediated encephalopathies (VTE). Recording ivNNA in the presence of pure human CSF could help to identify and monitor functionally relevant CSF alterations that directly result in VTEs, and the collected data might point to therapeutic ways to antagonize these alterations.
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Life and death of neurons in the aging brain
NASA Technical Reports Server (NTRS)
Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)
1997-01-01
Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.
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The Role of Sirt1 in Epileptogenesis
Brennan, Gary P.; Nguyen, Tiffany M.; Singh-Taylor, Akanksha; Mun, Hyun-Seung; Sargious, Mary J.
2017-01-01
Abstract The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults, including trauma, stroke, tumors, infections, and long seizures [status epilepticus (SE)], create a neuronal state of increased metabolic demand or decreased energy supply. Neurons express molecules that monitor their metabolic state, including sirtuins (Sirts). Sirtuins deacetylate cytoplasmic proteins and nuclear histones, and their epigenetic modulation of the chromatin governs the expression of many genes, influencing neuronal properties. Thus, sirtuins are poised to enduringly modulate neuronal properties following SE, potentially contributing to epileptogenesis, a hypothesis supported by the epilepsy-attenuating effects of blocking a downstream target of Sirt1, Neuron-Restrictive Silencer Factor (NRSF) also know as REST (RE1-Silencing Transcription factor). Here we used an adult male rat model of epileptogenesis provoked by kainic acid–induced SE (KA-SE). We assessed KA-SE-provoked Sirt1 activity, infused a Sirt1 inhibitor (EX-527) after KA-SE, and examined for epileptogenesis using continuous digital video–EEG. Sirt1 activity, measured using chromatin immunoprecipitation for Sirt1 binding at a target gene, increased rapidly after SE. Post hoc infusion of the Sirt1 inhibitor prevented Sirt1-mediated repression of a target gene. Blocking Sirt1 activity transiently after KA-SE did not significantly influence the time- course and all of the parameters of epilepsy development. Specifically, latency to first seizure and seizure number, duration, and severity (using the Racine scale and EEG measures) as well as the frequency and duration of interictal spike series, were all unchanged. KA-SE provoked a robust inflammatory response and modest cell loss, yet neither was altered by blocking Sirt1. In conclusion, blocking Sirt1 activity after KA-SE does not abrogate epilepsy development, suggesting that the mechanisms of such acquired epileptogenesis are independent of Sirt1 function. PMID:28197553
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Spitzer, M W; Semple, M N
1998-12-01
Transformation of binaural response properties in the ascending auditory pathway: influence of time-varying interaural phase disparity. J. Neurophysiol. 80: 3062-3076, 1998. Previous studies demonstrated that tuning of inferior colliculus (IC) neurons to interaural phase disparity (IPD) is often profoundly influenced by temporal variation of IPD, which simulates the binaural cue produced by a moving sound source. To determine whether sensitivity to simulated motion arises in IC or at an earlier stage of binaural processing we compared responses in IC with those of two major IPD-sensitive neuronal classes in the superior olivary complex (SOC), neurons whose discharges were phase locked (PL) to tonal stimuli and those that were nonphase locked (NPL). Time-varying IPD stimuli consisted of binaural beats, generated by presenting tones of slightly different frequencies to the two ears, and interaural phase modulation (IPM), generated by presenting a pure tone to one ear and a phase modulated tone to the other. IC neurons and NPL-SOC neurons were more sharply tuned to time-varying than to static IPD, whereas PL-SOC neurons were essentially uninfluenced by the mode of stimulus presentation. Preferred IPD was generally similar in responses to static and time-varying IPD for all unit populations. A few IC neurons were highly influenced by the direction and rate of simulated motion, but the major effect for most IC neurons and all SOC neurons was a linear shift of preferred IPD at high rates-attributable to response latency. Most IC and NPL-SOC neurons were strongly influenced by IPM stimuli simulating motion through restricted ranges of azimuth; simulated motion through partially overlapping azimuthal ranges elicited discharge profiles that were highly discontiguous, indicating that the response associated with a particular IPD is dependent on preceding portions of the stimulus. In contrast, PL-SOC responses tracked instantaneous IPD throughout the trajectory of simulated motion, resulting in highly contiguous discharge profiles for overlapping stimuli. This finding indicates that responses of PL-SOC units to time-varying IPD reflect only instantaneous IPD with no additional influence of dynamic stimulus attributes. Thus the neuronal representation of auditory spatial information undergoes a major transformation as interaural delay is initially processed in the SOC and subsequently reprocessed in IC. The finding that motion sensitivity in IC emerges from motion-insensitive input suggests that information about change of position is crucial to spatial processing at higher levels of the auditory system.
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Functional Characterization of Lamina X Neurons in ex-Vivo Spinal Cord Preparation.
Krotov, Volodymyr; Tokhtamysh, Anastasia; Kopach, Olga; Dromaretsky, Andrew; Sheremet, Yevhenii; Belan, Pavel; Voitenko, Nana
2017-01-01
Functional properties of lamina X neurons in the spinal cord remain unknown despite the established role of this area for somatosensory integration, visceral nociception, autonomic regulation and motoneuron output modulation. Investigations of neuronal functioning in the lamina X have been hampered by technical challenges. Here we introduce an ex-vivo spinal cord preparation with both dorsal and ventral roots still attached for functional studies of the lamina X neurons and their connectivity using an oblique LED illumination for resolved visualization of lamina X neurons in a thick tissue. With the elaborated approach, we demonstrate electrophysiological characteristics of lamina X neurons by their membrane properties, firing pattern discharge and fiber innervation (either afferent or efferent). The tissue preparation has been also probed using Ca 2+ imaging with fluorescent Ca 2+ dyes (membrane-impermeable or -permeable) to demonstrate the depolarization-induced changes in intracellular calcium concentration in lamina X neurons. Finally, we performed visualization of subpopulations of lamina X neurons stained by retrograde labeling with aminostilbamidine dye to identify sympathetic preganglionic and projection neurons in the lamina X. Thus, the elaborated approach provides a reliable tool for investigation of functional properties and connectivity in specific neuronal subpopulations, boosting research of lamina X of the spinal cord.
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Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C; Chen, Adam; Tamrazian, Eric; Babaniyi, Olusegun; Selig, Martin; Hynynen, Meri; Woolf, Clifford J; Brown, Robert H
2014-01-28
ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.
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Maximization of Learning Speed in the Motor Cortex Due to Neuronal Redundancy
Takiyama, Ken; Okada, Masato
2012-01-01
Many redundancies play functional roles in motor control and motor learning. For example, kinematic and muscle redundancies contribute to stabilizing posture and impedance control, respectively. Another redundancy is the number of neurons themselves; there are overwhelmingly more neurons than muscles, and many combinations of neural activation can generate identical muscle activity. The functional roles of this neuronal redundancy remains unknown. Analysis of a redundant neural network model makes it possible to investigate these functional roles while varying the number of model neurons and holding constant the number of output units. Our analysis reveals that learning speed reaches its maximum value if and only if the model includes sufficient neuronal redundancy. This analytical result does not depend on whether the distribution of the preferred direction is uniform or a skewed bimodal, both of which have been reported in neurophysiological studies. Neuronal redundancy maximizes learning speed, even if the neural network model includes recurrent connections, a nonlinear activation function, or nonlinear muscle units. Furthermore, our results do not rely on the shape of the generalization function. The results of this study suggest that one of the functional roles of neuronal redundancy is to maximize learning speed. PMID:22253586
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Translational neuropharmacology: the use of human isolated gastrointestinal tissues
Sanger, GJ; Broad, J; Kung, V; Knowles, CH
2013-01-01
Translational sciences increasingly emphasize the measurement of functions in native human tissues. However, such studies must confront variations in patient age, gender, genetic background and disease. Here, these are discussed with reference to neuromuscular and neurosecretory functions of the human gastrointestinal (GI) tract. Tissues are obtained after informed consent, in collaboration with surgeons (surgical techniques help minimize variables) and pathologists. Given the difficulties of directly recording from human myenteric neurones (embedded between muscle layers), enteric motor nerve functions are studied by measuring muscle contractions/relaxations evoked by electrical stimulation of intrinsic nerves; responses are regionally dependent, often involving cholinergic and nitrergic phenotypes. Enteric sensory functions can be studied by evoking the peristaltic reflex, involving enteric sensory and motor nerves, but this has rarely been achieved. As submucosal neurones are more accessible (after removing the mucosa), direct neuronal recordings are possible. Neurosecretory functions are studied by measuring changes in short-circuit current across the mucosa. For all experiments, basic questions must be addressed. Because tissues are from patients, what are the controls and the influence of disease? How long does it take before function fully recovers? What is the impact of age- and gender-related differences? What is the optimal sample size? Addressing these and other questions minimizes variability and raises the scientific credibility of human tissue research. Such studies also reduce animal use. Further, the many differences between animal and human GI functions also means that human tissue research must question the ethical validity of using strains of animals with unproved translational significance. Linked Article BJP published a themed issue on Translational Neuropharmacology in 2011. To view the articles in this themed issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:22946540
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The structure and function of serially homologous leg motor neurons in the locust. I. Anatomy.
Wilson, J A
1979-01-01
Twenty-one prothoracic and 17 mesothoracic motor neurons innervating leg muscles have been identified physiologically and subsequently injected with dye from a microelectrode. A tract containing the primary neurites of motor neurons innervating the retractor unquis, levator and depressor tarsus, flexor tibiae, and reductor femora is described. All motor neurons studied have regions in which their dendritic branches overlap with those of other leg motor neurons. Identified, serially homologous motor neurons in the three thoracic ganglia were found to have: (1) cell bodies at similar locations and morphologically similar primary neurites (e.g., flexor tibiae motor neurons), (2) cell bodies at different locations in each ganglion and morphologically different primary neurites in each ganglion (e.g., fast retractor unguis motor neurons), or (3) cell bodies at similar locations and morphologically similar primary neurites but with a functional switch in one ganglion relative to the function of the neurons in the other two ganglia. As an example of the latter, the morphology of the metathoracic slow extensor tibiae (SETi) motor neurons was similar to that of pro- and mesothoracic fast extensor tibiae (FETi) motor neurons. Similarly the metathoracic FETi bears a striking resemblance to the pro- and the mesothoracic SETi. It is proposed that in the metathoracic ganglion the two extensor tibiae motor neurons have switched functions while retaining similar morphologies relative to the structure and function of their pro- and mesothoracic serial homologues.
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Intrinsically active and pacemaker neurons in pluripotent stem cell-derived neuronal populations.
Illes, Sebastian; Jakab, Martin; Beyer, Felix; Gelfert, Renate; Couillard-Despres, Sébastien; Schnitzler, Alfons; Ritter, Markus; Aigner, Ludwig
2014-03-11
Neurons generated from pluripotent stem cells (PSCs) self-organize into functional neuronal assemblies in vitro, generating synchronous network activities. Intriguingly, PSC-derived neuronal assemblies develop spontaneous activities that are independent of external stimulation, suggesting the presence of thus far undetected intrinsically active neurons (IANs). Here, by using mouse embryonic stem cells, we provide evidence for the existence of IANs in PSC-neuronal networks based on extracellular multielectrode array and intracellular patch-clamp recordings. IANs remain active after pharmacological inhibition of fast synaptic communication and possess intrinsic mechanisms required for autonomous neuronal activity. PSC-derived IANs are functionally integrated in PSC-neuronal populations, contribute to synchronous network bursting, and exhibit pacemaker properties. The intrinsic activity and pacemaker properties of the neuronal subpopulation identified herein may be particularly relevant for interventions involving transplantation of neural tissues. IANs may be a key element in the regulation of the functional activity of grafted as well as preexisting host neuronal networks.
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Molecular and cellular organization of taste neurons in adult Drosophila pharynx
Chen, Yu-Chieh (David); Dahanukar, Anupama
2017-01-01
SUMMARY The Drosophila pharyngeal taste organs are poorly characterized despite their location at important sites for monitoring food quality. Functional analysis of pharyngeal neurons has been hindered by the paucity of molecular tools to manipulate them, as well as their relative inaccessibility for neurophysiological investigations. Here, we generate receptor-to-neuron maps of all three pharyngeal taste organs by performing a comprehensive chemoreceptor-GAL4/LexA expression analysis. The organization of pharyngeal neurons reveals similarities and distinctions in receptor repertoires and neuronal groupings compared to external taste neurons. We validate the mapping results by pinpointing a single pharyngeal neuron required for feeding avoidance of L-canavanine. Inducible activation of pharyngeal taste neurons reveals functional differences between external and internal taste neurons and functional subdivision within pharyngeal sweet neurons. Our results provide road maps of pharyngeal taste organs in an insect model system for probing the role of these understudied neurons in controlling feeding behaviors. PMID:29212040
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Antunes, Gabriela; Faria da Silva, Samuel F; Simoes de Souza, Fabio M
2018-06-01
Mirror neurons fire action potentials both when the agent performs a certain behavior and watches someone performing a similar action. Here, we present an original mirror neuron model based on the spike-timing-dependent plasticity (STDP) between two morpho-electrical models of neocortical pyramidal neurons. Both neurons fired spontaneously with basal firing rate that follows a Poisson distribution, and the STDP between them was modeled by the triplet algorithm. Our simulation results demonstrated that STDP is sufficient for the rise of mirror neuron function between the pairs of neocortical neurons. This is a proof of concept that pairs of neocortical neurons associating sensory inputs to motor outputs could operate like mirror neurons. In addition, we used the mirror neuron model to investigate whether channelopathies associated with autism spectrum disorder could impair the modeled mirror function. Our simulation results showed that impaired hyperpolarization-activated cationic currents (Ih) affected the mirror function between the pairs of neocortical neurons coupled by STDP.
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Intrinsically Active and Pacemaker Neurons in Pluripotent Stem Cell-Derived Neuronal Populations
Illes, Sebastian; Jakab, Martin; Beyer, Felix; Gelfert, Renate; Couillard-Despres, Sébastien; Schnitzler, Alfons; Ritter, Markus; Aigner, Ludwig
2014-01-01
Summary Neurons generated from pluripotent stem cells (PSCs) self-organize into functional neuronal assemblies in vitro, generating synchronous network activities. Intriguingly, PSC-derived neuronal assemblies develop spontaneous activities that are independent of external stimulation, suggesting the presence of thus far undetected intrinsically active neurons (IANs). Here, by using mouse embryonic stem cells, we provide evidence for the existence of IANs in PSC-neuronal networks based on extracellular multielectrode array and intracellular patch-clamp recordings. IANs remain active after pharmacological inhibition of fast synaptic communication and possess intrinsic mechanisms required for autonomous neuronal activity. PSC-derived IANs are functionally integrated in PSC-neuronal populations, contribute to synchronous network bursting, and exhibit pacemaker properties. The intrinsic activity and pacemaker properties of the neuronal subpopulation identified herein may be particularly relevant for interventions involving transplantation of neural tissues. IANs may be a key element in the regulation of the functional activity of grafted as well as preexisting host neuronal networks. PMID:24672755
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Waagepetersen, Helle; Melø, Torun; Schousboe, Arne; Sonnewald, Ursula
Neuronal function is highly influenced by the extracellular environment. To study the effect of the milieu on neurons from cerebellum and neocortex, cells from these brain areas were cultured under different conditions. Two sets of cultures, one neocortical and one cerebellar neurons, were maintained in media containing [U-(13)C]glucose for 8 days at initial concentrations of 12 and 28 mM glucose, respectively. Other sets of cultures (8 days in vitro) maintained in a medium containing initially 12 mM glucose were incubated subsequently for 4 hr either by addition of [U-(13)C]glucose to the culture medium (final concentration 3 mM) or by changing to fresh medium containing [U-(13)C]glucose (3 mM) but without glutamine and fetal calf serum. (13)C Nuclear magnetic resonance (NMR) spectra revealed extensive gamma-aminobutyric acid (GABA) synthesis in both cultured neocortical and cerebellar neurons after maintenance in medium containing [U-(13)C]glucose for 8 days, whereas no aspartate labeling was observed in these spectra. Mass spectrometry analysis, however, revealed high labeling intensity of aspartate, which was equal in the two types of neurons. Addition of [U-(13)C]glucose (4 hr) on Day 8 in culture led to a similar extent of labeling of GABA in neocortical and in cerebellar cultures, but the cellular content of GABA was considerably higher in the neocortical neurons. The cellular content of alanine was similar regardless of culture type. Comparing the amount of labeling, however, cerebellar neurons exhibited a higher capacity for alanine synthesis. This is compatible with the fact that cerebellar neurons could ameliorate a low alanine content after culturing in low glucose (12 mM) by a 4-hr incubation in medium containing 3 mM glucose. A low glucose concentration during the culture period and a subsequent medium change were associated with decreases in glutathione and taurine contents. Moreover, glutamate and GABA contents were reduced in cerebellar cultures under either of these conditions. In neocortical neurons, the GABA content was decreased by simultaneous exposure to low glucose and change of medium. These conditions also led to an increase in the aspartate content in both types of cultures, although most pronounced in the neocortical neurons. Further experiments are needed to elucidate these phenomena that underline the impact of extracellular environment on amino acid homeostasis. (c) 2004 Wiley-Liss, Inc.
