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Sample records for neurons controlling paradoxical

  1. Localization of the Brainstem GABAergic Neurons Controlling Paradoxical (REM) Sleep

    PubMed Central

    Bérod, Anne; Goutagny, Romain; Léger, Lucienne; Ravassard, Pascal; Clément, Olivier; Hanriot, Lucie; Fort, Patrice; Luppi, Pierre-Hervé

    2009-01-01

    Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles. PMID:19169414

  2. Paradoxes

    ERIC Educational Resources Information Center

    Partis, M.

    1972-01-01

    Examples of logical paradoxes, including the square root of two paradox, Achilles and the tortoise paradox, author paradox, Russell paradox, bibliomaniac paradox, and Berry paradox, are presented; some are resolved. (DT)

  3. Paradoxes

    ERIC Educational Resources Information Center

    Partis, M.

    1972-01-01

    Examples of logical paradoxes, including the square root of two paradox, Achilles and the tortoise paradox, author paradox, Russell paradox, bibliomaniac paradox, and Berry paradox, are presented; some are resolved. (DT)

  4. Evidence that Neurons of the Sublaterodorsal Tegmental Nucleus Triggering Paradoxical (REM) Sleep Are Glutamatergic

    PubMed Central

    Clément, Olivier; Sapin, Emilie; Bérod, Anne; Fort, Patrice; Luppi, Pierre-Hervé

    2011-01-01

    Study Objectives: To determine whether sublaterodorsal tegmental nucleus (SLD) neurons triggering paradoxical (REM) sleep (PS) are glutamatergic. Design: Three groups of rats were used: controls, rats deprived of PS for 72 h, and rats allowed to recover for 3 h after deprivation. Brain sections were processed for double labeling combining Fos immunohistochemistry and vesicular glutamate transporter 2 (vGLUT2) in situ hybridization. Measurements and Results: The number of single Fos+ and Fos/vGLUT2+ double-labeled neurons was counted for each experimental condition. A very large number of Fos+ neurons expressing vGLUT2 mRNA specifically after PS hypersomnia was counted in the SLD. These double-labeled cells accounted for 84% of the total number of Fos+ cells. Conclusions: This finding adds further evidence to the concept that PS-on neurons of the SLD generating PS are of small size and glutamatergic in nature. By means of their descending projections to medullary and/or spinal glycinergic/GABAergic premotoneurons, they may be especially important for the induction of muscle atonia during PS, a disturbed phenomenon in narcolepsy and REM sleep behavior disorder. Citation: Clément O; Sapin E; Bérod A; Fort P; Luppi PH. Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. SLEEP 2011;34(4):419-423. PMID:21461384

  5. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep

    PubMed Central

    Verret, Laure; Goutagny, Romain; Fort, Patrice; Cagnon, Laurène; Salvert, Denise; Léger, Lucienne; Boissard, Romuald; Salin, Paul; Peyron, Christelle; Luppi, Pierre-Hervé

    2003-01-01

    Background Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation. Results Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats). Further, we show that ICV administration of MCH induces a dose-dependant increase in PS (up to 200%) and slow wave sleep (up to 70%) quantities. Conclusion These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system. PMID:12964948

  6. Paradox of simple limiter control.

    PubMed

    Hilker, Frank M; Westerhoff, Frank H

    2006-05-01

    Chaos control by simple limiters is an easy-to-implement and effective method of stabilizing irregular fluctuations. Here we show that applying limiter control to a state variable can significantly shift its mean value. In many situations, this is a countereffective as well as unexpected result, when the aim of control is also to restrict the dynamics. We discuss this effect on the basis of a model of population dynamics and conclude that it can have severe implications for the management of pest species and epidemic spread.

  7. A Very Large Number of GABAergic Neurons Are Activated in the Tuberal Hypothalamus during Paradoxical (REM) Sleep Hypersomnia

    PubMed Central

    Sapin, Emilie; Bérod, Anne; Léger, Lucienne; Herman, Paul A.; Luppi, Pierre-Hervé; Peyron, Christelle

    2010-01-01

    We recently discovered, using Fos immunostaining, that the tuberal and mammillary hypothalamus contain a massive population of neurons specifically activated during paradoxical sleep (PS) hypersomnia. We further showed that some of the activated neurons of the tuberal hypothalamus express the melanin concentrating hormone (MCH) neuropeptide and that icv injection of MCH induces a strong increase in PS quantity. However, the chemical nature of the majority of the neurons activated during PS had not been characterized. To determine whether these neurons are GABAergic, we combined in situ hybridization of GAD67 mRNA with immunohistochemical detection of Fos in control, PS deprived and PS hypersomniac rats. We found that 74% of the very large population of Fos-labeled neurons located in the tuberal hypothalamus after PS hypersomnia were GAD-positive. We further demonstrated combining MCH immunohistochemistry and GAD67 in situ hybridization that 85% of the MCH neurons were also GAD-positive. Finally, based on the number of Fos-ir/GAD+, Fos-ir/MCH+, and GAD+/MCH+ double-labeled neurons counted from three sets of double-staining, we uncovered that around 80% of the large number of the Fos-ir/GAD+ neurons located in the tuberal hypothalamus after PS hypersomnia do not contain MCH. Based on these and previous results, we propose that the non-MCH Fos/GABAergic neuronal population could be involved in PS induction and maintenance while the Fos/MCH/GABAergic neurons could be involved in the homeostatic regulation of PS. Further investigations will be needed to corroborate this original hypothesis. PMID:20668680

  8. Paradoxical (rapid eye movement) sleep-on neurons in the laterodorsal pontine tegmentum in mice.

    PubMed

    Sakai, K

    2015-12-03

    A total of 211 neurons that discharged at the highest rate during sleep (sleep-active neurons) were recorded in non-anesthetized, head-restrained mice during the complete wake-sleep cycle in, and around, the laterodorsal (LDT) and sublaterodorsal (SubLDT) tegmental nuclei, which contain both cholinergic and non-cholinergic neurons. For the first time in mice, I reveal the presence, mainly in the SubLDT, of sleep-specific neurons displaying sustained tonic discharge either (i) just prior to, and during, paradoxical sleep (PS) (PS-on neurons) or (ii) during both slow-wave sleep (SWS) and PS (SWS/PS-on neurons). Both the PS-on and SWS/PS-on neurons showed either a low (< 10 Hz) or high (⩾ 10 Hz) rate of spontaneous firing and exhibited a biphasic narrow or medium-to-broad action potential, a characteristic of non-cholinergic neurons. At the transition from SWS to waking (W), the PS-on and SWS/PS-on neurons simultaneously ceased firing shortly before the onset of W, whereas, at the transition from W to SWS, only the SWS/PS-on neurons fired shortly after the onset of sleep. At the transition from SWS to PS, only the PS-on neurons exhibited a significant increase in discharge rate before PS onset, while, at the transition from PS to W, the SWS/PS-on neurons, then the PS-on neurons, displayed a significant decrease in the discharge rate before the end of PS. The SWS/PS-on neurons were more sensitive to the change in the electroencephalogram (EEG) than the PS-on neurons, as, during a PS episode, the slightest interruption of rhythmic theta activity resulted in cessation of discharge of the SWS/PS-on neurons. These findings support the view that, in the mouse SubLDT, PS-on neurons play an important role in the induction, maintenance, and cessation of PS, while SWS/PS-on neurons play a role in the maintenance of the PS state in particular and the sleep state in general.

  9. Increase in antidromic excitability in presumed serotonergic dorsal raphe neurons during paradoxical sleep in the cat.

    PubMed

    Sakai, K; Crochet, S

    2001-04-20

    Putative serotonergic dorsal raphe (DRN) neurons display a dramatic state-related change in behaviour, discharging regularly at a high rate during waking and at progressively slower rates during slow-wave sleep (SWS) and ceasing firing during paradoxical sleep (PS). Using the antidromic latency technique and extracellular recording, we have examined the change in neuronal excitability of presumed serotonergic DRN neurons during the wake-sleep cycle in freely moving cats. We found that, under normal conditions, suprathreshold stimulation of the main ascending serotonergic pathway resulted in a marked decrease in both the magnitude and variability of antidromic latency during PS, while subthreshold stimulation led to a marked increase in antidromic responsiveness during PS compared with during other behavioural states. The antidromic latency shift resulted from a change in the delay between the initial segment (IS) and soma-dendritic (SD) spikes, the antidromic latency being inversely related to the interval between the stimulus and the preceding spontaneous action potential. A marked decrease in the magnitude and variability of antidromic latency was also seen following suppression of the spontaneous discharge of DRN neurons by application of 5-HT autoreceptor agonists or muscimol, a potent GABA agonist. A marked IS-SD delay or blockage of SD spikes was, however, seen in association with the PS occurring during recovery from 5-HT autoreceptor agonist or during muscimol application. The present findings are discussed in the light of previous in vitro intracellular recording data and our recent findings of the disfacilitation mechanisms responsible for the cessation of discharge of DRN neurons during PS.

  10. Under-recognised paradox of neuropathy from rapid glycaemic control

    PubMed Central

    Leow, M; Wyckoff, J

    2005-01-01

    Insulin induced neuropathy has been reported previously in people with diabetes treated with insulin, and subsequently reported in patients with insulinomas. However, neuropathy caused by rapid glycaemic control in patients with poorly controlled diabetes with chronic hyperglycaemia is not a widely recognised entity among clinicians worldwide. It is expected that this phenomenon of paradoxical complication of neuropathy in the face of drastic decreases in glycosylated haemoglobin concentrations will assume greater importance with clinicians achieving glycaemic targets at a faster pace than before. PMID:15701742

  11. The Chinese Classroom Paradox: A Cross-Cultural Comparison of Teacher Controlling Behaviors

    ERIC Educational Resources Information Center

    Zhou, Ning; Lam, Shui-Fong; Chan, Kam Chi

    2012-01-01

    Chinese classrooms present an intriguing paradox to the claim of self-determination theory that autonomy facilitates learning. Chinese teachers appear to be controlling, but Chinese students do not have poor academic performance in international comparisons. The present study addressed this paradox by examining the cultural differences in…

  12. The Chinese Classroom Paradox: A Cross-Cultural Comparison of Teacher Controlling Behaviors

    ERIC Educational Resources Information Center

    Zhou, Ning; Lam, Shui-Fong; Chan, Kam Chi

    2012-01-01

    Chinese classrooms present an intriguing paradox to the claim of self-determination theory that autonomy facilitates learning. Chinese teachers appear to be controlling, but Chinese students do not have poor academic performance in international comparisons. The present study addressed this paradox by examining the cultural differences in…

  13. Paradoxical lower sensitivity of Locus Coeruleus than Substantia Nigra pars compacta neurons to acute actions of rotenone.

    PubMed

    Yee, Andrew G; Freestone, Peter S; Bai, Ji-Zhong; Lipski, Janusz

    2017-01-01

    Parkinson's disease (PD) is not only associated with degeneration of dopaminergic (DAergic) neurons in the Substantia Nigra, but also with profound loss of noradrenergic neurons in the Locus Coeruleus (LC). Remarkably, LC degeneration may exceed, or even precede the loss of nigral DAergic neurons, suggesting that LC neurons may be more susceptible to damage by various insults. Using a combination of electrophysiology, fluorescence imaging and electrochemistry, we directly compared the responses of LC, nigral DAergic and nigral non-dopaminergic (non-DAergic) neurons in rat brain slices to acute application of rotenone, a mitochondrial toxin used to create animal and in vitro models of PD. Rotenone (0.01-5.0μM) dose-dependently inhibited the firing of all three groups of neurons, primarily by activating KATP channels. The toxin also depolarised mitochondrial potential (Ψm) and released reactive oxygen species (H2O2). When KATP channels were blocked, rotenone (1μM) increased the firing of LC neurons by activating an inward current associated with dose-dependent increase of cytosolic free Ca(2+) ([Ca(2+)]i). This effect was attenuated by blocking oxidative stress-sensitive TRPM2 channels, and by pre-treatment of slices with anti-oxidants. These results demonstrate that rotenone inhibits the activity of LC neurons mainly by activating KATP channels, and increases [Ca(2+)]ivia TRPM2 channels. Since the responses of LC neurons were smaller than those of nigral DAergic neurons, our study shows that LC neurons are paradoxically less sensitive to acute effects of this parkinsonian toxin. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Are paradoxical cell cycle activities in neurons and glia related to the metabolic theory of Alzheimer's disease?

    PubMed

    Erol, Adnan

    2010-01-01

    The progression and outcome of neurological diseases are determined by the balance between neurodegeneration, neuroprotection, and neuroregeneration. In this context, astroglial cells are invariably involved in every kind of neuropathology. Mitotically, active glial cells provide metabolic support to active neurons, contribute to coupling between synaptic activity and local blood flow, and thus protect against oxidative stress. Disturbances of the complex neuron-glia interrelation are increasingly recognized as a potentially important pathophysiological mechanism in a wide variety of neurological disorders including those marked by neurodegeneration. Peripheral insulin resistance-mediated increased oxidative stress in glial cells, and consequent DNA damage, induces senescence in glial cells leads to the development of an inflammatory environment. The immune mediators released by senescent (activated) glial cells are considered to be neurotoxic and ultimately increase the oxidant load of neurons. While the neuron is viewed as the prototypical post-mitotic, fully differentiated cell, certain subsets of neurons reactivate cell-cycle activity in response to triggers of neuronal apoptosis, such as genotoxic stress generated by redox changes due to pathological alterations in supporting astroglial cells. Thus, a paradoxical cell cycle block in glial cells coupled with concomitant cell cycle re-entry in neurons (due to pathological alterations created by peripheral insulin resistance-induced neuroendocrine signaling changes) may cause neurodegeneration, such as seen in Alzheimer's disease.

  15. Tuberal hypothalamic neurons secreting the satiety molecule Nesfatin-1 are critically involved in paradoxical (REM) sleep homeostasis.

    PubMed

    Jego, Sonia; Salvert, Denise; Renouard, Leslie; Mori, Masatomo; Goutagny, Romain; Luppi, Pierre-Hervé; Fort, Patrice

    2012-01-01

    The recently discovered Nesfatin-1 plays a role in appetite regulation as a satiety factor through hypothalamic leptin-independent mechanisms. Nesfatin-1 is co-expressed with Melanin-Concentrating Hormone (MCH) in neurons from the tuberal hypothalamic area (THA) which are recruited during sleep states, especially paradoxical sleep (PS). To help decipher the contribution of this contingent of THA neurons to sleep regulatory mechanisms, we thus investigated in rats whether the co-factor Nesfatin-1 is also endowed with sleep-modulating properties. Here, we found that the disruption of the brain Nesfatin-1 signaling achieved by icv administration of Nesfatin-1 antiserum or antisense against the nucleobindin2 (NUCB2) prohormone suppressed PS with little, if any alteration of slow wave sleep (SWS). Further, the infusion of Nesfatin-1 antiserum after a selective PS deprivation, designed for elevating PS needs, severely prevented the ensuing expected PS recovery. Strengthening these pharmacological data, we finally demonstrated by using c-Fos as an index of neuronal activation that the recruitment of Nesfatin-1-immunoreactive neurons within THA is positively correlated to PS but not to SWS amounts experienced by rats prior to sacrifice. In conclusion, this work supports a functional contribution of the Nesfatin-1 signaling, operated by THA neurons, to PS regulatory mechanisms. We propose that these neurons, likely releasing MCH as a synergistic factor, constitute an appropriate lever by which the hypothalamus may integrate endogenous signals to adapt the ultradian rhythm and maintenance of PS in a manner dictated by homeostatic needs. This could be done through the inhibition of downstream targets comprised primarily of the local hypothalamic wake-active orexin- and histamine-containing neurons.

  16. Tuberal Hypothalamic Neurons Secreting the Satiety Molecule Nesfatin-1 Are Critically Involved in Paradoxical (REM) Sleep Homeostasis

    PubMed Central

    Jego, Sonia; Salvert, Denise; Renouard, Leslie; Mori, Masatomo; Goutagny, Romain; Luppi, Pierre-Hervé; Fort, Patrice

    2012-01-01

    The recently discovered Nesfatin-1 plays a role in appetite regulation as a satiety factor through hypothalamic leptin-independent mechanisms. Nesfatin-1 is co-expressed with Melanin-Concentrating Hormone (MCH) in neurons from the tuberal hypothalamic area (THA) which are recruited during sleep states, especially paradoxical sleep (PS). To help decipher the contribution of this contingent of THA neurons to sleep regulatory mechanisms, we thus investigated in rats whether the co-factor Nesfatin-1 is also endowed with sleep-modulating properties. Here, we found that the disruption of the brain Nesfatin-1 signaling achieved by icv administration of Nesfatin-1 antiserum or antisense against the nucleobindin2 (NUCB2) prohormone suppressed PS with little, if any alteration of slow wave sleep (SWS). Further, the infusion of Nesfatin-1 antiserum after a selective PS deprivation, designed for elevating PS needs, severely prevented the ensuing expected PS recovery. Strengthening these pharmacological data, we finally demonstrated by using c-Fos as an index of neuronal activation that the recruitment of Nesfatin-1-immunoreactive neurons within THA is positively correlated to PS but not to SWS amounts experienced by rats prior to sacrifice. In conclusion, this work supports a functional contribution of the Nesfatin-1 signaling, operated by THA neurons, to PS regulatory mechanisms. We propose that these neurons, likely releasing MCH as a synergistic factor, constitute an appropriate lever by which the hypothalamus may integrate endogenous signals to adapt the ultradian rhythm and maintenance of PS in a manner dictated by homeostatic needs. This could be done through the inhibition of downstream targets comprised primarily of the local hypothalamic wake-active orexin- and histamine-containing neurons. PMID:23300698

  17. Paradoxes of photoconductive target and optical control of secondary ion yield

    SciTech Connect

    Rokakh, A. G. Matasov, M. D.

    2010-01-15

    This study of the photoconductivity of semiconductors, in particular, cadmium chalcogenides as materials for targets of vacuum image converters followed the path of overcoming paradoxes. The concepts developed by the classics of photoelectricity also help to understand the paradoxes of the new secondary-ion photoelectric effect, especially, its spectral characteristic. The optical channel of secondary ion yield control via a photoconductive target opens the way to a new branch of nanotechnology, i.e., optoionics.

  18. Network of hypothalamic neurons that control appetite.

    PubMed

    Sohn, Jong-Woo

    2015-04-01

    The central nervous system (CNS) controls food intake and energy expenditure via tight coordinations between multiple neuronal populations. Specifically, two distinct neuronal populations exist in the arcuate nucleus of hypothalamus (ARH): the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC) neurons and the orexigenic (appetite-increasing) neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. The coordinated regulation of neuronal circuit involving these neurons is essential in properly maintaining energy balance, and any disturbance therein may result in hyperphagia/obesity or hypophagia/starvation. Thus, adequate knowledge of the POMC and NPY/AgRP neuron physiology is mandatory to understand the pathophysiology of obesity and related metabolic diseases. This review will discuss the history and recent updates on the POMC and NPY/AgRP neuronal circuits, as well as the general anorexigenic and orexigenic circuits in the CNS.

  19. Overcoming the Pigou-Downs Paradox Using Advanced Traffic Signal Control

    NASA Astrophysics Data System (ADS)

    Fowdur, S. C.; Rughooputh, S. D. D. V.

    2013-06-01

    Expansion of a road network has often been observed to cause more congestion and has led researchers to the formulation of traffic paradoxes such as the Pigou-Downs and the Braess paradoxes. In this paper, we present an application of advanced traffic signal control (ATSC) to overcome the Pigou-Downs paradox. Port Louis, the capital city of Mauritius is used to investigate the effect of using a harbor bridge to by-pass the city center. Using traffic cellular automata (TCA) simulations it has been shown how, if traffic is only gradually deviated along the by-pass, an overall longer travel time and decreased flux would result. By making use of ATSC, which involves traffic lights that sense the number of vehicles accumulated in the queue, better travel times and fluxes are achieved.

  20. Timing control by redundant inhibitory neuronal circuits

    NASA Astrophysics Data System (ADS)

    Tristan, I.; Rulkov, N. F.; Huerta, R.; Rabinovich, M.

    2014-03-01

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model.

  1. Timing control by redundant inhibitory neuronal circuits

    SciTech Connect

    Tristan, I. Rulkov, N. F.; Huerta, R.; Rabinovich, M.

    2014-03-15

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model.

  2. Remote control of neuronal signaling.

    PubMed

    Rogan, Sarah C; Roth, Bryan L

    2011-06-01

    A significant challenge for neuroscientists is to determine how both electrical and chemical signals affect the activity of cells and circuits and how the nervous system subsequently translates that activity into behavior. Remote, bidirectional manipulation of those signals with high spatiotemporal precision is an ideal approach to addressing that challenge. Neuroscientists have recently developed a diverse set of tools that permit such experimental manipulation with varying degrees of spatial, temporal, and directional control. These tools use light, peptides, and small molecules to primarily activate ion channels and G protein-coupled receptors (GPCRs) that in turn activate or inhibit neuronal firing. By monitoring the electrophysiological, biochemical, and behavioral effects of such activation/inhibition, researchers can better understand the links between brain activity and behavior. Here, we review the tools that are available for this type of experimentation. We describe the development of the tools and highlight exciting in vivo data. We focus primarily on designer GPCRs (receptors activated solely by synthetic ligands, designer receptors exclusively activated by designer drugs) and microbial opsins (e.g., channelrhodopsin-2, halorhodopsin, Volvox carteri channelrhodopsin) but also describe other novel techniques that use orthogonal receptors, caged ligands, allosteric modulators, and other approaches. These tools differ in the direction of their effect (activation/inhibition, hyperpolarization/depolarization), their onset and offset kinetics (milliseconds/minutes/hours), the degree of spatial resolution they afford, and their invasiveness. Although none of these tools is perfect, each has advantages and disadvantages, which we describe, and they are all still works in progress. We conclude with suggestions for improving upon the existing tools.

  3. Remote Control of Neuronal Signaling

    PubMed Central

    Rogan, Sarah C.

    2011-01-01

    A significant challenge for neuroscientists is to determine how both electrical and chemical signals affect the activity of cells and circuits and how the nervous system subsequently translates that activity into behavior. Remote, bidirectional manipulation of those signals with high spatiotemporal precision is an ideal approach to addressing that challenge. Neuroscientists have recently developed a diverse set of tools that permit such experimental manipulation with varying degrees of spatial, temporal, and directional control. These tools use light, peptides, and small molecules to primarily activate ion channels and G protein-coupled receptors (GPCRs) that in turn activate or inhibit neuronal firing. By monitoring the electrophysiological, biochemical, and behavioral effects of such activation/inhibition, researchers can better understand the links between brain activity and behavior. Here, we review the tools that are available for this type of experimentation. We describe the development of the tools and highlight exciting in vivo data. We focus primarily on designer GPCRs (receptors activated solely by synthetic ligands, designer receptors exclusively activated by designer drugs) and microbial opsins (e.g., channelrhodopsin-2, halorhodopsin, Volvox carteri channelrhodopsin) but also describe other novel techniques that use orthogonal receptors, caged ligands, allosteric modulators, and other approaches. These tools differ in the direction of their effect (activation/inhibition, hyperpolarization/depolarization), their onset and offset kinetics (milliseconds/minutes/hours), the degree of spatial resolution they afford, and their invasiveness. Although none of these tools is perfect, each has advantages and disadvantages, which we describe, and they are all still works in progress. We conclude with suggestions for improving upon the existing tools. PMID:21415127

  4. Genetic control of midbrain dopaminergic neuron development.

    PubMed

    Blaess, Sandra; Ang, Siew-Lan

    2015-01-01

    Midbrain dopaminergic neurons are involved in regulating motor control, reward behavior, and cognition. Degeneration or dysfunction of midbrain dopaminergic neurons is implicated in several neuropsychiatric disorders such as Parkinson's disease, substance use disorders, depression, and schizophrenia. Understanding the developmental processes that generate midbrain dopaminergic neurons will facilitate the generation of dopaminergic neurons from stem cells for cell replacement therapies to substitute degenerating cells in Parkinson's disease patients and will forward our understanding on how functional diversity of dopaminergic neurons in the adult brain is established. Midbrain dopaminergic neurons develop in a multistep process. Following the induction of the ventral midbrain, a distinct dopaminergic progenitor domain is specified and dopaminergic progenitors undergo proliferation, neurogenesis, and differentiation. Subsequently, midbrain dopaminergic neurons acquire a mature dopaminergic phenotype, migrate to their final position and establish projections and connections to their forebrain targets. This review will discuss insights gained on the signaling network of secreted molecules, cell surface receptors, and transcription factors that regulate specification and differentiation of midbrain dopaminergic progenitors and neurons, from the induction of the ventral midbrain to the migration of dopaminergic neurons. For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article. © 2015 Medical Research Council.

  5. Synchrony and Control of Neuronal Networks.

    NASA Astrophysics Data System (ADS)

    Schiff, Steven

    2001-03-01

    Cooperative behavior in the brain stems from the nature and strength of the interactions between neurons within a networked ensemble. Normal network activity takes place in a state of partial synchrony between neurons, and some pathological behaviors, such as epilepsy and tremor, appear to share a common feature of increased interaction strength. We have focused on the parallel paths of both detecting and characterizing the nonlinear synchronization present within neuronal networks, and employing feedback control methodology using electrical fields to modulate that neuronal activity. From a theoretical perspective, we see evidence for nonlinear generalized synchrony in networks of neurons that linear techniques are incapable of detecting (PRE 54: 6708, 1996), and we have described a decoherence transition between asymmetric nonlinear systems that is experimentally observable (PRL 84: 1689, 2000). In addition, we have seen evidence for unstable dimension variability in real neuronal systems that indicates certain physical limits of modelability when observing such systems (PRL 85, 2490, 2000). From an experimental perspective, we have achieved success in modulating epileptic seizures in neuronal networks using electrical fields. Extracellular neuronal activity is continuously recorded during field application through differential extracellular recording techniques, and the applied electric field strength is continuously updated using a computer controlled proportional feedback algorithm. This approach appears capable of sustained amelioration of seizure events when used with negative feedback. In negative feedback mode, such findings may offer a novel technology for seizure control. In positive feedback mode, adaptively applied electric fields may offer a more physiological means for neural modulation for prosthetic purposes than previously possible (J. Neuroscience, 2001).

  6. Nanomechanics controls neuronal precursors adhesion and differentiation.

    PubMed

    Migliorini, Elisa; Ban, Jelena; Grenci, Gianluca; Andolfi, Laura; Pozzato, Alessandro; Tormen, Massimo; Torre, Vincent; Lazzarino, Marco

    2013-08-01

    The ability to control the differentiation of stem cells into specific neuronal types has a tremendous potential for the treatment of neurodegenerative diseases. In vitro neuronal differentiation can be guided by the interplay of biochemical and biophysical cues. Different strategies to increase the differentiation yield have been proposed, focusing everything on substrate topography, or, alternatively on substrate stiffness. Both strategies demonstrated an improvement of the cellular response. However it was often impossible to separate the topographical and the mechanical contributions. Here we investigate the role of the mechanical properties of nanostructured substrates, aiming at understanding the ultimate parameters which govern the stem cell differentiation. To this purpose a set of different substrates with controlled stiffness and with or without nanopatterning are used for stem cell differentiation. Our results show that the neuronal differentiation yield depends mainly on the substrate mechanical properties while the geometry plays a minor role. In particular nanostructured and flat polydimethylsiloxane (PDMS) substrates with comparable stiffness show the same neuronal yield. The improvement in the differentiation yield obtained through surface nanopatterning in the submicrometer scale could be explained as a consequence of a substrate softening effect. Finally we investigate by single cell force spectroscopy the neuronal precursor adhesion on the substrate immediately after seeding, as a possible critical step governing the neuronal differentiation efficiency. We observed that neuronal precursor adhesion depends on substrate stiffness but not on surface structure, and in particular it is higher on softer substrates. Our results suggest that cell-substrate adhesion forces and mechanical response are the key parameters to be considered for substrate design in neuronal regenerative medicine.

  7. Inhibitory control of hippocampal inhibitory neurons

    PubMed Central

    Chamberland, Simon; Topolnik, Lisa

    2012-01-01

    Information processing within neuronal networks is determined by a dynamic partnership between principal neurons and local circuit inhibitory interneurons. The population of GABAergic interneurons is extremely heterogeneous and comprises, in many brain regions, cells with divergent morphological and physiological properties, distinct molecular expression profiles, and highly specialized functions. GABAergic interneurons have been studied extensively during the past two decades, especially in the hippocampus, which is a relatively simple cortical structure. Different types of hippocampal inhibitory interneurons control spike initiation [e.g., axo-axonic and basket cells (BCs)] and synaptic integration (e.g., bistratified and oriens–lacunosum moleculare interneurons) within pyramidal neurons and synchronize local network activity, providing a means for functional segregation of neuronal ensembles and proper routing of hippocampal information. Thus, it is thought that, at least in the hippocampus, GABAergic inhibitory interneurons represent critical regulating elements at all stages of information processing, from synaptic integration and spike generation to large-scale network activity. However, this raises an important question: if inhibitory interneurons are fundamental for network computations, what are the mechanisms that control the activity of the interneurons themselves? Given the essential role of synaptic inhibition in the regulation of neuronal activity, it would be logical to expect that specific inhibitory mechanisms have evolved to control the operation of interneurons. Here, we review the mechanisms of synaptic inhibition of interneurons and discuss their role in the operation of hippocampal inhibitory circuits. PMID:23162426

  8. Paradoxical Relations between Perceived Power and Maternal Control.

    ERIC Educational Resources Information Center

    Mills, Rosemary S. L.