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Qi, Yuchen; Zhang, Xin-Jun; Renier, Nicolas; Wu, Zhuhao; Atkin, Talia; Sun, Ziyi; Ozair, M. Zeeshan; Tchieu, Jason; Zimmer, Bastian; Fattahi, Faranak; Ganat, Yosif; Azevedo, Ricardo; Zeltner, Nadja; Brivanlou, Ali H.; Karayiorgou, Maria; Gogos, Joseph; Tomishima, Mark; Tessier-Lavigne, Marc; Shi, Song-Hai; Studer, Lorenz
2017-01-01
Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into functional neurons. However, the protracted timing of human neuron specification and functional maturation remains a key challenge that hampers the routine application of hPSC-derived lineages in disease modeling and regenerative medicine. Using a combinatorial small-molecule screen, we previously identified conditions for the rapid differentiation of hPSCs into peripheral sensory neurons. Here we generalize the approach to central nervous system (CNS) fates by developing a small-molecule approach for accelerated induction of early-born cortical neurons. Combinatorial application of 6 pathway inhibitors induces post-mitotic cortical neurons with functional electrophysiological properties by day 16 of differentiation, in the absence of glial cell co-culture. The resulting neurons, transplanted at 8 days of differentiation into the postnatal mouse cortex, are functional and establish long-distance projections, as shown using iDISCO whole brain imaging. Accelerated differentiation into cortical neuron fates should facilitate hPSC-based strategies for disease modeling and cell therapy in CNS disorders. PMID:28112759
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Lin, I-Chun; Xing, Dajun; Shapley, Robert
2014-01-01
One of the reasons the visual cortex has attracted the interest of computational neuroscience is that it has well-defined inputs. The lateral geniculate nucleus (LGN) of the thalamus is the source of visual signals to the primary visual cortex (V1). Most large-scale cortical network models approximate the spike trains of LGN neurons as simple Poisson point processes. However, many studies have shown that neurons in the early visual pathway are capable of spiking with high temporal precision and their discharges are not Poisson-like. To gain an understanding of how response variability in the LGN influences the behavior of V1, we study response properties of model V1 neurons that receive purely feedforward inputs from LGN cells modeled either as noisy leaky integrate-and-fire (NLIF) neurons or as inhomogeneous Poisson processes. We first demonstrate that the NLIF model is capable of reproducing many experimentally observed statistical properties of LGN neurons. Then we show that a V1 model in which the LGN input to a V1 neuron is modeled as a group of NLIF neurons produces higher orientation selectivity than the one with Poisson LGN input. The second result implies that statistical characteristics of LGN spike trains are important for V1's function. We conclude that physiologically motivated models of V1 need to include more realistic LGN spike trains that are less noisy than inhomogeneous Poisson processes. PMID:22684587
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Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture*
Mauceri, Daniela; Hagenston, Anna M.; Schramm, Kathrin; Weiss, Ursula; Bading, Hilmar
2015-01-01
Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. PMID:26231212
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Lin, I-Chun; Xing, Dajun; Shapley, Robert
2012-12-01
One of the reasons the visual cortex has attracted the interest of computational neuroscience is that it has well-defined inputs. The lateral geniculate nucleus (LGN) of the thalamus is the source of visual signals to the primary visual cortex (V1). Most large-scale cortical network models approximate the spike trains of LGN neurons as simple Poisson point processes. However, many studies have shown that neurons in the early visual pathway are capable of spiking with high temporal precision and their discharges are not Poisson-like. To gain an understanding of how response variability in the LGN influences the behavior of V1, we study response properties of model V1 neurons that receive purely feedforward inputs from LGN cells modeled either as noisy leaky integrate-and-fire (NLIF) neurons or as inhomogeneous Poisson processes. We first demonstrate that the NLIF model is capable of reproducing many experimentally observed statistical properties of LGN neurons. Then we show that a V1 model in which the LGN input to a V1 neuron is modeled as a group of NLIF neurons produces higher orientation selectivity than the one with Poisson LGN input. The second result implies that statistical characteristics of LGN spike trains are important for V1's function. We conclude that physiologically motivated models of V1 need to include more realistic LGN spike trains that are less noisy than inhomogeneous Poisson processes.
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Olesen, Louise Ørum; Sivasaravanaparan, Mithula; Severino, Maurizio; Babcock, Alicia A; Bouzinova, Elena V; West, Mark J; Wiborg, Ove; Finsen, Bente
2017-08-01
Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of APP swe /PS1 dE9 transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis, and spontaneous alternation behaviour, a measure of spatial working memory, in transgenic mice. We observed no difference in granular neurons between transgenic and wild type mice up till 18months of age, and no differences with age in wild type mice. The number of neuroblasts and the performance in the spontaneous alternation task was reduced in aged transgenic mice. Paroxetine treatment from 9 to 18months of age reduced hippocampal amyloidosis without affecting the number of neuroblasts or granular neurons. These findings suggest that the amyloidosis affects the differentiation of neuroblasts and spatial working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory. Copyright © 2017 Elsevier Inc. All rights reserved.
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Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks.
Chen, Yuncai; Baram, Tallie Z
2016-01-01
Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Adverse early-life experiences provoke the release and modify the expression of several stress mediators and neurotransmitters within specific brain regions. The interaction of these mediators with developing neurons and neuronal networks may lead to long-lasting structural and functional alterations associated with cognitive and emotional consequences. Although a vast body of work has linked quantitative and qualitative aspects of stress to adolescent and adult outcomes, a number of questions are unclear. What distinguishes 'normal' from pathologic or toxic stress? How are the effects of stress transformed into structural and functional changes in individual neurons and neuronal networks? Which ones are affected? We review these questions in the context of established and emerging studies. We introduce a novel concept regarding the origin of toxic early-life stress, stating that it may derive from specific patterns of environmental signals, especially those derived from the mother or caretaker. Fragmented and unpredictable patterns of maternal care behaviors induce a profound chronic stress. The aberrant patterns and rhythms of early-life sensory input might also directly and adversely influence the maturation of cognitive and emotional brain circuits, in analogy to visual and auditory brain systems. Thus, unpredictable, stress-provoking early-life experiences may influence adolescent cognitive and emotional outcomes by disrupting the maturation of the underlying brain networks. Comprehensive approaches and multiple levels of analysis are required to probe the protean consequences of early-life adversity on the developing brain. These involve integrated human and animal-model studies, and approaches ranging from in vivo imaging to novel neuroanatomical, molecular, epigenomic, and computational methodologies. Because early-life adversity is a powerful determinant of subsequent vulnerabilities to emotional and cognitive pathologies, understanding the underlying processes will have profound implications for the world's current and future children.
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Luebke, Anne E; Holt, Joseph C; Jordan, Paivi M; Wong, Yi Shan; Caldwell, Jillian S; Cullen, Kathleen E
2014-07-30
The neuroactive peptide calcitonin-gene related peptide (CGRP) is known to act at efferent synapses and their targets in hair cell organs, including the cochlea and lateral line. CGRP is also expressed in vestibular efferent neurons as well as a number of central vestibular neurons. Although CGRP-null (-/-) mice demonstrate a significant reduction in cochlear nerve sound-evoked activity compared with wild-type mice, it is unknown whether and how the loss of CGRP influence vestibular system function. Vestibular function was assessed by quantifying the vestibulo-ocular reflex (VOR) in alert mice. The loss of CGRP in (-/-) mice was associated with a reduction of the VOR gain of ≈50% without a concomitant change in phase. Using immunohistochemistry, we confirmed that, although CGRP staining was absent in the vestibular end-organs of null (-/-) mice, cholinergic staining appeared normal, suggesting that the overall gross development of vestibular efferent innervation was unaltered. We further confirmed that the observed deficit in vestibular function of null (-/-) mice was not the result of nontargeted effects at the level of the extraocular motor neurons and/or their innervation of extraocular muscles. Analysis of the relationship between vestibular quick phase amplitude and peak velocity revealed that extraocular motor function was unchanged, and immunohistochemistry revealed no abnormalities in motor endplates. Together, our findings show that the neurotransmitter CGRP plays a key role in ensuring VOR efficacy. Copyright © 2014 the authors 0270-6474/14/3410453-06$15.00/0.
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Prefrontal Contribution to Decision-Making under Free-Choice Conditions
Funahashi, Shintaro
2017-01-01
Executive function is thought to be the coordinated operation of multiple neural processes and allows to accomplish a current goal flexibly. The most important function of the prefrontal cortex is the executive function. Among a variety of executive functions in which the prefrontal cortex participates, decision-making is one of the most important. Although the prefrontal contribution to decision-making has been examined using a variety of behavioral tasks, recent studies using fMRI have shown that the prefrontal cortex participates in decision-making under free-choice conditions. Since decision-making under free-choice conditions represents the very first stage for any kind of decision-making process, it is important that we understand its neural mechanism. Although few studies have examined this issue while a monkey performed a free-choice task, those studies showed that, when the monkey made a decision to subsequently choose one particular option, prefrontal neurons showing selectivity to that option exhibited transient activation just before presentation of the imperative cue. Further studies have suggested that this transient increase is caused by the irregular fluctuation of spontaneous firing just before cue presentation, which enhances the response to the cue and biases the strength of the neuron's selectivity to the option. In addition, this biasing effect was observed only in neurons that exhibited sustained delay-period activity, indicating that this biasing effect not only influences the animal's decision for an upcoming choice, but also is linked to working memory mechanisms in the prefrontal cortex. PMID:28798662
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Tong, Ling; Strong, Melissa K; Kaur, Tejbeer; Juiz, Jose M; Oesterle, Elizabeth C; Hume, Clifford; Warchol, Mark E; Palmiter, Richard D; Rubel, Edwin W
2015-05-20
During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of DT resulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival. Copyright © 2015 the authors 0270-6474/15/357878-14$15.00/0.
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Naud, Richard; Gerstner, Wulfram
2012-01-01
The response of a neuron to a time-dependent stimulus, as measured in a Peri-Stimulus-Time-Histogram (PSTH), exhibits an intricate temporal structure that reflects potential temporal coding principles. Here we analyze the encoding and decoding of PSTHs for spiking neurons with arbitrary refractoriness and adaptation. As a modeling framework, we use the spike response model, also known as the generalized linear neuron model. Because of refractoriness, the effect of the most recent spike on the spiking probability a few milliseconds later is very strong. The influence of the last spike needs therefore to be described with high precision, while the rest of the neuronal spiking history merely introduces an average self-inhibition or adaptation that depends on the expected number of past spikes but not on the exact spike timings. Based on these insights, we derive a 'quasi-renewal equation' which is shown to yield an excellent description of the firing rate of adapting neurons. We explore the domain of validity of the quasi-renewal equation and compare it with other rate equations for populations of spiking neurons. The problem of decoding the stimulus from the population response (or PSTH) is addressed analogously. We find that for small levels of activity and weak adaptation, a simple accumulator of the past activity is sufficient to decode the original input, but when refractory effects become large decoding becomes a non-linear function of the past activity. The results presented here can be applied to the mean-field analysis of coupled neuron networks, but also to arbitrary point processes with negative self-interaction.
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How does our brain constitute defense mechanisms? First-person neuroscience and psychoanalysis.
Northoff, Georg; Bermpohl, Felix; Schoeneich, Frank; Boeker, Heinz
2007-01-01
Current progress in the cognitive and affective neurosciences is constantly influencing the development of psychoanalytic theory and practice. However, despite the emerging dialogue between neuroscience and psychoanalysis, the neuronal processes underlying psychoanalytic constructs such as defense mechanisms remain unclear. One of the main problems in investigating the psychodynamic-neuronal relationship consists in systematically linking the individual contents of first-person subjective experience to third-person observation of neuronal states. We therefore introduced an appropriate methodological strategy, 'first-person neuroscience', which aims at developing methods for systematically linking first- and third-person data. The utility of first-person neuroscience can be demonstrated by the example of the defense mechanism of sensorimotor regression as paradigmatically observed in catatonia. Combined psychodynamic and imaging studies suggest that sensorimotor regression might be associated with dysfunction in the neural network including the orbitofrontal, the medial prefrontal and the premotor cortices. In general sensorimotor regression and other defense mechanisms are psychoanalytic constructs that are hypothesized to be complex emotional-cognitive constellations. In this paper we suggest that specific functional mechanisms which integrate neuronal activity across several brain regions (i.e. neuronal integration) are the physiological substrates of defense mechanisms. We conclude that first-person neuroscience could be an appropriate methodological strategy for opening the door to a better understanding of the neuronal processes of defense mechanisms and their modulation in psychoanalytic psychotherapy. Copyright 2007 S. Karger AG, Basel.
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Lichtenhan, Jeffery T.; Chertoff, Mark E.
2008-01-01
An analytic compound action potential (CAP) obtained by convolving functional representations of the post-stimulus time histogram summed across auditory nerve neurons [P(t)] and a single neuron action potential [U(t)] was fit to human CAPs. The analytic CAP fit to pre- and postnoise-induced temporary hearing threshold shift (TTS) estimated in vivoP(t) and U(t) and the number of neurons contributing to the CAPs (N). The width of P(t) decreased with increasing signal level and was wider at the lowest signal level following noise exposure. P(t) latency decreased with increasing signal level and was shorter at all signal levels following noise exposure. The damping and oscillatory frequency of U(t) increased with signal level. For subjects with large amounts of TTS, U(t) had greater damping than before noise exposure particularly at low signal levels. Additionally, U(t) oscillation was lower in frequency at all click intensities following noise exposure. N increased with signal level and was smaller after noise exposure at the lowest signal level. Collectively these findings indicate that neurons contributing to the CAP during TTS are fewer in number, shorter in latency, and poorer in synchrony than before noise exposure. Moreover, estimates of single neuron action potentials may decay more rapidly and have a lower oscillatory frequency during TTS. PMID:18397026
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Faghihi, Faramarz; Moustafa, Ahmed A
2016-09-01
The separation of input patterns received from the entorhinal cortex (EC) by the dentate gyrus (DG) is a well-known critical step of information processing in the hippocampus. Although the role of interneurons in separation pattern efficiency of the DG has been theoretically known, the balance of neurogenesis of excitatory neurons and interneurons as well as its potential role in information processing in the DG is not fully understood. In this work, we study separation efficiency of the DG for different rates of neurogenesis of interneurons and excitatory neurons using a novel computational model in which we assume an increase in the synaptic efficacy between excitatory neurons and interneurons and then its decay over time. Information processing in the EC and DG was simulated as information flow in a two layer feed-forward neural network. The neurogenesis rate was modeled as the percentage of new born neurons added to the neuronal population in each time bin. The results show an important role of an optimal neurogenesis rate of interneurons and excitatory neurons in the DG in efficient separation of inputs from the EC in pattern separation tasks. The model predicts that any deviation of the optimal values of neurogenesis rates leads to different decreased levels of the separation deficits of the DG which influences its function to encode memory.
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Expression of PTHrP and PTH/PTHrP receptor 1 in the superior cervical ganglia of rats.
Filipović, Natalija; Vrdoljak, Marija; Vuica, Ana; Jerić, Milka; Jeličić Kadić, Antonia; Utrobičić, Toni; Mašek, Tomislav; Grković, Ivica
2014-12-01
PTHrP and its receptor PTHR1 are found in the CNS and peripheral nervous system. The presence of PTHrP mRNA has been detected in the superior cervical ganglion (SCG), but there are no data on the cellular distribution of PTHrP and PTHR1 in the SCG. Although it is known that ovarian activity and reproductive status influence sympathetic activity, and the PTHrP/PTHR1 system is influenced by estrogens in different tissues, it is not known whether these factors have a similar effect on expression of PTHrP and PTHR1 in the nervous system. Hence, we investigated the presence and distribution of PTHrP and PTHR1 in neurons and glia of the SCG of rats, as well as the influence of ovariectomy on their expression, by using immunohistochemistry. PTHrP and PTHR1 immunoreactivity was observed in cytoplasm as well as in nuclei of almost all neurons in the SCG. In male rats, intensity of PTHrP fluorescence was significantly higher in cytoplasm of NPY-, in comparison to NPY+ neurons (p < 0.05). In female rats, 2 months post-ovariectomy, significantly lower intensity of PTHrP fluorescence in cytoplasm of the SCG neurons was observed in comparison to sham operated animals (p < 0.05). In addition to neurons, PTHrP and PTHR1 immunoreactivity was observed in most of the glia and was not influenced by ovariectomy. Results show the expression of PTHrP and its receptor, PTHR1, in the majority of neurons and glial cells in the SCG of rats. Expression of PTHrP, but not PTHR1 in the cytoplasm of SCG neurons is influenced by ovarian activity. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Neuronal imprinting of human values.
Delgado, J M
2000-03-01
In the 21st century, psychophysiology will face the challenge of establishing ethical principles and practical means for the genetic and social influencing of the development of human beings. Neuronal imprinting of beliefs and morality within infantile minds will be necessary for the peaceful coexistence of races and cultures. This process requires study and consideration, among others, of the following psychophysiological facts: (1) Genes do not transmit moral values. (2) Material support of physiological activities is necessary for the existence and development of mental functions. (3) Imprinting of human values is based on material changes within neuronal structures. (4) Early neuronal imprinting is performed without personal awareness or consent of the individual and depends on sensory inputs, mainly from the social structure of the group. (5) Biological structures lack values. Personal and social antagonisms do not depend on genes, but on cultural indoctrination. (6) Pleasure and punishment (positive and negative reinforcement) are the two main elements, which regulate animal and human behavior. (7) Values must be chosen by adults, who decide the questions 'why'? 'when'? 'which ones'?, 'who should teach'?, 'what?' and 'how'? (8) Many biological imperatives are shared by all animals and by all people. Human beings may be considered the 'crickets of the Universe', unable to understand the mysteries of nature because of our insufficient neuronal capacity. (9) Our emotional life is mainly related to the structure of the limbic system controlled by the neocortex. (10) New theories based on the integration of physics, chemistry, biology and other specific areas of knowledge, as proposed by the General Theory of Systems, will avoid 'opposites', favoring the acceptance of complementary aspects of reality. (11) Early education will promote preferential learning which depends on both genetic endowment and neuronal development influenced by experience. It is the responsibility of psychophysiology to establish the guidelines for better education, clarifying the material and psychological aspects of the mind.
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Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg
2016-01-01
The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks. DOI: http://dx.doi.org/10.7554/eLife.15719.001 PMID:27525488
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Dopamine neurons share common response function for reward prediction error
Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige
2016-01-01
Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically-identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found striking homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we could describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal. PMID:26854803
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Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.
2011-01-01
SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257
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Parker, Jones G.; Wanat, Matthew J.; Soden, Marta E.; Ahmad, Kinza; Zweifel, Larry S.; Bamford, Nigel S.; Palmiter, Richard D.
2011-01-01
Phasic dopamine transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered dopamine signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how dopamine neuron activity is modulated. While excitatory drive onto dopamine neurons is critical for generating phasic dopamine responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in dopamine neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in dopamine neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. Dopamine neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked inhibitory post-synaptic currents. Furthermore, electrical stimulation of excitatory afferents to dopamine neurons elicited more dopamine release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto dopamine neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in dopamine neurons in appetitive learning and decision-making. PMID:22114279
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Ghrelin is involved in the paracrine communication between neurons and glial cells.
Avau, B; De Smet, B; Thijs, T; Geuzens, A; Tack, J; Vanden Berghe, P; Depoortere, I
2013-09-01
Ghrelin is the only known peripherally active orexigenic hormone produced by the stomach that activates vagal afferents to stimulate food intake and to accelerate gastric emptying. Vagal sensory neurons within the nodose ganglia are surrounded by glial cells, which are able to receive and transmit chemical signals. We aimed to investigate whether ghrelin activates or influences the interaction between both types of cells. The effect of ghrelin was compared with that of leptin and cholecystokinin (CCK). Cultures of rat nodose ganglia were characterized by immunohistochemistry and the functional effects of peptides, neurotransmitters, and pharmacological blockers were measured by Ca(2+) imaging using Fluo-4-AM as an indicator. Neurons responded to KCl and were immunoreactive for PGP-9.5 whereas glial cells responded to lysophosphatidic acid and had the typical SOX-10-positive nuclear staining. Neurons were only responsive to CCK (31 ± 5%) whereas glial cells responded equally to the applied stimuli: ghrelin (27 ± 2%), leptin (21 ± 2%), and CCK (30 ± 2%). In contrast, neurons stained more intensively for the ghrelin receptor than glial cells. ATP induced [Ca(2+) ]i rises in 90% of the neurons whereas ACh and the NO donor, SIN-1, mainly induced [Ca(2+) ]i changes in glial cells (41 and 51%, respectively). The percentage of ghrelin-responsive glial cells was not affected by pretreatment with suramin, atropine, hexamethonium or 1400 W, but was reduced by l-NAME and by tetrodotoxin. Neurons were shown to be immunoreactive for neuronal NO-synthase (nNOS). Our data show that ghrelin induces Ca(2+) signaling in glial cells of the nodose ganglion via the release of NO originating from the neurons. © 2013 John Wiley & Sons Ltd.
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Neuronal representation of individual heroin choices in the orbitofrontal cortex.
Guillem, Karine; Brenot, Viridiana; Durand, Audrey; Ahmed, Serge H
2018-05-01
Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action-which was the non-drug action in the large majority of individuals-progressively fired more than non-preferred action-coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice. © 2017 Society for the Study of Addiction.
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Buren, Caodu; Tu, Gaqi; Parsons, Matthew P; Sepers, Marja D; Raymond, Lynn A
2016-08-01
Corticostriatal cocultures are utilized to recapitulate the cortex-striatum connection in vitro as a convenient model to investigate the development, function, and regulation of synapses formed between cortical and striatal neurons. However, optimization of this dissociated neuronal system to more closely reproduce in vivo circuits has not yet been explored. We studied the effect of varying the plating ratio of cortical to striatal neurons on striatal spiny projection neuron (SPN) characteristics in primary neuronal cocultures. Despite the large difference in cortical-striatal neuron ratio (1:1 vs. 1:3) at day of plating, by 18 days in vitro the difference became modest (∼25% lower cortical-striatal neuron ratio in 1:3 cocultures) and the neuronal density was lower in the 1:3 cocultures, indicating enhanced loss of striatal SPNs. Comparing SPNs in cocultures plated at a 1:1 vs. 1:3 ratio, we found that resting membrane potential, input resistance, current injection-induced action potential firing rates, and input-output curves were similar in the two conditions. However, SPNs in the cocultures plated at the lower cortical ratio exhibited reduced membrane capacitance along with significantly shorter total dendritic length, decreased dendritic complexity, and fewer excitatory synapses, consistent with their trend toward reduced miniature excitatory postsynaptic current frequency. Strikingly, the proportion of NMDA receptors found extrasynaptically in recordings from SPNs was significantly higher in the less cortical coculture. Consistently, SPNs in cocultures with reduced cortical input showed decreased basal pro-survival signaling through cAMP response element binding protein and enhanced sensitivity to NMDA-induced apoptosis. Altogether, our study indicates that abundance of cortical input regulates SPN dendritic arborization and survival/death signaling. Copyright © 2016 the American Physiological Society.
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Dong, Jun; Xie, Xin-Hua; Lu, Da-Xiang; Fu, Yong-Mei
2007-01-09
Although there is considerable evidence supporting that fever evolved as a host defense response, it is important that the rise in body temperature would not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified. Endogenous antipyretics attenuate fever by influencing the thermoregulatory neurons in the preoptic anterior hypothalamus (POAH) and in adjacent septal areas including ventral septal area (VSA). Our previous study showed that intracerebroventricular (I.C.V.) injection of interleukin-1beta (IL-1beta) affected electrophysiological activities of thermosensitive neurons in VSA regions, and electrical stimulation of POAH reversed the effect of IL-1beta. To further investigate the functional electrophysiological connection between POAH and VSA and its mechanisms in thermoregulation, the firing rates of thermosensitive neurons in POAH of forty-seven unit discharge were recorded by using extracellular microelectrode technique in New Zealand white rabbits. Our results show that the firing rates of the warm-sensitive neurons decreased significantly and those of the cold-sensitive neurons increased in POAH when the pyrogen (IL-1beta) was injected I.C.V. The effects of IL-1beta on firing rates in thermosensitive neurons of POAH were reversed by electrical stimulation of VSA. An arginine vasopressin (AVP) V1 antagonist abolished the regulatory effects of VSA on the firing rates in thermosensitive neurons of POAH evoked by IL-1beta. However, an AVP V2 antagonist had no effects. These data indicated that VSA regulates the activities of the thermosensitive neurons of POAH through AVP V1 but not AVP V2 receptor.
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Proneurotrophin-3 may induce Sortilin dependent death in inner ear neurons
Tauris, Jacob; Gustafsen, Camilla; Christensen, Erik Ilsø; Jansen, Pernille; Nykjaer, Anders; Nyengaard, Jens R.; Teng, Kenneth K.; Schwarz, Elisabeth; Ovesen, Therese; Madsen, Peder; Petersen, Claus Munck
2010-01-01
The precursor of the neurotrophin NGF (proNGF) serves physiological functions distinct from its mature counterpart as it induces neuronal apoptosis through activation of a p75 neurotrophin receptor (p75NTR) and Sortilin death-signalling complex. The neurotrophins BDNF and NT3 provide essential trophic support to auditory neurons. Injury to the neurotrophin secreting cells in the inner ear is followed by irreversible degeneration of spiral ganglion neurons with consequences such as impaired hearing or deafness. Lack of mature neurotrophins may explain the degeneration of spiral ganglion neurons, but another mechanism is possible since unprocessed proNTs released from the injured cells may contribute to the degeneration by induction of apoptosis. Recent studies demonstrate that proBDNF, like proNGF, is a potent inducer of Sortilin:p75NTR mediated apoptosis. In addition, a coincident upregulation of proBDNF and p75NTR has been observed in degenerating spiral ganglion neurons, but the Sortilin expression in the inner ear is unresolved. Here we demonstrate that Sortilin and p75NTR are coexpressed in neurons of the neonatal inner ear. Furthermore, we establish that proNT3 exhibits high affinity binding to Sortilin and has the capacity to enhance cell surface Sortilin:p75NTR complex formation as well as to mediate apoptosis in neurons coexpressing p75NTR and Sortilin. Based on examination of wt and Sortilin deficient mouse embryos, Sortilin does not significantly influence the developmental selection of spiral ganglion neurons. However, our results suggest that proNT3 and proBDNF may play important roles in the response to noise-induced injuries or ototoxic damage via the Sortilin:p75NTR death-signalling complex. PMID:21261755
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Burst firing and modulation of functional connectivity in cat striate cortex.
Snider, R K; Kabara, J F; Roig, B R; Bonds, A B
1998-08-01
We studied the influences of the temporal firing patterns of presynaptic cat visual cortical cells on spike generation by postsynaptic cells. Multiunit recordings were dissected into the activity of individual neurons within the recorded group. Cross-correlation analysis was then used to identify directly coupled neuron pairs. The 22 multiunit groups recorded typically showed activity from two to six neurons, each containing between 1 and 15 neuron pairs. From a total of 241 neuron pairs, 91 (38%) had a shifted cross-correlation peak, which indicated a possible direct connection. Only two multiunit groups contained no shifted peaks. Burst activity, defined by groups of two or more spikes with intervals of
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Li, W; Thier, P; Wehrhahn, C
2000-02-01
We studied the effects of various patterns as contextual stimuli on human orientation discrimination, and on responses of neurons in V1 of alert monkeys. When a target line is presented along with various contextual stimuli (masks), human orientation discrimination is impaired. For most V1 neurons, responses elicited by a line in the receptive field (RF) center are suppressed by these contextual patterns. Orientation discrimination thresholds of human observers are elevated slightly when the target line is surrounded by orthogonal lines. For randomly oriented lines, thresholds are elevated further and even more so for lines parallel to the target. Correspondingly, responses of most V1 neurons to a line are suppressed. Although contextual lines inhibit the amplitude of orientation tuning functions of most V1 neurons, they do not systematically alter the tuning width. Elevation of human orientation discrimination thresholds decreases with increasing curvature of masking lines, so does the inhibition of V1 neuronal responses. A mask made of straight lines yields the strongest interference with human orientation discrimination and produces the strongest suppression of neuronal responses. Elevation of human orientation discrimination thresholds is highest when a mask covers only the immediate vicinity of the target line. Increasing the masking area results in less interference. On the contrary, suppression of neuronal responses in V1 increases with increasing mask size. Our data imply that contextual interference observed in human orientation discrimination is in part directly related to contextual inhibition of neuronal activity in V1. However, the finding that interference with orientation discrimination is weaker for larger masks suggests a figure-ground segregation process that is not located in V1.
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Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin
2010-09-01
Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.
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Mechanisms and models of REM sleep control.
McCarley, R W
2004-07-01
The first sections of this paper survey the history and recent developments relevant to the major neurotransmitters and neuromodulators involved in REM sleep control. The last portion of this paper proposes a structural model of cellular interaction that produces the REM sleep cycle, and constitutes a further revision of the reciprocal interaction model This paper proposes seven criteria to define a causal role in REM sleep control for putative neuro-transmitters/modulators. The principal criteria are measurements during behavioral state changes of the extracellular concentrations of the putative substances, and electrophysiological recording of their neuronal source. A cautionary note is that, while pharmacological manipulations are suggestive, they alone do not provide definitive causal evidence. The extensive body of in vivo and in vitro evidence supporting cholinergic promotion of REM sleep via LDT/PPT neuronal activity is surveyed. An interesting question raised by some studies is whether cholinergic influences in rat are less puissant than in cat. At least some of the apparent lesser REM-inducing effect of carbachol in the rat may be due to incomplete control of circadian influences; almost all experiments have been run only in the daytime, inactive period, when REM sleep is more prominent, rather than in the REM-sparse nighttime inactive period. Monoaminergic inhibition of cholinergic neurons, once thought to be the most shaky proposal of the reciprocal interaction model, now enjoys considerable support from both in vivo and in vitro data. However, the observed time course of monoaminergic neurons, their "turning off" discharge activity as REM sleep is approached and entered would seem to be difficult to produce from feedback inhibition, as originally postulated by the reciprocal interaction model. New data suggest the possibility that GABAergic inhibition of Locus Coeruleus and Dorsal Raphe monoaminergic neurons may account for the "REM-off" neurons turning off. However, the source(s) of GABAergic influences suggested by anatomical studies has yet to be definitively identified by electrophysiological recordings of GABAergic neurons that show the requisite inverse time course of activity relative to monoaminergic neurons. New and still preliminary microdialysis data suggest that reticular formation neurons, the effector neurons for REM sleep phenomena, might be disinhibited during REM sleep by decreased GABAergic influence, perhaps stemming from REM-on cholinergic neuronal inhibition of reticular formation GABAergic neurons. Whether the postulated cholinergic inhibition of GABAergic neurons is present is testable with in vitro recordings and double labeling. Taking into account the observed data on neuro-modulators/transmitters, a structural model incorporating interaction of REM-on and REM-off neurons and GABAergic influences is proposed. Finally, with respect to orexin and REM sleep, it is hypothesized that orexinergic activity may be a principal factor controlling REM sleep's absence from the active period in strongly circadian animals such as rat and man.
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Phase Transitions in Living Neural Networks
NASA Astrophysics Data System (ADS)
Williams-Garcia, Rashid Vladimir
Our nervous systems are composed of intricate webs of interconnected neurons interacting in complex ways. These complex interactions result in a wide range of collective behaviors with implications for features of brain function, e.g., information processing. Under certain conditions, such interactions can drive neural network dynamics towards critical phase transitions, where power-law scaling is conjectured to allow optimal behavior. Recent experimental evidence is consistent with this idea and it seems plausible that healthy neural networks would tend towards optimality. This hypothesis, however, is based on two problematic assumptions, which I describe and for which I present alternatives in this thesis. First, critical transitions may vanish due to the influence of an environment, e.g., a sensory stimulus, and so living neural networks may be incapable of achieving "critical" optimality. I develop a framework known as quasicriticality, in which a relative optimality can be achieved depending on the strength of the environmental influence. Second, the power-law scaling supporting this hypothesis is based on statistical analysis of cascades of activity known as neuronal avalanches, which conflate causal and non-causal activity, thus confounding important dynamical information. In this thesis, I present a new method to unveil causal links, known as causal webs, between neuronal activations, thus allowing for experimental tests of the quasicriticality hypothesis and other practical applications.
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BRAZ, JOÃO MANUEL; BASBAUM, ALLAN I.
2016-01-01
Despite the evidence for a significant contribution of brainstem serotonergic (5HT) systems to the control of spinal cord “pain” transmission neurons, attention has turned recently to the influence of nonserotonergic neurons, including the facilitatory and inhibitory controls that originate from so-called “on” and “off” cells of the rostroventral medulla (RVM). Unclear, however, is the extent to which these latter circuits interact with or are influenced by the serotonergic cell groups. To address this question we selectively targeted expression of a transneuronal tracer, wheat germ agglutinin (WGA), in the 5HT neurons so as to study the interplay between the 5HT and non-5HT systems. In addition to confirming the direct medullary 5HT projection to the spinal cord we also observed large numbers of non-5HT neurons, in the medullary nucleus reticularis gigantocellularis and magnocellularis, that were WGA-immunoreactive, i.e., were transneuronally labeled from 5HT neurons. Fluoro-Gold injections into the spinal cord established that these reticular neurons are not only postsynaptic to the 5HT neurons of the medulla, but that most are also at the origin of descending, bulbospinal pathways. By contrast, we found no evidence that neurons of the midbrain periaqueductal gray that project to the RVM are postsynaptic to midbrain or medullary 5HT neurons. Finally, we found very few examples of WGA-immunoreactive noradrenergic neurons, which suggests that there is considerable independence of the monoaminergic bulbospinal pathways. Our results indicate that 5HT neurons influence “pain” processing at the spinal cord level both directly and indirectly via feedforward connections with multiple non-5HT descending control pathways. PMID:18273889
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Mirror neurons and imitation: a computationally guided review.
Oztop, Erhan; Kawato, Mitsuo; Arbib, Michael
2006-04-01
Neurophysiology reveals the properties of individual mirror neurons in the macaque while brain imaging reveals the presence of 'mirror systems' (not individual neurons) in the human. Current conceptual models attribute high level functions such as action understanding, imitation, and language to mirror neurons. However, only the first of these three functions is well-developed in monkeys. We thus distinguish current opinions (conceptual models) on mirror neuron function from more detailed computational models. We assess the strengths and weaknesses of current computational models in addressing the data and speculations on mirror neurons (macaque) and mirror systems (human). In particular, our mirror neuron system (MNS), mental state inference (MSI) and modular selection and identification for control (MOSAIC) models are analyzed in more detail. Conceptual models often overlook the computational requirements for posited functions, while too many computational models adopt the erroneous hypothesis that mirror neurons are interchangeable with imitation ability. Our meta-analysis underlines the gap between conceptual and computational models and points out the research effort required from both sides to reduce this gap.
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Ramachandran, Kapil V.; Margolis, Seth S.
2017-01-01
In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It remains unclear how proteasomes can acutely regulate such processes, as this is inconsistent with their canonical role in proteostasis. Here, we made the discovery of a mammalian nervous system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellular peptides that can stimulate neuronal signaling. This proteasome complex is tightly associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of this membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked extracellular peptide production and attenuated neuronal activity-induced calcium signaling. Moreover, membrane proteasome-derived peptides are sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes primarily function to maintain proteostasis, and highlight a form of neuronal communication through a membrane proteasome complex. PMID:28287632
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Wallace, Sean W; Singhvi, Aakanksha; Liang, Yupu; Lu, Yun; Shaham, Shai
2016-04-19
Sensory neurons are an animal's gateway to the world, and their receptive endings, the sites of sensory signal transduction, are often associated with glia. Although glia are known to promote sensory-neuron functions, the molecular bases of these interactions are poorly explored. Here, we describe a post-developmental glial role for the PROS-1/Prospero/PROX1 homeodomain protein in sensory-neuron function in C. elegans. Using glia expression profiling, we demonstrate that, unlike previously characterized cell fate roles, PROS-1 functions post-embryonically to control sense-organ glia-specific secretome expression. PROS-1 functions cell autonomously to regulate glial secretion and membrane structure, and non-cell autonomously to control the shape and function of the receptive endings of sensory neurons. Known glial genes controlling sensory-neuron function are PROS-1 targets, and we identify additional PROS-1-dependent genes required for neuron attributes. Drosophila Prospero and vertebrate PROX1 are expressed in post-mitotic sense-organ glia and astrocytes, suggesting conserved roles for this class of transcription factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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Left-right asymmetry is required for the habenulae to respond to both visual and olfactory stimuli.
Dreosti, Elena; Vendrell Llopis, Nuria; Carl, Matthias; Yaksi, Emre; Wilson, Stephen W
2014-02-17
Left-right asymmetries are most likely a universal feature of bilaterian nervous systems and may serve to increase neural capacity by specializing equivalent structures on left and right sides for distinct roles. However, little is known about how asymmetries are encoded within vertebrate neural circuits and how lateralization influences processing of information in the brain. Consequently, it remains unclear the extent to which lateralization of the nervous system is important for normal cognitive and other brain functions and whether defects in lateralization contribute to neurological deficits. Here we show that sensory responses to light and odor are lateralized in larval zebrafish habenulae and that loss of brain asymmetry leads to concomitant loss of responsiveness to either visual or olfactory stimuli. We find that in wild-type zebrafish, most habenular neurons responding to light are present on the left, whereas neurons responding to odor are more frequent on the right. Manipulations that reverse the direction of brain asymmetry reverse the functional properties of habenular neurons, whereas manipulations that generate either double-left- or double-right-sided brains lead to loss of habenular responsiveness to either odor or light, respectively. Our results indicate that loss of brain lateralization has significant consequences upon sensory processing and circuit function. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Vascular cognitive impairment, dementia, aging and energy demand. A vicious cycle.
Popa-Wagner, A; Buga, Ana-Maria; Popescu, B; Muresanu, D
2015-08-01
To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect humans from one of the most devastating affliction, dementia. However, the underlying biological mechanisms are still not completely clear. Many studies demonstrated that the neurovascular unit is compromised in cerebrovascular diseases and also in other types of dementia. The hemodynamic neurovascular coupling ensures a strong increase of the cerebral blood flow (CBF) and an acute increase in neuronal glucose uptake upon increased neural activity. Dysfunction of cerebral autoregulation with increasing age along with age-related structural and functional alterations in cerebral blood vessels including accumulation of amyloid-beta (Aβ) in the media of cortical arterioles, neurovascular uncoupling due to astrocyte endfeet retraction, impairs the CBF and increases the neuronal degeneration and susceptibility to hypoxia and ischemia. A decreased cerebral glucose metabolism is an early event in Alzheimer's disease (AD) pathology and may precede the neuropathological Aβ deposition associated with AD. Aβ accumulation in turn leads to further decreases in the CBF closing the vicious cycle. Alzheimer, aging and diabetes are also influenced by insulin/insulin-like growth factor-1 signaling, and accumulated evidence indicates sporadic AD is associated with disturbed brain insulin metabolism. Understanding how vascular and metabolic factors interfere with progressive loss of functional neuronal networks becomes essential to develop efficient drugs to prevent cognitive decline in elderly.