    1998-01-01

    Mothers of 3-year-old girls completed measures of parenting patterns and perceived power. Fathers and mothers assessed their daughters' fearfulness and extraversion. Found that low-power mothers appeared to assert greater or lesser control depending on their daughter's temperamental characteristics; mothers behaved in a more authoritarian manner…

  9. Prefrontal Parvalbumin Neurons in Control of Attention

    PubMed Central

    Kim, Hoseok; Ährlund-Richter, Sofie; Wang, Xinming; Deisseroth, Karl; Carlén, Marie

    2016-01-01

    Summary While signatures of attention have been extensively studied in sensory systems, the neural sources and computations responsible for top-down control of attention are largely unknown. Using chronic recordings in mice, we found that fast-spiking parvalbumin (FS-PV) interneurons in medial prefrontal cortex (mPFC) uniformly show increased and sustained firing during goal-driven attentional processing, correlating to the level of attention. Elevated activity of FS-PV neurons on the timescale of seconds predicted successful execution of behavior. Successful allocation of attention was characterized by strong synchronization of FS-PV neurons, increased gamma oscillations, and phase locking of pyramidal firing. Phase-locked pyramidal neurons showed gamma-phase-dependent rate modulation during successful attentional processing. Optogenetic silencing of FS-PV neurons deteriorated attentional processing, while optogenetic synchronization of FS-PV neurons at gamma frequencies had pro-cognitive effects and improved goal-directed behavior. FS-PV neurons thus act as a functional unit coordinating the activity in the local mPFC circuit during goal-driven attentional processing. PMID:26771492

  10. Neuronal control of bone and muscle.

    PubMed

    Houweling, Peter; Kulkarni, Rishikesh N; Baldock, Paul A

    2015-11-01

    The functional interplay between bone and muscle that enables locomotion is a fundamental aspect of daily life. However, other interactions between bone and muscle continue to attract attention as our understanding of the breath and importance of this inter-relationship continues to expand. Of particular interest is the regulatory connection between bone and muscle, which adds a new insight to the coordination of the bone/muscle unit. We have appreciated the importance of neuronal signaling to the control of bone turnover and muscle contraction, but recent data indicate that neuronal inputs control a far wider range of bone and muscle physiology than previously appreciated. This review outlines the role of the sympathetic nervous system and neuronal/neuropeptide inputs upon the regulation of bone and muscle tissue, and the potential for co-regulatory actions, particularly involving the sympathetic nervous system. This article is part of a Special Issue entitled "Muscle Bone Interactions". Copyright © 2015. Published by Elsevier Inc.

  11. A control engineering approach to understanding the TGF-β paradox in cancer

    PubMed Central

    Chung, Seung-Wook; Cooper, Carlton R.; Farach-Carson, Mary C.; Ogunnaike, Babatunde A.

    2012-01-01

    TGF-β, a key cytokine that regulates diverse cellular processes, including proliferation and apoptosis, appears to function paradoxically as a tumour suppressor in normal cells, and as a tumour promoter in cancer cells, but the mechanisms underlying such contradictory roles remain unknown. In particular, given that this cytokine is primarily a tumour suppressor, the conundrum of the unusually high level of TGF-β observed in the primary cancer tissue and blood samples of cancer patients with the worst prognosis, remains unresolved. To provide a quantitative explanation of these paradoxical observations, we present, from a control theory perspective, a mechanistic model of TGF-β-driven regulation of cell homeostasis. Analysis of the overall system model yields quantitative insight into how cell population is regulated, enabling us to propose a plausible explanation for the paradox: with the tumour suppressor role of TGF-β unchanged from normal to cancer cells, we demonstrate that the observed increased level of TGF-β is an effect of cancer cell phenotypic progression (specifically, acquired TGF-β resistance), not the cause. We are thus able to explain precisely why the clinically observed correlation between elevated TGF-β levels and poor prognosis is in fact consistent with TGF-β's original (and unchanged) role as a tumour suppressor. PMID:22188767

  12. Paradoxical (REM) sleep deprivation in mice using the small-platforms-over-water method: polysomnographic analyses and melanin-concentrating hormone and hypocretin/orexin neuronal activation before, during and after deprivation.

    PubMed

    Arthaud, Sebastien; Varin, Christophe; Gay, Nadine; Libourel, Paul-Antoine; Chauveau, Frederic; Fort, Patrice; Luppi, Pierre-Herve; Peyron, Christelle

    2015-06-01

    Studying paradoxical sleep homeostasis requires the specific and efficient deprivation of paradoxical sleep and the evaluation of the subsequent recovery period. With this aim, the small-platforms-over-water technique has been used extensively in rats, but only rare studies were conducted in mice, with no sleep data reported during deprivation. Mice are used increasingly with the emergence of transgenic mice and technologies such as optogenetics, raising the need for a reliable method to manipulate paradoxical sleep. To fulfil this need, we refined this deprivation method and analysed vigilance states thoroughly during the entire protocol. We also studied activation of hypocretin/orexin and melanin-concentrating hormone neurones using Fos immunohistochemistry to verify whether mechanisms regulating paradoxical sleep in mice are similar to those in rats. We showed that 48 h of deprivation was highly efficient, with a residual amount of paradoxical sleep of only 2.2%. Slow wave sleep and wake quantities were similar to baseline, except during the first 4 h of deprivation, where slow wave sleep was strongly reduced. After deprivation, we observed a 124% increase in paradoxical sleep quantities during the first hour of rebound. In addition, 34% of hypocretin/orexin neurones were activated during deprivation, whereas melanin-concentrated hormone neurones were activated only during paradoxical sleep rebound. Corticosterone level showed a twofold increase after deprivation and returned to baseline level after 4 h of recovery. In summary, a fairly selective deprivation and a significant rebound of paradoxical sleep can be obtained in mice using the small-platforms-over-water method. As in rats, rebound is accompanied by a selective activation of melanin-concentrating hormone neurones.

  13. Robust Multiobjective Controllability of Complex Neuronal Networks.

    PubMed

    Tang, Yang; Gao, Huijun; Du, Wei; Lu, Jianquan; Vasilakos, Athanasios V; Kurths, Jurgen

    2016-01-01

    This paper addresses robust multiobjective identification of driver nodes in the neuronal network of a cat's brain, in which uncertainties in determination of driver nodes and control gains are considered. A framework for robust multiobjective controllability is proposed by introducing interval uncertainties and optimization algorithms. By appropriate definitions of robust multiobjective controllability, a robust nondominated sorting adaptive differential evolution (NSJaDE) is presented by means of the nondominated sorting mechanism and the adaptive differential evolution (JaDE). The simulation experimental results illustrate the satisfactory performance of NSJaDE for robust multiobjective controllability, in comparison with six statistical methods and two multiobjective evolutionary algorithms (MOEAs): nondominated sorting genetic algorithms II (NSGA-II) and nondominated sorting composite differential evolution. It is revealed that the existence of uncertainties in choosing driver nodes and designing control gains heavily affects the controllability of neuronal networks. We also unveil that driver nodes play a more drastic role than control gains in robust controllability. The developed NSJaDE and obtained results will shed light on the understanding of robustness in controlling realistic complex networks such as transportation networks, power grid networks, biological networks, etc.

  14. Prefrontal neuronal assemblies temporally control fear behaviour.

    PubMed

    Dejean, Cyril; Courtin, Julien; Karalis, Nikolaos; Chaudun, Fabrice; Wurtz, Hélène; Bienvenu, Thomas C M; Herry, Cyril

    2016-07-21

    Precise spike timing through the coordination and synchronization of neuronal assemblies is an efficient and flexible coding mechanism for sensory and cognitive processing. In cortical and subcortical areas, the formation of cell assemblies critically depends on neuronal oscillations, which can precisely control the timing of spiking activity. Whereas this form of coding has been described for sensory processing and spatial learning, its role in encoding emotional behaviour remains unknown. Fear behaviour relies on the activation of distributed structures, among which the dorsal medial prefrontal cortex (dmPFC) is known to be critical for fear memory expression. In the dmPFC, the phasic activation of neurons to threat-predicting cues, a spike-rate coding mechanism, correlates with conditioned fear responses and supports the discrimination between aversive and neutral stimuli. However, this mechanism does not account for freezing observed outside stimuli presentations, and the contribution of a general spike-time coding mechanism for freezing in the dmPFC remains to be established. Here we use a combination of single-unit and local field potential recordings along with optogenetic manipulations to show that, in the dmPFC, expression of conditioned fear is causally related to the organization of neurons into functional assemblies. During fear behaviour, the development of 4 Hz oscillations coincides with the activation of assemblies nested in the ascending phase of the oscillation. The selective optogenetic inhibition of dmPFC neurons during the ascending or descending phases of this oscillation blocks and promotes conditioned fear responses, respectively. These results identify a novel phase-specific coding mechanism, which dynamically regulates the development of dmPFC assemblies to control the precise timing of fear responses.

  15. Combined Optogenetic and Chemogenetic Control of Neurons

    PubMed Central

    Berglund, Ken; Tung, Jack K.; Higashikubo, Bryan; Gross, Robert E.; Moore, Christopher I.; Hochgeschwender, Ute

    2016-01-01

    Optogenetics provides an array of elements for specific biophysical control, while designer chemogenetic receptors provide a minimally invasive method to control circuits in vivo by peripheral injection. We developed a strategy for selective regulation of activity in specific cells that integrates opto- and chemogenetic approaches, and thus allows manipulation of neuronal activity over a range of spatial and temporal scales in the same experimental animal. Light-sensing molecules (opsins) are activated by biologically produced light through luciferases upon peripheral injection of a small molecule substrate. Such luminescent opsins, luminopsins, allow conventional fiber optic use of optogenetic sensors, while at the same time providing chemogenetic access to the same sensors. We describe applications of this approach in cultured neurons in vitro, in brain slices ex vivo, and in awake and anesthetized animals in vivo. PMID:26965125

  16. Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact.

    PubMed

    Belousov, Andrei B; Wang, Yongfu; Song, Ji-Hoon; Denisova, Janna V; Berman, Nancy E; Fontes, Joseph D

    2012-08-22

    In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI) and epilepsy. Recent studies in mice showed a critical role for neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemia-mediated neuronal death. Here, using controlled cortical impact (CCI) in adult mice, as a model of TBI, and Fluoro-Jade B staining for analysis of neuronal death, we set to determine whether neuronal gap junctions play a role in the CCI-mediated secondary neuronal death. We report that 24h post-CCI, substantial neuronal death is detected in a number of brain regions outside the injury core, including the striatum. The striatal neuronal death is reduced both in wild-type mice by systemic administration of mefloquine (a relatively selective blocker of neuronal gap junctions) and in knockout mice lacking connexin 36 (neuronal gap junction protein). It is also reduced by inactivation of group II metabotropic glutamate receptors (with LY341495) which, as reported previously, control the rapid increase in neuronal gap junction coupling following different types of neuronal injury. The results suggest that neuronal gap junctions play a critical role in the CCI-induced secondary neuronal death. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Investigating neuronal function with optically controllable proteins

    PubMed Central

    Zhou, Xin X.; Pan, Michael; Lin, Michael Z.

    2015-01-01

    In the nervous system, protein activities are highly regulated in space and time. This regulation allows for fine modulation of neuronal structure and function during development and adaptive responses. For example, neurite extension and synaptogenesis both involve localized and transient activation of cytoskeletal and signaling proteins, allowing changes in microarchitecture to occur rapidly and in a localized manner. To investigate the role of specific protein regulation events in these processes, methods to optically control the activity of specific proteins have been developed. In this review, we focus on how photosensory domains enable optical control over protein activity and have been used in neuroscience applications. These tools have demonstrated versatility in controlling various proteins and thereby cellular functions, and possess enormous potential for future applications in nervous systems. Just as optogenetic control of neuronal firing using opsins has changed how we investigate the function of cellular circuits in vivo, optical control may yet yield another revolution in how we study the circuitry of intracellular signaling in the brain. PMID:26257603

  18. Hybrid upconversion nanomaterials for optogenetic neuronal control

    NASA Astrophysics Data System (ADS)

    Shah, Shreyas; Liu, Jing-Jing; Pasquale, Nicholas; Lai, Jinping; McGowan, Heather; Pang, Zhiping P.; Lee, Ki-Bum

    2015-10-01

    Nanotechnology-based approaches offer the chemical control required to develop precision tools suitable for applications in neuroscience. We report a novel approach employing hybrid upconversion nanomaterials, combined with the photoresponsive ion channel channelrhodopsin-2 (ChR2), to achieve near-infrared light (NIR)-mediated optogenetic control of neuronal activity. Current optogenetic methodologies rely on using visible light (e.g. 470 nm blue light), which tends to exhibit high scattering and low tissue penetration, to activate ChR2. In contrast, our approach enables the use of 980 nm NIR light, which addresses the short-comings of visible light as an excitation source. This was facilitated by embedding upconversion nanomaterials, which can convert NIR light to blue luminescence, into polymeric scaffolds. These hybrid nanomaterial scaffolds allowed for NIR-mediated neuronal stimulation, with comparable efficiency as that of 470 nm blue light. Our platform was optimized for NIR-mediated optogenetic control by balancing multiple physicochemical properties of the nanomaterial (e.g. size, morphology, structure, emission spectra, concentration), thus providing an early demonstration of rationally-designing nanomaterial-based strategies for advanced neural applications.Nanotechnology-based approaches offer the chemical control required to develop precision tools suitable for applications in neuroscience. We report a novel approach employing hybrid upconversion nanomaterials, combined with the photoresponsive ion channel channelrhodopsin-2 (ChR2), to achieve near-infrared light (NIR)-mediated optogenetic control of neuronal activity. Current optogenetic methodologies rely on using visible light (e.g. 470 nm blue light), which tends to exhibit high scattering and low tissue penetration, to activate ChR2. In contrast, our approach enables the use of 980 nm NIR light, which addresses the short-comings of visible light as an excitation source. This was facilitated by

  19. New photochemical tools for controlling neuronal activity

    PubMed Central

    Kramer, Richard H.; Fortin, Doris L.; Trauner, Dirk

    2009-01-01

    Neurobiology has entered a new era in which optical methods are challenging electrophysiological techniques for their value in measuring and manipulating neuronal activity. This change is occurring largely because of the development of new photochemical tools, some synthesized by chemists and some provided by nature. This review is focused on the three types of photochemical tools for neuronal control that have emerged in recent years. Caged neurotransmitters, including caged glutamate, are synthetic molecules that enable highly localized activation of neurotransmitter receptors in response to light. Natural photosensitive proteins, including channelrhodopsin-2 and halorhodopsin, can be exogenously expressed in neurons and enable rapid photocontrol of action potential firing. Synthetic small-molecule photoswitches can bestow light-sensitivity on native or exogenously expressed proteins, including K+ channels and glutamate receptors, allowing photocontrol of action potential firing and synaptic events. At a rapid pace, these tools are being improved and new tools are being introduced, thanks to molecular biology and synthetic chemistry. The three families of photochemical tools have different capabilities and uses, but they all share in enabling precise and non-invasive exploration of neural function with light. PMID:19828309

  20. Hybrid upconversion nanomaterials for optogenetic neuronal control.

    PubMed

    Shah, Shreyas; Liu, Jing-Jing; Pasquale, Nicholas; Lai, Jinping; McGowan, Heather; Pang, Zhiping P; Lee, Ki-Bum

    2015-10-28

    Nanotechnology-based approaches offer the chemical control required to develop precision tools suitable for applications in neuroscience. We report a novel approach employing hybrid upconversion nanomaterials, combined with the photoresponsive ion channel channelrhodopsin-2 (ChR2), to achieve near-infrared light (NIR)-mediated optogenetic control of neuronal activity. Current optogenetic methodologies rely on using visible light (e.g. 470 nm blue light), which tends to exhibit high scattering and low tissue penetration, to activate ChR2. In contrast, our approach enables the use of 980 nm NIR light, which addresses the short-comings of visible light as an excitation source. This was facilitated by embedding upconversion nanomaterials, which can convert NIR light to blue luminescence, into polymeric scaffolds. These hybrid nanomaterial scaffolds allowed for NIR-mediated neuronal stimulation, with comparable efficiency as that of 470 nm blue light. Our platform was optimized for NIR-mediated optogenetic control by balancing multiple physicochemical properties of the nanomaterial (e.g. size, morphology, structure, emission spectra, concentration), thus providing an early demonstration of rationally-designing nanomaterial-based strategies for advanced neural applications.

  1. Paradoxical responses to positive end-expiratory pressure in patients with airway obstruction during controlled ventilation*

    PubMed Central

    Caramez, Maria Paula; Borges, Joao B.; Tucci, Mauro R.; Okamoto, Valdelis N.; Carvalho, Carlos R. R.; Kacmarek, Robert M.; Malhotra, Atul; Velasco, Irineu Tadeu; Amato, Marcelo B. P.

    2008-01-01

    Objective To reevaluate the clinical impact of external positive end-expiratory pressure (external-PEEP) application in patients with severe airway obstruction during controlled mechanical ventilation. The controversial occurrence of a paradoxic lung deflation promoted by PEEP was scrutinized. Design External-PEEP was applied stepwise (2 cm H2O, 5-min steps) from zero-PEEP to 150% of intrinsic-PEEP in patients already submitted to ventilatory settings minimizing overinflation. Two commonly used frequencies during permissive hypercapnia (6 and 9/min), combined with two different tidal volumes (VT: 6 and 9 mL/kg), were tested. Setting A hospital intensive care unit. Patients Eight patients were enrolled after confirmation of an obstructive lung disease (inspiratory resistance, >20 cm H2O/L per sec) and the presence of intrinsic-PEEP (≥5 cm H2O) despite the use of very low minute ventilation. Interventions All patients were continuously monitored for intra-arterial blood gas values, cardiac output, lung mechanics, and lung volume with plethysmography. Measurements and Main Results Three different responses to external-PEEP were observed, which were independent of ventilatory settings. In the biphasic response, isovolume-expiratory flows and lung volumes remained constant during progressive PEEP steps until a threshold, beyond which overinflation ensued. In the classic overinflation response, any increment of external-PEEP caused a decrease in isovolume-expiratory flows, with evident overinflation. In the paradoxic response, a drop in functional residual capacity during external-PEEP application (when compared to zero-external-PEEP) was commonly accompanied by decreased plateau pressures and total-PEEP, with increased isovolume-expiratory flows. The paradoxic response was observed in five of the eight patients (three with asthma and two with chronic obstructive pulmonary disease) during at least one ventilator pattern. Conclusions External-PEEP application may

  2. Predator interference effects on biological control: The "paradox" of the generalist predator revisited

    NASA Astrophysics Data System (ADS)

    Parshad, Rana D.; Bhowmick, Suman; Quansah, Emmanuel; Basheer, Aladeen; Upadhyay, Ranjit Kumar

    2016-10-01

    An interesting conundrum in biological control questions the efficiency of generalist predators as biological control agents. Theory suggests, generalist predators are poor agents for biological control, primarily due to mutual interference. However field evidence shows they are actually quite effective in regulating pest densities. In this work we provide a plausible answer to this paradox. We analyze a three species model, where a generalist top predator is introduced into an ecosystem as a biological control, to check the population of a middle predator, that in turn is depredating on a prey species. We show that the inclusion of predator interference alone, can cause the solution of the top predator equation to blow-up in finite time, while there is global existence in the no interference case. This result shows that interference could actually cause a population explosion of the top predator, enabling it to control the target species, thus corroborating recent field evidence. Our results might also partially explain the population explosion of certain species, introduced originally for biological control purposes, such as the cane toad (Bufo marinus) in Australia, which now functions as a generalist top predator. We also show both Turing instability and spatio-temporal chaos in the model. Lastly we investigate time delay effects.

  3. Neuronal control of locomotor handedness in Drosophila

    PubMed Central

    Buchanan, Sean M.; Kain, Jamey S.; de Bivort, Benjamin L.

    2015-01-01

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality. PMID:25953337

  4. Neuronal control of locomotor handedness in Drosophila.

    PubMed

    Buchanan, Sean M; Kain, Jamey S; de Bivort, Benjamin L

    2015-05-26

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality.

  5. The Paradoxical Role of Perceived Control in Late Life Health Behavior

    PubMed Central

    Chipperfield, Judith G.; Perry, Raymond P.; Pekrun, Reinhard; Barchfeld, Petra; Lang, Frieder R.; Hamm, Jeremy M.

    2016-01-01

    Research has established the health benefits of psychological factors, including the way individuals appraise outcomes. Although many studies confirm that appraising outcomes as controllable is adaptive for health, a paradoxical possibility is largely ignored: Perceived control may be detrimental under some conditions. Our premise was that appraising health as controllable but at the same time ascribing little value to it might signal a dysfunctional psychological mindset that fosters a mistaken sense of invincibility. During face-to-face interviews with a representative sample of older adults (age range = 72–99), we identified individuals with such a potentially maladaptive “invincible” mindset (high perceived control and low health value) and compared them to their counterparts on several outcomes. The findings were consistent with our hypotheses. The invincibles denied future risks, they lacked the activating emotion of fear, and they visited their physicians less often over a subsequent five-year period. Moreover, in contrast to their counterparts, the invincibles did not appear strategic in their approach to seeking care: Even poor health did not prompt them to seek the counsel of a physician. The recognition that psychological appraisals are modifiable highlights the promise of remedial methods to alter maladaptive mindsets, potentially improving quality of life. PMID:26974153

  6. Fascin controls neuronal class-specific dendrite arbor morphology.

    PubMed

    Nagel, Julia; Delandre, Caroline; Zhang, Yun; Förstner, Friedrich; Moore, Adrian W; Tavosanis, Gaia

    2012-08-01

    The branched morphology of dendrites represents a functional hallmark of distinct neuronal types. Nonetheless, how diverse neuronal class-specific dendrite branches are generated is not understood. We investigated specific classes of sensory neurons of Drosophila larvae to address the fundamental mechanisms underlying the formation of distinct branch types. We addressed the function of fascin, a conserved actin-bundling protein involved in filopodium formation, in class III and class IV sensory neurons. We found that the terminal branchlets of different classes of neurons have distinctive dynamics and are formed on the basis of molecularly separable mechanisms; in particular, class III neurons require fascin for terminal branching whereas class IV neurons do not. In class III neurons, fascin controls the formation and dynamics of terminal branchlets. Previous studies have shown that transcription factor combinations define dendrite patterns; we find that fascin represents a downstream component of such programs, as it is a major effector of the transcription factor Cut in defining class III-specific dendrite morphology. Furthermore, fascin defines the morphological distinction between class III and class IV neurons. In fact, loss of fascin function leads to a partial conversion of class III neurons to class IV characteristics, while the reverse effect is obtained by fascin overexpression in class IV neurons. We propose that dedicated molecular mechanisms underlie the formation and dynamics of distinct dendrite branch types to elicit the accurate establishment of neuronal circuits.

  7. Paradoxical response preceding control of Scedosporium apiospermum mycetoma with posaconazole treatment.

    PubMed

    Béraud, Guillaume; Desbois, Nicole; Coyo, Caroline; Quist, Danièle; Rozé, Benoit; Savorit, Luc; Cabié, André

    2015-01-01

    Mycetoma is a chronic granulomatous infection that is difficult to treat, notably when due to fungi such as Scedosporium apiospermum. Recent antifungal agents could be an option, but cases are rarely reported, and none with posaconazole. Paradoxical responses, defined as initial clinical worsening despite appropriate treatment, are common in tuberculosis but rare in deep mycoses in non-immunocompromised hosts. Hence, paradoxical responses in context other than mycobacterial infection in an immunocompromised host could provide insights into the pathophysiology and the optimal strategy for treatment. We report the first case of a mycetoma caused by S. apiospermum with bone involvement treated with posaconazole, and the paradoxical response observed at the beginning of the treatment. As with mycobacterial infections, a paradoxical response in deep mycosis could represent the earliest marker of therapeutic efficacy.

  8. Remote control of induced dopaminergic neurons in parkinsonian rats

    PubMed Central

    Dell’Anno, Maria Teresa; Caiazzo, Massimiliano; Leo, Damiana; Dvoretskova, Elena; Medrihan, Lucian; Colasante, Gaia; Giannelli, Serena; Theka, Ilda; Russo, Giovanni; Mus, Liudmila; Pezzoli, Gianni; Gainetdinov, Raul R.; Benfenati, Fabio; Taverna, Stefano; Dityatev, Alexander; Broccoli, Vania

    2014-01-01

    Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson’s disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell–based approaches. PMID:24937431

  9. The paradox of control: An ethnographic analysis of opiate maintenance treatment in a Norwegian prison.

    PubMed

    Mjåland, Kristian

    2015-08-01

    Opiate maintenance treatment (OMT) is increasingly being offered in prisons throughout Europe. The benefits of OMT in prison have been found to be similar to those produced by OMT in community settings. However, prison-based OMT has been a controversial issue because of fear of the diversion of OMT medications and the development of black markets for prescription drugs such as buprenorphine and methadone. Prison-based OMT thus involves a delicate balance between the considerations of control and treatment. This article reports on an ethnographic study of a prison-based OMT programme in a closed Norwegian prison. The data include field notes from eight months of participant observation in the prison as well as qualitative interviews with 23 prisoners and 12 prison staff. Midway through the fieldwork, the prison authorities established a separate unit for OMT-enrolled prisoners to reduce the widespread diversion of buprenorphine. This "natural experiment" is explored in the analysis. The prison-based OMT programme was characterised by strict and repressive control to prevent the diversion of buprenorphine, and the control became even stricter after the establishment of the OMT unit. However, the diversion of buprenorphine increased rather than decreased after the establishment of the OMT unit. To understand this "paradox of control", the article engages with theories of legitimacy, power and resistance. The excessive and repressive control was perceived as illegitimate and unfair by the majority of study participants. In various ways, many prisoners protested, confronted and subverted the OMT programme. The increase in buprenorphine diversion is interpreted as a form of collective resistance towards the perceived unfairness of the OMT programme. The article demonstrates that an unbalanced and control-dominated approach to prison-based OMT may have the opposite effect of what is intended. Copyright © 2015 The Author. Published by Elsevier B.V. All rights reserved.

  10. Evaluation of hydrogeologic aspects of proposed salinity control in Paradox Valley, Colorado

    USGS Publications Warehouse

    Konikow, Leonard F.; Bedinger, M.S.

    1978-01-01

    The salt load in the Dolores River increases by about 200,000 tons per year where it crosses Paradox Valley, Colorado, because of the discharge of a sodium chloride brine from an underlying aquifer. A ground-water management program to nearly eliminate this major source of salt, which eventually enters the Colorado River, can be designed on the basis of an accurate description of the hydrogeologic framework of Paradox Valley.

  11. Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.

    PubMed

    Johnston, Stephen T; Shtrahman, Matthew; Parylak, Sarah; Gonçalves, J Tiago; Gage, Fred H

    2016-03-01

    Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct neuronal representations, permitting the discrimination of highly similar stimuli in hippocampus-dependent tasks. However, the mechanism by which immature adult-born dentate granule neurons cells (abDGCs) perform this function remains unknown. Two theories of abDGC function, one by which abDGCs modulate and sparsify activity in the dentate gyrus and one by which abDGCs act as autonomous coding units, are generally suggested to be mutually exclusive. This review suggests that these two mechanisms work in tandem to dynamically regulate memory resolution while avoiding memory interference and maintaining memory robustness.

  12. Rapid Mechanically Controlled Rewiring of Neuronal Circuits

    PubMed Central

    Magdesian, Margaret H.; Lopez-Ayon, G. Monserratt; Mori, Megumi; Boudreau, Dominic; Goulet-Hanssens, Alexis; Sanz, Ricardo; Miyahara, Yoichi; Barrett, Christopher J.; Fournier, Alyson E.; De Koninck, Yves

    2016-01-01

    CNS injury may lead to permanent functional deficits because it is still not possible to regenerate axons over long distances and accurately reconnect them with an appropriate target. Using rat neurons, microtools, and nanotools, we show that new, functional neurites can be created and precisely positioned to directly (re)wire neuronal networks. We show that an adhesive contact made onto an axon or dendrite can be pulled to initiate a new neurite that can be mechanically guided to form new synapses at up to 0.8 mm distance in <1 h. Our findings challenge current understanding of the limits of neuronal growth and have direct implications for the development of new therapies and surgical techniques to achieve functional regeneration. SIGNIFICANCE STATEMENT Brain and spinal cord injury may lead to permanent disability and death because it is still not possible to regenerate neurons over long distances and accurately reconnect them with an appropriate target. Using microtools and nanotools we have developed a new method to rapidly initiate, elongate, and precisely connect new functional neuronal circuits over long distances. The extension rates achieved are ≥60 times faster than previously reported. Our findings have direct implications for the development of new therapies and surgical techniques to achieve functional regeneration after trauma and in neurodegenerative diseases. It also opens the door for the direct wiring of robust brain–machine interfaces as well as for investigations of fundamental aspects of neuronal signal processing and neuronal function. PMID:26791225

  13. Biological Investigations of Adaptive Networks: Neuronal Control of Conditioned Responses

    DTIC Science & Technology

    1989-07-01

    NO Boiling AFB, DC 203-4861102F 2312 Al I TI TLE (include Secunty Clamtfiation) Biological Investigations of Adaptive Networks: Neuronal Control of...based on mathematical models and computer simulation. Recordings were done from single brain stem neurons in awake, behaving animals for the purpose...single-unit recordings from awake behaving animals were developed. The relationship between single neurons ’ dynamic behavior and the CR in terms of

  14. Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons.

    PubMed

    Eriksson, Krister S; Sergeeva, Olga A; Selbach, Oliver; Haas, Helmut L

    2004-03-01

    High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.

  15. Insulin controls food intake and energy balance via NPY neurons.

    PubMed

    Loh, Kim; Zhang, Lei; Brandon, Amanda; Wang, Qiaoping; Begg, Denovan; Qi, Yue; Fu, Melissa; Kulkarni, Rishikesh; Teo, Jonathan; Baldock, Paul; Brüning, Jens C; Cooney, Gregory; Neely, Greg; Herzog, Herbert

    2017-06-01

    Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla. To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis. By specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity. Taken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases.

  16. Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function.

    PubMed

    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

  17. Parrondo’s paradox for chaos control and anticontrol of fractional-order systems

    NASA Astrophysics Data System (ADS)

    Marius-F, Danca; Wallace, K. S. Tang

    2016-01-01

    We present the generalized forms of Parrondo’s paradox existing in fractional-order nonlinear systems. The generalization is implemented by applying a parameter switching (PS) algorithm to the corresponding initial value problems associated with the fractional-order nonlinear systems. The PS algorithm switches a system parameter within a specific set of N ≥ 2 values when solving the system with some numerical integration method. It is proven that any attractor of the concerned system can be approximated numerically. By replacing the words “winning” and “loosing” in the classical Parrondo’s paradox with “order” and “chaos", respectively, the PS algorithm leads to the generalized Parrondo’s paradox: chaos1 + chaos2 + ··· + chaosN = order and order1 + order2 + ··· + orderN = chaos. Finally, the concept is well demonstrated with the results based on the fractional-order Chen system.

  18. Medial prefrontal D1 dopamine neurons control food intake

    PubMed Central

    Land, Benjamin B; Narayanan, Nandakumar S; Liu, Rong-Jian; Gianessi, Carol A; Brayton, Catherine E; Grimaldi, David; Sarhan, Maysa; Guarnieri, Douglas J; Deisseroth, Karl; Aghajanian, George K; Dileone, Ralph J

    2014-01-01

    Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake. PMID:24441680

  19. Astrocyte morphology is controlled by neuron-derived FGF

    PubMed Central

    Agarwal, Amit; Bergles, Dwight E.

    2014-01-01

    The highly ramified processes of astrocytes enable cellular interactions and extracellular homeostasis. In this issue of Neuron, Stork et al. (2014) report that extension and elaboration of astrocyte processes in Drosophila is controlled by the release of FGF by neurons. PMID:25033173

  20. Iterative learning control algorithm for spiking behavior of neuron model

    NASA Astrophysics Data System (ADS)

    Li, Shunan; Li, Donghui; Wang, Jiang; Yu, Haitao

    2016-11-01

    Controlling neurons to generate a desired or normal spiking behavior is the fundamental building block of the treatment of many neurologic diseases. The objective of this work is to develop a novel control method-closed-loop proportional integral (PI)-type iterative learning control (ILC) algorithm to control the spiking behavior in model neurons. In order to verify the feasibility and effectiveness of the proposed method, two single-compartment standard models of different neuronal excitability are specifically considered: Hodgkin-Huxley (HH) model for class 1 neural excitability and Morris-Lecar (ML) model for class 2 neural excitability. ILC has remarkable advantages for the repetitive processes in nature. To further highlight the superiority of the proposed method, the performances of the iterative learning controller are compared to those of classical PI controller. Either in the classical PI control or in the PI control combined with ILC, appropriate background noises are added in neuron models to approach the problem under more realistic biophysical conditions. Simulation results show that the controller performances are more favorable when ILC is considered, no matter which neuronal excitability the neuron belongs to and no matter what kind of firing pattern the desired trajectory belongs to. The error between real and desired output is much smaller under ILC control signal, which suggests ILC of neuron’s spiking behavior is more accurate.

  1. Tracking and control of neuronal Hodgkin-Huxley dynamics.

    PubMed

    Ullah, Ghanim; Schiff, Steven J

    2009-04-01

    Nonlinear ensemble state estimation offers a paradigm-shifting improvement in our ability to observe, predict, and control the state of spiking neuronal systems. We use an ensemble Kalman filter to predict hidden states and future trajectories in the Hodgkin-Huxley equations, reconstruct ion dynamics, control neuronal activity including a strategy for dynamic conductance clamping, and show the feasibility of controlling pathological cellular activity such as seizures.

  2. Controlling Chaos in Neuron Based on Lasalle Invariance Principle

    NASA Astrophysics Data System (ADS)

    Wei, Du-Qu; Qin, Ying-Hua

    2011-09-01

    A new control law is proposed to asymptotically stabilize the chaotic neuron system based on LaSalle invariant principle. The control technique does not require analytical knowledge of the system dynamics and operates without an explicit knowledge of the desired steady-state position. The well-known modified Hodgkin—Huxley (MHH) and Hindmarsh—Rose (HR) model neurons are taken as examples to verify the implementation of our method. Simulation results show the proposed control law is effective. The outcome of this study is significant since it is helpful to understand the learning process of a human brain towards the information processing, memory and abnormal discharge of the brain neurons.

  3. Motor neurons controlling fluid ingestion in Drosophila.

    PubMed

    Manzo, Andrea; Silies, Marion; Gohl, Daryl M; Scott, Kristin

    2012-04-17

    Rhythmic motor behaviors such as feeding are driven by neural networks that can be modulated by external stimuli and internal states. In Drosophila, ingestion is accomplished by a pump that draws fluid into the esophagus. Here we examine how pumping is regulated and characterize motor neurons innervating the pump. Frequency of pumping is not affected by sucrose concentration or hunger but is altered by fluid viscosity. Inactivating motor neurons disrupts pumping and ingestion, whereas activating them elicits arrhythmic pumping. These motor neurons respond to taste stimuli and show prolonged activity to palatable substances. This work describes an important component of the neural circuit for feeding in Drosophila and is a step toward understanding the rhythmic activity producing ingestion.

  4. Egr2-neurons control the adult respiratory response to hypercapnia

    PubMed Central

    Ray, Russell S.; Corcoran, Andrea E.; Brust, Rachael D.; Soriano, Laura P.; Nattie, Eugene E.; Dymecki, Susan M.

    2013-01-01

    ‘The early growth response 2 transcription factor, Egr2, establishes a population of brainstem neurons essential for normal breathing at birth. Egr2-null mice die perinatally of respiratory insufficiency characterized by subnormal respiratory rate and severe apneas. Here we bypass this lethality using a noninvasive pharmacogenetic approach to inducibly perturb neuron activity postnatally, and ask if Egr2-neurons control respiration in adult mice. We found that the normal ventilatory increase in response to elevated tissue CO2 was impaired, blunted by 63.1±8.7% after neuron perturbation due to deficits in both respiratory amplitude and frequency. By contrast, room-air breathing was unaffected, suggesting that the drive for baseline breathing may not require those Egr2-neurons manipulated here. Of the multiple brainstem sites proposed to affect ventilation in response to hypercapnia, only the retrotrapezoid nucleus, a portion of the serotonergic raphé, and a portion of the A5 nucleus have a history of Egr2 expression. We recently showed that acute inhibition of serotonergic neurons en masse blunts the CO2 chemoreflex in adults, causing a difference in hypercapnic response of ~50% after neuron perturbation through effects on respiratory amplitude only. The suppressed respiratory frequency upon perturbation of Egr2-neurons thus may stem from non-serotonergic neurons within the Egr2 domain. Perturbation of Egr2-neurons did not affect body temperature, even on exposure to ambient 4 °C. These findings support a model in which Egr2-neurons are a critical component of the respiratory chemoreflex into adulthood. Methodologically, these results highlight how pharmacogenetic approaches allow neuron function to be queried in unanesthetized adult animals, reaching beyond the roadblocks of developmental lethality and compensation as well as the anatomical disturbances associated with invasive methods. PMID:23261662

  5. A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons.

    PubMed Central

    Lévesque, D; Martres, M P; Diaz, J; Griffon, N; Lammers, C H; Sokoloff, P; Schwartz, J C

    1995-01-01

    The effects of interruption of dopaminergic transmission or sustained blockade of dopamine receptors by neuroleptics on the dopamine D3 receptor in the shell of the nucleus accumbens were investigated in rats. In this brain area the D3 receptor is abundant and may mediate antipsychotic drug effects. The D3 receptor density and mRNA abundance were evaluated with 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin and by quantitative PCR or image analysis of in situ hybridization signals, respectively. Unilateral dopamine neuron degeneration by 6-hydroxydopamine or sections triggered, after a few days, a marked decrease (up to 50%) in D3 receptor binding and mRNA in the nucleus accumbens. In contrast, a 2-week treatment with the neuroleptic haloperidol (20 mg/kg) had no effect on D3 receptor density and mRNA but enhanced D2 receptor density and mRNA level by > 50%. In addition, tolerance to the haloperidol-induced change of neurotensin mRNA mediated by the D2 receptor developed, but there was no tolerance to the opposite change mediated by the D3 receptor. Reserpine, a monoamine-depleting drug with antipsychotic activity, did not modify D3 receptor mRNA. These observations reinforce the idea that the D3 receptor may be an important target for neuroleptics whose antipsychotic actions, but not extrapyramidal motor actions, do not display tolerance. The D3 receptor mRNA level was also decreased by a unilateral injection in dopamine cell body areas of colchicine, a drug blocking the anterograde axonal transport, or by baclofen, a type A gamma-aminobutyric acid receptor agonist reducing dopamine neuron activity, but not by sustained blockade of D1-like and D2-like, neurotensin, or cholecystokinin receptors. We therefore propose that an anterograde factor present in mesolimbic dopaminergic neurons, but distinct from dopamine and known peptide cotransmitters, plays a positive role on transcription of the D3 receptor gene. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:7878047

  6. Analysis and application of neuronal network controllability and observability

    NASA Astrophysics Data System (ADS)

    Su, Fei; Wang, Jiang; Li, Huiyan; Deng, Bin; Yu, Haitao; Liu, Chen

    2017-02-01

    Controllability and observability analyses are important prerequisite for designing suitable neural control strategy, which can help lower the efforts required to control and observe the system dynamics. First, 3-neuron motifs including the excitatory motif, the inhibitory motif, and the mixed motif are constructed to investigate the effects of single neuron and synaptic dynamics on network controllability (observability). Simulation results demonstrate that for networks with the same topological structure, the controllability (observability) of the node always changes if the properties of neurons and synaptic coupling strengths vary. Besides, the inhibitory networks are more controllable (observable) than the excitatory networks when the coupling strengths are the same. Then, the numerically determined controllability results of 3-neuron excitatory motifs are generalized to the desynchronization control of the modular motif network. The control energy and neuronal synchrony measure indexes are used to quantify the controllability of each node in the modular network. The best driver node obtained in this way is the same as the deduced one from motif analysis.

  7. Linear control of neuronal spike timing using phase response curves.

    PubMed

    Stigen, Tyler; Danzl, Per; Moehlis, Jeff; Netoff, Theoden

    2009-01-01

    We propose a simple, robust, linear method to control the spike timing of a periodically firing neuron. The control scheme uses the neuron's phase response curve to identify an area of optimal sensitivity for the chosen stimulation parameters. The spike advance as a function of current pulse amplitude is characterized at the optimal phase and a linear least-squares regression is fit to the data. The inverted regression is used as the control function for this method. The efficacy of this method is demonstrated through numerical simulations of a Hodgkin-Huxley style neuron model as well as in real neurons from rat hippocampal slice preparations. The study shows a proof of concept for the application of a linear control scheme to control neuron spike timing in-vitro. This study was done on an individual cell level, but translation to a tissue or network level is possible. Control schemes of this type could be implemented in a closed loop implantable device to treat neuromotor disorders involving pathologically neuronal activity such as epilepsy or Parkinson's disease.

  8. Obesity paradoxes.

    PubMed

    McAuley, Paul A; Blair, Steven N

    2011-05-01

    In this review, we examine the original obesity paradox phenomenon (i.e. in cardiovascular disease populations, obese patients survive better), as well as three other related paradoxes (pre-obesity, "fat but fit" theory, and "healthy" obesity). An obesity paradox has been reported in a range of cardiovascular and non-cardiovascular conditions. Pre-obesity (defined as a body mass index of 25.0-29.9 kg · m⁻²) presents another paradox. Whereas "overweight" implies increased risk, it is in fact associated with decreased mortality risk compared with normal weight. Another paradox concerns the observation than when fitness is taken into account, the mortality risk associated with obesity is offset. The final paradox under consideration is the presence of a sizeable subset of obese individuals who are otherwise healthy. Consequently, a large segment of the overweight and obese population is not at increased risk for premature death. It appears therefore that low cardiorespiratory fitness and inactivity are a greater health threat than obesity, suggesting that more emphasis should be placed on increasing leisure time physical activity and cardiorespiratory fitness as the main strategy for reducing mortality risk in the broad population of overweight and obese adults.

  9. Ascending SAG neurons control sexual receptivity of Drosophila females.

    PubMed

    Feng, Kai; Palfreyman, Mark T; Häsemeyer, Martin; Talsma, Aaron; Dickson, Barry J

    2014-07-02

    Mating induces pronounced changes in female reproductive behavior, typically including a dramatic reduction in sexual receptivity. In Drosophila, postmating behavioral changes are triggered by sex peptide (SP), a male seminal fluid peptide that acts via a receptor (SPR) expressed in sensory neurons (SPSNs) of the female reproductive tract. Here, we identify second-order neurons that mediate the behavioral changes induced by SP. These SAG neurons receive synaptic input from SPSNs in the abdominal ganglion and project to the dorsal protocerebrum. Silencing SAG neurons renders virgin females unreceptive, whereas activating them increases the receptivity of females that have already mated. Physiological experiments demonstrate that SP downregulates the excitability of the SPSNs, and hence their input onto SAG neurons. These data thus provide a physiological correlate of mating status in the female central nervous system and a key entry point into the brain circuits that control sexual receptivity. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Inhibition Controls Asynchronous States of Neuronal Networks

    PubMed Central

    Treviño, Mario

    2016-01-01

    Computations in cortical circuits require action potentials from excitatory and inhibitory neurons. In this mini-review, I first provide a quick overview of findings that indicate that GABAergic neurons play a fundamental role in coordinating spikes and generating synchronized network activity. Next, I argue that these observations helped popularize the notion that network oscillations require a high degree of spike correlations among interneurons which, in turn, produce synchronous inhibition of the local microcircuit. The aim of this text is to discuss some recent experimental and computational findings that support a complementary view: one in which interneurons participate actively in producing asynchronous states in cortical networks. This requires a proper mixture of shared excitation and inhibition leading to asynchronous activity between neighboring cells. Such contribution from interneurons would be extremely important because it would tend to reduce the spike correlation between neighboring pyramidal cells, a drop in redundancy that could enhance the information-processing capacity of neural networks. PMID:27274721

  11. Mechanosensory neurons control sweet sensing in Drosophila

    PubMed Central

    Jeong, Yong Taek; Oh, Soo Min; Shim, Jaewon; Seo, Jeong Taeg; Kwon, Jae Young; Moon, Seok Jun

    2016-01-01

    Animals discriminate nutritious food from toxic substances using their sense of taste. Since taste perception requires taste receptor cells to come into contact with water-soluble chemicals, it is a form of contact chemosensation. Concurrent with that contact, mechanosensitive cells detect the texture of food and also contribute to the regulation of feeding. Little is known, however, about the extent to which chemosensitive and mechanosensitive circuits interact. Here, we show Drosophila prefers soft food at the expense of sweetness and that this preference requires labellar mechanosensory neurons (MNs) and the mechanosensory channel Nanchung. Activation of these labellar MNs causes GABAergic inhibition of sweet-sensing gustatory receptor neurons, reducing the perceived intensity of a sweet stimulus. These findings expand our understanding of the ways different sensory modalities cooperate to shape animal behaviour. PMID:27641708

  12. Mechanosensory neurons control sweet sensing in Drosophila.

    PubMed

    Jeong, Yong Taek; Oh, Soo Min; Shim, Jaewon; Seo, Jeong Taeg; Kwon, Jae Young; Moon, Seok Jun

    2016-09-19

    Animals discriminate nutritious food from toxic substances using their sense of taste. Since taste perception requires taste receptor cells to come into contact with water-soluble chemicals, it is a form of contact chemosensation. Concurrent with that contact, mechanosensitive cells detect the texture of food and also contribute to the regulation of feeding. Little is known, however, about the extent to which chemosensitive and mechanosensitive circuits interact. Here, we show Drosophila prefers soft food at the expense of sweetness and that this preference requires labellar mechanosensory neurons (MNs) and the mechanosensory channel Nanchung. Activation of these labellar MNs causes GABAergic inhibition of sweet-sensing gustatory receptor neurons, reducing the perceived intensity of a sweet stimulus. These findings expand our understanding of the ways different sensory modalities cooperate to shape animal behaviour.

  13. Change in types of neuronal excitability via bifurcation control.

    PubMed

    Xie, Yong; Aihara, Kazuyuki; Kang, Yan Mei

    2008-02-01

    This paper proposes an approach to changing the types of neuronal excitability via bifurcation control. A washout filter-aided dynamic feedback controller is introduced to bifurcation dynamics of a two-dimensional Hindmarsh-Rose type model neuron, which shows a saddle-node on invariant circle (SNIC) bifurcation from quiescence to periodic spiking and then exhibits type-I excitability. At first, a Hopf bifurcation is created at a desired parameter value before the SNIC bifurcation occurs, and then the criticality of the created Hopf bifurcation is regulated by choosing appropriate values of the controller parameters. In this manner, the model neuron starts to show type-II excitability. Therefore the type of neuronal excitability is transformed from type-I excitability to type-II excitability for the model neuron via the washout filter-aided dynamic feedback controller. In such a controller, the linear control gain is determined by the two basic critical conditions for the Hopf bifurcation, i.e., the eigenvalue assignment and the transversality condition. We apply the center manifold and normal form theory to deduce a closed-form analytic expression for the bifurcation stability coefficient, which is a function with respect to the nonlinear control gain. A suitable nonlinear control gain is chosen to make the bifurcation stability coefficient negative, and thus the criticality of the created Hopf bifurcation can be changed from subcritical to supercritical. In addition, the amplitude of the corresponding periodic solution can be also regulated by the nonlinear control gain.

  14. Signal Propagation between Neuronal Populations Controlled by Micropatterning

    PubMed Central

    Albers, Jonas; Offenhäusser, Andreas

    2016-01-01

    The central nervous system consists of an unfathomable number of functional networks enabling highly sophisticated information processing. Guided neuronal growth with a well-defined connectivity and accompanying polarity is essential for the formation of these networks. To investigate how two-dimensional protein patterns influence neuronal outgrowth with respect to connectivity and functional polarity between adjacent populations of neurons, a microstructured model system was established. Exclusive cell growth on patterned substrates was achieved by transferring a mixture of poly-l-lysine and laminin to a cell-repellent glass surface by microcontact printing. Triangular structures with different opening angle, height, and width were chosen as a pattern to achieve network formation with defined behavior at the junction of adjacent structures. These patterns were populated with dissociated primary cortical embryonic rat neurons and investigated with respect to their impact on neuronal outgrowth by immunofluorescence analysis, as well as their functional connectivity by calcium imaging. Here, we present a highly reproducible technique to devise neuronal networks in vitro with a predefined connectivity induced by the design of the gateway. Daisy-chained neuronal networks with predefined connectivity and functional polarity were produced using the presented micropatterning method. Controlling the direction of signal propagation among populations of neurons provides insights to network communication and offers the chance to investigate more about learning processes in networks by external manipulation of cells and signal cascades. PMID:27379230

  15. [Progress in our understanding of the architecture of paradoxical sleep since William Dement and Michel Jouvet].

    PubMed

    Luppi, Pierre-Hervé

    2011-10-01

    Paradoxical or REM sleep, characterized by cortical activation combined with muscle atonia and rapid eye movements, was discovered at the end of the 1950s by Michel Jouvet and William C. Dement. Studies over the next twenty years suggested that the onset and maintenance of paradoxical sleep was due to a reciprocal inhibitory interaction between monoaminergic neurons inhibiting PS and cholinergic neurons generating PS located in a small part of the pontine reticular formation called the sublaterodorsal tegmental nucleus. Our recent studies rather indicate that these neurons are respectively GABAergic and glutamatergic. Further, they suggest that three populations of GABAergic neurons and population of hypothalamic neurons expressing melanin concentrating hormone, a peptide, play a important role in PS control.

  16. Stochastic optimal control of single neuron spike trains.

    PubMed

    Iolov, Alexandre; Ditlevsen, Susanne; Longtin, André

    2014-08-01

    External control of spike times in single neurons can reveal important information about a neuron's sub-threshold dynamics that lead to spiking, and has the potential to improve brain-machine interfaces and neural prostheses. The goal of this paper is the design of optimal electrical stimulation of a neuron to achieve a target spike train under the physiological constraint to not damage tissue. We pose a stochastic optimal control problem to precisely specify the spike times in a leaky integrate-and-fire (LIF) model of a neuron with noise assumed to be of intrinsic or synaptic origin. In particular, we allow for the noise to be of arbitrary intensity. The optimal control problem is solved using dynamic programming when the controller has access to the voltage (closed-loop control), and using a maximum principle for the transition density when the controller only has access to the spike times (open-loop control). We have developed a stochastic optimal control algorithm to obtain precise spike times. It is applicable in both the supra-threshold and sub-threshold regimes, under open-loop and closed-loop conditions and with an arbitrary noise intensity; the accuracy of control degrades with increasing intensity of the noise. Simulations show that our algorithms produce the desired results for the LIF model, but also for the case where the neuron dynamics are given by more complex models than the LIF model. This is illustrated explicitly using the Morris-Lecar spiking neuron model, for which an LIF approximation is first obtained from a spike sequence using a previously published method. We further show that a related control strategy based on the assumption that there is no noise performs poorly in comparison to our noise-based strategies. The algorithms are numerically intensive and may require efficiency refinements to achieve real-time control; in particular, the open-loop context is more numerically demanding than the closed-loop one. Our main contribution is the

  17. Stochastic optimal control of single neuron spike trains

    NASA Astrophysics Data System (ADS)

    Iolov, Alexandre; Ditlevsen, Susanne; Longtin, André

    2014-08-01

    Objective. External control of spike times in single neurons can reveal important information about a neuron's sub-threshold dynamics that lead to spiking, and has the potential to improve brain-machine interfaces and neural prostheses. The goal of this paper is the design of optimal electrical stimulation of a neuron to achieve a target spike train under the physiological constraint to not damage tissue. Approach. We pose a stochastic optimal control problem to precisely specify the spike times in a leaky integrate-and-fire (LIF) model of a neuron with noise assumed to be of intrinsic or synaptic origin. In particular, we allow for the noise to be of arbitrary intensity. The optimal control problem is solved using dynamic programming when the controller has access to the voltage (closed-loop control), and using a maximum principle for the transition density when the controller only has access to the spike times (open-loop control). Main results. We have developed a stochastic optimal control algorithm to obtain precise spike times. It is applicable in both the supra-threshold and sub-threshold regimes, under open-loop and closed-loop conditions and with an arbitrary noise intensity; the accuracy of control degrades with increasing intensity of the noise. Simulations show that our algorithms produce the desired results for the LIF model, but also for the case where the neuron dynamics are given by more complex models than the LIF model. This is illustrated explicitly using the Morris-Lecar spiking neuron model, for which an LIF approximation is first obtained from a spike sequence using a previously published method. We further show that a related control strategy based on the assumption that there is no noise performs poorly in comparison to our noise-based strategies. The algorithms are numerically intensive and may require efficiency refinements to achieve real-time control; in particular, the open-loop context is more numerically demanding than the closed

  18. Control of cortical neuronal migration by glutamate and GABA

    PubMed Central

    Luhmann, Heiko J.; Fukuda, A.; Kilb, W.

    2015-01-01

    Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca2+ transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis. PMID:25688185

  19. Control of cortical neuronal migration by glutamate and GABA.

    PubMed

    Luhmann, Heiko J; Fukuda, A; Kilb, W

    2015-01-01

    Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca(2+) transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis.

  20. Illumination controls differentiation of dopamine neurons regulating behaviour.

    PubMed

    Dulcis, Davide; Spitzer, Nicholas C

    2008-11-13

    Specification of the appropriate neurotransmitter is a crucial step in neuronal differentiation because it enables signalling among populations of neurons. Experimental manipulations demonstrate that both autonomous and activity-dependent genetic programs contribute to this process during development, but whether natural environmental stimuli specify transmitter expression in a neuronal population is unknown. We investigated neurons of the ventral suprachiasmatic nucleus that regulate neuroendocrine pituitary function in response to light in teleosts, amphibia and primates. Here we show that altering light exposure, which changes the sensory input to the circuit controlling adaptation of skin pigmentation to background, changes the number of neurons expressing dopamine in larvae of the amphibian Xenopus laevis in a circuit-specific and activity-dependent manner. Neurons newly expressing dopamine then regulate changes in camouflage colouration in response to illumination. Thus, physiological activity alters the numbers of behaviourally relevant amine-transmitter-expressing neurons in the brain at postembryonic stages of development. The results may be pertinent to changes in cognitive states that are regulated by biogenic amines.

  1. Neuronal circuitry controlling the near response.

    PubMed

    Mays, L E; Gamlin, P D

    1995-12-01

    Experiments in primates have contributed greatly to our understanding of the neural mechanisms involved in the eye movements required to view objects at different distances. Early work focused on the circuitry for generating horizontal vergence eye movements alone. However, vergence eye movements are associated with lens accommodation and are usually accompanied by saccadic eye movements, so more recent work has been directed at understanding the interactions between vergence and accommodation, and between vergence and saccades. A new model explains the neural basis for interactions between vergence and accommodation by a neural network in which pre-motor elements are shared by these two systems. The effects of saccades on vergence eye movements appear to be the result of shared pre-motor circuits as well. Current evidence suggests that pontine omnipause neurons, known to be crucial for the generation of saccades, play an important role in the vergence pre-motor circuitry.

  2. Optical Imaging and Control of Neurons

    NASA Astrophysics Data System (ADS)

    Song, Yoon-Kyu

    Although remarkable progress has been made in our understanding of the function, organization, and development of the brain by various approaches of modern science and technology, how the brain performs its marvelous function remains unsolved or incompletely understood. This is mainly attributed to the insufficient capability of currently available research tools and conceptual frameworks to deal with enormous complexity of the brain. Hence, in the last couple of decades, a significant effort has been made to crack the complexity of brain by utilizing research tools from diverse scientific areas. The research tools include the optical neurotechnology which incorporates the exquisite characteristics of optics, such as multi-parallel access and non-invasiveness, in sensing and stimulating the excitable membrane of a neuron, the basic functional unit of the brain. This chapter is aimed to serve as a short introduction to the optical neurotechnology for those who wish to use optical techniques as one of their brain research tools.

  3. Galileo's Paradox

    NASA Astrophysics Data System (ADS)

    Greenslade, Thomas B.

    2008-05-01

    The paradox is a wonderful teaching tool. The sleepy student in the back row is surprised and wakes up, and the student with the instantly memorized answer is forced into the analytical mode. The diagram in Fig. 1 has the following paradox: A body sliding freely down a chord from the edge of the circle reaches the lowest point on the circle at the same time as a body released simultaneously from the top. This result was first mentioned in a 1602 letter from Galileo Galilei to Guidobaldo dal Monte.