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Tabor, Rico; Yaksi, Emre; Friedrich, Rainer W
2008-07-01
gamma-Aminobutyric acid (GABA)ergic synapses are thought to play pivotal roles in the processing of activity patterns in the olfactory bulb (OB), but their functions have been difficult to study during odor responses in the intact system. We pharmacologically manipulated GABA(A) and GABA(B) receptors in the OB of zebrafish and analysed the effects on odor responses of the output neurons, the mitral cells (MCs), by electrophysiological recordings and temporally deconvolved two-photon Ca2+ imaging. The blockade of GABA(B) receptors enhanced presynaptic Ca2+ influx into afferent axon terminals, and changed the amplitude and time course of a subset of MC responses, indicating that GABA(B) receptors have a modulatory influence on OB output activity. The blockade of GABA(A) receptors induced epileptiform firing, enhanced excitatory responses and abolished fast oscillations in the local field potential. Moreover, the topological reorganization and decorrelation of MC activity patterns during the initial phase of the response was perturbed. These results indicate that GABA(A) receptor-containing circuits participate in the balance of excitation and inhibition, the regulation of total OB output activity, the synchronization of odor-dependent neuronal ensembles, and the reorganization of odor-encoding activity patterns. GABA(A) and GABA(B) receptors are therefore differentially involved in multiple functions of neuronal circuits in the OB.
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Oligodendrocytes as Regulators of Neuronal Networks during Early Postnatal Development
Ramos, Maria; Ikrar, Taruna; Kinoshita, Chisato; De Mei, Claudia; Tirotta, Emanuele; Xu, Xiangmin; Borrelli, Emiliana
2011-01-01
Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development. PMID:21589880
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Sonic Hedgehog Expression in Corticofugal Projection Neurons Directs Cortical Microcircuit Formation
Harwell, Corey C.; Parker, Philip R.L.; Gee, Steven M.; Okada, Ami; McConnell, Susan K.; Kreitzer, Anatol C.; Kriegstein, Arnold R.
2012-01-01
SUMMARY The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. PMID:22445340
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Synaptic communication between neurons and NG2+ cells.
Paukert, Martin; Bergles, Dwight E
2006-10-01
Chemical synaptic transmission provides the basis for much of the rapid signaling that occurs within neuronal networks. However, recent studies have provided compelling evidence that synapses are not used exclusively for communication between neurons. Physiological and anatomical studies indicate that a distinct class of glia known as NG2(+) cells also forms direct synaptic junctions with both glutamatergic and GABAergic neurons. Glutamatergic signaling can influence intracellular Ca(2+) levels in NG2(+) cells by activating Ca(2+) permeable AMPA receptors, and these inputs can be potentiated through high frequency stimulation. Although the significance of this highly differentiated form of communication remains to be established, these neuro-glia synapses might enable neurons to influence rapidly the behavior of this ubiquitous class of glial progenitors.
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Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.
2015-01-01
Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitro inhibited the acid-sensitive K+ current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activity in vivo using freely behaving wild-type (n = 12) and ChAT-Cre:TASKf/f mice (n = 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/f mice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activation in vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrain in vivo. SIGNIFICANCE STATEMENT Attentive states and cognitive function are associated with the generation of γ EEG activity. Basal forebrain cholinergic neurons are important modulators of cortical arousal and γ activity, and in this study we investigated the mechanism by which these neurons are activated by the wake-active neurotransmitter histamine. We found that histamine inhibited a class of K+ leak channels called TASK channels and that deletion of TASK channels selectively on cholinergic neurons modulated baseline EEG activity as well as histamine-induced changes in γ activity. By identifying a discrete brain circuit where TASK channels can influence γ activity, these results represent new knowledge that enhances our understanding of how subcortical arousal systems may contribute to the generation of attentive states. PMID:26446210
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The Role of Glia in Sleep Regulation and Function.
Frank, Marcos G
2018-01-28
The cellular mechanisms governing the expression, regulation, and function of sleep are not entirely understood. The traditional view is that these mechanisms are neuronal. An alternative view is that glial brain cells may play important roles in these processes. Their ubiquity in the central nervous system makes them well positioned to modulate neuronal circuits that gate sleep and wake. Their ability to respond to chemical neuronal signals suggests that they form feedback loops with neurons that may globally regulate neuronal activity. Their potential role in detoxifying the brain, regulating neuronal metabolism, and promoting synaptic plasticity raises the intriguing possibility that glia mediate important functions ascribed to sleep.
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Boyadjieva, Nadka I.; Ortigüela, María; Arjona, Alvaro; Cheng, Xiaodong; Sarkar, Dipak K.
2010-01-01
Background Natural killer (NK) cell dysfunction is associated with hyperresponse of corticotropin releasing hormone (CRH) to immune challenge and with a loss of β-endorphin (BEP) neurons in fetal alcohol exposed animals. Recently, we established a method to differentiate neural stem cells into BEP neurons using cyclic adenosine monophosphate (cAMP)-elevating agents in cultures. Hence, we determined whether in vitro differentiated BEP neurons could be used for reversing the compromised stress response and immune function in fetal alcohol exposed rats. Methods To determine the effect of BEP neuron transplants on NK cell function, we implanted in vitro differentiated BEP neurons into the paraventricular nucleus of pubertal and adult male rats exposed to ethanol or control in utero. The functionality of transplanted BEP neurons was determined by measuring proopiomelanocortin (POMC) gene expression in these cells and their effects on CRH gene expression under basal and after lipopolysaccaride (LPS) challenge. In addition, the effectiveness of BEP neurons in activating NK cell functions is determined by measuring NK cell cytolytic activity and interferon-γ (IFN-γ) production in the spleen and in the peripheral blood mononuclear cell (PBMC) following cell transplantation. Results We showed here that when these in vitro differentiated BEP neurons were transplanted into the hypothalamus, they maintain biological functions by producing POMC and reducing the CRH neuronal response to the LPS challenge. BEP neuronal transplants significantly increased NK cell cytolytic activity in the spleen and in the PBMC and increased plasma levels of IFN-γ in control and fetal alcohol exposed rats. Conclusions These data further establish the BEP neuronal regulatory role in the control of CRH and NK cell cytolytic function and identify a possible novel therapy to treat stress hyper-response and immune deficiency in fetal alcohol exposed subjects. PMID:19320628
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Sriperumbudur, Kiran Kumar; Pau, Hans Wilhelm; van Rienen, Ursula
2018-03-01
Electric stimulation of the auditory nerve by cochlear implants has been a successful clinical intervention to treat the sensory neural deafness. In this pathological condition of the cochlea, type-1 spiral ganglion neurons in Rosenthal's canal play a vital role in the action potential initiation. Various morphological studies of the human temporal bones suggest that the spiral ganglion neurons are surrounded by heterogeneous structures formed by a variety of cells and tissues. However, the existing simulation models have not considered the tissue heterogeneity in the Rosenthal's canal while studying the electric field interaction with spiral ganglion neurons. Unlike the existing models, we have implemented the tissue heterogeneity in the Rosenthal's canal using a computationally inexpensive image based method in a two-dimensional finite element model. Our simulation results suggest that the spatial heterogeneity of surrounding tissues influences the electric field distribution in the Rosenthal's canal, and thereby alters the transmembrane potential of the spiral ganglion neurons. In addition to the academic interest, these results are especially useful to understand how the latest tissue regeneration methods such as gene therapy and drug-induced resprouting of peripheral axons, which probably modify the density of the tissues in the Rosenthal's canal, affect the cochlear implant functionality.
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Functional Magnetic Resonance Imaging (fMRI) Neurofeedback: Implementations and Applications
DEWIPUTRI, Wan Ilma; AUER, Tibor
2013-01-01
Neurofeedback (NFB) allows subjects to learn how to volitionally influence the neuronal activation in the brain by employing real-time neural activity as feedback. NFB has already been performed with electroencephalography (EEG) since the 1970s. Functional MRI (fMRI), offering a higher spatial resolution, has further increased the spatial specificity. In this paper, we briefly outline the general principles behind NFB, the implementation of fMRI-NFB studies, the feasibility of fMRI-NFB, and the application of NFB as a supplementary therapy tool. PMID:24643368
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Blumenthal, Nils R; Hermanson, Ola; Heimrich, Bernd; Shastri, V Prasad
2014-11-11
Extracellular soluble signals are known to play a critical role in maintaining neuronal function and homeostasis in the CNS. However, the CNS is also composed of extracellular matrix macromolecules and glia support cells, and the contribution of the physical attributes of these components in maintenance and regulation of neuronal function is not well understood. Because these components possess well-defined topography, we theorize a role for topography in neuronal development and we demonstrate that survival and function of hippocampal neurons and differentiation of telencephalic neural stem cells is modulated by nanoroughness. At roughnesses corresponding to that of healthy astrocytes, hippocampal neurons dissociated and survived independent from astrocytes and showed superior functional traits (increased polarity and calcium flux). Furthermore, telencephalic neural stem cells differentiated into neurons even under exogenous signals that favor astrocytic differentiation. The decoupling of neurons from astrocytes seemed to be triggered by changes to astrocyte apical-surface topography in response to nanoroughness. Blocking signaling through mechanosensing cation channels using GsMTx4 negated the ability of neurons to sense the nanoroughness and promoted decoupling of neurons from astrocytes, thus providing direct evidence for the role of nanotopography in neuron-astrocyte interactions. We extrapolate the role of topography to neurodegenerative conditions and show that regions of amyloid plaque buildup in brain tissue of Alzheimer's patients are accompanied by detrimental changes in tissue roughness. These findings suggest a role for astrocyte and ECM-induced topographical changes in neuronal pathologies and provide new insights for developing therapeutic targets and engineering of neural biomaterials.
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Functional model of biological neural networks.
Lo, James Ting-Ho
2010-12-01
A functional model of biological neural networks, called temporal hierarchical probabilistic associative memory (THPAM), is proposed in this paper. THPAM comprises functional models of dendritic trees for encoding inputs to neurons, a first type of neuron for generating spike trains, a second type of neuron for generating graded signals to modulate neurons of the first type, supervised and unsupervised Hebbian learning mechanisms for easy learning and retrieving, an arrangement of dendritic trees for maximizing generalization, hardwiring for rotation-translation-scaling invariance, and feedback connections with different delay durations for neurons to make full use of present and past informations generated by neurons in the same and higher layers. These functional models and their processing operations have many functions of biological neural networks that have not been achieved by other models in the open literature and provide logically coherent answers to many long-standing neuroscientific questions. However, biological justifications of these functional models and their processing operations are required for THPAM to qualify as a macroscopic model (or low-order approximate) of biological neural networks.
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Szymanska, Kamila; Makowska, Krystyna; Gonkowski, Slawomir
2018-03-20
Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT-used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms.
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Zikopoulos, Basilis; Höistad, Malin; John, Yohan; Barbas, Helen
2017-05-17
The bidirectional dialogue of the primate posterior orbitofrontal cortex (pOFC) with the amygdala is essential in cognitive-emotional functions. The pOFC also sends a uniquely one-way excitatory pathway to the amygdalar inhibitory intercalated masses (IM), which inhibit the medial part of the central amygdalar nucleus (CeM). Inhibition of IM has the opposite effect, allowing amygdalar activation of autonomic structures and emotional arousal. Using multiple labeling approaches to identify pathways and their postsynaptic sites in the amygdala in rhesus monkeys, we found that the anterior cingulate cortex innervated mostly the basolateral and CeM amygdalar nuclei, poised to activate CeM for autonomic arousal. By contrast, a pathway from pOFC to IM exceeded all other pathways to the amygdala by density and size and proportion of large and efficient terminals. Moreover, whereas pOFC terminals in IM innervated each of the three distinct classes of inhibitory neurons, most targeted neurons expressing dopamine- and cAMP-regulated phosphoprotein (DARPP-32+), known to be modulated by dopamine. The predominant pOFC innervation of DARPP-32+ neurons suggests activation of IM and inhibition of CeM, resulting in modulated autonomic function. By contrast, inhibition of DARPP-32 neurons in IM by high dopamine levels disinhibits CeM and triggers autonomic arousal. The findings provide a mechanism to help explain how a strong pOFC pathway, which is poised to moderate activity of CeM, through IM, can be undermined by the high level of dopamine during stress, resulting in collapse of potent inhibitory mechanisms in the amygdala and heightened autonomic drive, as seen in chronic anxiety disorders. SIGNIFICANCE STATEMENT The dialogue between prefrontal cortex and amygdala allows thoughts and emotions to influence actions. The posterior orbitofrontal cortex sends a powerful pathway that targets a special class of amygdalar intercalated mass (IM) inhibitory neurons, whose wiring may help modulate autonomic function. By contrast, the anterior cingulate cortex innervates other amygdalar parts, activating circuits to help avoid danger. Most IM neurons in primates label for the protein DARPP-32, known to be activated or inhibited based on the level of dopamine. Stress markedly increases dopamine release and inhibits IM neurons, compromises prefrontal control of the amygdala, and sets off a general alarm system as seen in affective disorders, such as chronic anxiety and post-traumatic stress disorder. Copyright © 2017 the authors 0270-6474/17/375051-14$15.00/0.
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ON THE PERCEPTION OF PROBABLE THINGS
Albright, Thomas D.
2012-01-01
SUMMARY Perception is influenced both by the immediate pattern of sensory inputs and by memories acquired through prior experiences with the world. Throughout much of its illustrious history, however, study of the cellular basis of perception has focused on neuronal structures and events that underlie the detection and discrimination of sensory stimuli. Relatively little attention has been paid to the means by which memories interact with incoming sensory signals. Building upon recent neurophysiological/behavioral studies of the cortical substrates of visual associative memory, I propose a specific functional process by which stored information about the world supplements sensory inputs to yield neuronal signals that can account for visual perceptual experience. This perspective represents a significant shift in the way we think about the cellular bases of perception. PMID:22542178
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Tsoi, Shuk C; Aiya, Utsav V; Wasner, Kobi D; Phan, Mimi L; Pytte, Carolyn L; Vicario, David S
2014-01-01
Many brain regions exhibit lateral differences in structure and function, and also incorporate new neurons in adulthood, thought to function in learning and in the formation of new memories. However, the contribution of new neurons to hemispheric differences in processing is unknown. The present study combines cellular, behavioral, and physiological methods to address whether 1) new neuron incorporation differs between the brain hemispheres, and 2) the degree to which hemispheric lateralization of new neurons correlates with behavioral and physiological measures of learning and memory. The songbird provides a model system for assessing the contribution of new neurons to hemispheric specialization because songbird brain areas for vocal processing are functionally lateralized and receive a continuous influx of new neurons in adulthood. In adult male zebra finches, we quantified new neurons in the caudomedial nidopallium (NCM), a forebrain area involved in discrimination and memory for the complex vocalizations of individual conspecifics. We assessed song learning and recorded neural responses to song in NCM. We found significantly more new neurons labeled in left than in right NCM; moreover, the degree of asymmetry in new neuron numbers was correlated with the quality of song learning and strength of neuronal memory for recently heard songs. In birds with experimentally impaired song quality, the hemispheric difference in new neurons was diminished. These results suggest that new neurons may contribute to an allocation of function between the hemispheres that underlies the learning and processing of complex signals.
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Wasner, Kobi D.; Phan, Mimi L.; Pytte, Carolyn L.; Vicario, David S.
2014-01-01
Many brain regions exhibit lateral differences in structure and function, and also incorporate new neurons in adulthood, thought to function in learning and in the formation of new memories. However, the contribution of new neurons to hemispheric differences in processing is unknown. The present study combines cellular, behavioral, and physiological methods to address whether 1) new neuron incorporation differs between the brain hemispheres, and 2) the degree to which hemispheric lateralization of new neurons correlates with behavioral and physiological measures of learning and memory. The songbird provides a model system for assessing the contribution of new neurons to hemispheric specialization because songbird brain areas for vocal processing are functionally lateralized and receive a continuous influx of new neurons in adulthood. In adult male zebra finches, we quantified new neurons in the caudomedial nidopallium (NCM), a forebrain area involved in discrimination and memory for the complex vocalizations of individual conspecifics. We assessed song learning and recorded neural responses to song in NCM. We found significantly more new neurons labeled in left than in right NCM; moreover, the degree of asymmetry in new neuron numbers was correlated with the quality of song learning and strength of neuronal memory for recently heard songs. In birds with experimentally impaired song quality, the hemispheric difference in new neurons was diminished. These results suggest that new neurons may contribute to an allocation of function between the hemispheres that underlies the learning and processing of complex signals. PMID:25251077
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Bernard-Marissal, Nathalie; Médard, Jean-Jacques; Azzedine, Hamid; Chrast, Roman
2015-04-01
Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Structure-function analysis of genetically defined neuronal populations.
Groh, Alexander; Krieger, Patrik
2013-10-01
Morphological and functional classification of individual neurons is a crucial aspect of the characterization of neuronal networks. Systematic structural and functional analysis of individual neurons is now possible using transgenic mice with genetically defined neurons that can be visualized in vivo or in brain slice preparations. Genetically defined neurons are useful for studying a particular class of neurons and also for more comprehensive studies of the neuronal content of a network. Specific subsets of neurons can be identified by fluorescence imaging of enhanced green fluorescent protein (eGFP) or another fluorophore expressed under the control of a cell-type-specific promoter. The advantages of such genetically defined neurons are not only their homogeneity and suitability for systematic descriptions of networks, but also their tremendous potential for cell-type-specific manipulation of neuronal networks in vivo. This article describes a selection of procedures for visualizing and studying the anatomy and physiology of genetically defined neurons in transgenic mice. We provide information about basic equipment, reagents, procedures, and analytical approaches for obtaining three-dimensional (3D) cell morphologies and determining the axonal input and output of genetically defined neurons. We exemplify with genetically labeled cortical neurons, but the procedures are applicable to other brain regions with little or no alterations.
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Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease.
Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G; Grison, Alice; Gustincich, Stefano
2016-01-01
Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells' own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain.
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Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease
Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G.; Grison, Alice; Gustincich, Stefano
2016-01-01
Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells’ own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372
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Domi, Esi; Uhrig, Stefanie; Soverchia, Laura; Spanagel, Rainer; Hansson, Anita C; Barbier, Estelle; Heilig, Markus; Ciccocioppo, Roberto; Ubaldi, Massimo
2016-12-14
PPARγ is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPARγ is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPARγ is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPARγ in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPARγ by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPARγ (PPARγ NestinCre ), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPARγ antagonist, elicited a marked anxiogenic response in PPARγ wild-type (WT), but not in PPARγ NestinCre knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPARγ NestinCre KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPARγ colocalizes with GABAergic cells. These findings demonstrate that neuronal PPARγ is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPARγ. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) is a classical target for antidiabetic therapies with thiazolidinedione compounds. PPARγ agonists such as rosiglitazone and pioglitazone are in clinical use for the treatment of insulin resistance. PPARγ has recently attracted attention for its involvement in the regulation of CNS immune response and functions. Here, we demonstrate that neuronal PPARγ activation prevented the negative emotional effects of stress and exerted anxiolytic actions without influencing hypothalamic-pituitary-adrenal axis function. Conversely, pharmacological blockade or genetic deletion of PPARγ enhanced anxiogenic responses and increased vulnerability to stress. These effects appear to be controlled by PPARγ neuronal-mediated mechanisms in the amygdala. Copyright © 2016 the authors 0270-6474/16/3612612-13$15.00/0.