  4. Simpson's Paradox, Lord's Paradox, and Suppression Effects are the same phenomenon – the reversal paradox

    PubMed Central

    Tu, Yu-Kang; Gunnell, David; Gilthorpe, Mark S

    2008-01-01

    This article discusses three statistical paradoxes that pervade epidemiological research: Simpson's paradox, Lord's paradox, and suppression. These paradoxes have important implications for the interpretation of evidence from observational studies. This article uses hypothetical scenarios to illustrate how the three paradoxes are different manifestations of one phenomenon – the reversal paradox – depending on whether the outcome and explanatory variables are categorical, continuous or a combination of both; this renders the issues and remedies for any one to be similar for all three. Although the three statistical paradoxes occur in different types of variables, they share the same characteristic: the association between two variables can be reversed, diminished, or enhanced when another variable is statistically controlled for. Understanding the concepts and theory behind these paradoxes provides insights into some controversial or contradictory research findings. These paradoxes show that prior knowledge and underlying causal theory play an important role in the statistical modelling of epidemiological data, where incorrect use of statistical models might produce consistent, replicable, yet erroneous results. PMID:18211676

  5. Direct control of paralysed muscles by cortical neurons.

    PubMed

    Moritz, Chet T; Perlmutter, Steve I; Fetz, Eberhard E

    2008-12-04

    A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.

  6. Direct control of paralyzed muscles by cortical neurons

    PubMed Central

    Moritz, Chet T.; Perlmutter, Steve I.; Fetz, Eberhard E.

    2011-01-01

    A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury via artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralyzed limbs1–3. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms4–10, and paralyzed muscles have been activated by functional electrical stimulation (FES)11–13. Here we show that monkeys can directly control stimulation of muscles using the activity of neurons in motor cortex, thereby restoring goal-directed movements to a transiently paralyzed arm. Moreover, neurons could control functional stimulation equally well regardless of any prior association to movement, a finding that significantly expands the source of control signals for brain-machine interfaces. Monkeys learned to utilize these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralyzed limbs. PMID:18923392

  7. Euthanasia: moral paradoxes.

    PubMed

    ten Have, H A

    2001-11-01

    Over the past 30 years, euthanasia has been under continuous debate in The Netherlands. This contribution aims to provide a moral assessment of this debate. It is argued that euthanasia should be understood within a historical context, as a protest against medical power and as a way to bring about good death. Within the euthanasia debate, two paradoxes are identified which make the issue inherently complex and hard to regulate. The first paradox results from the dialectical relation between individual autonomy and relief of suffering as the major justifications of euthanasia. Although euthanasia represents an ultimate effort to give the individual patient control over his dying, the result of the debate is an increase of medical power. The second paradox is that although euthanasia emerged from a commitment to good death, it is resulting in a reduced range of options to bring about good death.

  8. Early Commissural Diencephalic Neurons Control Habenular Axon Extension and Targeting.

    PubMed

    Beretta, Carlo A; Dross, Nicolas; Guglielmi, Luca; Bankhead, Peter; Soulika, Marina; Gutierrez-Triana, Jose A; Paolini, Alessio; Poggi, Lucia; Falk, Julien; Ryu, Soojin; Kapsimali, Marika; Engel, Ulrike; Carl, Matthias

    2017-01-23

    Most neuronal populations form on both the left and right sides of the brain. Their efferent axons appear to grow synchronously along similar pathways on each side, although the neurons or their environment often differ between the two hemispheres [1-4]. How this coordination is controlled has received little attention. Frequently, neurons establish interhemispheric connections, which can function to integrate information between brain hemispheres (e.g., [5]). Such commissures form very early, suggesting their potential developmental role in coordinating ipsilateral axon navigation during embryonic development [4]. To address the temporal-spatial control of bilateral axon growth, we applied long-term time-lapse imaging to visualize the formation of the conserved left-right asymmetric habenular neural circuit in the developing zebrafish embryo [6]. Although habenular neurons are born at different times across brain hemispheres [7], we found that elongation of habenular axons occurs synchronously. The initiation of axon extension is not controlled within the habenular network itself but through an early developing proximal diencephalic network. The commissural neurons of this network influence habenular axons both ipsilaterally and contralaterally. Their unilateral absence impairs commissure formation and coordinated habenular axon elongation and causes their subsequent arrest on both sides of the brain. Thus, habenular neural circuit formation depends on a second intersecting commissural network, which facilitates the exchange of information between hemispheres required for ipsilaterally projecting habenular axons. This mechanism of network formation may well apply to other circuits, and has only remained undiscovered due to technical limitations.

  9. Control of REM sleep by ventral medulla GABAergic neurons.

    PubMed

    Weber, Franz; Chung, Shinjae; Beier, Kevin T; Xu, Min; Luo, Liqun; Dan, Yang

    2015-10-15

    Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation, and the neural circuits in the pons have since been studied extensively. The medulla also contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.

  10. Independent controls for neocortical neuron production and histogenetic cell death

    NASA Technical Reports Server (NTRS)

    Verney, C.; Takahashi, T.; Bhide, P. G.; Nowakowski, R. S.; Caviness, V. S. Jr

    2000-01-01

    We estimated the proportion of cells eliminated by histogenetic cell death during the first 2 postnatal weeks in areas 1, 3 and 40 of the mouse parietal neocortex. For each layer and for the subcortical white matter in each neocortical area, the number of dying cells per mm(2) was calculated and the proportionate cell death for each day of the 2-week interval was estimated. The data show that cell death proceeds essentially uniformly across the neocortical areas and layers and that it does not follow either the spatiotemporal gradient of cell cycle progression in the pseudostratified ventricular epithelium of the cerebral wall, the source of neocortical neurons, or the 'inside-out' neocortical neuronogenetic sequence. Therefore, we infer that the control mechanisms of neocortical histogenetic cell death are independent of mechanisms controlling neuronogenesis or neuronal migration but may be associated with the ingrowth, expansion and a system-wide matching of neuronal connectivity. Copyright 2000 S. Karger AG, Basel.

  11. Independent controls for neocortical neuron production and histogenetic cell death

    NASA Technical Reports Server (NTRS)

    Verney, C.; Takahashi, T.; Bhide, P. G.; Nowakowski, R. S.; Caviness, V. S. Jr

    2000-01-01

    We estimated the proportion of cells eliminated by histogenetic cell death during the first 2 postnatal weeks in areas 1, 3 and 40 of the mouse parietal neocortex. For each layer and for the subcortical white matter in each neocortical area, the number of dying cells per mm(2) was calculated and the proportionate cell death for each day of the 2-week interval was estimated. The data show that cell death proceeds essentially uniformly across the neocortical areas and layers and that it does not follow either the spatiotemporal gradient of cell cycle progression in the pseudostratified ventricular epithelium of the cerebral wall, the source of neocortical neurons, or the 'inside-out' neocortical neuronogenetic sequence. Therefore, we infer that the control mechanisms of neocortical histogenetic cell death are independent of mechanisms controlling neuronogenesis or neuronal migration but may be associated with the ingrowth, expansion and a system-wide matching of neuronal connectivity. Copyright 2000 S. Karger AG, Basel.

  12. Synaptic mechanisms underlying cholinergic control of thalamic reticular nucleus neurons

    PubMed Central

    Beierlein, Michael

    2014-01-01

    Neuronal networks of the thalamus are the target of extensive cholinergic projections from the basal forebrain and the brainstem. Activation of these afferents can regulate neuronal excitability, transmitter release, and firing patterns in thalamic networks, thereby altering the flow of sensory information during distinct behavioural states. However, cholinergic regulation in the thalamus has been primarily examined by using receptor agonist and antagonist, which has precluded a detailed understanding of the spatiotemporal dynamics that govern cholinergic signalling under physiological conditions. This review summarizes recent studies on cholinergic synaptic transmission in the thalamic reticular nucleus (TRN), a brain structure intimately involved in the control of sensory processing and the generation of rhythmic activity in the thalamocortical system. This work has shown that acetylcholine (ACh) released from individual axons can rapidly and reliably activate both pre- and postsynaptic cholinergic receptors, thereby controlling TRN neuronal activity with high spatiotemporal precision. PMID:24973413

  13. Genetic networks controlling the development of midbrain dopaminergic neurons

    PubMed Central

    Prakash, Nilima; Wurst, Wolfgang

    2006-01-01

    Recent data have substantially advanced our understanding of midbrain dopaminergic neuron development. Firstly, a Wnt1-regulated genetic network, including Otx2 and Nkx2-2, and a Shh-controlled genetic cascade, including Lmx1a, Msx1 and Nkx6-1, have been unravelled, acting in parallel or sequentially to establish a territory competent for midbrain dopaminergic precursor production at relatively early stages of neural development. Secondly, the same factors (Wnt1 and Lmx1a/Msx1) appear to regulate midbrain dopaminergic and/or neuronal fate specification in the postmitotic progeny of these precursors by controlling the expression of midbrain dopaminergic-specific and/or general proneural factors at later stages of neural development. For the first time, early inductive events have thus been linked to later differentiation processes in midbrain dopaminergic neuron development. Given the pivotal importance of this neuronal population for normal function of the human brain and its involvement in severe neurological and psychiatric disorders such as Parkinson's Disease, these advances open new prospects for potential stem cell-based therapies. We will summarize these new findings in the overall context of midbrain dopaminergic neuron development in this review. PMID:16825303

  14. On-line, voluntary control of human temporal lobe neurons.

    PubMed

    Cerf, Moran; Thiruvengadam, Nikhil; Mormann, Florian; Kraskov, Alexander; Quiroga, Rodrigo Quian; Koch, Christof; Fried, Itzhak

    2010-10-28

    Daily life continually confronts us with an exuberance of external, sensory stimuli competing with a rich stream of internal deliberations, plans and ruminations. The brain must select one or more of these for further processing. How this competition is resolved across multiple sensory and cognitive regions is not known; nor is it clear how internal thoughts and attention regulate this competition. Recording from single neurons in patients implanted with intracranial electrodes for clinical reasons, here we demonstrate that humans can regulate the activity of their neurons in the medial temporal lobe (MTL) to alter the outcome of the contest between external images and their internal representation. Subjects looked at a hybrid superposition of two images representing familiar individuals, landmarks, objects or animals and had to enhance one image at the expense of the other, competing one. Simultaneously, the spiking activity of their MTL neurons in different subregions and hemispheres was decoded in real time to control the content of the hybrid. Subjects reliably regulated, often on the first trial, the firing rate of their neurons, increasing the rate of some while simultaneously decreasing the rate of others. They did so by focusing onto one image, which gradually became clearer on the computer screen in front of their eyes, and thereby overriding sensory input. On the basis of the firing of these MTL neurons, the dynamics of the competition between visual images in the subject's mind was visualized on an external display.

  15. Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

    PubMed Central

    Pierrot, Nathalie; Tyteca, Donatienne; D'auria, Ludovic; Dewachter, Ilse; Gailly, Philippe; Hendrickx, Aurélie; Tasiaux, Bernadette; Haylani, Laetitia El; Muls, Nathalie; N'Kuli, Francisca; Laquerrière, Annie; Demoulin, Jean-Baptiste; Campion, Dominique; Brion, Jean-Pierre; Courtoy, Pierre J; Kienlen-Campard, Pascal; Octave, Jean-Noël

    2013-01-01

    Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity. PMID:23554170

  16. On-line, voluntary control of human temporal lobe neurons

    PubMed Central

    Cerf, Moran; Thiruvengadam, Nikhil; Mormann, Florian; Kraskov, Alexander; Quiroga, Rodrigo Quian; Koch, Christof; Fried, Itzhak

    2010-01-01

    Daily life continually confronts us with an exuberance of external, sensory stimuli competing with a rich stream of internal deliberations, plans and ruminations. The brain must select one or more of these for further processing. How this competition is resolved across multiple sensory and cognitive regions is not known; nor is it clear how internal thoughts and attention regulate this competition1–4. Recording from single neurons in patients implanted with intracranial electrodes for clinical reasons5–9, here we demonstrate that humans can regulate the activity of their neurons in the medial temporal lobe (MTL) to alter the outcome of the contest between external images and their internal representation. Subjects looked at a hybrid superposition of two images representing familiar individuals, landmarks, objects or animals and had to enhance one image at the expense of the other, competing one. Simultaneously, the spiking activity of their MTL neurons in different subregions and hemispheres was decoded in real time to control the content of the hybrid. Subjects reliably regulated, often on the first trial, the firing rate of their neurons, increasing the rate of some while simultaneously decreasing the rate of others. They did so by focusing onto one image, which gradually became clearer on the computer screen in front of their eyes, and thereby overriding sensory input. On the basis of the firing of these MTL neurons, the dynamics of the competition between visual images in the subject's mind was visualized on an external display. PMID:20981100

  17. Optogenetic photochemical control of designer K+ channels in mammalian neurons

    PubMed Central

    Fortin, Doris L.; Dunn, Timothy W.; Fedorchak, Alexis; Allen, Duane; Montpetit, Rachel; Banghart, Matthew R.; Trauner, Dirk; Adelman, John P.

    2011-01-01

    Currently available optogenetic tools, including microbial light-activated ion channels and transporters, are transforming systems neuroscience by enabling precise remote control of neuronal firing, but they tell us little about the role of indigenous ion channels in controlling neuronal function. Here, we employ a chemical-genetic strategy to engineer light sensitivity into several mammalian K+ channels that have different gating and modulation properties. These channels provide the means for photoregulating diverse electrophysiological functions. Photosensitivity is conferred on a channel by a tethered ligand photoswitch that contains a cysteine-reactive maleimide (M), a photoisomerizable azobenzene (A), and a quaternary ammonium (Q), a K+ channel pore blocker. Using mutagenesis, we identify the optimal extracellular cysteine attachment site where MAQ conjugation results in pore blockade when the azobenzene moiety is in the trans but not cis configuration. With this strategy, we have conferred photosensitivity on channels containing Kv1.3 subunits (which control axonal action potential repolarization), Kv3.1 subunits (which contribute to rapid-firing properties of brain neurons), Kv7.2 subunits (which underlie “M-current”), and SK2 subunits (which are Ca2+-activated K+ channels that contribute to synaptic responses). These light-regulated channels may be overexpressed in genetically targeted neurons or substituted for native channels with gene knockin technology to enable precise optopharmacological manipulation of channel function. PMID:21525363

  18. Control of REM Sleep by Ventral Medulla GABAergic Neurons

    PubMed Central

    Weber, Franz; Chung, Shinjae; Beier, Kevin T.; Luo, Liqun; Dan, Yang

    2015-01-01

    Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram (EEG) and complete skeletal muscle paralysis, and it is associated with vivid dreams1-3. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation2, and the neural circuits in the pons have since been studied extensively4-8. The medulla also contains neurons that are active during REM sleep9-13, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic pathway originating from the ventral medulla (vM) powerfully promotes REM sleep. Optogenetic activation of vM GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin 2 (ChR2)-tagged vM GABAergic neurons showed that they were most active during REM sleep (REM-max), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate vM neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are likely mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG). These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions. PMID:26444238

  19. The stochastic properties of input spike trains control neuronal arithmetic.

    PubMed

    Bures, Zbynek

    2012-02-01

    In the nervous system, the representation of signals is based predominantly on the rate and timing of neuronal discharges. In most everyday tasks, the brain has to carry out a variety of mathematical operations on the discharge patterns. Recent findings show that even single neurons are capable of performing basic arithmetic on the sequences of spikes. However, the interaction of the two spike trains, and thus the resulting arithmetic operation may be influenced by the stochastic properties of the interacting spike trains. If we represent the individual discharges as events of a random point process, then an arithmetical operation is given by the interaction of two point processes. Employing a probabilistic model based on detection of coincidence of random events and complementary computer simulations, we show that the point process statistics control the arithmetical operation being performed and, particularly, that it is possible to switch from subtraction to division solely by changing the distribution of the inter-event intervals of the processes. Consequences of the model for evaluation of binaural information in the auditory brainstem are demonstrated. The results accentuate the importance of the stochastic properties of neuronal discharge patterns for information processing in the brain; further studies related to neuronal arithmetic should therefore consider the statistics of the interacting spike trains.

  20. The Neuronal Control of Flying Prey Interception in Dragonflies

    DTIC Science & Technology

    2014-08-19

    activity rotates the head as well in the direction opposite the preferred target direction. Two TSDNs also move the legs and mouthparts. Insect ...flight, Prey interception, Insect vision, Receptive field, Dragonfly U U U UU 0 Robert M. Olberg 518 388 6509 THE NEURONAL CONTROL OF FLYING PREY...reconstruct, in 3D, the flight trajectory of an aerial predator (killer fly: C. attenuata) and its potential prey (small flying insects such as fungus gnats

  1. [Obesity paradox].

    PubMed

    Aursulesei, Viviana; Cozma, A; Datcu, M D

    2009-01-01

    Obesity has reached global epidemic proportions and is associated with major cardiovascular diseases and reduced overall survival. This paper reviews the metabolic and vascular consequences of dysfunctional adipocytokines in obesity as well as the pathological effects on blood pressure, cardiovascular structure and function. Despite this adverse association, numerous studies have documented an obesity paradox in which overweight and obese population with established cardiovascular disease have a better prognosis. There are potential explanations offered by literature for these puzzling data. For obese hypertensive patients the paradox is possibly linked to the lower systemic vascular resistance and plasma renin activity. In heart failure the excess body weight may confer some protective effects on mortality, due to a more metabolic reserve, higher levels of arterial pressure compatible with higher doses of cardioprotective medications, and a specific neuroendocrine profile with lower levels of circulating natriuretic atrial peptides, attenuated sympathetic nervous system and renin-angiotensin responses. For coronary heart disease and peripheral arterial disease the mechanisms are still uncertain. There are discussed a lesser severity of coronary lesions and left ventricular dysfunction, or a reduced prevalence of moderate-severe chronic obstructive pulmonary disease in patients selected for surgery. On the other hand, the constellation of data which supports purposeful weight reduction in the prevention and treatment of cardiovascular diseases, induces a controversial position regarding this new concept.

  2. Identifying Controlling Nodes in Neuronal Networks in Different Scales

    PubMed Central

    Tang, Yang; Gao, Huijun; Zou, Wei; Kurths, Jürgen

    2012-01-01

    Recent studies have detected hubs in neuronal networks using degree, betweenness centrality, motif and synchronization and revealed the importance of hubs in their structural and functional roles. In addition, the analysis of complex networks in different scales are widely used in physics community. This can provide detailed insights into the intrinsic properties of networks. In this study, we focus on the identification of controlling regions in cortical networks of cats’ brain in microscopic, mesoscopic and macroscopic scales, based on single-objective evolutionary computation methods. The problem is investigated by considering two measures of controllability separately. The impact of the number of driver nodes on controllability is revealed and the properties of controlling nodes are shown in a statistical way. Our results show that the statistical properties of the controlling nodes display a concave or convex shape with an increase of the allowed number of controlling nodes, revealing a transition in choosing driver nodes from the areas with a large degree to the areas with a low degree. Interestingly, the community Auditory in cats’ brain, which has sparse connections with other communities, plays an important role in controlling the neuronal networks. PMID:22848475

  3. Identifying controlling nodes in neuronal networks in different scales.

    PubMed

    Tang, Yang; Gao, Huijun; Zou, Wei; Kurths, Jürgen

    2012-01-01

    Recent studies have detected hubs in neuronal networks using degree, betweenness centrality, motif and synchronization and revealed the importance of hubs in their structural and functional roles. In addition, the analysis of complex networks in different scales are widely used in physics community. This can provide detailed insights into the intrinsic properties of networks. In this study, we focus on the identification of controlling regions in cortical networks of cats' brain in microscopic, mesoscopic and macroscopic scales, based on single-objective evolutionary computation methods. The problem is investigated by considering two measures of controllability separately. The impact of the number of driver nodes on controllability is revealed and the properties of controlling nodes are shown in a statistical way. Our results show that the statistical properties of the controlling nodes display a concave or convex shape with an increase of the allowed number of controlling nodes, revealing a transition in choosing driver nodes from the areas with a large degree to the areas with a low degree. Interestingly, the community Auditory in cats' brain, which has sparse connections with other communities, plays an important role in controlling the neuronal networks.

  4. Genomic control of neuronal demographics in the retina.

    PubMed

    Reese, Benjamin E; Keeley, Patrick W

    2016-11-01

    The mature retinal architecture is composed of various types of neuron, each population differing in size and constrained to particular layers, wherein the cells achieve a characteristic patterning in their local organization. These demographic features of retinal nerve cell populations are each complex traits controlled by multiple genes affecting different processes during development, and their genetic determinants can be dissected by correlating variation in these traits with their genomic architecture across recombinant-inbred mouse strains. Using such a resource, we consider how the variation in the numbers of twelve different types of retinal neuron are independent of one another, including those sharing transcriptional regulation as well as those that are synaptically-connected, each mapping to distinct genomic loci. Using the populations of two retinal interneurons, the horizontal cells and the cholinergic amacrine cells, we present in further detail examples where the variation in neuronal number, as well as the variation in mosaic patterning or in laminar positioning, each maps to discrete genomic loci where allelic variants modulating these features must be present. At those loci, we identify candidate genes which, when rendered non-functional, alter those very demographic properties, and in turn, we identify candidate coding or regulatory variants that alter protein structure or gene expression, respectively, being prospective contributors to the variation in phenotype. This forward-genetic approach provides an alternative means for dissecting the molecular genetic control of neuronal population dynamics, with each genomic locus serving as a causal anchor from which we may ultimately understand the developmental principles responsible for the control of those traits.

  5. Autophagy Paradox and Ceramide

    PubMed Central

    Jiang, Wenhui; Ogretmen, Besim

    2013-01-01

    Sphingolipid molecules act as bioactive lipid messengers and exert their actions on the regulation of various cellular signaling pathways. Sphingolipids play essential roles in numerous cellular functions, including controlling cell inflammation, proliferation, death, migration, senescence, tumor metastasis and/or autophagy. Dysregulated sphingolipid metabolism has been also implicated in many human cancers. Macroatuophagy (referred to here as autophagy) “self-eating”, is characterized by nonselective sequestering of cytosolic materials by an isolation membrane, which can be either protective or lethal for cells. Ceramide (Cer), a central molecule of sphingolipid metabolism, has been extensively implicated in the control of autophagy. The increasing evidence suggests Cer is highly involved in mediating two opposing autophagic pathways, which regulate either cell survival or death, autophagy paradox. However, the underlying mechanism that regulates the autophagy paradox remains unclear. Therefore, this review focuses on recent studies with regard to the regulation of autophagy by Cer and elucidate the roles and mechanisms of action of Cer in controlling autophagy paradox. PMID:24055889

  6. Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors

    NASA Astrophysics Data System (ADS)

    Tochitsky, Ivan; Banghart, Matthew R.; Mourot, Alexandre; Yao, Jennifer Z.; Gaub, Benjamin; Kramer, Richard H.; Trauner, Dirk

    2012-02-01

    Advances in synthetic chemistry, structural biology, molecular modelling and molecular cloning have enabled the systematic functional manipulation of transmembrane proteins. By combining genetically manipulated proteins with light-sensitive ligands, innately ‘blind’ neurobiological receptors can be converted into photoreceptors, which allows them to be photoregulated with high spatiotemporal precision. Here, we present the optochemical control of neuronal nicotinic acetylcholine receptors (nAChRs) with photoswitchable tethered agonists and antagonists. Using structure-based design, we produced heteromeric α3β4 and α4β2 nAChRs that can be activated or inhibited with deep-violet light, but respond normally to acetylcholine in the dark. The generation of these engineered receptors should facilitate investigation of the physiological and pathological functions of neuronal nAChRs and open a general pathway to photosensitizing pentameric ligand-gated ion channels.

  7. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

    PubMed

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

  8. Kalman meets neuron - the intersection of control theory and neuroscience

    NASA Astrophysics Data System (ADS)

    Schiff, Steven

    2009-03-01

    Since the 1950s, we have developed mature theories of modern control theory and computational neuroscience with almost no interaction between these disciplines. With the advent of computationally efficient nonlinear Kalman filtering techniques, along with improved neuroscience models which provide increasingly accurate reconstruction of dynamics in a variety of important normal and disease states in the brain, the prospects for a synergistic interaction between these fields are now strong. I will show recent examples of the use of nonlinear control theory for the assimilation and control of single neuron dynamics, a novel framework for dynamic clamp, the modulation of oscillatory wave dynamics in brain cortex, a control framework for Parkinsonian dynamics and seizures, and the use of optimized parameter model networks to assimilate complex network data.

  9. From Stimulation to Undulation: A Neuronal Pathway for the Control of Swimming in the Leech

    NASA Astrophysics Data System (ADS)

    Brodfuehrer, Peter D.; Friesen, W. Otto

    1986-11-01

    Initiation and performance of the swimming movement in the leech (Hirudo medicinalis) are controlled by neurons organized at at least four functional levels--sensory neurons, gating neurons, oscillator neurons, and motor neurons. A paired neuron, designated as Tr1, in the subesophageal ganglion of the leech has now been shown to define a fifth level, interposed between sensory and gating neurons. Cell Tr1 is activated by pressure and nociceptive mechanosensory neurons, which mediate body-wall stimulus--evoked swimming activity in intact leeches. In the isolated leech nervous system, brief stimulation of cell Tr1 elicits sustained activation of the gating neurons and triggers the onset of swimming activity. The synaptic interactions between all five levels of control are direct. Discovery of the Tr1 cells thus completes the identification of a synaptic pathway by which mechanosensory stimulation leads to the swimming movements of the leech.

  10. Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles.

    PubMed

    Stefanelli, Thomas; Bertollini, Cristina; Lüscher, Christian; Muller, Dominique; Mendez, Pablo

    2016-03-02

    Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG), we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin-positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory.

  11. Training a Network of Electronic Neurons for Control of a Mobile Robot

    NASA Astrophysics Data System (ADS)

    Vromen, T. G. M.; Steur, E.; Nijmeijer, H.

    An adaptive training procedure is developed for a network of electronic neurons, which controls a mobile robot driving around in an unknown environment while avoiding obstacles. The neuronal network controls the angular velocity of the wheels of the robot based on the sensor readings. The nodes in the neuronal network controller are clusters of neurons rather than single neurons. The adaptive training procedure ensures that the input-output behavior of the clusters is identical, even though the constituting neurons are nonidentical and have, in isolation, nonidentical responses to the same input. In particular, we let the neurons interact via a diffusive coupling, and the proposed training procedure modifies the diffusion interaction weights such that the neurons behave synchronously with a predefined response. The working principle of the training procedure is experimentally validated and results of an experiment with a mobile robot that is completely autonomously driving in an unknown environment with obstacles are presented.

  12. Beyond Parrondo's Paradox

    PubMed Central

    SHU, Jian-Jun; WANG, Qi-Wen

    2014-01-01

    The Parrondo's paradox is a counterintuitive phenomenon where individually-losing strategies can be combined in producing a winning expectation. In this paper, the issues surrounding the Parrondo's paradox are investigated. The focus is lying on testifying whether the same paradoxical effect can be reproduced by using a simple capital dependent game. The paradoxical effect generated by the Parrondo's paradox can be explained by placing all the parameters in one probability space. Based on this framework, it is able to generate other possible paradoxical effects by manipulating the parameters in the probability space. PMID:24577586

  13. Neuron-glia communication in the control of oligodendrocyte function and myelin biogenesis.

    PubMed

    Simons, Mikael; Trajkovic, Katarina

    2006-11-01

    During the development of the central nervous system the reciprocal communication between neurons and oligodendrocytes is essential for the generation of myelin, a multilamellar insulating membrane that ensheathes the axons. Neuron-derived signalling molecules regulate the proliferation, differentiation and survival of oligodendrocytes. Furthermore, neurons control the onset and timing of myelin membrane growth. In turn, signals from oligodendrocytes to neurons direct the assembly of specific subdomains in neurons at the node of Ranvier. Recent work has begun to shed light on the molecules and signaling systems used to coordinate the interaction of neurons and oligodendrocytes. For example, the neuronal signals seem to control the membrane trafficking machinery in oligodendrocytes that leads to myelination. These interconnections at multiple levels show how neurons and glia cooperate to build a complex network during development.

  14. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism

    PubMed Central

    Zhang, Eric E.; Chapeau, Emilie; Hagihara, Kazuki; Feng, Gen-Sheng

    2004-01-01

    Shp2, a Src homology 2-containing tyrosine phosphatase, has been implicated in a variety of growth factor or cytokine signaling pathways. However, it is conceivable that this enzyme acts predominantly in one pathway versus the others in a cell, depending on the cellular context. To determine the putative functions of Shp2 in the adult brain, we selectively deleted Shp2 in postmitotic forebrain neurons by crossing CaMKIIα-Cre transgenic mice with a conditional Shp2 mutant (Shp2flox) strain. Surprisingly, a prominent phenotype of the mutant (CaMKIIα-Cre:Shp2flox/flox or CaSKO) mice was the development of early-onset obesity, with increased serum levels of leptin, insulin, glucose, and triglycerides. The mutant mice were not hyperphagic but developed enlarged and steatotic liver. Consistent with previous in vitro data, we found that Shp2 down-regulates Jak2/Stat3 (signal transducer and activator of transcription 3) activation by leptin in the hypothalamus. However, Jak2/Stat3 down-regulation is offset by a dominant Shp2 promotion of the leptin-stimulated Erk pathway, leading to induction rather than suppression of leptin resistance upon Shp2 deletion in the brain. Collectively, these results suggest that a primary function of Shp2 in postmitotic forebrain neurons is to control energy balance and metabolism, and that this phosphatase is a critical signaling component of leptin receptor ObRb in the hypothalamus. Shp2 shows potential as a neuronal target for pharmaceutical sensitization of obese patients to leptin action. PMID:15520383

  15. Receptors controlling transmitter release from sympathetic neurons in vitro.

    PubMed

    Boehm, S; Huck, S

    1997-02-01

    Primary cultures of postganglionic sympathetic neurons were established more than 30 years ago. More recently, these cultures have been used to characterize various neurotransmitter receptors that govern sympathetic transmitter release. These receptors may be categorized into at least three groups: (1) receptors which evoke transmitter release: (2) receptors which facilitate; (3) receptors which inhibit, depolarization-evoked release. Group (1) comprises nicotinic and muscarinic acetylcholine receptors, P2X purinoceptors and pyrimidinoceptors. Group (2) currently harbours beta-adrenoceptors, P2 purinoceptors, receptors for PACAP and VIP, as well as prostanoid EP1 receptors. In group (3), muscarinic cholinoceptors, alpha 2- and beta-adrenoceptors, P2 purinoceptors, and receptors for the neuropeptides NPY, somatostatin (SRIF1) and LHRH, as well as opioid (delta and kappa) receptors can be found. Receptors which regulate transmitter release from neurons in cell culture may be located either at the somatodendritic region or at the sites of exocytosis, i.e. the presynaptic specializations of axons. Most of the receptors that evoke release are located at the soma. There ionotropic receptors cause depolarizations to generate action potentials which then trigger Ca(2+)-dependent exocytosis at axon terminals. The signalling mechanisms of metabotropic receptors which evoke release still remain to be identified. Receptors which facilitate depolarization-evoked release appear to be located preferentially at presynaptic sites and presumably act via an increase in cyclic AMP. Receptors which inhibit stimulation evoked release are also presynaptic origin and most commonly rely on a G protein-mediated blockade of voltage-gated Ca2+ channels. Results obtained with primary cell cultures of postganglionic sympathetic neurons have now supplemented previous data about neurotransmitter receptors involved in the regulation of ganglionic as well as sympatho-effector transmission. In the

  16. Population paradoxes.

    PubMed

    Meyer, P A

    1992-07-01

    The global population growth rate began accelerating rapidly early this century, passed 1% around 1940, and peaked at around 2.1% in the latter half of the 1960s, when the world's population was about 4 billion. Since then, the growth rate has declined slowly to the present estimate of 1.7%, and now the figure is nearly 5.5 billion. The first population paradox is that the annual increments in global population are still increasing, even though the rate of growth has begun to decline. In the late 1960s the annual increment was about 80 million and the 1992 figures equaled 93.5 million. This annual increment will probably begin to decline before the turn of the century, but will still remain above 80 million until about 2020. Most of these added people will be in the developing countries, (80-90 million every year), most of them in poverty. Demographers now believe that humanity will achieve global replacement-level fertility around the year 2040, given current trends. By 2040 the population will be about 9 billion. They expect an ultimate world population sometime late next century of about 11 billion. The less optimistic scenarios have global replacement-level fertility delayed to 2060, yielding an ultimate population of 12.5 billion. Indonesia is a good example of the optimistic category. It will achieve replacement-level fertility perhaps by the year 2005. In the mid 1970s the annual growth rates were still increasing, peaking at over 2.3%. At that time, Indonesia was growing at 3.5 million people per year. The growth rate is now below 1.7% and, with the population at about 180 million, the annual increments are just 3 million. Indonesia began this century with a population of around 40 million, and will end it with a population around 210 million. Indonesia's ultimate population will be well in excess of 300 million, indicating the force of momentum.

  17. A Novel Mechanism for Activator-Controlled Initiation of DNA Replication that Resolves the Auto-regulation Sequestration Paradox

    NASA Astrophysics Data System (ADS)

    Nilsson, K.; Ehrenberg, M.

    For bacterial genes to be inherited to the next bacterial generation, the gene containing DNA sequences must be duplicated before cell division so that each daughter cell contains a complete set of genes. The duplication process is called DNA replication and it starts at one defined site on the DNA molecule called the origin of replication (oriC) [1]. In addition to chromosomal DNA, bacteria often also contain plasmid DNA. Plasmids are extra-chromosomal DNA molecules carrying genes that increase the fitness of their host in certain environments, with genes encoding antibiotic resistance as a notorious example [2]. The chromosome is found at a low per cell copy number and initiation of replication takes place synchronously once every cell generation [3,4], while many plasmids exist at a high copy number and replication initiates asynchronously, throughout the cell generation [5]. In this chapter we present a novel mechanism for the control of initiation of replication, where one type of molecule may activate a round of replication by binding to the origin of replication and also regulate its own synthesis accurately. This mechanism of regulating the initiation of replication also offers a novel solution to the so-called auto-regulation sequestration paradox, i.e. how a molecule sequestered by binding to DNA may at the same time accurately regulate its own synthesis [6]. The novel regulatory mechanism is inspired by the molecular set-up of the replication control of the chromosome in the bacterium Escherichia coli and is here transferred into a plasmid model. This allows us to illustrate principles of replication control in a simple way and to put the novel mechanism into the context of a previous analysis of plasmids regulated by inhibitor-dilution copy number control [7]. We analyze factors important for a sensitive response of the replication initiation rate to changes in plasmid concentration in an asynchronous model and discover a novel mechanism for creating a

  18. Paradoxical effects of pirenzepine on parasympathetic activity in chronic heart failure and control.

    PubMed

    Hayano, T; Shimizu, A; Ikeda, Y; Yamamoto, T; Yamagata, T; Ueyama, T; Furutani, Y; Matsuzaki, M

    1999-01-01

    We studied the effect of intravenous pirenzepine (3 mg) in normal subjects (n=15, 43+/-16 years old) and in patients with chronic heart failure (n=15, 61+/-12 years old) to assess the effect of low-dose pirenzepine on vagal activity. R-R intervals and the standard deviations, low-frequency power (LF: ln ms2, 0.04-0.15 Hz), high-frequency power (HF: ln ms2, 0.15-0.40 Hz) and the ratio of low- to high-frequency power (LF/HF ratio) were measured 10 min before and after pirenzepine using a Holter analysis system. Pirenzepine was found to cause a significant increase in the R-R interval from 903+/-112 to 956+/-129 ms in the control group (P<0.0001) and from 927+/-141 to 958+/-168 ms in patients with chronic heart failure (P<0.01). Pirenzepine also increased HF significantly from 4.29+/-0.32 to 5.16+/-0.38 ln ms2 in the control group (P<0.0001) and from 4.04+/-0.16 to 4.48+/-0.24 ln ms2 in the chronic heart failure group (P<0.05). Pirenzepine did not significantly alter the LF/HF ratio in either group. We emphasize that pirenzepine appears to have a vagoinimetic effect in patients with chronic heart failure and that it may be useful for augmenting vagal control of the heart in some patients with chronic heart failure.

  19. Dynamic Control of Synchronous Activity in Networks of Spiking Neurons

    PubMed Central

    Hutt, Axel; Mierau, Andreas; Lefebvre, Jérémie

    2016-01-01

    Oscillatory brain activity is believed to play a central role in neural coding. Accumulating evidence shows that features of these oscillations are highly dynamic: power, frequency and phase fluctuate alongside changes in behavior and task demands. The role and mechanism supporting this variability is however poorly understood. We here analyze a network of recurrently connected spiking neurons with time delay displaying stable synchronous dynamics. Using mean-field and stability analyses, we investigate the influence of dynamic inputs on the frequency of firing rate oscillations. We show that afferent noise, mimicking inputs to the neurons, causes smoothing of the system’s response function, displacing equilibria and altering the stability of oscillatory states. Our analysis further shows that these noise-induced changes cause a shift of the peak frequency of synchronous oscillations that scales with input intensity, leading the network towards critical states. We lastly discuss the extension of these principles to periodic stimulation, in which externally applied driving signals can trigger analogous phenomena. Our results reveal one possible mechanism involved in shaping oscillatory activity in the brain and associated control principles. PMID:27669018

  20. Neuronal control of fixation and fixational eye movements

    PubMed Central

    2017-01-01

    Ocular fixation is a dynamic process that is actively controlled by many of the same brain structures involved in the control of eye movements, including the superior colliculus, cerebellum and reticular formation. In this article, we review several aspects of this active control. First, the decision to move the eyes not only depends on target-related signals from the peripheral visual field, but also on signals from the currently fixated target at the fovea, and involves mechanisms that are shared between saccades and smooth pursuit. Second, eye position during fixation is actively controlled and depends on bilateral activity in the superior colliculi and medio-posterior cerebellum; disruption of activity in these circuits causes systematic deviations in eye position during both fixation and smooth pursuit eye movements. Third, the eyes are not completely still during fixation but make continuous miniature movements, including ocular drift and microsaccades, which are controlled by the same neuronal mechanisms that generate larger saccades. Finally, fixational eye movements have large effects on visual perception. Ocular drift transforms the visual input in ways that increase spatial acuity; microsaccades not only improve vision by relocating the fovea but also cause momentary changes in vision analogous to those caused by larger saccades. This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’. PMID:28242738

  1. Neuronal control of breathing: sex and stress hormones.

    PubMed

    Behan, Mary; Kinkead, Richard

    2011-10-01

    There is a growing public awareness that hormones can have a significant impact on most biological systems, including the control of breathing. This review will focus on the actions of two broad classes of hormones on the neuronal control of breathing: sex hormones and stress hormones. The majority of these hormones are steroids; a striking feature is that both groups are derived from cholesterol. Stress hormones also include many peptides which are produced primarily within the paraventricular nucleus of the hypothalamus (PVN) and secreted into the brain or into the circulatory system. In this article we will first review and discuss the role of sex hormones in respiratory control throughout life, emphasizing how natural fluctuations in hormones are reflected in ventilatory metrics and how disruption of their endogenous cycle can predispose to respiratory disease. These effects may be mediated directly by sex hormone receptors or indirectly by neurotransmitter systems. Next, we will discuss the origins of hypothalamic stress hormones and their relationship with the respiratory control system. This relationship is 2-fold: (i) via direct anatomical connections to brainstem respiratory control centers, and (ii) via steroid hormones released from the adrenal gland in response to signals from the pituitary gland. Finally, the impact of stress on the development of neural circuits involved in breathing is evaluated in animal models, and the consequences of early stress on respiratory health and disease is discussed.

  2. Control of abdominal muscles by brain stem respiratory neurons in the cat

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

    1985-01-01

    The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

  3. Diverse neuronal lineages make stereotyped contributions to the Drosophila locomotor control center, the central complex

    PubMed Central

    He, Yisheng; Ding, Peng; Kao, Jui-Chun; Lee, Tzumin

    2013-01-01

    Summary The Drosophila central brain develops from a fixed number of neuroblasts. Each neuroblast makes a clone of neurons that exhibit common trajectories. Here we identified 15 distinct clones that carry larval-born neurons innervating the Drosophila central complex (CX), which consists of four midline structures including the protocerebral bridge (PB), fan-shape body (FB), ellipsoid body (EB), and noduli (NO). Clonal analysis revealed that the small-field CX neurons, which establish intricate projections across different CX substructures, exist in four isomorphic groups that respectively derive from four complex posterior asense-negative lineages. About the region-characteristic large-field CX neurons, we found that two lineages make PB neurons, ten lineages produce FB neurons, three lineages generate EB neurons, and two lineages yield NO neurons. The diverse FB developmental origins reflect the discrete input pathways for different FB subcompartments. Clonal analysis enlightens both development and anatomy of the insect locomotor control center. PMID:23696496

  4. Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition.

    PubMed

    Singh, Shalini; Howell, Danielle; Trivedi, Niraj; Kessler, Ketty; Ong, Taren; Rosmaninho, Pedro; Raposo, Alexandre Asf; Robinson, Giles; Roussel, Martine F; Castro, Diogo S; Solecki, David J

    2016-05-14

    In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers.

  5. Control of abdominal muscles by brain stem respiratory neurons in the cat

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

    1985-01-01

    The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

  6. Repressor element-1 silencing transcription factor (REST) is present in human control and Huntington's disease neurones.

    PubMed

    Schiffer, Davide; Caldera, Valentina; Mellai, Marta; Conforti, Paola; Cattaneo, Elena; Zuccato, Chiara

    2014-12-01

    The repressor element-1 silencing transcription factor/neurone-restrictive silencer factor (REST/NRSF) is a master regulator of neuronal gene expression. REST/NRSF functions by recruiting other cofactors to genomic loci that contain the repressor element 1/neurone restrictive silencer element (RE1/NRSE) binding motif. In brain, demonstration of REST protein presence in neurones has remained controversial. However, RE1/NRSE containing neuronal genes are actively modulated and REST dysregulation is implicated in Huntington's disease (HD). We aimed to investigate REST distribution in autopsy brain from control and HD patients. Brain tissues from six controls and six HD cases (Vonsattel grade 3 and 4) were investigated using immunohistochemical analysis. REST was present in neurones and glial cells of the cortex, caudate nucleus, hippocampus and cerebellum. REST labelling was mainly cytoplasmic in neurones while preferential nuclear staining of REST was found in glial cells. We also found that REST and huntingtin (HTT) colocalize in human neurones. Low levels of cytoplasmic REST were detected in neurones of the HD cortex and caudate but no direct relationship between decreased neuronal REST expression and disease grade was observed. These data support the notion of REST presence in human brain neurones and glial cells and indicate the importance of developing compounds able to restore REST-regulated transcription of neuronal genes in HD. © 2014 British Neuropathological Society.

  7. p53 controls neuronal death in the CA3 region of the newborn mouse hippocampus.

    PubMed

    Murase, Sachiko; Poser, Steve W; Joseph, Joby; McKay, Ronald D

    2011-08-01

    It is important to determine the mechanisms controlling the number of neurons in the nervous system. Previously, we reported that neuronal activity plays a central role in controlling neuron number in the neonatal hippocampus of rodents. Neuronal survival requires sustained activation of the serine-threonine kinase Akt, which is initiated by neurotrophins and continued for several hours by neuronal activity and integrin signaling. Here, we focus on the CA3 region to show that neuronal apoptosis requires p53. As in wild-type animals, neuronal death occurs in the first postnatal week and ends by postnatal day (P)10 in p53(-/-) mice. During this period, the CA3 region of p53(-/-) mice contains significantly lower numbers of apoptotic cells, and at the end of the death period, it contains more neurons than the wild type. At P10, the p53(-/-) CA3 region contains a novel subpopulation of neurons with small soma size. These neurons show normal levels of tropomyosin receptor kinase receptor activation, but lower levels of activated Akt than the neurons with somata of normal size. These results suggest that p53 is the key downstream regulator of the novel survival-signaling pathway that regulates the number of CA3 neurons in the first 10 days of postnatal life.

  8. Biochemical pharmacology of paradoxical sleep

    PubMed Central

    Gaillard, J. -M.

    1983-01-01

    1 The role of noradrenergic cells in the regulation of paradoxical sleep is still controversial, and experimental data have given rise to contradictory interpretations. 2 Early investigations focused primarily on chemical neurotransmissions. However, the process of information transmission between cells involves many other factors, and the cell surface is an important site for transduction of messages into modifications of the activity of postsynaptic cells. 3 α-adrenoceptors are believed to play an important role in the control of wakefulness and paradoxical sleep. Experimental evidence suggests that physiological modulation of receptor sensitivity, possibly by specific neuro-modulators, may be a key mechanism in synaptic transmission. 4 In the investigation of the mechanisms involved in paradoxical sleep regulation, lesions of the locus coeruleus have given equivocal results. Collateral inhibition, probably mediated by α2-adrenoceptors, appears to be a powerful mechanism. The exact temporal relationship between noradrenergic cell activation and paradoxical sleep production is not established, but 5-HT appears to be involved. Differences between paradoxical sleep and waking may be related to a physiological modulation of α2-adrenoceptor sensitivity. PMID:6140943

  9. Central Control of Circadian Phase in Arousal-Promoting Neurons

    PubMed Central

    Mahoney, Carrie E.; McKinley Brewer, Judy; Bittman, Eric L.

    2013-01-01

    Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per) genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO) and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature. PMID:23826226

  10. On controllability of neuronal networks with constraints on the average of control gains.

    PubMed

    Tang, Yang; Wang, Zidong; Gao, Huijun; Qiao, Hong; Kurths, Jürgen

    2014-12-01

    Control gains play an important role in the control of a natural or a technical system since they reflect how much resource is required to optimize a certain control objective. This paper is concerned with the controllability of neuronal networks with constraints on the average value of the control gains injected in driver nodes, which are in accordance with engineering and biological backgrounds. In order to deal with the constraints on control gains, the controllability problem is transformed into a constrained optimization problem (COP). The introduction of the constraints on the control gains unavoidably leads to substantial difficulty in finding feasible as well as refining solutions. As such, a modified dynamic hybrid framework (MDyHF) is developed to solve this COP, based on an adaptive differential evolution and the concept of Pareto dominance. By comparing with statistical methods and several recently reported constrained optimization evolutionary algorithms (COEAs), we show that our proposed MDyHF is competitive and promising in studying the controllability of neuronal networks. Based on the MDyHF, we proceed to show the controlling regions under different levels of constraints. It is revealed that we should allocate the control gains economically when strong constraints are considered. In addition, it is found that as the constraints become more restrictive, the driver nodes are more likely to be selected from the nodes with a large degree. The results and methods presented in this paper will provide useful insights into developing new techniques to control a realistic complex network efficiently.

  11. Intracellular ion control in lobster stretch receptor neurone.

    PubMed

    Edman, A; Gestrelius, S; Grampp, W

    1983-07-01

    The control of intracellular ion concentrations by means of passive and active transmembrane ion transports was investigated in the lobster stretch neurone using electrophysiological and pharmacological techniques in combination with recording with ion-sensitive microelectrodes. In resting conditions [Na+]i, [K+]i, and [Cl-]i were, in both slowly and rapidly adapting cells, found to be in the order of 20, 155, and 50 mM, respectively. In the slowly adapting cell impulse firing at stationary frequencies of 7-10 Hz caused an increase in [Na+]i and a decrease in [K+]i of 20-30 mM; [Cl-]i was only little affected, the rise in [Na+]i led to an enhanced Na-K pump activity noticeable as an increase in pump current production. In stationary conditions the quotient between pump current and Na+ influx increments was about 0.3, which is compatible with 3:2 Na-K pumping ratio in the present preparation. From measurements of the pump current activation during stationary firing at maximum tolerable frequencies an estimate was made of the cell's maximum pump current production. The measurements were used in the formulation of a mathematical model of the intracellular ion control in which expressions of active and passive transmembrane ion transports are incorporated into the continuity equation for the ion fluxes involved.

  12. Control of food intake and energy expenditure by Nos1 neurons of the paraventricular hypothalamus.

    PubMed

    Sutton, Amy K; Pei, Hongjuan; Burnett, Korri H; Myers, Martin G; Rhodes, Christopher J; Olson, David P

    2014-11-12

    The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis. The roles of specific PVH neuronal subtypes in energy balance have yet to be defined, however. The PVH contains nitric oxide synthase-1 (Nos1)-expressing (Nos1(PVH)) neurons of unknown function; these represent a subset of the larger population of Sim1-expressing PVH (Sim1(PVH)) neurons. To determine the role of Nos1(PVH) neurons in energy balance, we used Cre-dependent viral vectors to both map their efferent projections and test their functional output in mice. Here we show that Nos1(PVH) neurons project to hindbrain and spinal cord regions important for food intake and energy expenditure control. Moreover, pharmacogenetic activation of Nos1(PVH) neurons suppresses feeding to a similar extent as Sim1(PVH) neurons, and increases energy expenditure and activity. Furthermore, we found that oxytocin-expressing PVH neurons (OXT(PVH)) are a subset of Nos1(PVH) neurons. OXT(PVH) cells project to preganglionic, sympathetic neurons in the thoracic spinal cord and increase energy expenditure upon activation, though not to the same extent as Nos1(PVH) neurons; their activation fails to alter feeding, however. Thus, Nos1(PVH) neurons promote negative energy balance through changes in feeding and energy expenditure, whereas OXT(PVH) neurons regulate energy expenditure alone, suggesting a crucial role for non-OXT Nos1(PVH) neurons in feeding regulation. Copyright © 2014 the authors 0270-6474/14/3415306-13$15.00/0.

  13. Cell biology in neuroscience: Architects in neural circuit design: glia control neuron numbers and connectivity.

    PubMed

    Corty, Megan M; Freeman, Marc R

    2013-11-11

    Glia serve many important functions in the mature nervous system. In addition, these diverse cells have emerged as essential participants in nearly all aspects of neural development. Improved techniques to study neurons in the absence of glia, and to visualize and manipulate glia in vivo, have greatly expanded our knowledge of glial biology and neuron-glia interactions during development. Exciting studies in the last decade have begun to identify the cellular and molecular mechanisms by which glia exert control over neuronal circuit formation. Recent findings illustrate the importance of glial cells in shaping the nervous system by controlling the number and connectivity of neurons.

  14. Understanding Schroeder's Paradox

    NASA Astrophysics Data System (ADS)

    Weber, Adam; Kusoglu, Ahmet

    2012-02-01

    Schroeder's paradox is a well known, but not fully understood, phenomenon that exists in many polymers and gels. Essentially, the uptake of solvent in the polymer depends on the interaction with the boundary phase. Nafion, a polymer of interest for many electrochemical energy applications, is a classic example where the water uptake almost doubles by placement in liquid water versus saturated water vapor. In this talk, we examine the origin of this paradox through examination of Nafion morphology and water-uptake time constants using experiments in various solvents, vacuum, and small-angle X-ray scattering techniques. The results show that the interface controls the water uptake (even in bulk membranes) and that the interfacial morphology depends on the interactions of the different polymer moieties with the external environment including its density and dielectric constant. In addition, interactions with solid phases will be discussed which show similar impact on water uptake depending on whether they are hydrophilic or hydrophobic. Understanding the morphological changes and their associated impact on membrane properties is critical for optimizing polymers for use in energy applications.

  15. Zbtb20 defines a hippocampal neuronal identity through direct repression of genes that control projection neuron development in the isocortex.

    PubMed

    Nielsen, Jakob V; Thomassen, Mads; Møllgård, Kjeld; Noraberg, Jens; Jensen, Niels A

    2014-05-01

    Hippocampal pyramidal neurons are important for encoding and retrieval of spatial maps and episodic memories. While previous work has shown that Zbtb20 is a cell fate determinant for CA1 pyramidal neurons, the regulatory mechanisms governing this process are not known. In this study, we demonstrate that Zbtb20 binds to genes that control neuronal subtype specification in the developing isocortex, including Cux1, Cux2, Fezf2, Foxp2, Mef2c, Rorb, Satb2, Sox5, Tbr1, Tle4, and Zfpm2. We show that Zbtb20 represses these genes during ectopic CA1 pyramidal neuron development in transgenic mice. These data reveal a novel regulatory mechanism by which Zbtb20 suppresses the acquisition of an isocortical fate during archicortical neurogenesis to ensure commitment to a CA1 pyramidal neuron fate. We further show that the expression pattern of Zbtb20 is evolutionary conserved in the fetal human hippocampus, where it is complementary to the expression pattern of the Zbtb20 target gene Tbr1. Therefore, the disclosed Zbtb20-mediated transcriptional repressor mechanism may be involved in development of the human archicortex.

  16. Respiratory control by ventral surface chemoreceptor neurons in rats.

    PubMed

    Mulkey, Daniel K; Stornetta, Ruth L; Weston, Matthew C; Simmons, Johnny R; Parker, Anson; Bayliss, Douglas A; Guyenet, Patrice G

    2004-12-01

    A long-standing theory posits that central chemoreception, the CNS mechanism for CO(2) detection and regulation of breathing, involves neurons located at the ventral surface of the medulla oblongata (VMS). Using in vivo and in vitro electrophysiological recordings, we identify VMS neurons within the rat retrotrapezoid nucleus (RTN) that have characteristics befitting these elusive chemoreceptors. These glutamatergic neurons are vigorously activated by CO(2) in vivo, whereas serotonergic neurons are not. Their CO(2) sensitivity is unaffected by pharmacological blockade of the respiratory pattern generator and persists without carotid body input. RTN CO(2)-sensitive neurons have extensive dendrites along the VMS and they innervate key pontomedullary respiratory centers. In brainstem slices, a subset of RTN neurons with markedly similar morphology is robustly activated by acidification and CO(2). Their pH sensitivity is intrinsic and involves a background K(+) current. In short, the CO(2)-sensitive neurons of the RTN are good candidates for the long sought-after VMS chemoreceptors.

  17. apterous Brain Neurons Control Receptivity to Male Courtship in Drosophila Melanogaster Females

    PubMed Central

    Aranha, Márcia M.; Herrmann, Dennis; Cachitas, Hugo; Neto-Silva, Ricardo M.; Dias, Sophie; Vasconcelos, Maria Luísa

    2017-01-01

    Courtship behaviours allow animals to interact and display their qualities before committing to reproduction. In fly courtship, the female decides whether or not to mate and is thought to display receptivity by slowing down to accept the male. Very little is known on the neuronal brain circuitry controlling female receptivity. Here we use genetic manipulation and behavioural studies to identify a novel set of neurons in the brain that controls sexual receptivity in the female without triggering the postmating response. We show that these neurons, defined by the expression of the transcription factor apterous, affect the modulation of female walking speed during courtship. Interestingly, we found that the apterous neurons required for female receptivity are neither doublesex nor fruitless positive suggesting that apterous neurons are not specified by the sex-determination cascade. Overall, these findings identify a neuronal substrate underlying female response to courtship and highlight the central role of walking speed in the receptivity behaviour. PMID:28401905

  18. Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control

    PubMed Central

    Kuo, Sheng-Han; Tai, Chun-Hwei; Liou, Jyun-You; Pei, Ju-Chun; Chang, Chia-Yuan; Wang, Yi-Mei; Liu, Wen-Chuan; Wang, Tien-Rei

    2016-01-01

    Neuronal oscillations at beta frequencies (20–50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson’s disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy. PMID:27797341

  19. Control of Neuronal Migration and Aggregation by Reelin Signaling in the Developing Cerebral Cortex.

    PubMed

    Hirota, Yuki; Nakajima, Kazunori

    2017-01-01

    The mammalian cerebral neocortex has a well-organized laminar structure, achieved by the highly coordinated control of neuronal migration. During cortical development, excitatory neurons born near the lateral ventricle migrate radially to reach their final positions to form the cortical plate. During this process, dynamic changes are observed in the morphologies and migration modes, including multipolar migration, locomotion, and terminal translocation, of the newborn neurons. Disruption of these migration processes can result in neuronal disorders such as lissencephaly and periventricular heterotopia. The extracellular protein, Reelin, mainly secreted by the Cajal-Retzius neurons in the marginal zone during development, plays a crucial role in the neuronal migration and neocortical lamination. Reelin signaling, which exerts essential roles in the formation of the layered neocortex, is triggered by the binding of Reelin to its receptors, ApoER2 and VLDLR, followed by phosphorylation of the Dab1 adaptor protein. Accumulating evidence suggests that Reelin signaling controls multiple steps of neuronal migration, including the transition from multipolar to bipolar neurons, terminal translocation, and termination of migration beneath the marginal zone. In addition, it has been shown that ectopically expressed Reelin can cause neuronal aggregation via an N-cadherin-mediated manner. This review attempts to summarize our knowledge of the roles played by Reelin in neuronal migration and the underlying mechanisms.

  20. Activity Clamp Provides Insights into Paradoxical Effects of the Anti-Seizure Drug Carbamazepine

    PubMed Central

    Leite, Marco; Kullmann, Dimitri M.

    2017-01-01

    A major challenge in experimental epilepsy research is to reconcile the effects of anti-epileptic drugs (AEDs) on individual neurons with their network-level actions. Highlighting this difficulty, it is unclear why carbamazepine (CBZ), a frontline AED with a known molecular mechanism, has been reported to increase epileptiform activity in several clinical and experimental studies. We confirmed in an in vitro mouse model (in both sexes) that the frequency of interictal bursts increased after CBZ perfusion. To address the underlying mechanisms, we developed a method, activity clamp, to distinguish the response of individual neurons from network-level actions of CBZ. We first recorded barrages of synaptic conductances from neurons during epileptiform activity and then replayed them in pharmacologically isolated neurons under control conditions and in the presence of CBZ. CBZ consistently decreased the reliability of the second action potential in each burst of activity. Conventional current-clamp recordings using excitatory ramp or square-step current injections failed to reveal this effect. Network modeling showed that a CBZ-induced decrease of neuron recruitment during epileptic bursts can lead to an increase in burst frequency at the network level by reducing the refractoriness of excitatory transmission. By combining activity clamp with computer simulations, the present study provides a potential explanation for the paradoxical effects of CBZ on epileptiform activity. SIGNIFICANCE STATEMENT The effects of anti-epileptic drugs on individual neurons are difficult to separate from their network-level actions. Although carbamazepine (CBZ) has a known anti-epileptic mechanism, paradoxically, it has also been reported to increase epileptiform activity in clinical and experimental studies. To investigate this paradox during realistic neuronal epileptiform activity, we developed a method, activity clamp, to distinguish the effects of CBZ on individual neurons from network

  1. Surface strategies for control of neuronal cell adhesion: A review

    NASA Astrophysics Data System (ADS)

    Roach, P.; Parker, T.; Gadegaard, N.; Alexander, M. R.