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GW182 controls Drosophila circadian behavior and PDF-receptor signaling.
Zhang, Yong; Emery, Patrick
2013-04-10
The neuropeptide PDF is crucial for Drosophila circadian behavior: it keeps circadian neurons synchronized. Here, we identify GW182 as a key regulator of PDF signaling. Indeed, GW182 downregulation results in phenotypes similar to those of Pdf and Pdf-receptor (Pdfr) mutants. gw182 genetically interacts with Pdfr and cAMP signaling, which is essential for PDFR function. GW182 mediates miRNA-dependent gene silencing through its interaction with AGO1. Consistently, GW182's AGO1 interaction domain is required for GW182's circadian function. Moreover, our results indicate that GW182 modulates PDFR signaling by silencing the expression of the cAMP phosphodiesterase DUNCE. Importantly, this repression is under photic control, and GW182 activity level--which is limiting in circadian neurons--influences the responses of the circadian neural network to light. We propose that GW182's gene silencing activity functions as a rheostat for PDFR signaling and thus profoundly impacts the circadian neural network and its response to environmental inputs. Copyright © 2013 Elsevier Inc. All rights reserved.
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Peptides, serotonin, and breathing: the role of the raphe in the control of respiration.
Pilowsky, Paul M
2014-01-01
Over the last 20 years, it has become clear that many functionally defined autonomic neurons in the brainstem contain many more than one neurotransmitter. Here, the possible role and functions of colocalized neuropeptides in the caudal raphe nuclei of the medulla oblongata are discussed. Caudal raphe neurons provide an extensive input to neurons throughout the brainstem and spinal cord, including respiratory and cardiovascular neurons. It is concluded that one plausible function of colocalized neuropeptides is to maintain the membrane potential of target neurons within a defined window so that they remain able to function at extremes of activity. © 2014 Elsevier B.V. All rights reserved.
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A Co-operative Regulation of Neuronal Excitability by UNC-7 Innexin and NCA/NALCN Leak Channel
2011-01-01
Gap junctions mediate the electrical coupling and intercellular communication between neighboring cells. Some gap junction proteins, namely connexins and pannexins in vertebrates, and innexins in invertebrates, may also function as hemichannels. A conserved NCA/Dmα1U/NALCN family cation leak channel regulates the excitability and activity of vertebrate and invertebrate neurons. In the present study, we describe a genetic and functional interaction between the innexin UNC-7 and the cation leak channel NCA in Caenorhabditis elegans neurons. While the loss of the neuronal NCA channel function leads to a reduced evoked postsynaptic current at neuromuscular junctions, a simultaneous loss of the UNC-7 function restores the evoked response. The expression of UNC-7 in neurons reverts the effect of the unc-7 mutation; moreover, the expression of UNC-7 mutant proteins that are predicted to be unable to form gap junctions also reverts this effect, suggesting that UNC-7 innexin regulates neuronal activity, in part, through gap junction-independent functions. We propose that, in addition to gap junction-mediated functions, UNC-7 innexin may also form hemichannels to regulate C. elegans' neuronal activity cooperatively with the NCA family leak channels. PMID:21489288
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Nakano, Rei; Edamura, Kazuya; Sugiya, Hiroshi; Narita, Takanori; Okabayashi, Ken; Moritomo, Tadaaki; Teshima, Kenji; Asano, Kazushi; Nakayama, Tomohiro
2013-10-01
To investigate the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into functional, mature neurons. Bone marrow from 6 adult dogs. BMSCs were isolated from bone marrow and chemically induced to develop into neurons. The morphology of the BMSCs during neuronal induction was monitored, and immunocytochemical analyses for neuron markers were performed after the induction. Real-time PCR methods were used to evaluate the mRNA expression levels of markers for neural stem or progenitor cells, neurons, and ion channels, and western blotting was used to assess the expression of neuronal proteins before and after neuronal induction. The electrophysiological properties of the neuron-like cells induced from canine BMSCs were evaluated with fluorescent dye to monitor Ca(2)+ influx. Canine BMSCs developed a neuron-like morphology after neuronal induction. Immunocytochemical analysis revealed that these neuron-like cells were positive for neuron markers. After induction, the cells' mRNA expression levels of almost all neuron and ion channel markers increased, and the protein expression levels of nestin and neurofilament-L increased significantly. However, the neuron-like cells derived from canine BMSCs did not have the Ca(2)+ influx characteristic of spiking neurons. Although canine BMSCs had neuron-like morphological and biochemical properties after induction, they did not develop the electrophysiological characteristics of neurons. Thus, these results have suggested that canine BMSCs could have the capacity to differentiate into a neuronal lineage, but the differentiation protocol used may have been insufficient to induce development into functional neurons.
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How to make spinal motor neurons.
Davis-Dusenbery, Brandi N; Williams, Luis A; Klim, Joseph R; Eggan, Kevin
2014-02-01
All muscle movements, including breathing, walking, and fine motor skills rely on the function of the spinal motor neuron to transmit signals from the brain to individual muscle groups. Loss of spinal motor neuron function underlies several neurological disorders for which treatment has been hampered by the inability to obtain sufficient quantities of primary motor neurons to perform mechanistic studies or drug screens. Progress towards overcoming this challenge has been achieved through the synthesis of developmental biology paradigms and advances in stem cell and reprogramming technology, which allow the production of motor neurons in vitro. In this Primer, we discuss how the logic of spinal motor neuron development has been applied to allow generation of motor neurons either from pluripotent stem cells by directed differentiation and transcriptional programming, or from somatic cells by direct lineage conversion. Finally, we discuss methods to evaluate the molecular and functional properties of motor neurons generated through each of these techniques.
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Harnett, Mark T; Magee, Jeffrey C; Williams, Stephen R
2015-01-21
The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons. Copyright © 2015 the authors 0270-6474/15/351024-14$15.00/0.
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Duffy, Kevin R; Holman, Kaitlyn D; Mitchell, Donald E
2014-05-01
The parallel processing of visual features by distinct neuron populations is a central characteristic of the mammalian visual system. In the A laminae of the cat dorsal lateral geniculate nucleus (dLGN), parallel processing streams originate from two principal neuron types, called X and Y cells. Disruption of visual experience early in life by monocular deprivation has been shown to alter the structure and function of Y cells, but the extent to which deprivation influences X cells remains less clear. A transcription factor, FoxP2, has recently been shown to selectively label X cells in the ferret dLGN and thus provides an opportunity to examine whether monocular deprivation alters the soma size of X cells. In this study, FoxP2 labeling was examined in the dLGN of normal and monocularly deprived cats. The characteristics of neurons labeled for FoxP2 were consistent with FoxP2 being a marker for X cells in the cat dLGN. Monocular deprivation for either a short (7 days) or long (7 weeks) duration did not alter the density of FoxP2-positive neurons between nondeprived and deprived dLGN layers. However, for each deprived animal examined, measurement of the cross-sectional area of FoxP2-positive neurons (X cells) revealed that within deprived layers, X cells were smaller by approximately 20% after 7 days of deprivation, and by approximately 28% after 7 weeks of deprivation. The observed alteration to the cross-sectional area of X cells indicates that perturbation of this major pathway contributes to the functional impairments that develop from monocular deprivation.
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Model-Free Reconstruction of Excitatory Neuronal Connectivity from Calcium Imaging Signals
Stetter, Olav; Battaglia, Demian; Soriano, Jordi; Geisel, Theo
2012-01-01
A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting). Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non-causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections are characterized by an elevated level of clustering compared to a random graph (although not extreme) and can be markedly non-local. PMID:22927808
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Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons
Bradford, Aaron B; McNutt, Patrick M
2015-01-01
Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments. PMID:26240679
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LTP Induction Modifies Functional Relationship among Hippocampal Neurons
ERIC Educational Resources Information Center
Yun, Sung H.; Lee, Deok S.; Lee, Hyunjung; Baeg, Eun H.; Kim, Yun B.; Jung, Min W.
2007-01-01
To obtain evidence linking long-term potentiation (LTP) and memory, we examined whether LTP induction modifies functional relationship among neurons in the rat hippocampus. In contrast to neurons in low-frequency stimulated or AP5-treated slices, LTP induction altered "functional connectivity," as defined by the degree of synchronous firing, among…
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NASA Astrophysics Data System (ADS)
Bauer, Adam Q.; Kraft, Andrew; Baxter, Grant A.; Bruchas, Michael R.; Lee, Jin-Moo; Culver, Joseph P.
2017-02-01
Recent fcMRI studies examining spontaneous brain activity after stoke have revealed disrupted global patterns of functional connectivity (FC). Interestingly, acute interhemispheric homotopic FC has been shown to be predictive of recovery potential. While substantial indirect evidence also suggests that homotopic brain activity may directly impact recovery, results in humans are extremely varied. A better understanding of how activity within networks functionally-connected to lesioned tissue influences brain plasticity might improve therapeutic strategies. We combine cell-type specific optogenetic targeting with optical intrinsic signal (OIS) imaging to assess the effects of homotopic contralesional activity (specifically in excitatory CamKIIa pyramidal neurons) on FC, cortical remapping, and behavior after stroke. Thirty-one mice were housed in enriched cages for the experiment. OIS imaging was performed before, 1, and 4 weeks after photothrombosis of left forepaw somatosensory cortex (S1fp). On day 1 after stroke, 17 mice were subjected to chronic, intermittent optical stimulation of right S1fp for 10 min, 5 days/week for 4 weeks. New cortical representations of left S1fp appeared in non-stimulated mice at week 1, but not in stimulated mice (p=0.005). Evoked responses were comparable in both groups at week 4 (p=0.57). Homotopic FC between left and right S1fp regions was equally reduced in both groups (p=0.012) at week 1. However, in non-stimulated mice, behavioral performance and FC between right S1fp and left perilesional S1 cortex was significantly higher by 4 weeks compared to stimulated mice (p=0.009). Our results suggest that increased homotopic, contralesional activity in excitatory neurons negatively influences spontaneous recovery following ischemic stroke.
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The Role of Adult-Born Neurons in the Constantly Changing Olfactory Bulb Network
Malvaut, Sarah; Saghatelyan, Armen
2016-01-01
The adult mammalian brain is remarkably plastic and constantly undergoes structurofunctional modifications in response to environmental stimuli. In many regions plasticity is manifested by modifications in the efficacy of existing synaptic connections or synapse formation and elimination. In a few regions, however, plasticity is brought by the addition of new neurons that integrate into established neuronal networks. This type of neuronal plasticity is particularly prominent in the olfactory bulb (OB) where thousands of neuronal progenitors are produced on a daily basis in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) towards the OB. In the OB, these neuronal precursors differentiate into local interneurons, mature, and functionally integrate into the bulbar network by establishing output synapses with principal neurons. Despite continuous progress, it is still not well understood how normal functioning of the OB is preserved in the constantly remodelling bulbar network and what role adult-born neurons play in odor behaviour. In this review we will discuss different levels of morphofunctional plasticity effected by adult-born neurons and their functional role in the adult OB and also highlight the possibility that different subpopulations of adult-born cells may fulfill distinct functions in the OB neuronal network and odor behaviour. PMID:26839709
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Tornero, Daniel; Tsupykov, Oleg; Granmo, Marcus; Rodriguez, Cristina; Grønning-Hansen, Marita; Thelin, Jonas; Smozhanik, Ekaterina; Laterza, Cecilia; Wattananit, Somsak; Ge, Ruimin; Tatarishvili, Jemal; Grealish, Shane; Brüstle, Oliver; Skibo, Galina; Parmar, Malin; Schouenborg, Jens; Lindvall, Olle; Kokaia, Zaal
2017-03-01
Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Temperature and neuronal circuit function: compensation, tuning and tolerance.
Robertson, R Meldrum; Money, Tomas G A
2012-08-01
Temperature has widespread and diverse effects on different subcellular components of neuronal circuits making it difficult to predict precisely the overall influence on output. Increases in temperature generally increase the output rate in either an exponential or a linear manner. Circuits with a slow output tend to respond exponentially with relatively high Q(10)s, whereas those with faster outputs tend to respond in a linear fashion with relatively low temperature coefficients. Different attributes of the circuit output can be compensated by virtue of opposing processes with similar temperature coefficients. At the extremes of the temperature range, differences in the temperature coefficients of circuit mechanisms cannot be compensated and the circuit fails, often with a reversible loss of ion homeostasis. Prior experience of temperature extremes activates conserved processes of phenotypic plasticity that tune neuronal circuits to be better able to withstand the effects of temperature and to recover more rapidly from failure. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Functional Convergence of Neurons Generated in the Developing and Adult Hippocampus
Piatti, Verónica C; Morgenstern, Nicolás A; Zhao, Chunmei; van Praag, Henriette; Gage, Fred H; Schinder, Alejandro F
2006-01-01
The dentate gyrus of the hippocampus contains neural progenitor cells (NPCs) that generate neurons throughout life. Developing neurons of the adult hippocampus have been described in depth. However, little is known about their functional properties as they become fully mature dentate granule cells (DGCs). To compare mature DGCs generated during development and adulthood, NPCs were labeled at both time points using retroviruses expressing different fluorescent proteins. Sequential electrophysiological recordings from neighboring neurons of different ages were carried out to quantitatively study their major synaptic inputs: excitatory projections from the entorhinal cortex and inhibitory afferents from local interneurons. Our results show that DGCs generated in the developing and adult hippocampus display a remarkably similar afferent connectivity with regard to both glutamate and GABA, the major neurotransmitters. We also demonstrate that adult-born neurons can fire action potentials in response to an excitatory drive, exhibiting a firing behavior comparable to that of neurons generated during development. We propose that neurons born in the developing and adult hippocampus constitute a functionally homogeneous neuronal population. These observations are critical to understanding the role of adult neurogenesis in hippocampal function. PMID:17121455
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Stepien, Anna E; Tripodi, Marco; Arber, Silvia
2010-11-04
Movement is the behavioral output of neuronal activity in the spinal cord. Motor neurons are grouped into motor neuron pools, the functional units innervating individual muscles. Here we establish an anatomical rabies virus-based connectivity assay in early postnatal mice. We employ it to study the connectivity scheme of premotor neurons, the neuronal cohorts monosynaptically connected to motor neurons, unveiling three aspects of organization. First, motor neuron pools are connected to segmentally widely distributed yet stereotypic interneuron populations, differing for pools innervating functionally distinct muscles. Second, depending on subpopulation identity, interneurons take on local or segmentally distributed positions. Third, cholinergic partition cells involved in the regulation of motor neuron excitability segregate into ipsilaterally and bilaterally projecting populations, the latter exhibiting preferential connections to functionally equivalent motor neuron pools bilaterally. Our study visualizes the widespread yet precise nature of the connectivity matrix for premotor interneurons and reveals exquisite synaptic specificity for bilaterally projecting cholinergic partition cells. Copyright © 2010 Elsevier Inc. All rights reserved.
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Luccioli, Stefano; Ben-Jacob, Eshel; Barzilai, Ari; Bonifazi, Paolo; Torcini, Alessandro
2014-01-01
It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrate population activity. PMID:25255443
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Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z
2017-07-01
Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.
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Fletcher, Emily V.; Simon, Christian M.; Pagiazitis, John G.; Chalif, Joshua I.; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z.
2017-01-01
Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contribution of their synaptic partners to the disease process is largely unknown. Here, we show that in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission we observed a decrease in the motor neuron firing which could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Increasing neuronal activity pharmacologically by chronic exposure in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease. PMID:28504671
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GSK3 as a Sensor Determining Cell Fate in the Brain.
Cole, Adam R
2012-01-01
Glycogen synthase kinase 3 (GSK3) is an unusual serine/threonine kinase that controls many neuronal functions, including neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. It mediates these functions by phosphorylating a wide range of substrates involved in gene transcription, metabolism, apoptosis, cytoskeletal dynamics, signal transduction, lipid membrane dynamics, and trafficking, amongst others. This complicated list of diverse substrates generally follow a more simple pattern: substrates negatively regulated by GSK3-mediated phosphorylation favor a proliferative/survival state, while substrates positively regulated by GSK3 favor a more differentiated/functional state. Accordingly, GSK3 activity is higher in differentiated cells than undifferentiated cells and physiological (Wnt, growth factors) and pharmacological inhibitors of GSK3 promote the proliferative capacity of embryonic stem cells. In the brain, the level of GSK3 activity influences neural progenitor cell proliferation/differentiation in neuroplasticity and repair, as well as efficient neurotransmission in differentiated adult neurons. While defects in GSK3 activity are unlikely to be the primary cause of neurodegenerative diseases, therapeutic regulation of its activity to promote a proliferative/survival versus differentiated/mature functional environment in the brain could be a powerful strategy for treatment of neurodegenerative and other mental disorders.
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GSK3 as a Sensor Determining Cell Fate in the Brain
Cole, Adam R.
2012-01-01
Glycogen synthase kinase 3 (GSK3) is an unusual serine/threonine kinase that controls many neuronal functions, including neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. It mediates these functions by phosphorylating a wide range of substrates involved in gene transcription, metabolism, apoptosis, cytoskeletal dynamics, signal transduction, lipid membrane dynamics, and trafficking, amongst others. This complicated list of diverse substrates generally follow a more simple pattern: substrates negatively regulated by GSK3-mediated phosphorylation favor a proliferative/survival state, while substrates positively regulated by GSK3 favor a more differentiated/functional state. Accordingly, GSK3 activity is higher in differentiated cells than undifferentiated cells and physiological (Wnt, growth factors) and pharmacological inhibitors of GSK3 promote the proliferative capacity of embryonic stem cells. In the brain, the level of GSK3 activity influences neural progenitor cell proliferation/differentiation in neuroplasticity and repair, as well as efficient neurotransmission in differentiated adult neurons. While defects in GSK3 activity are unlikely to be the primary cause of neurodegenerative diseases, therapeutic regulation of its activity to promote a proliferative/survival versus differentiated/mature functional environment in the brain could be a powerful strategy for treatment of neurodegenerative and other mental disorders. PMID:22363258
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α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons.
Froula, Jessica M; Henderson, Benjamin W; Gonzalez, Jose Carlos; Vaden, Jada H; Mclean, John W; Wu, Yumei; Banumurthy, Gokulakrishna; Overstreet-Wadiche, Linda; Herskowitz, Jeremy H; Volpicelli-Daley, Laura A
2018-05-01
Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca 2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.
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Variation in motor output and motor performance in a centrally generated motor pattern
Norris, Brian J.; Doloc-Mihu, Anca; Calabrese, Ronald L.