    2010-06-01

    Material engineering methods have been used for many years to develop biomedical devices for use within the body to augment, repair or replace damaged tissues ranging from contact lenses to heart valves. Here we review the findings gathered from the wide and varied surface analytical approaches applied to study the interaction between biology and man-made materials. The key material characteristics identified to be important for biological recognition are surface chemistry, topography and compliance. Model surfaces with controlled chemistry and topography have provided insight into biological response to various types of topographical features over a wide range of length scales from nano to micrometres, along with 3D matrices that have been used as scaffolds to support cells for tissue formation. The cellular response to surfaces with localised areas of patterned chemistry and to those presenting gradually changing chemistry are discussed. Where previous reviews have been structured around specific classes of surface modification, e.g. self-assembly, or have broadly examined the response of various cells to numerous surfaces, we aim in this article to focus in particular on the tissues involved in the nervous system whilst providing a broad overview of key issues from the field of cell and protein surface interactions with surfaces. The goal of repair and treatment of diseases related to the central and peripheral nervous systems rely on understanding the local interfacial environment and controlling responses at the cellular level. The role of the protein layer deposited from serum containing media onto man-made surfaces is discussed. We highlight the particular problems associated with the repair of the nervous system, and review how neuronal attachment and axon guidance can be accomplished using various surface cues when cultured with single and multiple cell types. We include a brief glossary of techniques discussed in the body of this article aimed at the

  2. Neurohormones, rikkunshito and hypothalamic neurons interactively control appetite and anorexia.

    PubMed

    Yada, Toshihiko; Kohno, Daisuke; Maejima, Yuko; Sedbazar, Udval; Arai, Takeshi; Toriya, Masako; Maekawa, Fumihiko; Kurita, Hedeharu; Niijima, Akira; Yakabi, Koji

    2012-01-01

    Ghrelin is the orexigenic peptide produced in the periphery, and its plasma level shows remarkable pre/postprandial changes. Ghrelin is considered a pivotal signal to the brain to stimulate feeding. Hence, characterizing the target neurons for ghrelin in the hypothalamic feeding center and the signaling cascade in the target neurons are essential for understanding the mechanisms regulating appetite. Anorexia and cachexia associated with gastric surgery, stress-related diseases, and use of anti-cancer drugs cause the health problems, markedly deteriorating the quality of life. The anorexia involves several neurotransmitters and neuropeptides in the hypothalamic feeding center, in which corticotropin-releasing hormone (CRH), urocortine, serotonin (5HT) and brain-derived neurotrophic factor (BDNF) play a pivotal role. A Japanese herbal medicine, rikkunshito, has been reported to ameliorate the anorexia by promoting the appetite. This review describes 1) the interaction of ghrelin with the orexigenic neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) and underlying signaling cascade in NPY neurons, 2) the anorectic pathway driven by BDNF-CRH/urocortine and 5HTCRH/ urocortine pathways, 3) the effect of rikkunshito on the interaction of ghrelin and NPY neurons in ARC, and 4) the effect of rikkunshito on the interaction of 5HT on CRH neurons in paraventricular nucleus (PVN).

  3. The Integration Paradox

    PubMed Central

    Verkuyten, Maykel

    2016-01-01

    The integration paradox refers to the phenomenon of the more highly educated and structurally integrated immigrants turning away from the host society, rather than becoming more oriented toward it. This article provides an overview of the empirical evidence documenting this paradox in the Netherlands. In addition, the theoretical arguments and the available findings about the social psychological processes involved in this paradox are considered. The existing evidence for the integration paradox and what might explain it form the basis for making suggestion for future theoretical work and empirical research, and for discussing possible policy implications. PMID:27152028

  4. Aharonov-bohm paradox.

    NASA Technical Reports Server (NTRS)

    Trammel, G. T.

    1964-01-01

    Aharonov-bohm paradox involving charge particle interaction with stationary current distribution showing that vector potential term in canonical momenta expression represents electromagnetic field momentum

  5. Aharonov-bohm paradox.

    NASA Technical Reports Server (NTRS)

    Trammel, G. T.

    1964-01-01

    Aharonov-bohm paradox involving charge particle interaction with stationary current distribution showing that vector potential term in canonical momenta expression represents electromagnetic field momentum

  6. Dynamics of neurons controlling movements of a locust hind leg. III. Extensor tibiae motor neurons.

    PubMed

    Newland, P L; Kondoh, Y

    1997-06-01

    Imposed movements of the apodeme of the femoral chordotonal organ (FeCO) of the locust hind leg elicit resistance reflexes in extensor and flexor tibiae motor neurons. The synaptic responses of the fast and slow extensor tibiae motor neurons (FETi and SETi, respectively) and the spike responses of SETi were analyzed with the use of the Wiener kernel white noise method to determine their response properties. The first-order Wiener kernels computed from soma recordings were essentially monophasic, or low passed, indicating that the motor neurons were primarily sensitive to the position of the tibia about the femorotibial joint. The responses of both extensor motor neurons had large nonlinear components. The second-order kernels of the synaptic responses of FETi and SETi had large on-diagonal peaks with two small off-diagonal valleys. That of SETi had an additional elongated valley on the diagonal, which was accompanied by two off-diagonal depolarizing peaks at a cutoff frequency of 58 Hz. These second-order components represent a half-wave rectification of the position-sensitive depolarizing response in FETi and SETi, and a delayed inhibitory input to SETi, indicating that both motor neurons were directionally sensitive. Model predictions of the responses of the motor neurons showed that the first-order (linear) characterization poorly predicted the actual responses of FETi and SETi to FeCO stimulation, whereas the addition of the second-order (nonlinear) term markedly improved the performance of the model. Simultaneous recordings from the soma and a neuropilar process of FETi showed that its synaptic responses to FeCO stimulation were phase delayed by about -30 degrees at 20 Hz, and reduced in amplitude by 30-40% when recorded in the soma. Similar configurations of the first and second-order kernels indicated that the primary process of FETi acted as a low-pass filter. Cross-correlation between a white noise stimulus and a unitized spike discharge of SETi again

  7. Adaptive Fractional-order Control for Synchronization of Two Coupled Neurons in the External Electrical Stimulation

    PubMed Central

    Mehdiabadi, M. R. Rahmani; Rouhani, E.; Mashhadi, S. K. Mousavi; Jalali, A. A.

    2014-01-01

    This paper addresses synchronizing two coupled chaotic FitzHugh–Nagumo (FHN) neurons with weakly gap junction under external electrical stimulation (EES). To transmit information among coupled neurons, by generalization of the integer-order FHN equations of the coupled system into the fractional-order in frequency domain using Crone approach, the behavior of each coupled neuron relies on its past behavior and the memorized system can be a better fit for the neuron response. An adaptive fractional-order controller based on the Lyaponuv stability theory was designed to synchronize two neurons electrically coupled with gap junction in EES. The proposed controller is also robust to the inevitable random noise such as disturbances of ionic channels. The simulation results demonstrate the effectiveness of the control scheme. PMID:25337373

  8. Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex

    PubMed Central

    Shinmyo, Yohei; Asrafuzzaman Riyadh, M.; Ahmed, Giasuddin; Bin Naser, Iftekhar; Hossain, Mahmud; Takebayashi, Hirohide; Kawasaki, Hiroshi; Ohta, Kunimasa; Tanaka, Hideaki

    2015-01-01

    The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin−/− mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons. Genetic interaction data suggest that draxin acts through Deleted in colorectal cancer (DCC) and Neogenin (Neo1), to regulate thalamocortical projections in vivo. Draxin promotes the outgrowth of thalamic axons in vitro and this effect is abolished in thalamic neurons from Dcc and Neo1 double mutants. These results suggest that draxin from neocortical neurons controls thalamocortical projections into the neocortex, and that this effect is mediated through the DCC and Neo1 receptors. PMID:26659141

  9. Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex.

    PubMed

    Shinmyo, Yohei; Asrafuzzaman Riyadh, M; Ahmed, Giasuddin; Bin Naser, Iftekhar; Hossain, Mahmud; Takebayashi, Hirohide; Kawasaki, Hiroshi; Ohta, Kunimasa; Tanaka, Hideaki

    2015-12-14

    The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin(-/-) mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons. Genetic interaction data suggest that draxin acts through Deleted in colorectal cancer (DCC) and Neogenin (Neo1), to regulate thalamocortical projections in vivo. Draxin promotes the outgrowth of thalamic axons in vitro and this effect is abolished in thalamic neurons from Dcc and Neo1 double mutants. These results suggest that draxin from neocortical neurons controls thalamocortical projections into the neocortex, and that this effect is mediated through the DCC and Neo1 receptors.

  10. Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2

    NASA Astrophysics Data System (ADS)

    Liske, Holly; Qian, Xiang; Anikeeva, Polina; Deisseroth, Karl; Delp, Scott

    2013-10-01

    The effect of electrical stimulation on neuronal membrane potential is frequency dependent. Low frequency electrical stimulation can evoke action potentials, whereas high frequency stimulation can inhibit action potential transmission. Optical stimulation of channelrhodopsin-2 (ChR2) expressed in neuronal membranes can also excite action potentials. However, it is unknown whether optical stimulation of ChR2-expressing neurons produces a transition from excitation to inhibition with increasing light pulse frequencies. Here we report optical inhibition of motor neuron and muscle activity in vivo in the cooled sciatic nerves of Thy1-ChR2-EYFP mice. We also demonstrate all-optical single-wavelength control of neuronal excitation and inhibition without co-expression of inhibitory and excitatory opsins. This all-optical system is free from stimulation-induced electrical artifacts and thus provides a new approach to investigate mechanisms of high frequency inhibition in neuronal circuits in vivo and in vitro.

  11. Dopaminergic Neurons Controlling Anterior Pituitary Functions: Anatomy and Ontogenesis in Zebrafish.

    PubMed

    Fontaine, Romain; Affaticati, Pierre; Bureau, Charlotte; Colin, Ingrid; Demarque, Michaël; Dufour, Sylvie; Vernier, Philippe; Yamamoto, Kei; Pasqualini, Catherine

    2015-08-01

    Dopaminergic (DA) neurons located in the preoptico-hypothalamic region of the brain exert a major neuroendocrine control on reproduction, growth, and homeostasis by regulating the secretion of anterior pituitary (or adenohypophysis) hormones. Here, using a retrograde tract tracing experiment, we identified the neurons playing this role in the zebrafish. The DA cells projecting directly to the anterior pituitary are localized in the most anteroventral part of the preoptic area, and we named them preoptico-hypophyseal DA (POHDA) neurons. During development, these neurons do not appear before 72 hours postfertilization (hpf) and are the last dopaminergic cell group to differentiate. We found that the number of neurons in this cell population continues to increase throughout life proportionally to the growth of the fish. 5-Bromo-2'-deoxyuridine incorporation analysis suggested that this increase is due to continuous neurogenesis and not due to a phenotypic change in already-existing neurons. Finally, expression profiles of several genes (foxg1a, dlx2a, and nr4a2a/b) were different in the POHDA compared with the adjacent suprachiasmatic DA neurons, suggesting that POHDA neurons develop as a distinct DA cell population in the preoptic area. This study offers some insights into the regional identity of the preoptic area and provides the first bases for future functional genetic studies on the development of DA neurons controlling anterior pituitary functions.

  12. Counterbalance between BAG and URX neurons via guanylate cyclases controls lifespan homeostasis in C. elegans

    PubMed Central

    Liu, Tiewen; Cai, Dongsheng

    2013-01-01

    Lifespan of C. elegans is affected by the nervous system; however, the underlying neural integration still remains unclear. In this work, we targeted an antagonistic neural system consisting of low-oxygen sensing BAG neurons and high-oxygen sensing URX neurons. While ablation of BAG neurons increases lifespan of C. elegans, ablation of URX neurons decreases lifespan. Genetic analysis revealed that BAG and URX neurons counterbalance each other via different guanylate cyclases (GCYs) to control lifespan balance. Lifespan-modulating effects of GCYs in these neurons are independent of the actions from insulin/IGF-1 signalling, germline signalling, sensory perception, or dietary restriction. Given the known gas-sensing property of these neurons, we profiled that lifespan of C. elegans is promoted under moderately low oxygen (4–12%) or moderately high carbon dioxide (5%) but inhibited under high-level oxygen (40%); however, these pro-longevity and anti-longevity effects are counteracted, respectively, by BAG and URX neurons via different GCYs. In conclusion, BAG and URX neurons work as a neural-regulatory system to counterbalance each other via different GCYs to control lifespan homeostasis. PMID:23584532

  13. Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons

    PubMed Central

    Palomer, Ernest; Carretero, Javier; Benvegnù, Stefano; Dotti, Carlos G.; Martin, Mauricio G.

    2016-01-01

    It has been recently described that in embryonic stem cells, the expression of some important developmentally regulated genes is repressed, but poised for fast activation under the appropriate stimuli. In this work we show that Bdnf promoters are repressed by Polycomb Complex 2 in mature hippocampal neurons, and basal expression is guaranteed by the coexistence with activating histone marks. Neuronal stimulation triggered by N-methyl-D-aspartate application induces the transcription of these promoters by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28 leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. Our data show that the fast transient expression of Bdnf promoters II and VI after neuronal stimulation is dependent on acetylation of histone H3K27 by CREB-p/CBP. Thus, regulatory mechanisms established during development seem to remain after differentiation controlling genes induced by different stimuli, as would be the case of early memory genes in mature neurons. PMID:27010597

  14. Ventromedial hypothalamic neurons control a defensive emotion state.

    PubMed

    Kunwar, Prabhat S; Zelikowsky, Moriel; Remedios, Ryan; Cai, Haijiang; Yilmaz, Melis; Meister, Markus; Anderson, David J

    2015-03-06

    Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

  15. Addictive neurons

    PubMed Central

    Kodirov, Sodikdjon A.

    2017-01-01

    Since the reward center is considered to be the area tegmentalis ventralis of the hypothalamus, logically its neurons could mainly be responsible for addiction. However, the literature asserts that almost any neurons of CNS can respond to one or another addictive compound. Obviously not only addictive nicotine, but also alcohol, amphetamine, cannabis, cocaine, heroin and morphine may influence dopaminergic cells alone in VTA. Moreover, paradoxically some of these drugs ameliorate symptoms, counterbalance syndromes, cure diseases and improve health, not only those related to the CNS and in adults, but also almost all other organs and in children, e.g. epilepsy. PMID:28649663

  16. Optogenetic control of hypocretin (orexin) neurons and arousal circuits.

    PubMed

    de Lecea, Luis

    2015-01-01

    In 1998, our group discovered a cDNA that encoded the precursor of two putative neuropeptides that we called hypocretins for their hypothalamic expression and their similarity to the secretin family of neuropeptides. In the last 16 years, numerous studies have placed the hypocretin system as an integrator of homeostatic functions with a crucial, non-redundant function as arousal stabilizer. We recently applied optogenetic methods to interrogate the role of individual neuronal circuits in sleep-to-wake transitions. The neuronal connections between the hypocretin system and the locus coeruleus (LC) seem to be crucial in establishing the appropriate dynamic of spontaneous awakenings.

  17. Optogenetic Control of Hypocretin (Orexin) Neurons and Arousal Circuits

    PubMed Central

    de Lecea, Luis

    2016-01-01

    In 1998, our group discovered a cDNA that encoded the precursor of two putative neuropeptides that we called hypocretins for their hypothalamic expression and their similarity to the secretin family of neuropeptides. In the last 16 years, numerous studies have placed the hypocretin system as an integrator of homeostatic functions with a crucial, non-redundant function as arousal stabilizer. We recently applied optogenetic methods to interrogate the role of individual neuronal circuits in sleep-to-wake transitions. The neuronal connections between the hypocretin system and the locus coeruleus (LC) seem to be crucial in establishing the appropriate dynamic of spontaneous awakenings. PMID:25502546

  18. Paradoxes in dermatology

    PubMed Central

    Adya, Keshavmurthy A.; Inamadar, Arun C.; Palit, Aparna

    2013-01-01

    Many paradoxical phenomena related to clinical, immunological, and therapeutic dermatology have been described. While some of them can be explained logically, the cause for others can only be speculated. Whenever encountered in clinical practice, background knowledge of such paradoxes may be useful to the clinician. PMID:23741675

  19. The Paradoxical Young Person

    ERIC Educational Resources Information Center

    Vishnevskii, Iu. R.; Shapko, V. T.

    2007-01-01

    The social transformations in Russian society in the past two decades have made relevant the problem of paradoxality, including its application to young people. The results of many years of sociological studies by the authors investigating the social problems of young people completely confirm Toshchenko's conclusion that "paradoxality of…

  20. ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons

    PubMed Central

    Kim, Kyung-Tai; Kim, Namhee; Kim, Hwan-Ki; Lee, Hojae; Gruner, Hannah N.; Gergics, Peter; Park, Chungoo; Mastick, Grant S.; Park, Hae-Chul; Song, Mi-Ryoung

    2016-01-01

    LIM-homeodomain (HD) transcription factors form a multimeric complex and assign neuronal subtype identities, as demonstrated by the hexameric ISL1-LHX3 complex which gives rise to somatic motor (SM) neurons. However, the roles of combinatorial LIM code in motor neuron diversification and their subsequent differentiation is much less well understood. In the present study, we demonstrate that the ISL1 controls postmitotic cranial branchiomotor (BM) neurons including the positioning of the cell bodies and peripheral axon pathfinding. Unlike SM neurons, which transform into interneurons, BM neurons are normal in number and in marker expression in Isl1 mutant mice. Nevertheless, the movement of trigeminal and facial BM somata is stalled, and their peripheral axons are fewer or misrouted, with ectopic branches. Among genes whose expression level changes in previous ChIP-seq and microarray analyses in Isl1-deficient cell lines, we found that Slit2 transcript was almost absent from BM neurons of Isl1 mutants. Both ISL1-LHX3 and ISL1-LHX4 bound to the Slit2 enhancer and drove endogenous Slit2 expression in SM and BM neurons. Our findings suggest that combinations of ISL1 and LHX factors establish cell-type specificity and functional diversity in terms of motor neuron identities and/or axon development. PMID:27819291

  1. Activity-Dependent Neuronal Control of Gap-Junctional Communication in Astrocytes

    PubMed Central

    Rouach, Nathalie; Glowinski, Jacques; Giaume, Christian

    2000-01-01

    A typical feature of astrocytes is their high degree of intercellular communication through gap junction channels. Using different models of astrocyte cultures and astrocyte/neuron cocultures, we have demonstrated that neurons upregulate gap-junctional communication and the expression of connexin 43 (Cx43) in astrocytes. The propagation of intercellular calcium waves triggered in astrocytes by mechanical stimulation was also increased in cocultures. This facilitation depends on the age and number of neurons, indicating that the state of neuronal differentiation and neuron density constitute two crucial factors of this interaction. The effects of neurons on astrocytic communication and Cx43 expression were reversed completely after neurotoxic treatments. Moreover, the neuronal facilitation of glial coupling was suppressed, without change in Cx43 expression, after prolonged pharmacological treatments that prevented spontaneous synaptic activity. Altogether, these results demonstrate that neurons exert multiple and differential controls on astrocytic gap-junctional communication. Since astrocytes have been shown to facilitate synaptic efficacy, our findings suggest that neuronal and astrocytic networks interact actively through mutual setting of their respective modes of communication. PMID:10871289

  2. The neuronal control of cardiac functions in Molluscs☆

    PubMed Central

    Kodirov, Sodikdjon A.

    2017-01-01

    In this manuscript, I review the current and relevant classical studies on properties of the Mollusca heart and their central nervous system including ganglia, neurons, and nerves involved in cardiomodulation. Similar to mammalian brain hemispheres, these invertebrates possess symmetrical pairs of ganglia albeit visceral (only one) ganglion and the parietal ganglia (the right ganglion is bigger than the left one). Furthermore, there are two major regulatory drives into the compartments (pericard, auricle, and ventricle) and cardiomyocytes of the heart. These are the excitatory and inhibitory signals that originate from a few designated neurons and their putative neurotransmitters. Many of these neurons are well-identified, their specific locations within the corresponding ganglion are mapped, and some are termed as either heart excitatory (HE) or inhibitory (HI) cells. The remaining neurons are classified as cardio-regulatory, and their direct and indirect actions on the heart’s function have been documented. The cardiovascular anatomy of frequently used experimental animals, Achatina, Aplysia, Helix, and Lymnaea is relatively simple. However, as in humans, it possesses all major components including even trabeculae and atrio-ventricular valves. Since the myocardial cells are enzymatically dispersible, multiple voltage dependent cationic currents in isolated cardiomyocytes are described. The latter include at least the A-type K+, delayed rectifier K+, TTX-sensitive Na+, and L-type Ca2+ channels. PMID:21736949

  3. Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control

    PubMed Central

    Zhang, Tianhe C.; Janik, John J.; Peters, Ryan V.; Chen, Gang; Ji, Ru-Rong

    2015-01-01

    Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry. PMID:25972582

  4. Controlling growth and electrical connectivity of neuronal cells patterned on surfaces

    NASA Astrophysics Data System (ADS)

    Beighley, Ross; Spedden, Elise; White, James; Staii, Cristian

    2012-02-01

    In the developing brain biochemical and geometrical cues are an essential source of information used by neurons when wiring up the nervous system. However, our current understanding of the mechanisms by which various guidance factors control the path that growing axons/dendrites follow to reach their targets and form functional electrical connections remains qualitative. A current limitation for the study of neural network formation is the ability to precisely control the growth and interconnectivity of small numbers of neurons. Here we present a combined Atomic Force Microscopy - Fluorescence Spectroscopy approach for patterning neurons on 2-dimensional substrates and precisely controlling their location, growth and interconnectivity. We demonstrate that this approach allows one to: a) form simple neuronal circuits in well-controlled geometries; b) guide the formation of functional synapses between neurons, and c) measure the electrical activity of small groups of neurons. We also discuss the implications of these results for our current understanding of the fundamental mechanisms that govern the development of electrical connections between neurons.

  5. Electrophysiological recording from neurons controlling sensory and motor functions of the esophagus.

    PubMed

    Sengupta, J N

    2001-12-03

    contractions of the distal esophagus. This response undergoes inhibition in response to proximal distension. In addition, there is a second, nonrhythmic firing response that occurs both proximal and distal esophageal distension. This observation suggests that swallow-induced inhibition of the distal esophagus is controlled by the preganglionic motor neurons in the brain stem. Electrophysiological studies allow direct understanding of neuronal activities regulating esophageal functions. In vivo recording has an advantage for studying functional roles of the neurons in regulatory reflexes, whereas in vitro recording is useful for more accurate study of receptor pharmacology. Recordings from the central nervous system allow study of the neurotransmitters involved in neuronal function and the circuitry of different reflex mechanisms.

  6. Neural prosthesis in the wake of nanotechnology: controlled growth of neurons using surface nanostructures.

    PubMed

    Lee, J K; Baac, H; Song, S H; Jang, E; Lee, S D; Park, D; Kim, S J

    2006-01-01

    Neural prosthesis has been successfully applied to patients with motional or sensory disabilities for clinical purpose. To enhance the performance of the neural prosthetic device, the electrodes for the biosignal recording or electrical stimulation should be located in closer proximity to target neurons than they are now. Instead of revising the prior implanting surgery to improve the electrical contact of neurons, we propose a technique that can bring the neurons closer to the electrode sites. A new method is investigated that can control the direction of neural cell growth using surface nanostructures. We successfully guide the neurons to the position of the microelectrodes by providing a surface topographical cue presented by the surface nanostructure on a photoresponsive polymer material. Because the surface structure formed by laser holography is reversible and repeatable, the geometrical positioning of the neurons to microelectrodes can be adjusted by applying laser treatment during the surgery for the purpose of improving the performance of neural prosthetic device.

  7. Gain control of synaptic transfer from second- to third-order neurons of cockroach ocelli

    PubMed Central

    1996-01-01

    Synaptic transmission from second- to third-order neurons of cockroach ocelli occurs in an exponentially rising part of the overall sigmoidal characteristic curve relating pre- and postsynaptic voltage. Because of the nonlinear nature of the synapse, linear responses of second-order neurons to changes in ligh intensity are half-wave rectified, i.e., the response to a decrement in light is amplified whereas that to an increment in light is compressed. Here I report that the gain of synaptic transmission from second- to third-order neurons changes by ambient light levels and by wind stimulation applied to the cerci. Transfer characteristics of the synapse were studied by simultaneous intracellular recordings of second- and third-order neurons. Potential changes were evoked in second-order neurons by a sinusoidally modulated light with various mean luminances. With a decrease in the mean luminance (a) the mean membrane potential of second-order neurons was depolarized, (b) the synapse between the second- and third-order neurons operated in a steeper range of the exponential characteristic curve, where the gain to transmit modulatory signals was higher, and (c) the gain of third-order neurons to detect a decrement in light increased. Second-order neurons were depolarized when a wind or tactile stimulus was applied to various parts of the body including the cerci. During a wind-evoked depolarization, the synapse operated in a steeper range of the characteristic curve, which resulted in an increased gain of third-order neurons to detect light decrements. I conclude that the nonlinear nature of the synapse between the second- and third-order neurons provides an opportunity for an adjustment of gain to transmit signals of intensity change. The possibility that a similar gain control occurs in other visual systems and underlies a more advanced visual function, i.e., detection of motion, is discussed. PMID:8741734

  8. Lower Motor Control Modeled by Neuron With Fuzzy Synapses

    DTIC Science & Technology

    2007-11-02

    seen in parkinsonism , chorea, cerebellar disorders, and spasticity. In most cases, muscles work in opposing pairs: one muscle opens or extends a joint...performances of predictor schemes based on neurons with fuzzy synapses of order P = 3 in tremor prediction applications. The rules of these particular...Chelaru, A. Kandel, I. Tofan, M. Irimia, “Fuzzy methods in tremor assessment, prediction, and rehabilitation”, Artificial Intelligence in Medicine

  9. Neuron-conditioned media differentially affect the survival of activated or unstimulated microglia: evidence for neuronal control on apoptotic elimination of activated microglia.

    PubMed

    Polazzi, Elisabetta; Contestabile, Antonio

    2003-04-01

    It is presently unknown what types of neuronal signals maintain microglial cells resting in the normal brain or control their activation in neuropathology. Recent data suggest that microglia activation induces apoptosis and that healthy neurons are controllers of the activation state and immune functions of microglia. In the present study we have evaluated, on microglial cells in cultures, whether neurons are able to affect their survival in resting conditions or upon activation with the bacterial endotoxin, lipopolysaccharide (LPS). We report that neuron-conditioned culture media induced apoptosis of LPS-stimulated, but not of unstimulated, microglia. This effect was, however, only present when conditioned media had been exposed to differentiated neurons and not to immature ones, and was absent when glutamate receptors had been pharmacologically blocked in neuronal cultures. The effect was also blocked by heat-inactivation of the conditioned media. Media conditioned with either differentiated or undifferentiated cerebellar granule neurons positively affected the survival of unstimulated microglial cells when the standard concentration of fetal bovine serum (10%) was included in the culture media. Our results highlight the ability of differentiated neurons to maintain a controlled inflammatory state through production of factor(s) favoring the apoptotic elimination of activated microglia. They also suggest that immature neurons may, on the contrary, favor the survival of microglia during development.