2014-01-01
Central pattern generators (CPGs) produce motor patterns that ultimately drive motor outputs. We studied how functional motor performance is achieved, specifically, whether the variation seen in motor patterns is reflected in motor performance and whether fictive motor patterns differ from those in vivo. We used the leech heartbeat system in which a bilaterally symmetrical CPG coordinates segmental heart motor neurons and two segmented heart tubes into two mutually exclusive coordination modes: rear-to-front peristaltic on one side and nearly synchronous on the other, with regular side-to-side switches. We assessed individual variability of the motor pattern and the beat pattern in vivo. To quantify the beat pattern we imaged intact adults. To quantify the phase relations between motor neurons and heart constrictions we recorded extracellularly from two heart motor neurons and movement from the corresponding heart segments in minimally dissected leeches. Variation in the motor pattern was reflected in motor performance only in the peristaltic mode, where larger intersegmental phase differences in the motor neurons resulted in larger phase differences between heart constrictions. Fictive motor patterns differed from those in vivo only in the synchronous mode, where intersegmental phase differences in vivo had a larger front-to-rear bias and were more constrained. Additionally, load-influenced constriction timing might explain the amplification of the phase differences between heart segments in the peristaltic mode and the higher variability in motor output due to body shape assumed in this soft-bodied animal. The motor pattern determines the beat pattern, peristaltic or synchronous, but heart mechanics influence the phase relations achieved. PMID:24717348
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Vijayakrishnan, Niranjana; Phillips, Scott E.; Broadie, Kendal
2010-01-01
Drosophila temperature-sensitive rolling blackout (rbots) mutants display a total block of endocytosis in non-neuronal cells and a weaker, partial defect at neuronal synapses. RBO is an integral plasma membrane protein and is predicted to be a serine esterase. To determine if lipase activity is required for RBO function, we mutated the catalytic serine 358 to alanine in the G-X-S-X-G active site, and assayed genomic rescue of rbo mutant non-neuronal and neuronal phenotypes. The rboS358A mutant is unable to rescue rbo null 100% embryonic lethality, indicating that the lipase-domain is critical for RBO essential function. Likewise, the rboS358A mutant cannot provide any rescue of endocytic blockade in rbots Garland cells, demonstrating that the lipase-domain is indispensable for non-neuronal endocytosis. In contrast, rbots conditional paralysis, synaptic transmission block and synapse endocytic defects are all fully rescued by the rboS358A mutant, showing that the RBO lipase-domain is dispensable in neuronal contexts. We identified a synthetic lethal interaction between rbots and the well-characterized dynamin GTPase conditional shibire (shits1) mutant. In both non-neuronal cells and neuronal synapses, shits1;rbots phenocopies shits1 endocytic defects, indicating that dynamin and RBO act in the same pathway, with dynamin functioning upstream of RBO. We conclude that RBO possesses both lipase-domain dependent and scaffolding functions with differential requirements in non-neuronal versus neuronal endocytosis mechanisms downstream of dynamin GTPase activity. PMID:21029287
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Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J
2012-06-20
The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.
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Vasculo-Neuronal Coupling: Retrograde Vascular Communication to Brain Neurons.
Kim, Ki Jung; Ramiro Diaz, Juan; Iddings, Jennifer A; Filosa, Jessica A
2016-12-14
Continuous cerebral blood flow is essential for neuronal survival, but whether vascular tone influences resting neuronal function is not known. Using a multidisciplinary approach in both rat and mice brain slices, we determined whether flow/pressure-evoked increases or decreases in parenchymal arteriole vascular tone, which result in arteriole constriction and dilation, respectively, altered resting cortical pyramidal neuron activity. We present evidence for intercellular communication in the brain involving a flow of information from vessel to astrocyte to neuron, a direction opposite to that of classic neurovascular coupling and referred to here as vasculo-neuronal coupling (VNC). Flow/pressure increases within parenchymal arterioles increased vascular tone and simultaneously decreased resting pyramidal neuron firing activity. On the other hand, flow/pressure decreases evoke parenchymal arteriole dilation and increased resting pyramidal neuron firing activity. In GLAST-CreERT2; R26-lsl-GCaMP3 mice, we demonstrate that increased parenchymal arteriole tone significantly increased intracellular calcium in perivascular astrocyte processes, the onset of astrocyte calcium changes preceded the inhibition of cortical pyramidal neuronal firing activity. During increases in parenchymal arteriole tone, the pyramidal neuron response was unaffected by blockers of nitric oxide, GABA A , glutamate, or ecto-ATPase. However, VNC was abrogated by TRPV4 channel, GABA B , as well as an adenosine A 1 receptor blocker. Differently to pyramidal neuron responses, increases in flow/pressure within parenchymal arterioles increased the firing activity of a subtype of interneuron. Together, these data suggest that VNC is a complex constitutive active process that enables neurons to efficiently adjust their resting activity according to brain perfusion levels, thus safeguarding cellular homeostasis by preventing mismatches between energy supply and demand. We present evidence for vessel-to-neuron communication in the brain slice defined here as vasculo-neuronal coupling. We showed that, in response to increases in parenchymal arteriole tone, astrocyte intracellular Ca 2+ increased and cortical neuronal activity decreased. On the other hand, decreasing parenchymal arteriole tone increased resting cortical pyramidal neuron activity. Vasculo-neuronal coupling was partly mediated by TRPV4 channels as genetic ablation, or pharmacological blockade impaired increased flow/pressure-evoked neuronal inhibition. Increased flow/pressure-evoked neuronal inhibition was blocked in the presence of adenosine A1 receptor and GABA B receptor blockade. Results provide evidence for the concept of vasculo-neuronal coupling and highlight the importance of understanding the interplay between basal CBF and resting neuronal activity. Copyright © 2016 the authors 0270-6474/16/3612624-16$15.00/0.
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Forecasting the prognosis of choroidal melanoma with an artificial neural network.
Kaiserman, Igor; Rosner, Mordechai; Pe'er, Jacob
2005-09-01
To develop an artificial neural network (ANN) that will forecast the 5-year mortality from choroidal melanoma. Retrospective, comparative, observational cohort study. One hundred fifty-three eyes of 153 consecutive patients with choroidal melanoma (age, 58.4+/-14.6 years) who were treated with ruthenium 106 brachytherapy between 1988 and 1998 at the Department of Ophthalmology, Hadassah University Hospital, Jerusalem, Israel. Patients were observed clinically and ultrasonographically (A- and B-mode standardized ultrasonography). Metastatic screening included liver function tests and liver imaging. Backpropagation ANNs composed of 3 or 4 layers of neurons with various types of transfer functions and training protocols were assessed for their ability to predict the 5-year mortality. The ANNs were trained on 77 randomly selected patients and tested on a different set of 76 patients. Artificial neural networks were compared based on their sensitivity, specificity, forecasting accuracy, area under the receiver operating curves, and likelihood ratios (LRs). The best ANN was compared with the results of logistic regression and the performance of an ocular oncologist. The ability of the ANNs to forecast the 5-year mortality from choroidal melanoma. Thirty-one patients died during the follow-up period of metastatic choroidal melanoma. The best ANN (one hidden layer of 16 neurons) had 84% forecasting accuracy and an LR of 31.5. The number of hidden neurons significantly influenced the ANNs' performance (P<0.001). The performance of the ANNs was not significantly influenced by the training protocol, the number of hidden layers, or the type of transfer function. In comparison, logistic regression reached 86% forecasting accuracy, with a very low LR (0.8), whereas the human expert forecasting ability was <70% (LR, 1.85). Artificial neural networks can be used for forecasting the prognosis of choroidal melanoma and may support decision-making in treating this malignancy.
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Oligodendrocyte-Neuron Interactions: Impact on Myelination and Brain Function.
Shimizu, Takeshi; Osanai, Yasuyuki; Ikenaka, Kazuhiro
2018-01-01
In the past, glial cells were considered to be 'glue' cells whose primary role was thought to be merely filling gaps in neural circuits. However, a growing number of reports have indicated the role of glial cells in higher brain function through their interaction with neurons. Myelin was originally thought to be just a sheath structure surrounding neuronal axons, but recently it has been shown that myelin exerts effects on the conduction velocity of neuronal axons even after myelin formation. Therefore, the investigation of glial cell properties and the neuron-glial interactions is important for understanding higher brain function. Moreover, since there are many neurological disorders caused by glial abnormalities, further understanding of glial cell-related diseases and the development of effective therapeutic strategies are warranted. In this review, we focused on oligodendrocyte-neuron interactions, with particular attention on (1) axonal signals underlying oligodendrocyte differentiation and myelination, (2) neuronal activity-dependent myelination and (3) the effects of myelination on higher brain function.
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Harwell, Corey C; Parker, Philip R L; Gee, Steven M; Okada, Ami; McConnell, Susan K; Kreitzer, Anatol C; Kriegstein, Arnold R
2012-03-22
The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. Copyright © 2012 Elsevier Inc. All rights reserved.
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Barton, Alan J; Valdés, Julio J; Orchard, Robert
2009-01-01
Classical neural networks are composed of neurons whose nature is determined by a certain function (the neuron model), usually pre-specified. In this paper, a type of neural network (NN-GP) is presented in which: (i) each neuron may have its own neuron model in the form of a general function, (ii) any layout (i.e network interconnection) is possible, and (iii) no bias nodes or weights are associated to the connections, neurons or layers. The general functions associated to a neuron are learned by searching a function space. They are not provided a priori, but are rather built as part of an Evolutionary Computation process based on Genetic Programming. The resulting network solutions are evaluated based on a fitness measure, which may, for example, be based on classification or regression errors. Two real-world examples are presented to illustrate the promising behaviour on classification problems via construction of a low-dimensional representation of a high-dimensional parameter space associated to the set of all network solutions.
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Unexpected Variation in Neuroanatomy among Diverse Nematode Species
Han, Ziduan; Boas, Stephanie; Schroeder, Nathan E.
2016-01-01
Nematodes are considered excellent models for understanding fundamental aspects of neuron function. However, nematodes are less frequently used as models for examining the evolution of nervous systems. While the habitats and behaviors of nematodes are diverse, the neuroanatomy of nematodes is often considered highly conserved. A small number of nematode species greatly influences our understanding of nematode neurobiology. The free-living species Caenorhabditis elegans and, to a lesser extent, the mammalian gastrointestinal parasite Ascaris suum are, historically, the primary sources of knowledge regarding nematode neurobiology. Despite differences in size and habitat, C. elegans and A. suum share a surprisingly similar neuroanatomy. Here, we examined species across several clades in the phylum Nematoda and show that there is a surprising degree of neuroanatomical variation both within and among nematode clades when compared to C. elegans and Ascaris. We found variation in the numbers of neurons in the ventral nerve cord and dye-filling pattern of sensory neurons. For example, we found that Pristionchus pacificus, a bacterial feeding species used for comparative developmental research had 20% fewer ventral cord neurons compared to C. elegans. Steinernema carpocapsae, an insect-parasitic nematode capable of jumping behavior, had 40% more ventral cord neurons than C. elegans. Interestingly, the non-jumping congeneric nematode, S. glaseri showed an identical number of ventral cord neurons as S. carpocapsae. There was also variability in the timing of neurodevelopment of the ventral cord with two of five species that hatch as second-stage juveniles showing delayed neurodevelopment. We also found unexpected variation in the dye-filling of sensory neurons among examined species. Again, sensory neuron dye-filling pattern did not strictly correlate with phylogeny. Our results demonstrate that variation in nematode neuroanatomy is more prevalent than previously assumed and recommend this diverse phylum for future “evo-devo-neuro” studies. PMID:26778973
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Development of raphe serotonin neurons from specification to guidance.
Kiyasova, Vera; Gaspar, Patricia
2011-11-01
The main features of the development of the serotonin (5-HT) raphe neurons have been known for many years but more recent molecular studies, using mouse genetics, have since unveiled several intriguing aspects of the specification of the raphe serotonergic system. These studies indicated that, although all 5-HT neurons in the raphe follow the same general program for their specification, there are also clear regional differences in the way that these neurons are specified and are guided towards different brain targets. Here we overview recent progress made in the understanding of the developmental programming of serotonergic neurons in the mouse raphe, emphasizing data showing how heterogeneous subsets of 5-HT neurons may be generated. Serotonergic progenitors are produced in the brainstem in different rhombomeres under the influence of a set of secreted factors, sonic hedgehog and fibroblast growth factors, which determine their position in the neural tube. Two main transcriptional gene networks are involved in the specification of 5-HT identity, with Lmx1b and Pet1 transcription factors as main players. A differential requirement for Pet1 was, however, revealed, which underlies an anatomical and functional diversity. Transcriptional programs controlling 5-HT identity could also impact axon guidance mechanisms directing 5-HT neurons to their targets. Although no direct links have yet been established, a large set of molecular determinants have already been shown to be involved in the growth, axon guidance and targeting of 5-HT raphe neurons, particularly within the forebrain. Alterations in the molecular mechanisms involved in 5-HT development are likely to have significant roles in mood disease predisposition. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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Spatial and Feature-Based Attention in a Layered Cortical Microcircuit Model
Wagatsuma, Nobuhiko; Potjans, Tobias C.; Diesmann, Markus; Sakai, Ko; Fukai, Tomoki
2013-01-01
Directing attention to the spatial location or the distinguishing feature of a visual object modulates neuronal responses in the visual cortex and the stimulus discriminability of subjects. However, the spatial and feature-based modes of attention differently influence visual processing by changing the tuning properties of neurons. Intriguingly, neurons' tuning curves are modulated similarly across different visual areas under both these modes of attention. Here, we explored the mechanism underlying the effects of these two modes of visual attention on the orientation selectivity of visual cortical neurons. To do this, we developed a layered microcircuit model. This model describes multiple orientation-specific microcircuits sharing their receptive fields and consisting of layers 2/3, 4, 5, and 6. These microcircuits represent a functional grouping of cortical neurons and mutually interact via lateral inhibition and excitatory connections between groups with similar selectivity. The individual microcircuits receive bottom-up visual stimuli and top-down attention in different layers. A crucial assumption of the model is that feature-based attention activates orientation-specific microcircuits for the relevant feature selectively, whereas spatial attention activates all microcircuits homogeneously, irrespective of their orientation selectivity. Consequently, our model simultaneously accounts for the multiplicative scaling of neuronal responses in spatial attention and the additive modulations of orientation tuning curves in feature-based attention, which have been observed widely in various visual cortical areas. Simulations of the model predict contrasting differences between excitatory and inhibitory neurons in the two modes of attentional modulations. Furthermore, the model replicates the modulation of the psychophysical discriminability of visual stimuli in the presence of external noise. Our layered model with a biologically suggested laminar structure describes the basic circuit mechanism underlying the attention-mode specific modulations of neuronal responses and visual perception. PMID:24324628
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Yang, Dongren; Kania-Korwel, Izabela; Ghogha, Atefeh; Chen, Hao; Stamou, Marianna; Bose, Diptiman D.; Pessah, Isaac N.; Lehmler, Hans-Joachim; Lein, Pamela J.
2014-01-01
We recently demonstrated that polychlorinated biphenyl (PCB) congeners with multiple ortho chlorine substitutions sensitize ryanodine receptors (RyRs), and this activity promotes Ca2+-dependent dendritic growth in cultured neurons. Many ortho-substituted congeners display axial chirality, and we previously reported that the chiral congener PCB 136 (2,2′,3,3′,6,6′-hexachlorobiphenyl) atropselectively sensitizes RyRs. Here, we test the hypothesis that PCB 136 atropisomers differentially alter dendritic growth and other parameters of neuronal connectivity influenced by RyR activity. (−)-PCB 136, which potently sensitizes RyRs, enhances dendritic growth in primary cultures of rat hippocampal neurons, whereas (+)-PCB 136, which lacks RyR activity, has no effect on dendritic growth. The dendrite-promoting activity of (−)-PCB 136 is observed at concentrations ranging from 0.1 to 100nM and is blocked by pharmacologic RyR antagonism. Neither atropisomer alters axonal growth or cell viability. Quantification of PCB 136 atropisomers in hippocampal cultures indicates that atropselective effects on dendritic growth are not due to differential partitioning of atropisomers into cultured cells. Imaging of hippocampal neurons loaded with Ca2+-sensitive dye demonstrates that (−)-PCB 136 but not (+)-PCB 136 increases the frequency of spontaneous Ca2+ oscillations. Similarly, (−)-PCB 136 but not (+)-PCB 136 increases the activity of hippocampal neurons plated on microelectrode arrays. These data support the hypothesis that atropselective effects on RyR activity translate into atropselective effects of PCB 136 atropisomers on neuronal connectivity, and suggest that the variable atropisomeric enrichment of chiral PCBs observed in the human population may be a significant determinant of individual susceptibility for adverse neurodevelopmental outcomes following PCB exposure. PMID:24385416
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Coding and Decoding with Adapting Neurons: A Population Approach to the Peri-Stimulus Time Histogram
Naud, Richard; Gerstner, Wulfram
2012-01-01
The response of a neuron to a time-dependent stimulus, as measured in a Peri-Stimulus-Time-Histogram (PSTH), exhibits an intricate temporal structure that reflects potential temporal coding principles. Here we analyze the encoding and decoding of PSTHs for spiking neurons with arbitrary refractoriness and adaptation. As a modeling framework, we use the spike response model, also known as the generalized linear neuron model. Because of refractoriness, the effect of the most recent spike on the spiking probability a few milliseconds later is very strong. The influence of the last spike needs therefore to be described with high precision, while the rest of the neuronal spiking history merely introduces an average self-inhibition or adaptation that depends on the expected number of past spikes but not on the exact spike timings. Based on these insights, we derive a ‘quasi-renewal equation’ which is shown to yield an excellent description of the firing rate of adapting neurons. We explore the domain of validity of the quasi-renewal equation and compare it with other rate equations for populations of spiking neurons. The problem of decoding the stimulus from the population response (or PSTH) is addressed analogously. We find that for small levels of activity and weak adaptation, a simple accumulator of the past activity is sufficient to decode the original input, but when refractory effects become large decoding becomes a non-linear function of the past activity. The results presented here can be applied to the mean-field analysis of coupled neuron networks, but also to arbitrary point processes with negative self-interaction. PMID:23055914
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ALS-related misfolded protein management in motor neurons and muscle cells.
Galbiati, Mariarita; Crippa, Valeria; Rusmini, Paola; Cristofani, Riccardo; Cicardi, Maria Elena; Giorgetti, Elisa; Onesto, Elisa; Messi, Elio; Poletti, Angelo
2014-12-01
Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Developmental time windows for axon growth influence neuronal network topology.
Lim, Sol; Kaiser, Marcus
2015-04-01
Early brain connectivity development consists of multiple stages: birth of neurons, their migration and the subsequent growth of axons and dendrites. Each stage occurs within a certain period of time depending on types of neurons and cortical layers. Forming synapses between neurons either by growing axons starting at similar times for all neurons (much-overlapped time windows) or at different time points (less-overlapped) may affect the topological and spatial properties of neuronal networks. Here, we explore the extreme cases of axon formation during early development, either starting at the same time for all neurons (parallel, i.e., maximally overlapped time windows) or occurring for each neuron separately one neuron after another (serial, i.e., no overlaps in time windows). For both cases, the number of potential and established synapses remained comparable. Topological and spatial properties, however, differed: Neurons that started axon growth early on in serial growth achieved higher out-degrees, higher local efficiency and longer axon lengths while neurons demonstrated more homogeneous connectivity patterns for parallel growth. Second, connection probability decreased more rapidly with distance between neurons for parallel growth than for serial growth. Third, bidirectional connections were more numerous for parallel growth. Finally, we tested our predictions with C. elegans data. Together, this indicates that time windows for axon growth influence the topological and spatial properties of neuronal networks opening up the possibility to a posteriori estimate developmental mechanisms based on network properties of a developed network.
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Chemically Functionalized Carbon Nanotubes as Substrates for Neuronal Growth
Hu, Hui; Ni, Yingchun; Montana, Vedrana; Haddon, Robert C.; Parpura, Vladimir
2009-01-01
We report the use of chemically modified carbon nanotubes as a substrate for cultured neurons. The morphological features of neurons that directly reflect their potential capability in synaptic transmission are characterized. The chemical properties of carbon nanotubes are systematically varied by attaching different functional groups that confer known characteristics to the substrate. By manipulating the charge carried by functionalized carbon nanotubes we are able to control the outgrowth and branching pattern of neuronal processes. PMID:21394241
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Allaman, Igor; Gavillet, Mathilde; Bélanger, Mireille; Laroche, Thierry; Viertl, David; Lashuel, Hilal A; Magistretti, Pierre J
2010-03-03
Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.
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Newcomb, James M.; Sakurai, Akira; Lillvis, Joshua L.; Gunaratne, Charuni A.; Katz, Paul S.
2012-01-01
How neural circuit evolution relates to behavioral evolution is not well understood. Here the relationship between neural circuits and behavior is explored with respect to the swimming behaviors of the Nudipleura (Mollusca, Gastropoda, Opithobranchia). Nudipleura is a diverse monophyletic clade of sea slugs among which only a small percentage of species can swim. Swimming falls into a limited number of categories, the most prevalent of which are rhythmic left–right body flexions (LR) and rhythmic dorsal–ventral body flexions (DV). The phylogenetic distribution of these behaviors suggests a high degree of homoplasy. The central pattern generator (CPG) underlying DV swimming has been well characterized in Tritonia diomedea and in Pleurobranchaea californica. The CPG for LR swimming has been elucidated in Melibe leonina and Dendronotus iris, which are more closely related. The CPGs for the categorically distinct DV and LR swimming behaviors consist of nonoverlapping sets of homologous identified neurons, whereas the categorically similar behaviors share some homologous identified neurons, although the exact composition of neurons and synapses in the neural circuits differ. The roles played by homologous identified neurons in categorically distinct behaviors differ. However, homologous identified neurons also play different roles even in the swim CPGs of the two LR swimming species. Individual neurons can be multifunctional within a species. Some of those functions are shared across species, whereas others are not. The pattern of use and reuse of homologous neurons in various forms of swimming and other behaviors further demonstrates that the composition of neural circuits influences the evolution of behaviors. PMID:22723353
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Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture.
Mauceri, Daniela; Hagenston, Anna M; Schramm, Kathrin; Weiss, Ursula; Bading, Hilmar
2015-09-18
Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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Kojima, Satoshi; Doupe, Allison J.
2008-01-01
Acoustic experience critically influences auditory cortical development as well as emergence of highly selective auditory neurons in the songbird sensorimotor circuit. In adult zebra finches, these “song-selective” neurons respond better to the bird's own song (BOS) than to songs of other conspecifics. Birds learn their songs by memorizing a tutor's song and then matching auditory feedback of their voice to the tutor song memory. Song-selective neurons in the pallial-basal ganglia circuit called the anterior forebrain pathway (AFP) reflect the development of BOS. However, during learning, they also respond strongly to tutor song and are compromised in their adult selectivity when birds are prevented from matching BOS to tutor, suggesting that selectivity depends on tutor song learning as well as sensorimotor matching of BOS feedback to the tutor song memory. We examined the contribution of sensory learning of tutor song to song selectivity by recording from AFP neurons in birds reared without exposure to adult conspecifics. We found that AFP neurons in these “isolate” birds had highly tuned responses to isolate BOS. The selectivity was as high, and in the striato-pallidal nucleus Area X, even higher than that in normal birds, due to abnormally weak responsiveness to conspecific song. These results demonstrate that sensory learning of tutor song is not necessary for BOS tuning of AFP neurons. Because isolate birds develop their song via sensorimotor learning, our data further illustrate the importance of individual sensorimotor learning for song selectivity and provide insight into possible functions of song-selective neurons. PMID:17625059
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Toharia, Pablo; Robles, Oscar D; Fernaud-Espinosa, Isabel; Makarova, Julia; Galindo, Sergio E; Rodriguez, Angel; Pastor, Luis; Herreras, Oscar; DeFelipe, Javier; Benavides-Piccione, Ruth
2015-01-01
This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron.
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Toharia, Pablo; Robles, Oscar D.; Fernaud-Espinosa, Isabel; Makarova, Julia; Galindo, Sergio E.; Rodriguez, Angel; Pastor, Luis; Herreras, Oscar; DeFelipe, Javier; Benavides-Piccione, Ruth
2016-01-01
This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron. PMID:26778972
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Cholinergic modulation of dopaminergic neurons in the mouse olfactory bulb.
Pignatelli, Angela; Belluzzi, Ottorino
2008-04-01
Considerable evidence exists for an extrinsic cholinergic influence in the maturation and function of the main olfactory bulb. In this study, we addressed the muscarinic modulation of dopaminergic neurons in this structure. We used different patch-clamp techniques to characterize the diverse roles of muscarinic agonists on identified dopaminergic neurons in a transgenic animal model expressing a reporter protein (green fluorescent protein) under the tyrosine hydroxylase promoter. Bath application of acetylcholine (1 mM) in slices and in enzymatically dissociated cells reduced the spontaneous firing of dopaminergic neurons recorded in cell-attached mode. In whole-cell configuration no effect of the agonist was observed, unless using the perforated patch technique, thus suggesting the involvement of a diffusible second messenger. The effect was mediated by metabotropic receptors as it was blocked by atropine and mimicked by the m2 agonist oxotremorine (10 muM). The reduction of periglomerular cell firing by muscarinic activation results from a membrane-potential hyperpolarization caused by activation of a potassium conductance. This modulation of dopaminergic interneurons may be important in the processing of sensory information and may be relevant to understand the mechanisms underlying the olfactory dysfunctions occurring in neurodegenerative diseases affecting the dopaminergic and/or cholinergic systems.
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Sundberg, Kristy A.; Mitchell, Jude F.; Gawne, Timothy J.
2012-01-01
Many previous studies have demonstrated that changes in selective attention can alter the response magnitude of visual cortical neurons, but there has been little evidence for attention affecting response latency. Small latency differences, though hard to detect, can potentially be of functional importance, and may also give insight into the mechanisms of neuronal computation. We therefore reexamined the effect of attention on the response latency of both single units and the local field potential (LFP) in primate visual cortical area V4. We find that attention does produce small (1–2 ms) but significant reductions in the latency of both the spiking and LFP responses. Though attention, like contrast elevation, reduces response latencies, we find that the two have different effects on the magnitude of the LFP. Contrast elevations increase and attention decreases the magnitude of the initial deflection of the stimulus-evoked LFP. Both contrast elevation and attention increase the magnitude of the spiking response. We speculate that latencies may be reduced at higher contrast because stronger stimulus inputs drive neurons more rapidly to spiking threshold, while attention may reduce latencies by placing neurons in a more depolarized state closer to threshold before stimulus onset. PMID:23136440
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Jeong, Jae-Kyo; Lee, Ju-Hee; Moon, Ji-Hong; Lee, You-Jin; Park, Sang-Youel
2014-11-01
Activation of β-catenin in neurons regulates mitochondrial function and protects against protein misfolding disorders, including Alzheimer's disease and Huntington's disease. Melatonin, a natural secretory product of the pineal gland, exerts neuroprotective effects through the activation of β-catenin. In this study, melatonin increased β-catenin protein expression and activation in human neuroblastoma cell lines SH-SY5Y cells. Melatonin also inhibited PrP (106-126)-induced neurotoxicity and the inhibition attenuated by treatment of β-catenin inhibitor ICG-001. Activation of β-catenin blocked PrP (106-126)-mediated downregulation of anti-apoptotic protein survivin and Bcl-2. Reduction of mitochondrial membrane potential, translocation of Bax, and cytochrome c release which induced by PrP (106-126) treatment were inhibited by β-catenin activation, which contributed to prevented PrP (106-126)-induced neuronal cell death. In conclusion, β-catenin activation by melatonin prevented PrP (106-126)-induced neuronal cell death through regulating anti-apoptotic proteins and mitochondrial pathways. These results also suggest the therapeutic value of Wnt/β-catenin signaling in prion-related disorders as influenced by melatonin. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Noise-enhanced coupling between two oscillators with long-term plasticity
NASA Astrophysics Data System (ADS)
Lücken, Leonhard; Popovych, Oleksandr V.; Tass, Peter A.; Yanchuk, Serhiy
2016-03-01
Spike timing-dependent plasticity is a fundamental adaptation mechanism of the nervous system. It induces structural changes of synaptic connectivity by regulation of coupling strengths between individual cells depending on their spiking behavior. As a biophysical process its functioning is constantly subjected to natural fluctuations. We study theoretically the influence of noise on a microscopic level by considering only two coupled neurons. Adopting a phase description for the neurons we derive a two-dimensional system which describes the averaged dynamics of the coupling strengths. We show that a multistability of several coupling configurations is possible, where some configurations are not found in systems without noise. Intriguingly, it is possible that a strong bidirectional coupling, which is not present in the noise-free situation, can be stabilized by the noise. This means that increased noise, which is normally expected to desynchronize the neurons, can be the reason for an antagonistic response of the system, which organizes itself into a state of stronger coupling and counteracts the impact of noise. This mechanism, as well as a high potential for multistability, is also demonstrated numerically for a coupled pair of Hodgkin-Huxley neurons.
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Daigle, Tanya L; Caron, Marc G
2012-08-15
Although G-protein-coupled receptor kinase 2 (GRK2) is the most widely studied member of a family of kinases that has been shown to exert powerful influences on a variety of G-protein-coupled receptors, its role in the brain remains largely unknown. Here we report the localization of GRK2 in the mouse brain and generate novel conditional knock-out (KO) mice to assess the physiological importance of this kinase in cholinergic neurons. Mice with the selective deletion of GRK2 in this cell population (ChAT(IRES-cre)Grk2(f/f) KO mice) exhibit reduced behavioral responsiveness to challenge with oxotremorine-M (Oxo-M), a nonselective muscarinic acetylcholine receptor agonist. Specifically, Oxo-M-induced hypothermia, hypolocomotion, and salivation were markedly reduced in these animals, while analgesic responses were unaltered. In contrast, we found that GRK2 deficiency in cholinergic neurons does not alter cocaine-induced psychomotor activation, behavioral sensitization, or conditioned place preference. These results demonstrate that the elimination of GRK2 in cholinergic neurons reduces sensitivity to select muscarinic-mediated behaviors, while dopaminergic effects remain intact and further suggests that GRK2 may selectively impair muscarinic acetylcholine receptor-mediated function in vivo.
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Optogenetics and pharmacogenetics: principles and applications.
Jiang, Jingwei; Cui, Huxing; Rahmouni, Kamal
2017-12-01
Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin, and archaerhodopsins) from the bacteria have made it possible to use light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G protein-coupled receptors, which can be activated by otherwise inert drug-like small molecules such as the designer receptors exclusively activated by designer drug, a form of chemogenetics. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience that allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. These novel toolboxes are enabling significant advances in deciphering how the nervous system works and its influence on various physiological processes in health and disease. Here, we discuss the fundamental elements of optogenetics and chemogenetics approaches and some of the applications that yielded significant advances in various areas of neuroscience and beyond. Copyright © 2017 the American Physiological Society.
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Schroeter, Aileen; Grandjean, Joanes; Schlegel, Felix; Saab, Bechara J; Rudin, Markus
2017-07-01
Previously, we reported widespread bilateral increases in stimulus-evoked functional magnetic resonance imaging signals in mouse brain to unilateral sensory paw stimulation. We attributed the pattern to arousal-related cardiovascular changes overruling cerebral autoregulation thereby masking specific signal changes elicited by local neuronal activity. To rule out the possibility that interhemispheric neuronal communication might contribute to bilateral functional magnetic resonance imaging responses, we compared stimulus-evoked functional magnetic resonance imaging responses to unilateral hindpaw stimulation in acallosal I/LnJ, C57BL/6, and BALB/c mice. We found bilateral blood-oxygenation-level dependent signal changes in all three strains, ruling out a dominant contribution of transcallosal communication as reason for bilaterality. Analysis of functional connectivity derived from resting-state functional magnetic resonance imaging, revealed that bilateral cortical functional connectivity is largely abolished in I/LnJ animals. Cortical functional connectivity in all strains correlated with structural connectivity in corpus callosum as revealed by diffusion tensor imaging. Given the profound influence of systemic hemodynamics on stimulus-evoked functional magnetic resonance imaging outcomes, we evaluated whether functional connectivity data might be affected by cerebrovascular parameters, i.e. baseline cerebral blood volume, vascular reactivity, and reserve. We found that effects of cerebral hemodynamics on functional connectivity are largely outweighed by dominating contributions of structural connectivity. In contrast, contributions of transcallosal interhemispheric communication to the occurrence of ipsilateral functional magnetic resonance imaging response of equal amplitude to unilateral stimuli seem negligible.
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Effects of cerebrolysin on motor-neuron-like NSC-34 cells
DOE Office of Scientific and Technical Information (OSTI.GOV)
Keilhoff, Gerburg, E-mail: Gerburg.keilhoff@med.ovgu.de; Lucas, Benjamin; Pinkernelle, Josephine
Although the peripheral nervous system is capable of regeneration, this capability is limited. As a potential means of augmenting nerve regeneration, the effects of cerebrolysin (CL) – a proteolytic peptide fraction – were tested in vitro on the motor-neuron-like NSC-34 cell line and organotypic spinal cord cultures. Therefore, NSC-34 cells were subjected to mechanical stress by changing media and metabolic stress by oxygen glucose deprivation. Afterwards, cell survival/proliferation using MTT and BrdU-labeling (FACS) and neurite sprouting using ImageJ analysis were evaluated. Calpain-1, Src and α-spectrin protein expression were analyzed by Western blot. In organotypic cultures, the effect of CL onmore » motor neuron survival and neurite sprouting was tested by immunohistochemistry. CL had a temporary anti-proliferative but initially neuroprotective effect on OGD-stressed NSC-34 cells. High-dosed or repeatedly applied CL was deleterious for cell survival. CL amplified neurite reconstruction to limited extent, affected calpain-1 protein expression and influenced calpain-mediated spectrin cleavage as a function of Src expression. In organotypic spinal cord slice cultures, CL was not able to support motor neuron survival/neurite sprouting. Moreover, it hampered astroglia and microglia activities. The data suggest that CL may have only isolated positive effects on injured spinal motor neurons. High-dosed or accumulated CL seemed to have adverse effects in treatment of spinal cord injury. Further experiments are required to optimize the conditions for a safe clinical administration of CL in spinal cord injuries. - Highlights: • Cerebrolysin (CL) is anti-proliferative but initially neuroprotective in OGD-stressed NSC-34 cells. • CL amplified neurite reconstruction of NSC-34 cells. • CL affected calpain-1 expression and calpain-mediated spectrin cleavage as function of Src expression. • In organotypic spinal cord cultures, CL hampered motor neuron survival and glia activity. • Findings pose a contraindication for unchallenged use of CL in spinal cord injuries.« less
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Following the crowd: Brain Substrates of Long-Term Memory Conformity
Edelson, Micah; Sharot, Tali; Dolan, Raymond J; Dudai, Yadin
2012-01-01
Human memory is strikingly susceptible to social influences, yet we know little about the underlying mechanisms. We examined how socially induced memory errors are generated in the brain by studying the memory of individuals exposed to recollections of others. Participants exhibited a strong tendency to conform to erroneous recollections of the group, producing both long-lasting and temporary errors, even when their initial memory was strong and accurate. Functional brain imaging revealed that social influence modified the neuronal representation of memory. Specifically, a particular brain signature of enhanced amygdala activity and enhanced amygdala-hippocampus connectivity predicted long-lasting, but not temporary memory alterations. Our findings reveal how social manipulation can alter memory and extend the known functions of the amygdala to encompass socially-mediated memory distortions. PMID:21719681
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NASA Astrophysics Data System (ADS)
Zhou, Zhaoli
Cell-surface interaction is crucial in many cellular functions such as movement, growth, differentiation, proliferation and survival. In the present work, we have developed several strategies to design and prepare synthetic polymeric materials with selected cues to control cell attachment. To promote neuronal cell adhesion on the surfaces, biocompatible, non-adhesive PEG-based materials were modified with neurotransmitter acetylcholine functionalities to produce hydrogels with a range of porous structures, swollen states, and mechanical strengths. Mice hippocampal cells cultured on the hydrogels showed differences in number, length of processes and exhibited different survival rates, thereby highlighting the importance of chemical composition and structure in biomaterials. Similar strategies were used to prepare polymer brushes to assess how topographical cues influence neuronal cell behaviors. The brushes were prepared using the "grown from" method through surface-initiated atom transfer radical polymerization (SI-ATRP) reactions and further patterned via UV photolithography. Protein absorption tests and hippocampal neuronal cell culture of the brush patterns showed that both protein and neuronal cells can adhere to the patterns and therefore can be guided by the patterns at certain length scales. We also prepared functional polymers to discourage attachment of undesirable cells on the surfaces. For example, we synthesized PEG-perfluorinated alkyl amphiphilic surfactants to modify polystyrene-block-poly(ethylene-ran-butylene)- block-polyisoprene (SEBI or K3) triblock copolymers for marine antifouling/fouling release surface coatings. Initial results showed that the polymer coated surfaces can facilitate removal of Ulva sporelings on the surfaces. In addition, we prepared both bioactive and dual functional biopassive/bioactive antimicrobial coatings based on SEBI polymers. Incubating the polymer coated surfaces with gram-positive bacteria (S. aureus), gram-negative bacteria (E. coli) and marine bacteria (C. marina ) species demonstrated that, unlike biopassive surfaces, the dual functionality polymer coated surfaces can significantly reduce both live and dead cells, without killing the cells in the culture media. The knowledge gained from those studies offers opportunities for further modification and potential applications of those types of polymers in the future.
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Xie, Zhihui; Eagleson, Kathie L.
2016-01-01
MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine142 (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex. PMID:27595133
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Perceptual learning and adult cortical plasticity.
Gilbert, Charles D; Li, Wu; Piech, Valentin
2009-06-15
The visual cortex retains the capacity for experience-dependent changes, or plasticity, of cortical function and cortical circuitry, throughout life. These changes constitute the mechanism of perceptual learning in normal visual experience and in recovery of function after CNS damage. Such plasticity can be seen at multiple stages in the visual pathway, including primary visual cortex. The manifestation of the functional changes associated with perceptual learning involve both long term modification of cortical circuits during the course of learning, and short term dynamics in the functional properties of cortical neurons. These dynamics are subject to top-down influences of attention, expectation and perceptual task. As a consequence, each cortical area is an adaptive processor, altering its function in accordance to immediate perceptual demands.