  10. Circadian Neuron Feedback Controls the Drosophila Sleep-Activity Profile

    PubMed Central

    Guo, Fang; Yu, Junwei; Jung, Hyung Jae; Abruzzi, Katharine C.; Luo, Weifei; Griffith, Leslie C.; Rosbash, Michael

    2016-01-01

    SUMMARY Little is known about the ability of Drosophila circadian neurons to promote sleep. We show here with optogenetic manipulations and video recording that a subset of dorsal clock neurons (DN1s) are potent sleep-promoting cells, releasing glutamate to directly inhibit key pacemaker neurons. These pacemakers promote morning arousal by activating these same DN1s, implying that there is a late-day feedback circuit to drive siesta and nighttime sleep. To address more plastic aspects of the sleep program, we used a novel calcium assay to monitor and compared the real-time DN1 activity of freely behaving males and females. It revealed a dramatic sexual dimorphism, which parallels the well-known difference in daytime sleep. DN1 activity is also enhanced by elevated temperature, consistent with its known effect on sleep. These new approaches indicate that the DN1s have a major impact on the fly sleep-wake profile and integrate environmental information with the circadian molecular program. PMID:27479324

  11. Ventromedial hypothalamic neurons control a defensive emotion state

    PubMed Central

    Kunwar, Prabhat S; Zelikowsky, Moriel; Remedios, Ryan; Cai, Haijiang; Yilmaz, Melis; Meister, Markus; Anderson, David J

    2015-01-01

    Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers. DOI: http://dx.doi.org/10.7554/eLife.06633.001 PMID:25748136

  12. Factors that control amplitude of EPSPs in dendritic neurons.

    PubMed

    Lev-Tov, A; Miller, J P; Burke, R E; Rall, W

    1983-08-01

    We have used a computer-based mathematical model of alpha-motoneurons and of group Ia synaptic input to them, based on anatomical and electrophysiological data from the cat spinal cord, in order to examine the effects of variations in neuron size and input resistance and of conductance magnitude and duration on the generation of excitatory postsynaptic potentials (EPSPs). The first set of calculations were designed to test the possible role of nonlinear EPSP summation in producing a differential distribution of posttetanic potentiation of group Ia EPSPs, described in the preceding paper (25; see also Refs. 26, 27). The results suggest that the negative correlations observed between the degree of posttetanic potentiation of Ia EPSPs and initial (pretetanic) EPSP amplitude as well as with the input resistance of the postsynaptic motoneurons can be explained in part by the inherent non-linearity between conductance change and the resultant potential change at chemical synapses. In a second set of calculations, we used the same model system to evaluate the effects produced by variations in neuronal membrane area, input resistance, and specific membrane resistivity, as well as of the density of excitatory synaptic input on the peak amplitude of EPSPs. With parameters constrained to match the properties of alpha-motoneurons and group Ia synaptic input, EPSP amplitudes were most sensitive to changes in synaptic density and were much less sensitive to alterations in neuron input resistance and specific membrane resistivity when synaptic density was constant.

  13. Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition

    PubMed Central

    Singh, Shalini; Howell, Danielle; Trivedi, Niraj; Kessler, Ketty; Ong, Taren; Rosmaninho, Pedro; Raposo, Alexandre ASF; Robinson, Giles; Roussel, Martine F; Castro, Diogo S; Solecki, David J

    2016-01-01

    In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers. DOI: http://dx.doi.org/10.7554/eLife.12717.001 PMID:27178982

  14. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors

    PubMed Central

    Alexander, Georgia M.; Rogan, Sarah C.; Abbas, Atheir I.; Armbruster, Blaine N.; Pei, Ying; Allen, John A.; Nonneman, Randal J.; Hartmann, John; Moy, Sheryl S.; Nicolelis, Miguel A.; McNamara, James O.; Roth, Bryan L.

    2009-01-01

    Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely-distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures. These results demonstrate a novel and powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo. PMID:19607790

  15. The Simpson's paradox unraveled

    PubMed Central

    Hernán, Miguel A; Clayton, David; Keiding, Niels

    2011-01-01

    Background In a famous article, Simpson described a hypothetical data example that led to apparently paradoxical results. Methods We make the causal structure of Simpson's example explicit. Results We show how the paradox disappears when the statistical analysis is appropriately guided by subject-matter knowledge. We also review previous explanations of Simpson's paradox that attributed it to two distinct phenomena: confounding and non-collapsibility. Conclusion Analytical errors may occur when the problem is stripped of its causal context and analyzed merely in statistical terms. PMID:21454324

  16. The paradoxical nature of surrender.

    PubMed

    Holley, Dorothy E Adamson

    2007-01-01

    Surrender is one of the most fundamental, important aspects of spirituality and of integration. It is crucial to our relationship to God, to self, and to others. While surrender is essential for any real attempt at authenticity and integration, it is also one of the most challenging aspects of any spiritual pursuit or endeavor. The inability or unwillingness to surrender is a serious impediment to our relationship with God, with others, and even with ourselves. Paradoxically, there is great freedom and an increased sense of control that is experienced when one is able to surrender. This article explores two themes that the author believes are involved in surrender: fear and trust. Clinical as well as personal examples of the paradoxical nature and transformational power of surrender are offered.

  17. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue.

    PubMed

    Steculorum, Sophie M; Ruud, Johan; Karakasilioti, Ismene; Backes, Heiko; Engström Ruud, Linda; Timper, Katharina; Hess, Martin E; Tsaousidou, Eva; Mauer, Jan; Vogt, Merly C; Paeger, Lars; Bremser, Stephan; Klein, Andreas C; Morgan, Donald A; Frommolt, Peter; Brinkkötter, Paul T; Hammerschmidt, Philipp; Benzing, Thomas; Rahmouni, Kamal; Wunderlich, F Thomas; Kloppenburg, Peter; Brüning, Jens C

    2016-03-24

    Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

  18. Automatic parameter estimation of multicompartmental neuron models via minimization of trace error with control adjustment

    PubMed Central

    Goeritz, Marie L.; Marder, Eve

    2014-01-01

    We describe a new technique to fit conductance-based neuron models to intracellular voltage traces from isolated biological neurons. The biological neurons are recorded in current-clamp with pink (1/f) noise injected to perturb the activity of the neuron. The new algorithm finds a set of parameters that allows a multicompartmental model neuron to match the recorded voltage trace. Attempting to match a recorded voltage trace directly has a well-known problem: mismatch in the timing of action potentials between biological and model neuron is inevitable and results in poor phenomenological match between the model and data. Our approach avoids this by applying a weak control adjustment to the model to promote alignment during the fitting procedure. This approach is closely related to the control theoretic concept of a Luenberger observer. We tested this approach on synthetic data and on data recorded from an anterior gastric receptor neuron from the stomatogastric ganglion of the crab Cancer borealis. To test the flexibility of this approach, the synthetic data were constructed with conductance models that were different from the ones used in the fitting model. For both synthetic and biological data, the resultant models had good spike-timing accuracy. PMID:25008414

  19. Dendrite complexity of sympathetic neurons is controlled during postnatal development by BMP signaling.

    PubMed

    Majdazari, Afsaneh; Stubbusch, Jutta; Müller, Christian M; Hennchen, Melanie; Weber, Marlen; Deng, Chu-Xia; Mishina, Yuji; Schütz, Günther; Deller, Thomas; Rohrer, Hermann

    2013-09-18

    Dendrite development is controlled by the interplay of intrinsic and extrinsic signals affecting initiation, growth, and maintenance of complex dendrites. Bone morphogenetic proteins (BMPs) stimulate dendrite growth in cultures of sympathetic, cortical, and hippocampal neurons but it was unclear whether BMPs control dendrite morphology in vivo. Using a conditional knock-out strategy to eliminate Bmpr1a and Smad4 in immature noradrenergic sympathetic neurons we now show that dendrite length, complexity, and neuron cell body size are reduced in adult mice deficient of Bmpr1a. The combined deletion of Bmpr1a and Bmpr1b causes no further decrease in dendritic features. Sympathetic neurons devoid of Bmpr1a/1b display normal Smad1/5/8 phosphorylation, which suggests that Smad-independent signaling paths are involved in dendritic growth control downstream of BMPR1A/B. Indeed, in the Smad4 conditional knock-out dendrite and cell body size are not affected and dendrite complexity and number are increased. Together, these results demonstrate an in vivo function for BMPs in the generation of mature sympathetic neuron dendrites. BMPR1 signaling controls dendrite complexity postnatally during the major dendritic growth period of sympathetic neurons.

  20. Slippery Signaling: Palmitoylation-dependent Control of Neuronal Kinase Localization and Activity

    PubMed Central

    Montersino, Audrey; Thomas, Gareth M.

    2016-01-01

    Modification of proteins with the lipid palmitate, a process called palmitoylation, is important for the normal function of neuronal cells. However, most attention has focused on how palmitoylation regulates the targeting and trafficking of neurotransmitter receptors and non-enzymatic scaffold proteins. In this review we discuss recent studies that suggest that palmitoylation also plays additional roles in neurons by controlling the localization, interactions and perhaps even the activity of protein kinases that play key roles in physiological neuronal regulation and in neuropathological processes. PMID:27241460

  1. Glucose responsive neurons of the paraventricular thalamus control sucrose-seeking behavior

    PubMed Central

    Labouèbe, Gwenaël; Boutrel, Benjamin; Tarussio, David; Thorens, Bernard

    2016-01-01

    Feeding behavior is governed by homeostatic needs and motivational drive to obtain palatable foods. Here, we identify a population of glutamatergic neurons in the paraventricular thalamus, which express the glucose transporter Glut2 (Scl2a2) and project to the nucleus accumbens. These neurons are activated by hypoglycemia and, in freely moving mice, their activation by optogenetics or Slc2a2 inactivation increases motivated sucrose but not saccharin-seeking behavior. These neurons may control sugar overconsumption in obesity and diabetes. PMID:27322418

  2. Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

    PubMed

    Zhou, Li; Liu, Ming-Zhe; Li, Qing; Deng, Juan; Mu, Di; Sun, Yan-Gang

    2017-03-21

    Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN.

  3. Important messages in the 'post': recent discoveries in 5-HT neurone feedback control.

    PubMed

    Sharp, Trevor; Boothman, Laura; Raley, Josie; Quérée, Philip

    2007-12-01

    The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) mediates important brain functions and contributes to the pathophysiology and successful drug treatment of many common psychiatric disorders, especially depression. It is established that a key mechanism involved in the control of 5-HT neurones is feedback inhibition by presynaptic 5-HT autoreceptors, which are located on 5-HT cell bodies and nerve terminals. However, recent experiments have discovered an unexpected complexity of 5-HT neurone control, specifically in the form of postsynaptic 5-HT feedback mechanisms. These mechanisms have the physiological effects of 5-HT autoreceptors but use additional 5-HT receptor subtypes and operate through neural inputs to 5-HT neurones. A postsynaptic feedback system that excites 5-HT neurones has also been reported. This article discusses current knowledge of the pharmacology and physiology of these new found 5-HT feedback mechanisms and considers their possible contribution to depression pathophysiology and utility as a resource of novel antidepressant drug strategies.

  4. Thermal Expansion "Paradox."

    ERIC Educational Resources Information Center

    Fakhruddin, Hasan

    1993-01-01

    Describes a paradox in the equation for thermal expansion. If the calculations for heating a rod and subsequently cooling a rod are determined, the new length of the cool rod is shorter than expected. (PR)

  5. Thermal Expansion "Paradox."

    ERIC Educational Resources Information Center

    Fakhruddin, Hasan

    1993-01-01

    Describes a paradox in the equation for thermal expansion. If the calculations for heating a rod and subsequently cooling a rod are determined, the new length of the cool rod is shorter than expected. (PR)

  6. Length Paradox in Relativity

    ERIC Educational Resources Information Center

    Martins, Roberto de A.

    1978-01-01

    Describes a thought experiment using a general analysis approach with Lorentz transformations to show that the apparent self-contradictions of special relativity concerning the length-paradox are really non-existant. (GA)

  7. The core paradox.

    NASA Technical Reports Server (NTRS)

    Kennedy, G. C.; Higgins, G. H.

    1973-01-01

    Rebuttal of suggestions from various critics attempting to provide an escape from the seeming paradox originated by Higgins and Kennedy's (1971) proposed possibility that the liquid in the outer core was thermally stably stratified and that this stratification might prove a powerful inhibitor to circulation of the outer core fluid of the kind postulated for the generation of the earth's magnetic field. These suggestions are examined and shown to provide no reasonable escape from the core paradox.

  8. The core paradox.

    NASA Technical Reports Server (NTRS)

    Kennedy, G. C.; Higgins, G. H.

    1973-01-01

    Rebuttal of suggestions from various critics attempting to provide an escape from the seeming paradox originated by Higgins and Kennedy's (1971) proposed possibility that the liquid in the outer core was thermally stably stratified and that this stratification might prove a powerful inhibitor to circulation of the outer core fluid of the kind postulated for the generation of the earth's magnetic field. These suggestions are examined and shown to provide no reasonable escape from the core paradox.

  9. Emergent Functional Properties of Neuronal Networks with Controlled Topology

    PubMed Central

    Marconi, Emanuele; Nieus, Thierry; Maccione, Alessandro; Valente, Pierluigi; Simi, Alessandro; Messa, Mirko; Dante, Silvia; Baldelli, Pietro; Berdondini, Luca; Benfenati, Fabio

    2012-01-01

    The interplay between anatomical connectivity and dynamics in neural networks plays a key role in the functional properties of the brain and in the associated connectivity changes induced by neural diseases. However, a detailed experimental investigation of this interplay at both cellular and population scales in the living brain is limited by accessibility. Alternatively, to investigate the basic operational principles with morphological, electrophysiological and computational methods, the activity emerging from large in vitro networks of primary neurons organized with imposed topologies can be studied. Here, we validated the use of a new bio-printing approach, which effectively maintains the topology of hippocampal cultures in vitro and investigated, by patch-clamp and MEA electrophysiology, the emerging functional properties of these grid-confined networks. In spite of differences in the organization of physical connectivity, our bio-patterned grid networks retained the key properties of synaptic transmission, short-term plasticity and overall network activity with respect to random networks. Interestingly, the imposed grid topology resulted in a reinforcement of functional connections along orthogonal directions, shorter connectivity links and a greatly increased spiking probability in response to focal stimulation. These results clearly demonstrate that reliable functional studies can nowadays be performed on large neuronal networks in the presence of sustained changes in the physical network connectivity. PMID:22493706

  10. The quercetin paradox

    SciTech Connect

    Boots, Agnes W. . E-mail: a.boots@farmaco.unimaas.nl; Li, Hui; Schins, Roel P.F.; Duffin, Rodger; Heemskerk, Johan W.M.; Bast, Aalt; Haenen, Guido R.M.M.

    2007-07-01

    Free radical scavenging antioxidants, such as quercetin, are chemically converted into oxidation products when they protect against free radicals. The main oxidation product of quercetin, however, displays a high reactivity towards thiols, which can lead to the loss of protein function. The quercetin paradox is that in the process of offering protection, quercetin is converted into a potential toxic product. In the present study, this paradox is evaluated using rat lung epithelial (RLE) cells. It was found that quercetin efficiently protects against H{sub 2}O{sub 2}-induced DNA damage in RLE cells, but this damage is swapped for a reduction in GSH level, an increase in LDH leakage as well as an increase of the cytosolic free calcium concentration. To our knowledge, this is the first study that indicates that the quercetin paradox, i.e. the exchange of damage caused by quercetin and its metabolites, also occurs in living lung cells. Following depletion of GSH in the cells by BSO pre-treatment, this quercetin paradox becomes more pronounced, confirming that the formation of thiol reactive quercetin metabolites is involved in the quercetin paradox. The quercetin paradox in living cells implies that the anti-oxidant directs oxidative damage selectively to thiol arylation. Apparently, the potential toxicity of metabolites formed during the actual antioxidant activity of free radical scavengers should be considered in antioxidant supplementation.

  11. Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass

    NASA Technical Reports Server (NTRS)

    Elefteriou, Florent; Takeda, Shu; Liu, Xiuyun; Armstrong, Dawna; Karsenty, Gerard

    2003-01-01

    Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

  12. Motor neurons control blood vessel patterning in the developing spinal cord

    PubMed Central

    Himmels, Patricia; Paredes, Isidora; Adler, Heike; Karakatsani, Andromachi; Luck, Robert; Marti, Hugo H.; Ermakova, Olga; Rempel, Eugen; Stoeckli, Esther T.; Ruiz de Almodóvar, Carmen

    2017-01-01

    Formation of a precise vascular network within the central nervous system is of critical importance to assure delivery of oxygen and nutrients and for accurate functionality of neuronal networks. Vascularization of the spinal cord is a highly stereotypical process. However, the guidance cues controlling blood vessel patterning in this organ remain largely unknown. Here we describe a new neuro-vascular communication mechanism that controls vessel guidance in the developing spinal cord. We show that motor neuron columns remain avascular during a developmental time window, despite expressing high levels of the pro-angiogenic vascular endothelial growth factor (VEGF). We describe that motor neurons express the VEGF trapping receptor sFlt1 via a Neuropilin-1-dependent mechanism. Using a VEGF gain-of-function approach in mice and a motor neuron-specific sFlt1 loss-of-function approach in chicken, we show that motor neurons control blood vessel patterning by an autocrine mechanism that titrates motor neuron-derived VEGF via their own expression of sFlt1. PMID:28262664

  13. Control of proliferation rate of N27 dopaminergic neurons using Transcranial Magnetic Stimulation orientation

    NASA Astrophysics Data System (ADS)

    Meng, Yiwen; Hadimani, Ravi; Anantharam, Vellareddy; Kanthasamy, Anumantha; Jiles, David

    2015-03-01

    Transcranial magnetic stimulation (TMS) has been used to investigate possible treatments for a variety of neurological disorders. However, the effect that magnetic fields have on neurons has not been well documented in the literature. We have investigated the effect of different orientation of magnetic field generated by TMS coils with a monophasic stimulator on the proliferation rate of N27 neuronal cells cultured in flasks and multi-well plates. The proliferation rate of neurons would increase by exposed horizontally adherent N27 cells to a magnetic field pointing upward through the neuronal proliferation layer compared with the control group. On the other hand, proliferation rate would decrease in cells exposed to a magnetic field pointing downward through the neuronal growth layer compared with the control group. We confirmed results obtained from the Trypan-blue and automatic cell counting methods with those from the CyQuant and MTS cell viability assays. Our findings could have important implications for the preclinical development of TMS treatments of neurological disorders and represents a new method to control the proliferation rate of neuronal cells.

  14. Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass

    NASA Technical Reports Server (NTRS)

    Elefteriou, Florent; Takeda, Shu; Liu, Xiuyun; Armstrong, Dawna; Karsenty, Gerard

    2003-01-01

    Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

  15. Stepping Out of the Shade: Control of Neuronal Activity by the Scaffold Protein Kidins220/ARMS

    PubMed Central

    Scholz-Starke, Joachim; Cesca, Fabrizia

    2016-01-01

    The correct functioning of the nervous system depends on the exquisitely fine control of neuronal excitability and synaptic plasticity, which relies on an intricate network of protein-protein interactions and signaling that shapes neuronal homeostasis during development and in adulthood. In this complex scenario, Kinase D interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning (Kidins220/ARMS) acts as a multi-functional scaffold protein with preferential expression in the nervous system. Engaged in a plethora of interactions with membrane receptors, cytosolic signaling components and cytoskeletal proteins, Kidins220/ARMS is implicated in numerous cellular functions including neuronal survival, neurite outgrowth and maturation and neuronal activity, often in the context of neurotrophin (NT) signaling pathways. Recent studies have highlighted a number of cell- and context-specific roles for this protein in the control of synaptic transmission and neuronal excitability, which are at present far from being completely understood. In addition, some evidence has began to emerge, linking alterations of Kidins220 expression to the onset of various neurodegenerative diseases and neuropsychiatric disorders. In this review, we present a concise summary of our fragmentary knowledge of Kidins220/ARMS biological functions, focusing on the mechanism(s) by which it controls various aspects of neuronal activity. We have tried, where possible, to discuss the available evidence in the wider context of NT-mediated regulation, and to outline emerging roles of Kidins220/ARMS in human pathologies. PMID:27013979

  16. Tangentially migrating transient glutamatergic neurons control neurogenesis and maintenance of cerebral cortical progenitor pools.

    PubMed

    Teissier, A; Waclaw, R R; Griveau, A; Campbell, K; Pierani, A

    2012-02-01

    The relative contribution of intrinsic and extrinsic cues in the regulation of cortical neurogenesis remains a crucial challenge in developmental neurobiology. We previously reported that a transient population of glutamatergic neurons, the cortical plate (CP) transient neurons, migrates from the ventral pallium (VP) over long distances and participate in neocortical development. Here, we show that the genetic ablation of this population leads to a reduction in the number of cortical neurons especially fated to superficial layers. These defects result from precocious neurogenesis followed by a depletion of the progenitor pools. Notably, these changes progress from caudolateral to rostrodorsal pallial territories between E12.5 and E14.5 along the expected trajectory of the ablated cells. Conversely, we describe enhanced proliferation resulting in an increase in the number of cortical neurons in the Gsx2 mutants which present an expansion of the VP and a higher number of CP transient neurons migrating into the pallium. Our findings indicate that these neurons act to maintain the proliferative state of neocortical progenitors and delay differentiation during their migration from extraneocortical regions and, thus, participate in the extrinsic control of cortical neuronal numbers.

  17. Rapid Sequence Evolution of Transcription Factors Controlling Neuron Differentiation in Caenorhabditis

    PubMed Central

    2009-01-01

    Whether phenotypic evolution proceeds predominantly through changes in regulatory sequences is a controversial issue in evolutionary genetics. Ample evidence indicates that the evolution of gene regulatory networks via changes in cis-regulatory sequences is an important determinant of phenotypic diversity. However, recent experimental work suggests that the role of transcription factor (TF) divergence in developmental evolution may be underestimated. In order to help understand what levels of constraints are acting on the coding sequence of developmental regulatory genes, evolutionary rates were investigated among 48 TFs required for neuronal development in Caenorhabditis elegans. Allelic variation was then sampled for 28 of these genes within a population of the related species Caenorhabditis remanei. Neuronal TFs are more divergent, both within and between species, than structural genes. TFs affecting different neuronal classes are under different levels of selective constraints. The regulatory genes controlling the differentiation of chemosensory neurons evolve particularly fast and exhibit higher levels of within- and between-species nucleotide variation than TFs required for the development of several neuronal classes and TFs required for motorneuron differentiation. The TFs affecting chemosensory neuron development are also more divergent than chemosensory genes expressed in the neurons they differentiate. These results illustrate that TFs are not as highly constrained as commonly thought and suggest that the role of divergence in developmental regulatory genes during the evolution of gene regulatory networks requires further attention. PMID:19589887

  18. Modular control of glutamatergic neuronal identity in C.elegans by distinct homeodomain proteins

    PubMed Central

    Serrano-Saiz, Esther; Poole, Richard J.; Felton, Terry; Zhang, Feifan; De La Cruz, Estanisla Daniel; Hobert, Oliver

    2013-01-01

    The choice of using one of many possible neurotransmitter systems is a critical step in defining the identity of an individual neuron type. We show here that the key defining feature of glutamatergic neurons, the vesicular glutamate transporter EAT-4/VGLUT is expressed in 38 of the 118 anatomically defined neuron classes of the C.elegans nervous system. We show that eat-4/VGLUT expression is controlled in a modular manner, with distinct cis-regulatory modules driving expression in distinct glutamatergic neuron classes. We identify 13 different transcription factors, 11 of them homeodomain proteins, that act in specific combinations in 25 different glutamatergic neuron classes to initiate and maintain eat-4/VGLUT expression. We show that the adoption of a glutamatergic phenotype is linked to the adoption of other terminal identity features of a neuron, including cotransmitter phenotypes. Examination of mouse orthologs of these homeodomain proteins resulted in the identification of mouse LHX1 as a regulator of glutamatergic neurons in the brainstem. PMID:24243022

  19. Laser speckle contrast reveals cerebral blood flow dynamics evoked by optogenetically controlled neuronal activity

    NASA Astrophysics Data System (ADS)

    Li, Nan; Thakor, Nitish V.; Pelled, Galit

    2013-03-01

    As a critical basis of functional brain imaging, neurovascular coupling describes the link between neuronal and hemodynamic changes. The majority of in vivo neurovascular coupling studies was performed by inducing sensory stimulation via afferent inputs. Unfortunately such an approach results in recruiting of multiple types of cells, which confounds the explanation of neuronal roles in stimulus evoked hemodynamic changes. Recently optogenetics has emerged to provide immediate control of neurons by exciting or inhibiting genetically engineered neurons expressing light sensitive proteins. However, there is a need for optical methods capable of imaging the concurrent hemodynamic changes. We utilize laser speckle contrast imaging (LSCI) to obtain high resolution display of cerebral blood flow (CBF) in the vicinity of the targeted neural population. LSCI is a minimally invasive method for imaging CBF in microvessels through thinned skull, and produces images with high spatiotemporal resolution, wide field of view. In the integrated system light sources with different wavelengths and band-passing/blocking filters were used to allow simultaneous optical manipulation of neuronal activities and optical imaging of corresponding CBF. Experimental studies were carried out in a rodent model expressing channalrhodopsin (ChR2) in excitatory neurons in the somatosensory cortex (S1). The results demonstrated significant increases of CBF in response to ChR2 stimulation (exciting neuronal firing) comparable to the CBF response to contralateral forepaw stimulation. The approach promises to be an exciting minimally invasive method to study neurovascular coupling. The complete system provides a novel approach for broad neuroscience applications.

  20. Control of neuronal morphology by the atypical cadherin Fat3

    PubMed Central

    Deans, Michael R.; Krol, Alexandra; Abraira, Victoria E.; Copley, Catherine O.; Tucker, Andrew F.; Goodrich, Lisa V.

    2012-01-01

    Neurons receive signals through dendrites that vary widely in number and organization, ranging from one primary dendrite to multiple complex dendritic trees. For example, retinal amacrine cells (ACs) project primary dendrites into a discrete synaptic layer called the inner plexiform layer (IPL) and only rarely extend processes into other retinal layers. Here, we show that the atypical cadherin Fat3 ensures that ACs develop this unipolar morphology. AC precursors are initially multipolar, but lose neurites as they migrate through the neuroblastic layer. In fat3 mutants, pruning is unreliable and ACs elaborate two dendritic trees: one in the IPL and a second projecting away from the IPL that stratifies to form an additional synaptic layer. Since complex nervous systems are characterized by the addition of layers, these results demonstrate that mutations in a single gene can cause fundamental changes in circuit organization that may drive nervous system evolution. PMID:21903076

  1. Munc13 controls the location and efficiency of dense-core vesicle release in neurons.

    PubMed

    van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K; de Jong, Arthur; de Wit, Heidi; Verhage, Matthijs; Toonen, Ruud F

    2012-12-10

    Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2-null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

  2. Munc13 controls the location and efficiency of dense-core vesicle release in neurons

    PubMed Central

    van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K.; de Jong, Arthur; de Wit, Heidi

    2012-01-01

    Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2–null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically. PMID:23229896

  3. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.

    PubMed

    Berg, Daniel A; Kirkham, Matthew; Wang, Heng; Frisén, Jonas; Simon, András

    2011-04-08

    Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.

  4. Control of visually guided behavior by distinct populations of spinal projection neurons.

    PubMed

    Orger, Michael B; Kampff, Adam R; Severi, Kristen E; Bollmann, Johann H; Engert, Florian

    2008-03-01

    A basic question in the field of motor control is how different actions are represented by activity in spinal projection neurons. We used a new behavioral assay to identify visual stimuli that specifically drive basic motor patterns in zebrafish. These stimuli evoked consistent patterns of neural activity in the neurons projecting to the spinal cord, which we could map throughout the entire population using in vivo two-photon calcium imaging. We found that stimuli that drive distinct behaviors activated distinct subsets of projection neurons, consisting, in some cases, of just a few cells. This stands in contrast to the distributed activation seen for more complex behaviors. Furthermore, targeted cell by cell ablations of the neurons associated with evoked turns abolished the corresponding behavioral response. This description of the functional organization of the zebrafish motor system provides a framework for identifying the complete circuit underlying a vertebrate behavior.