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Semework, Mulugeta; DiStasio, Marcello
2014-01-01
Recording the activity of large populations of neurons requires new methods to analyze and use the large volumes of time series data thus created. Fast and clear methods for finding functional connectivity are an important step toward the goal of understanding neural processing. This problem presents itself readily in somatosensory neuroprosthesis (SSNP) research, which uses microstimulation (MiSt) to activate neural tissue to mimic natural stimuli, and has the capacity to potentiate, depotentiate, or even destroy functional connections. As the aim of SSNP engineering is artificially creating neural responses that resemble those observed during natural inputs, a central goal is describing the influence of MiSt on activity structure among groups of neurons, and how this structure may be altered to affect perception or behavior. In this paper, we demonstrate the concept of Granger causality, combined with maximum likelihood methods, applied to neural signals recorded before, during, and after natural and electrical stimulation. We show how these analyses can be used to evaluate the changing interactions in the thalamocortical somatosensory system in response to repeated perturbation. Using LFPs recorded from the ventral posterolateral thalamus (VPL) and somatosensory cortex (S1) in anesthetized rats, we estimated pair-wise functional interactions between functional microdomains. The preliminary results demonstrate input-dependent modulations in the direction and strength of information flow during and after application of MiSt. Cortico-cortical interactions during cortical MiSt and baseline conditions showed the largest causal influence differences, while there was no statistically significant difference between pre- and post-stimulation baseline causal activities. These functional connectivity changes agree with physiologically accepted communication patterns through the network, and their particular parameters have implications for both rehabilitation and brain—machine interface SSNP applications. PMID:25249973
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Li, Yan; Chen, Xin; Dzakpasu, Rhonda; Conant, Katherine
2017-02-01
Oscillatory activity occurs in cortical and hippocampal networks with specific frequency ranges thought to be critical to working memory, attention, differentiation of neuronal precursors, and memory trace replay. Synchronized activity within relatively large neuronal populations is influenced by firing and bursting frequency within individual cells, and the latter is modulated by changes in intrinsic membrane excitability and synaptic transmission. Published work suggests that dopamine, a potent modulator of learning and memory, acts on dopamine receptor 1-like dopamine receptors to influence the phosphorylation and trafficking of glutamate receptor subunits, along with long-term potentiation of excitatory synaptic transmission in striatum and prefrontal cortex. Prior studies also suggest that dopamine can influence voltage gated ion channel function and membrane excitability in these regions. Fewer studies have examined dopamine's effect on related endpoints in hippocampus, or potential consequences in terms of network burst dynamics. In this study, we record action potential activity using a microelectrode array system to examine the ability of dopamine to modulate baseline and glutamate-stimulated bursting activity in an in vitro network of cultured murine hippocampal neurons. We show that dopamine stimulates a dopamine type-1 receptor-dependent increase in number of overall bursts within minutes of its application. Notably, however, at the concentration used herein, dopamine did not increase the overall synchrony of bursts between electrodes. Although the number of bursts normalizes by 40 min, bursting in response to a subsequent glutamate challenge is enhanced by dopamine pretreatment. Dopamine-dependent potentiation of glutamate-stimulated bursting was not observed when the two modulators were administered concurrently. In parallel, pretreatment of murine hippocampal cultures with dopamine stimulated lasting increases in the phosphorylation of the glutamate receptor subunit GluA1 at serine 845. This effect is consistent with the possibility that enhanced membrane insertion of GluAs may contribute to a more slowly evolving dopamine-dependent potentiation of glutamate-stimulated bursting. Together, these results are consistent with the possibility that dopamine can influence hippocampal bursting by at least two temporally distinct mechanisms, contributing to an emerging appreciation of dopamine-dependent effects on network activity in the hippocampus. © 2016 International Society for Neurochemistry.
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Shining light on neurons--elucidation of neuronal functions by photostimulation.
Eder, Matthias; Zieglgänsberger, Walter; Dodt, Hans-Ulrich
2004-01-01
Many neuronal functions can be elucidated by techniques that allow for a precise stimulation of defined regions of a neuron and its afferents. Photolytic release of neurotransmitters from 'caged' derivates in the vicinity of visualized neurons in living brain slices meets this request. This technique allows the study of the subcellular distribution and properties of functional native neurotransmitter receptors. These are prerequisites for a detailed analysis of the expression and spatial specificity of synaptic plasticity. Photostimulation can further be used to fast map the synaptic connectivity between nearby and, more importantly, distant cells in a neuronal network. Here we give a personal review of some of the technical aspects of photostimulation and recent findings, which illustrate the advantages of this technique.
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Sagal, Jonathan; Zhan, Xiping; Xu, Jinchong; Tilghman, Jessica; Karuppagounder, Senthilkumar S; Chen, Li; Dawson, Valina L; Dawson, Ted M; Laterra, John; Ying, Mingyao
2014-08-01
Human pluripotent stem cells (PSCs) are a promising cell resource for various applications in regenerative medicine. Highly efficient approaches that differentiate human PSCs into functional lineage-specific neurons are critical for modeling neurological disorders and testing potential therapies. Proneural transcription factors are crucial drivers of neuron development and hold promise for driving highly efficient neuronal conversion in PSCs. Here, we study the functions of proneural transcription factor Atoh1 in the neuronal differentiation of PSCs. We show that Atoh1 is induced during the neuronal conversion of PSCs and that ectopic Atoh1 expression is sufficient to drive PSCs into neurons with high efficiency. Atoh1 induction, in combination with cell extrinsic factors, differentiates PSCs into functional dopaminergic (DA) neurons with >80% purity. Atoh1-induced DA neurons recapitulate key biochemical and electrophysiological features of midbrain DA neurons, the degeneration of which is responsible for clinical symptoms in Parkinson's disease (PD). Atoh1-induced DA neurons provide a reliable disease model for studying PD pathogenesis, such as neurotoxin-induced neurodegeneration in PD. Overall, our results determine the role of Atoh1 in regulating neuronal differentiation and neuron subtype specification of human PSCs. Our Atoh1-mediated differentiation approach will enable large-scale applications of PD patient-derived midbrain DA neurons in mechanistic studies and drug screening for both familial and sporadic PD. ©AlphaMed Press.
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Goldie, Belinda J; Fitzsimmons, Chantel; Weidenhofer, Judith; Atkins, Joshua R; Wang, Dan O; Cairns, Murray J
2017-01-01
While the cytoplasmic function of microRNA (miRNA) as post-transcriptional regulators of mRNA has been the subject of significant research effort, their activity in the nucleus is less well characterized. Here we use a human neuronal cell model to show that some mature miRNA are preferentially enriched in the nucleus. These molecules were predominantly primate-specific and contained a sequence motif with homology to the consensus MAZ transcription factor binding element. Precursor miRNA containing this motif were shown to have affinity for MAZ protein in nuclear extract. We then used Ago1/2 RIP-Seq to explore nuclear miRNA-associated mRNA targets. Interestingly, the genes for Ago2-associated transcripts were also significantly enriched with MAZ binding sites and neural function, whereas Ago1-transcripts were associated with general metabolic processes and localized with SC35 spliceosomes. These findings suggest the MAZ transcription factor is associated with miRNA in the nucleus and may influence the regulation of neuronal development through Ago2-associated miRNA induced silencing complexes. The MAZ transcription factor may therefore be important for organizing higher order integration of transcriptional and post-transcriptional processes in primate neurons.
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Failure tolerance of spike phase synchronization in coupled neural networks
NASA Astrophysics Data System (ADS)
Jalili, Mahdi
2011-09-01
Neuronal synchronization plays an important role in the various functionality of nervous system such as binding, cognition, information processing, and computation. In this paper, we investigated how random and intentional failures in the nodes of a network influence its phase synchronization properties. We considered both artificially constructed networks using models such as preferential attachment, Watts-Strogatz, and Erdős-Rényi as well as a number of real neuronal networks. The failure strategy was either random or intentional based on properties of the nodes such as degree, clustering coefficient, betweenness centrality, and vulnerability. Hindmarsh-Rose model was considered as the mathematical model for the individual neurons, and the phase synchronization of the spike trains was monitored as a function of the percentage/number of removed nodes. The numerical simulations were supplemented by considering coupled non-identical Kuramoto oscillators. Failures based on the clustering coefficient, i.e., removing the nodes with high values of the clustering coefficient, had the least effect on the spike synchrony in all of the networks. This was followed by errors where the nodes were removed randomly. However, the behavior of the other three attack strategies was not uniform across the networks, and different strategies were the most influential in different network structure.
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Thyroid hormones: Possible roles in epilepsy pathology.
Tamijani, Seyedeh Masoumeh Seyedhoseini; Karimi, Benyamin; Amini, Elham; Golpich, Mojtaba; Dargahi, Leila; Ali, Raymond Azman; Ibrahim, Norlinah Mohamed; Mohamed, Zahurin; Ghasemi, Rasoul; Ahmadiani, Abolhassan
2015-09-01
Thyroid hormones (THs) L-thyroxine and L-triiodothyronine, primarily known as metabolism regulators, are tyrosine-derived hormones produced by the thyroid gland. They play an essential role in normal central nervous system development and physiological function. By binding to nuclear receptors and modulating gene expression, THs influence neuronal migration, differentiation, myelination, synaptogenesis and neurogenesis in developing and adult brains. Any uncorrected THs supply deficiency in early life may result in irreversible neurological and motor deficits. The development and function of GABAergic neurons as well as glutamatergic transmission are also affected by THs. Though the underlying molecular mechanisms still remain unknown, the effects of THs on inhibitory and excitatory neurons may affect brain seizure activity. The enduring predisposition of the brain to generate epileptic seizures leads to a complex chronic brain disorder known as epilepsy. Pathologically, epilepsy may be accompanied by mitochondrial dysfunction, oxidative stress and eventually dysregulation of excitatory glutamatergic and inhibitory GABAergic neurotransmission. Based on the latest evidence on the association between THs and epilepsy, we hypothesize that THs abnormalities may contribute to the pathogenesis of epilepsy. We also review gender differences and the presumed underlying mechanisms through which TH abnormalities may affect epilepsy here. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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Modeling the Value of Strategic Actions in the Superior Colliculus
Thevarajah, Dhushan; Webb, Ryan; Ferrall, Christopher; Dorris, Michael C.
2009-01-01
In learning models of strategic game play, an agent constructs a valuation (action value) over possible future choices as a function of past actions and rewards. Choices are then stochastic functions of these action values. Our goal is to uncover a neural signal that correlates with the action value posited by behavioral learning models. We measured activity from neurons in the superior colliculus (SC), a midbrain region involved in planning saccadic eye movements, while monkeys performed two saccade tasks. In the strategic task, monkeys competed against a computer in a saccade version of the mixed-strategy game ”matching-pennies”. In the instructed task, saccades were elicited through explicit instruction rather than free choices. In both tasks neuronal activity and behavior were shaped by past actions and rewards with more recent events exerting a larger influence. Further, SC activity predicted upcoming choices during the strategic task and upcoming reaction times during the instructed task. Finally, we found that neuronal activity in both tasks correlated with an established learning model, the Experience Weighted Attraction model of action valuation (Camerer and Ho, 1999). Collectively, our results provide evidence that action values hypothesized by learning models are represented in the motor planning regions of the brain in a manner that could be used to select strategic actions. PMID:20161807
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McCool, Brian A.; Frye, Gerald D.; Pulido, Marisa D.; Botting, Shaleen K.
2010-01-01
It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABAA and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABAA receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptor’s response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABAA receptors composed of unique α subunits were differentially sensitive to acute ethanol. Likewise, the presence of the β subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the α2 subunit. Our results suggest that the facilitation of GABAA receptors during chronic ethanol exposure may help explain the maintenance of ethanol’s anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABAA and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure. PMID:12560122
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McCool, Brian A; Frye, Gerald D; Pulido, Marisa D; Botting, Shaleen K
2003-02-14
It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABA(A) and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABA(A) receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptor's response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABA(A) receptors composed of unique alpha subunits were differentially sensitive to acute ethanol. Likewise, the presence of the beta subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the alpha(2) subunit. Our results suggest that the facilitation of GABA(A) receptors during chronic ethanol exposure may help explain the maintenance of ethanol's anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABA(A) and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure.
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Gaglia, Marta M; Jeong, Dae-Eun; Ryu, Eun-A; Lee, Dongyeop; Kenyon, Cynthia; Lee, Seung-Jae
2012-01-01
The sensory systems of multicellular organisms are designed to provide information about the environment and thus elicit appropriate changes in physiology and behavior. In the nematode Caenorhabditis elegans, sensory neurons affect the decision to arrest during development in a diapause state, the dauer larva, and modulate the lifespan of the animals in adulthood. However, the mechanisms underlying these effects are incompletely understood. Using whole-genome microarray analysis, we identified transcripts whose levels are altered by mutations in the intraflagellar transport protein daf-10, which result in impaired development and function of many sensory neurons in C. elegans. In agreement with existing genetic data, the expression of genes regulated by the transcription factor DAF-16/FOXO was affected by daf-10 mutations. In addition, we found altered expression of transcriptional targets of the DAF-12/nuclear hormone receptor in the daf-10 mutants and showed that this pathway influences specifically the dauer formation phenotype of these animals. Unexpectedly, pathogen-responsive genes were repressed in daf-10 mutant animals, and these sensory mutants exhibited altered susceptibility to and behavioral avoidance of bacterial pathogens. Moreover, we found that a solute transporter gene mct-1/2, which was induced by daf-10 mutations, was necessary and sufficient for longevity. Thus, sensory input seems to influence an extensive transcriptional network that modulates basic biological processes in C. elegans. This situation is reminiscent of the complex regulation of physiology by the mammalian hypothalamus, which also receives innervations from sensory systems, most notably the visual and olfactory systems.
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Localization and regulation of PML bodies in the adult mouse brain.
Hall, Małgorzata H; Magalska, Adriana; Malinowska, Monika; Ruszczycki, Błażej; Czaban, Iwona; Patel, Satyam; Ambrożek-Latecka, Magdalena; Zołocińska, Ewa; Broszkiewicz, Hanna; Parobczak, Kamil; Nair, Rajeevkumar R; Rylski, Marcin; Pawlak, Robert; Bramham, Clive R; Wilczyński, Grzegorz M
2016-06-01
PML is a tumor suppressor protein involved in the pathogenesis of promyelocytic leukemia. In non-neuronal cells, PML is a principal component of characteristic nuclear bodies. In the brain, PML has been implicated in the control of embryonic neurogenesis, and in certain physiological and pathological phenomena in the adult brain. Yet, the cellular and subcellular localization of the PML protein in the brain, including its presence in the nuclear bodies, has not been investigated comprehensively. Because the formation of PML bodies appears to be a key aspect in the function of the PML protein, we investigated the presence of these structures and their anatomical distribution, throughout the adult mouse brain. We found that PML is broadly expressed across the gray matter, with the highest levels in the cerebral and cerebellar cortices. In the cerebral cortex PML is present exclusively in neurons, in which it forms well-defined nuclear inclusions containing SUMO-1, SUMO 2/3, but not Daxx. At the ultrastructural level, the appearance of neuronal PML bodies differs from the classic one, i.e., the solitary structure with more or less distinctive capsule. Rather, neuronal PML bodies have the form of small PML protein aggregates located in the close vicinity of chromatin threads. The number, size, and signal intensity of neuronal PML bodies are dynamically influenced by immobilization stress and seizures. Our study indicates that PML bodies are broadly involved in activity-dependent nuclear phenomena in adult neurons.
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Kwakowsky, Andrea; Milne, Michael R; Waldvogel, Henry J; Faull, Richard L
2016-12-17
The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.
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Kwakowsky, Andrea; Milne, Michael R.; Waldvogel, Henry J.; Faull, Richard L.
2016-01-01
The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease. PMID:27999310
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Bienefeld, Kaspar; Beye, Martin
2012-01-01
Division of labor in social insects has made the evolution of collective traits possible that cannot be achieved by individuals alone. Differences in behavioral responses produce variation in engagement in behavioral tasks, which as a consequence, generates a division of labor. We still have little understanding of the genetic components influencing these behaviors, although several candidate genomic regions and genes influencing individual behavior have been identified. Here, we report that mixing of worker honeybees with different genotypes influences the expression of individual worker behaviors and the transcription of genes in the neuronal substrate. These indirect genetic effects arise in a colony because numerous interactions between workers produce interacting phenotypes and genotypes across organisms. We studied hygienic behavior of honeybee workers, which involves the cleaning of diseased brood cells in the colony. We mixed ∼500 newly emerged honeybee workers with genotypes of preferred Low (L) and High (H) hygienic behaviors. The L/H genotypic mixing affected the behavioral engagement of L worker bees in a hygienic task, the cooperation among workers in uncapping single brood cells, and switching between hygienic tasks. We found no evidence that recruiting and task-related stimuli are the primary source of the indirect genetic effects on behavior. We suggested that behavioral responsiveness of L bees was affected by genotypic mixing and found evidence for changes in the brain in terms of 943 differently expressed genes. The functional categories of cell adhesion, cellular component organization, anatomical structure development, protein localization, developmental growth and cell morphogenesis were overrepresented in this set of 943 genes, suggesting that indirect genetic effects can play a role in modulating and modifying the neuronal substrate. Our results suggest that genotypes of social partners affect the behavioral responsiveness and the neuronal substrate of individual workers, indicating a complex genetic architecture underlying the expression of behavior. PMID:22348118
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Abdallah, Luna; Bonasera, Stephen J; Hopf, F Woodward; O'Dell, Laura; Giorgetti, Marco; Jongsma, Minke; Carra, Scott; Pierucci, Massimo; Di Giovanni, Giuseppe; Esposito, Ennio; Parsons, Loren H; Bonci, Antonello; Tecott, Laurence H
2009-06-24
The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT(2C)R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.
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Enrichment rescues contextual discrimination deficit associated with immediate shock.
Clemenson, Gregory D; Lee, Star W; Deng, Wei; Barrera, Vanessa R; Iwamoto, Kei S; Fanselow, Michael S; Gage, Fred H
2015-03-01
Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE-induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear-conditioning (FC) procedure to tease out the behavioral differences between RUN-induced neurogenesis and EE-induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE-induced neurogenesis, suggesting a fundamental functional difference between RUN-induced neurogenesis and EE-induced neurogenesis. © 2014 Wiley Periodicals, Inc.
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Enrichment Rescues Contextual Discrimination Deficit Associated With Immediate Shock
Clemenson, Gregory D.; Lee, Star W.; Deng, Wei; Barrera, Vanessa R.; Iwamoto, Kei S.; Fanselow, Michael S.; Gage, Fred H.
2015-01-01
Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE-induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear-conditioning (FC) procedure to tease out the behavioral differences between RUN-induced neurogenesis and EE-induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE-induced neurogenesis, suggesting a fundamental functional difference between RUN-induced neurogenesis and EE-induced neurogenesis. PMID:25330953