  5. Diode probes for spatiotemporal optical control of multiple neurons in freely moving animals

    PubMed Central

    Koos, Tibor; Buzsáki, György

    2012-01-01

    Neuronal control with high temporal precision is possible with optogenetics, yet currently available methods do not enable to control independently multiple locations in the brains of freely moving animals. Here, we describe a diode-probe system that allows real-time and location-specific control of neuronal activity at multiple sites. Manipulation of neuronal activity in arbitrary spatiotemporal patterns is achieved by means of an optoelectronic array, manufactured by attaching multiple diode-fiber assemblies to high-density silicon probes or wire tetrodes and implanted into the brains of animals that are expressing light-responsive opsins. Each diode can be controlled separately, allowing localized light stimulation of neuronal activators and silencers in any temporal configuration and concurrent recording of the stimulated neurons. Because the only connections to the animals are via a highly flexible wire cable, unimpeded behavior is allowed for circuit monitoring and multisite perturbations in the intact brain. The capacity of the system to generate unique neural activity patterns facilitates multisite manipulation of neural circuits in a closed-loop manner and opens the door to addressing novel questions. PMID:22496529

  6. Otx2 Requires Lmx1b to Control the Development of Mesodiencephalic Dopaminergic Neurons

    PubMed Central

    Sherf, Orna; Nashelsky Zolotov, Limor; Liser, Keren; Tilleman, Hadas; Jovanovic, Vukasin M.; Zega, Ksenija; Jukic, Marin M.; Brodski, Claude

    2015-01-01

    Studying the development of mesodiencephalic dopaminergic (mdDA) neurons provides an important basis for better understanding dopamine-associated brain functions and disorders and is critical for establishing cell replacement therapy for Parkinson’s disease. The transcription factors Otx2 and Lmx1b play a key role in the development of mdDA neurons. However, little is known about the genes downstream of Otx2 and Lmx1b in the pathways controlling the formation of mdDA neurons in vivo. Here we report on our investigation of Lmx1b as downstream target of Otx2 in the formation of mdDA neurons. Mouse mutants expressing Otx2 under the control of the En1 promoter (En1+/Otx2) showed increased Otx2 expression in the mid-hindbrain region, resulting in upregulation of Lmx1b and expansion of mdDA neurons there. In contrast, Lmx1b-/- mice showed decreased expression of Otx2 and impairments in several aspects of mdDA neuronal formation. To study the functional interaction between Otx2 and Lmx1b, we generated compound mutants in which Otx2 expression was restored in mice lacking Lmx1b (En1+/Otx2;Lmx1b-/-). In these animals Otx2 was not sufficient to rescue any of the aberrations in the formation of mdDA neurons caused by the loss of Lmx1b, but rescued the loss of ocular motor neurons. Gene expression studies in Lmx1b-/- embryos indicated that in these mutants Wnt1, En1 and Fgf8 expression are induced but subsequently lost in the mdDA precursor domain and the mid-hindbrain organizer in a specific, spatio-temporal manner. In summary, we demonstrate that Otx2 critically depends on Lmx1b for the formation of mdDA neurons, but not for the generation of ocular motor neurons. Moreover, our data suggest that Lmx1b precisely maintains the expression pattern of Wnt1, Fgf8 and En1, which are essential for mid-hindbrain organizer function and the formation of mdDA neurons. PMID:26444681

  7. Control of hair cell excitability by vestibular primary sensory neurons

    PubMed Central

    Brugeaud, Aurore; Travo, Cécile; Demêmes, Danielle; Lenoir, Marc; Llorens, Jordi; Puel, Jean-Luc; Chabbert, Christian

    2007-01-01

    In the rat utricle, synaptic contacts between hair cells and the nerve fibers arising from the vestibular primary neurons form during the first week after birth. During that period, the sodium-based excitability that characterizes neonate utricle sensory cells is switched off. To investigate whether the establishment of synaptic contacts was responsible for the modulation of the hair cell excitability, we used an organotypic culture of rat utricle in which the setting of synapses was prevented. Under this condition, the voltage-gated sodium current and the underlying action potentials persisted in a large proportion of non-afferented hair cells. We then studied whether impairment of nerve terminals in utricle of adult rats may also affect hair cell excitability. We induced selective and transient damages of afferent terminals using glutamate excitotoxicity in vivo. The efficiency of the excitotoxic injury was attested by selective swellings of the terminals and underlying altered vestibular behavior. Under this condition, the sodium-based excitability transiently recovered in hair cells. These results indicate that the modulation of hair cells excitability depends on the state of the afferent terminals. In adult utricle hair cells this property may be essential to set the conditions required for restoration of the sensory network after damage. This is achieved via re-expression of a biological process that occurs during synaptogenesis. PMID:17392466

  8. Spatiotemporally controlled and multifactor involved assay of neuronal compartment regeneration after chemical injury in an integrated microfluidics.

    PubMed

    Li, Li; Ren, Li; Liu, Wenming; Wang, Jian-Chun; Wang, Yaolei; Tu, Qin; Xu, Juan; Liu, Rui; Zhang, Yanrong; Yuan, Mao-Sen; Li, Tianbao; Wang, Jinyi

    2012-08-07

    Studies on the degeneration and regeneration of neurons as individual compartments of axons or somata can provide critical information for the clinical therapy of nervous system diseases. A controllable in vitro platform for multiple purposes is key to such studies. In the present study, we describe an integrated microfluidic device designed for achieving localized stimulation to neuronal axons or somata. We observed neuronal compartment degeneration after localized chemical stimulation and regeneration under the accessorial function of an interesting compound treatment or coculture with desired cells in controllable chambers. In a spatiotemporally controlled manner, this device was used to investigate hippocampal neuronal soma and axon degeneration after acrylamide stimulation, as well as subsequent regeneration after treatment with the monosialoganglioside GM1 or with cocultured glial cells (astrocytes or Schwann cells). To gain insight into the molecular mechanisms that mediate neuronal injury and regeneration, as well as to investigate whether acrylamide stimulation to neurons induces changes in Ca(2+) concentrations, the related neuronal genes and real-time Ca(2+) signal in neurons were also analyzed. The results showed that neuronal axons were more resistant to acrylamide injury than neuronal somata. Under localized stimulation, axons had self-destruct programs different from somata, and somatic injury caused the secondary response of axon collapse. This study provides a foundation for future in-depth analyses of spatiotemporally controlled and multifactor neuronal compartment regeneration after various injuries. The microfluidic device is also useful in evaluating potential therapeutic strategies to treat chemical injuries involving the central nervous system.

  9. Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.

    PubMed

    Tabet, Ricardos; Moutin, Enora; Becker, Jérôme A J; Heintz, Dimitri; Fouillen, Laetitia; Flatter, Eric; Krężel, Wojciech; Alunni, Violaine; Koebel, Pascale; Dembélé, Doulaye; Tassone, Flora; Bardoni, Barbara; Mandel, Jean-Louis; Vitale, Nicolas; Muller, Dominique; Le Merrer, Julie; Moine, Hervé

    2016-06-28

    Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.

  10. Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

    PubMed Central

    Tabet, Ricardos; Moutin, Enora; Becker, Jérôme A. J.; Heintz, Dimitri; Fouillen, Laetitia; Flatter, Eric; Krężel, Wojciech; Alunni, Violaine; Koebel, Pascale; Dembélé, Doulaye; Tassone, Flora; Bardoni, Barbara; Mandel, Jean-Louis; Vitale, Nicolas; Muller, Dominique; Le Merrer, Julie; Moine, Hervé

    2016-01-01

    Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine. PMID:27233938

  11. Controlling automatic imitative tendencies: interactions between mirror neuron and cognitive control systems.

    PubMed

    Cross, Katy A; Torrisi, Salvatore; Reynolds Losin, Elizabeth A; Iacoboni, Marco

    2013-12-01

    Humans have an automatic tendency to imitate others. Although several regions commonly observed in social tasks have been shown to be involved in imitation control, there is little work exploring how these regions interact with one another. We used fMRI and dynamic causal modeling to identify imitation-specific control mechanisms and examine functional interactions between regions. Participants performed a pre-specified action (lifting their index or middle finger) in response to videos depicting the same two actions (biological cues) or dots moving with similar trajectories (non-biological cues). On congruent trials, the stimulus and response were similar (e.g. index finger response to index finger or left side dot stimulus), while on incongruent trials the stimulus and response were dissimilar (e.g. index finger response to middle finger or right side dot stimulus). Reaction times were slower on incongruent compared to congruent trials for both biological and non-biological stimuli, replicating previous findings that suggest the automatic imitative or spatially compatible (congruent) response must be controlled on incongruent trials. Neural correlates of the congruency effects were different depending on the cue type. The medial prefrontal cortex, anterior cingulate, inferior frontal gyrus pars opercularis (IFGpo) and the left anterior insula were involved specifically in controlling imitation. In addition, the IFGpo was also more active for biological compared to non-biological stimuli, suggesting that the region represents the frontal node of the human mirror neuron system (MNS). Effective connectivity analysis exploring the interactions between these regions, suggests a role for the mPFC and ACC in imitative conflict detection and the anterior insula in conflict resolution processes, which may occur through interactions with the frontal node of the MNS. We suggest an extension of the previous models of imitation control involving interactions between imitation

  12. Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons

    PubMed Central

    van Welie, Ingrid

    2011-01-01

    Large conductance K+ (BK) channels are a key determinant of neuronal excitability. Medial vestibular nucleus (MVN) neurons regulate eye movements to ensure image stabilization during head movement, and changes in their intrinsic excitability may play a critical role in plasticity of the vestibulo-ocular reflex. Plasticity of intrinsic excitability in MVN neurons is mediated by kinases, and BK channels influence excitability, but whether endogenous BK channels are directly modulated by kinases is unknown. Double somatic patch-clamp recordings from MVN neurons revealed large conductance potassium channel openings during spontaneous action potential firing. These channels displayed Ca2+ and voltage dependence in excised patches, identifying them as BK channels. Recording isolated single channel currents at physiological temperature revealed a novel kinase-mediated bidirectional control in the range of voltages over which BK channels are activated. Application of activated Ca2+/calmodulin-dependent kinase II (CAMKII) increased BK channel open probability by shifting the voltage activation range towards more hyperpolarized potentials. An opposite shift in BK channel open probability was revealed by inhibition of phosphatases and was occluded by blockade of protein kinase C (PKC), suggesting that active PKC associated with BK channel complexes in patches was responsible for this effect. Accordingly, direct activation of endogenous PKC by PMA induced a decrease in BK open probability. BK channel activity affects excitability in MVN neurons and bidirectional control of BK channels by CAMKII, and PKC suggests that cellular signaling cascades engaged during plasticity may dynamically control excitability by regulating BK channel open probability. PMID:21307321

  13. Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons

    PubMed Central

    Harnett, Mark T.; Xu, Ning-Long; Magee, Jeffrey C.; Williams, Stephen R.

    2013-01-01

    Active dendritic synaptic integration enhances the computational power of neurons. Such nonlinear processing generates an object-localization signal in the apical dendritic tuft of layer 5B cortical pyramidal neurons during sensory-motor behaviour. Here we employ electrophysiological and optical approaches in brain-slices and behaving animals to investigate how excitatory synaptic input to this distal dendritic compartment influences neuronal output. We find that active dendritic integration throughout the apical dendritic tuft is highly compartmentalized by voltage-gated potassium (KV) channels. A high-density of both transient and sustained KV channels was observed in all apical dendritic compartments. These channels potently regulated the interaction between apical dendritic tuft, trunk, and axo-somatic integration zones to control neuronal output in vitro as well as the engagement of dendritic nonlinear processing in vivo during sensory-motor behaviour. Thus, KV channels dynamically tune the interaction between active dendritic integration compartments in layer 5B pyramidal neurons to shape behaviourally relevant neuronal computations. PMID:23931999

  14. Functional control of transplantable human ESC-derived neurons via optogenetic targeting

    PubMed Central

    Weick, Jason P.; Johnson, M. Austin; Skroch, Steven P.; Williams, Justin C.; Deisseroth, Karl; Zhang, Su-Chun

    2010-01-01

    Current methods to examine and regulate the functional integration and plasticity of human embryonic stem cell (hESC)-derived neurons are cumbersome and technically challenging. Here we engineered hESCs and their derivatives to express the light-gated Channelrhodopsin-2 (ChR2) protein to overcome these deficiencies. Optogenetic targeting of hESC-derived neurons with ChR2 linked to the mCherry fluorophore allowed reliable cell tracking as well as light-induced spiking at physiological frequencies. Optically-induced excitatory and inhibitory post-synaptic currents could be elicited in either ChR2+ or ChR2- neurons in vitro and in acute brain slices taken from transplanted SCID mice. Furthermore, we created a clonal hESC line that expresses ChR2-mCherry under the control of the synapsin-1 promoter. Upon neuronal differentiation, ChR2-mCherry expression was restricted to neurons and was stably expressed for at least six months, providing more predictable light-induced currents than transient infections. This pluripotent cell line will allow both in vitro and in vivo analysis of functional development as well as the integration capacity of neuronal populations for cell-replacement strategies. PMID:20827747

  15. A microfluidic platform for controlled biochemical stimulation of twin neuronal networks.

    PubMed

    Biffi, Emilia; Piraino, Francesco; Pedrocchi, Alessandra; Fiore, Gianfranco B; Ferrigno, Giancarlo; Redaelli, Alberto; Menegon, Andrea; Rasponi, Marco

    2012-06-01

    Spatially and temporally resolved delivery of soluble factors is a key feature for pharmacological applications. In this framework, microfluidics coupled to multisite electrophysiology offers great advantages in neuropharmacology and toxicology. In this work, a microfluidic device for biochemical stimulation of neuronal networks was developed. A micro-chamber for cell culturing, previously developed and tested for long term neuronal growth by our group, was provided with a thin wall, which partially divided the cell culture region in two sub-compartments. The device was reversibly coupled to a flat micro electrode array and used to culture primary neurons in the same microenvironment. We demonstrated that the two fluidically connected compartments were able to originate two parallel neuronal networks with similar electrophysiological activity but functionally independent. Furthermore, the device allowed to connect the outlet port to a syringe pump and to transform the static culture chamber in a perfused one. At 14 days invitro, sub-networks were independently stimulated with a test molecule, tetrodotoxin, a neurotoxin known to block action potentials, by means of continuous delivery. Electrical activity recordings proved the ability of the device configuration to selectively stimulate each neuronal network individually. The proposed microfluidic approach represents an innovative methodology to perform biological, pharmacological, and electrophysiological experiments on neuronal networks. Indeed, it allows for controlled delivery of substances to cells, and it overcomes the limitations due to standard drug stimulation techniques. Finally, the twin network configuration reduces biological variability, which has important outcomes on pharmacological and drug screening.

  16. Robust observer-based tracking control of hodgkin-huxley neuron systems under environmental disturbances.

    PubMed

    Chen, Bor-Sen; Li, Cheng-Wei

    2010-12-01

    A nervous system consists of a large number of highly interconnected nerve cells. Nerve cells communicate by generation and transmission of short electrical pulses (action potential). In addition, membrane voltage is the only measurable state in nervous systems. A robust observer-based model reference tracking control is proposed for Hodgkin-Huxley (HH) neuron systems to generate a desired reference response in spite of environmental noises, uncertain initial values, and diffusion currents from other interconnected nerve cells. In order to simplify the robust tracking control design of nonlinear stochastic HH neuron systems, a fuzzy interpolation method is employed to interpolate several linear stochastic systems to approximate a nonlinear stochastic HH neuron system so that the nonlinear robust tracking control problem can be solved by the linear matrix inequality (LMI) technique with the help of Robust Control Toolbox in Matlab. The proposed robust observer-based tracking control scheme can provide new methods for desired action potential generation, suppression of oscillations, and blockage of action potential transmission under environmental noise and diffusion currents. These new methods are useful for patients with different neuron system dysfunctions. Finally, three simulation examples of tracking control of nervous systems are given to illustrate the design procedure and confirm the tracking performance of the proposed method.

  17. Role of non-neuronal cells in body weight and appetite control.

    PubMed

    Argente-Arizón, Pilar; Freire-Regatillo, Alejandra; Argente, Jesús; Chowen, Julie A

    2015-01-01

    The brain is composed of neurons and non-neuronal cells, with the latter encompassing glial, ependymal and endothelial cells, as well as pericytes and progenitor cells. Studies aimed at understanding how the brain operates have traditionally focused on neurons, but the importance of non-neuronal cells has become increasingly evident. Once relegated to supporting roles, it is now indubitable that these diverse cell types are fundamental for brain development and function, including that of metabolic circuits, and they may play a significant role in obesity onset and complications. They participate in processes of neurogenesis, synaptogenesis, and synaptic plasticity of metabolic circuits both during development and in adulthood. Some glial cells, such as tanycytes and astrocytes, transport circulating nutrients and metabolic factors that are fundamental for neuronal viability and activity into and within the hypothalamus. All of these cell types express receptors for a variety of metabolic factors and hormones, suggesting that they participate in metabolic function. They are the first line of defense against any assault to neurons. Indeed, microglia and astrocytes participate in the hypothalamic inflammatory response to high fat diet (HFD)-induced obesity, with this process contributing to inflammatory-related insulin and leptin resistance. Moreover, HFD-induced obesity and hyperleptinemia modify hypothalamic astroglial morphology, which is associated with changes in the synaptic inputs to neuronal metabolic circuits. Astrocytic contact with the microvasculature is increased by HFD intake and this could modify nutrient/hormonal uptake into the brain. In addition, progenitor cells in the hypothalamus are now known to have the capacity to renew metabolic circuits, and this can be affected by HFD intake and obesity. Here, we discuss our current understanding of how non-neuronal cells participate in physiological and physiopathological metabolic control.

  18. Role of Non-Neuronal Cells in Body Weight and Appetite Control

    PubMed Central

    Argente-Arizón, Pilar; Freire-Regatillo, Alejandra; Argente, Jesús; Chowen, Julie A.

    2015-01-01

    The brain is composed of neurons and non-neuronal cells, with the latter encompassing glial, ependymal and endothelial cells, as well as pericytes and progenitor cells. Studies aimed at understanding how the brain operates have traditionally focused on neurons, but the importance of non-neuronal cells has become increasingly evident. Once relegated to supporting roles, it is now indubitable that these diverse cell types are fundamental for brain development and function, including that of metabolic circuits, and they may play a significant role in obesity onset and complications. They participate in processes of neurogenesis, synaptogenesis, and synaptic plasticity of metabolic circuits both during development and in adulthood. Some glial cells, such as tanycytes and astrocytes, transport circulating nutrients and metabolic factors that are fundamental for neuronal viability and activity into and within the hypothalamus. All of these cell types express receptors for a variety of metabolic factors and hormones, suggesting that they participate in metabolic function. They are the first line of defense against any assault to neurons. Indeed, microglia and astrocytes participate in the hypothalamic inflammatory response to high fat diet (HFD)-induced obesity, with this process contributing to inflammatory-related insulin and leptin resistance. Moreover, HFD-induced obesity and hyperleptinemia modify hypothalamic astroglial morphology, which is associated with changes in the synaptic inputs to neuronal metabolic circuits. Astrocytic contact with the microvasculature is increased by HFD intake and this could modify nutrient/hormonal uptake into the brain. In addition, progenitor cells in the hypothalamus are now known to have the capacity to renew metabolic circuits, and this can be affected by HFD intake and obesity. Here, we discuss our current understanding of how non-neuronal cells participate in physiological and physiopathological metabolic control. PMID:25859240

  19. Zeno's Paradox of Immortality.

    PubMed

    Olshansky, S Jay; Carnes, Bruce A

    2013-01-01

    Scientists who speculate on the future of human longevity have a broad range of views ranging from the promise of immortality, to radical life extension, to declines in life expectancy. Among those who contend that radical life extension is already here, or on the horizon, or immortality is forthcoming, elements of their reasoning appear surprisingly close, if not identical, to a famous mathematical paradox posed by the ancient Greek mathematician known as Zeno. Here we examine the underlying assumptions behind the views that much longer life expectancies are forthcoming or have already arrived, and place their line of reasoning within the context of a new Zeno paradox described here as The Paradox of Immortality.

  20. Black Hole Paradoxes

    NASA Astrophysics Data System (ADS)

    Joshi, Pankaj S.; Narayan, Ramesh

    2016-10-01

    We propose here that the well-known black hole paradoxes such as the information loss and teleological nature of the event horizon are restricted to a particular idealized case, which is the homogeneous dust collapse model. In this case, the event horizon, which defines the boundary of the black hole, forms initially, and the singularity in the interior of the black hole at a later time. We show that, in contrast, gravitational collapse from physically more realistic initial conditions typically leads to the scenario in which the event horizon and space-time singularity form simultaneously. We point out that this apparently simple modification can mitigate the causality and teleological paradoxes, and also lends support to two recently suggested solutions to the information paradox, namely, the ‘firewall’ and ‘classical chaos’ proposals.

  1. The MedDRA Paradox

    PubMed Central

    Merrill, Gary H.

    2008-01-01

    MedDRA (the Medical Dictionary for Regulatory Activities Terminology) is a controlled vocabulary widely used as a medical coding scheme. However, MedDRA’s characterization of its structural hierarchy exhibits some confusing and paradoxical features. The goal of this paper is to examine these features, determine whether there is a coherent view of the MedDRA hierarchy that emerges, and explore what lessons are to be learned from this for using MedDRA and similar terminologies in a broad medical informatics context that includes relations among multiple disparate terminologies, thesauri, and ontologies. PMID:18998828

  2. The MedDRA paradox.

    PubMed

    Merrill, Gary H

    2008-11-06

    MedDRA (the Medical Dictionary for Regulatory Activities Terminology) is a controlled vocabulary widely used as a medical coding scheme. However, MedDRA's characterization of its structural hierarchy exhibits some confusing and paradoxical features. The goal of this paper is to examine these features, determine whether there is a coherent view of the MedDRA hierarchy that emerges, and explore what lessons are to be learned from this for using MedDRA and similar terminologies in a broad medical informatics context that includes relations among multiple disparate terminologies, thesauri, and ontologies.

  3. MicroRNA targeting of CoREST controls polarization of migrating cortical neurons.

    PubMed

    Volvert, Marie-Laure; Prévot, Pierre-Paul; Close, Pierre; Laguesse, Sophie; Pirotte, Sophie; Hemphill, James; Rogister, Florence; Kruzy, Nathalie; Sacheli, Rosalie; Moonen, Gustave; Deiters, Alexander; Merkenschlager, Matthias; Chariot, Alain; Malgrange, Brigitte; Godin, Juliette D; Nguyen, Laurent

    2014-05-22

    The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.

  4. Control of bursting synchronization in networks of Hodgkin-Huxley-type neurons with chemical synapses

    NASA Astrophysics Data System (ADS)

    Batista, C. A. S.; Viana, R. L.; Ferrari, F. A. S.; Lopes, S. R.; Batista, A. M.; Coninck, J. C. P.

    2013-04-01

    Thermally sensitive neurons present bursting activity for certain temperature ranges, characterized by fast repetitive spiking of action potential followed by a short quiescent period. Synchronization of bursting activity is possible in networks of coupled neurons, and it is sometimes an undesirable feature. Control procedures can suppress totally or partially this collective behavior, with potential applications in deep-brain stimulation techniques. We investigate the control of bursting synchronization in small-world networks of Hodgkin-Huxley-type thermally sensitive neurons with chemical synapses through two different strategies. One is the application of an external time-periodic electrical signal and another consists of a time-delayed feedback signal. We consider the effectiveness of both strategies in terms of protocols of applications suitable to be applied by pacemakers.

  5. Control of bursting synchronization in networks of Hodgkin-Huxley-type neurons with chemical synapses.

    PubMed

    Batista, C A S; Viana, R L; Ferrari, F A S; Lopes, S R; Batista, A M; Coninck, J C P

    2013-04-01

    Thermally sensitive neurons present bursting activity for certain temperature ranges, characterized by fast repetitive spiking of action potential followed by a short quiescent period. Synchronization of bursting activity is possible in networks of coupled neurons, and it is sometimes an undesirable feature. Control procedures can suppress totally or partially this collective behavior, with potential applications in deep-brain stimulation techniques. We investigate the control of bursting synchronization in small-world networks of Hodgkin-Huxley-type thermally sensitive neurons with chemical synapses through two different strategies. One is the application of an external time-periodic electrical signal and another consists of a time-delayed feedback signal. We consider the effectiveness of both strategies in terms of protocols of applications suitable to be applied by pacemakers.

  6. Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System.

    PubMed

    Mapelli, Lisa; Gagliano, Giuseppe; Soda, Teresa; Laforenza, Umberto; Moccia, Francesco; D'Angelo, Egidio U

    2017-02-01

    Neurovascular coupling (NVC) is the process whereby neuronal activity controls blood vessel diameter. In the cerebellum, the molecular layer is regarded as the main NVC determinant. However, the granular layer is a region with variable metabolic demand caused by large activity fluctuations that shows a prominent expression of NMDA receptors (NMDARs) and nitric oxide synthase (NOS) and is therefore much more suitable for effective NVC. Here, we show, in the granular layer of acute rat cerebellar slices, that capillary diameter changes rapidly after mossy fiber stimulation. Vasodilation required neuronal NMDARs and NOS stimulation and subsequent guanylyl cyclase activation that probably occurred in pericytes. Vasoconstriction required metabotropic glutamate receptors and CYP ω-hydroxylase, the enzyme regulating 20-hydroxyeicosatetraenoic acid production. Therefore, granular layer capillaries are controlled by the balance between vasodilating and vasoconstricting systems that could finely tune local blood flow depending on neuronal activity changes at the cerebellar input stage.

  7. Does an Obesity Paradox Really Exist After Cardiovascular Intervention?: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies

    PubMed Central

    Bundhun, Pravesh Kumar; Li, Nuo; Chen, Meng-Hua

    2015-01-01

    Abstract Several studies have shown the existence of an obesity paradox after Percutaneous Coronary Intervention (PCI). However, other studies have shown its absence. This study sought to perform a systematic review and meta-analysis of studies comparing the mortality risk between high body mass index patients and normal weight patients after PCI. We have searched PubMed, Embase, and Chinese medical journal for randomized controlled trials (RCTs) and observational studies published between the year 2000 and 2015 by typing the keywords “percutaneous coronary intervention” and “obesity paradox.” The main outcome was “all-cause mortality”. RevMan 5.3 software was used to calculate the risk ratio (RR) with 95% confidence interval (CI) to express the pooled effect on discontinuous variables. Twenty-two studies have been included in this meta-analysis consisting of a total of 242,377 patients with 73,143 normal weight patients, 103,608 overweight, and 65,626 obese patients. Younger age, higher cardiovascular risk factors and the intensive use of medications have mainly been observed among obese patients followed by overweight and normal weight patients respectively. In-hospital, 12 months and ≥ 1 year (long-term) mortality risks were significantly lower in the overweight and obese groups with (RR: 0.67; 95% CI: 0.63–0.72, P < 0.00001) and (RR: 0.60; 95% CI: 0.56–0.65, P < 0.00001) respectively in the in-hospital follow-up (RR: 0.62; 95% CI: 0.55–0.71 and 0.57; 95% CI: 0.52–0.63, P < 0.00001) at 12 months, and (RR: 0.70; 95% CI: 0.64–0.76; P < 0.00001) and (RR: 0.80; 95% CI: 0.71–0.91, P = 0.0006) respectively for the long-term follow-up after PCI. This “obesity paradox” does exist after PCI. The mortality in overweight and obese patients is really significantly lower compared to the normal weight patients. However, the exact reasons for this phenomenon need further exploration and research in the future. PMID:26554791

  8. Neuronal release of d-serine: a physiological pathway controlling extracellular d-serine concentration

    PubMed Central

    Rosenberg, Dina; Kartvelishvily, Elena; Shleper, Maria; Klinker, Chanda M. C.; Bowser, Michael T.; Wolosker, Herman

    2010-01-01

    d-Serine is thought to be a glia-derived transmitter that activates N-methyl d-aspartate receptors (NMDARs) in the brain. Here, we investigate the pathways for d-serine release using primary cultures, brain slices, and in vivo microdialysis. In contrast with the notion that d-serine is exclusively released from astrocytes, we found that d-serine is released by neuronal depolarization both in vitro and in vivo. Veratridine (50 μM) or depolarization by 40 mM KCl elicits a significant release of endogenous d-serine from primary neuronal cultures. Controls with astrocyte cultures indicate that glial cells are insensitive to veratridine, but release d-serine mainly by the opening of volume-regulated anion channels. In cortical slices perfused with veratridine, endogenous d-serine release is 10-fold higher than glutamate receptor-evoked release. Release of d-serine from slices does not require internal or external Ca2+, suggesting a nonvesicular release mechanism. To confirm the neuronal origin of d-serine, we selectively loaded neurons in cortical slices with d-[3H]serine or applied d-alanine, which specifically releases d-serine from neurons. Depolarization with veratridine promotes d-serine release in vivo monitored by high temporal resolution microdialysis of the striatum. Our data indicate that the neuronal pool of d-serine plays a major role in d-serine dynamics, with implications for the regulation of NMDAR transmission. Rosenberg, D., Kartvelishvily, E., Shleper, M., Klinker, C. M. C., Bowser, M. T., Wolosker, H. Neuronal release of d-serine: a physiological pathway controlling extracellular d-serine concentration. PMID:20371631

  9. Creative Paradoxical Thinking and Its Implications for Teaching and Learning Motor Skills

    ERIC Educational Resources Information Center

    Chen, David

    2011-01-01

    A paradox is a statement or situation that involves two or more contradictory, mutually exclusive elements that operate at the same time. This article examines a number of findings in motor-learning and motor-control research and categorizes them into six paradoxes. Based on those research findings, the concept of creative paradoxical thinking is…

  10. Creative Paradoxical Thinking and Its Implications for Teaching and Learning Motor Skills

    ERIC Educational Resources Information Center

    Chen, David

    2011-01-01

    A paradox is a statement or situation that involves two or more contradictory, mutually exclusive elements that operate at the same time. This article examines a number of findings in motor-learning and motor-control research and categorizes them into six paradoxes. Based on those research findings, the concept of creative paradoxical thinking is…

  11. Training in cortical control of neuroprosthetic devices improves signal extraction from small neuronal ensembles.

    PubMed

    Helms Tillery, S I; Taylor, D M; Schwartz, A B

    2003-01-01

    We have recently developed a closed-loop environment in which we can test the ability of primates to control the motion of a virtual device using ensembles of simultaneously recorded neurons /29/. Here we use a maximum likelihood method to assess the information about task performance contained in the neuronal ensemble. We trained two animals to control the motion of a computer cursor in three dimensions. Initially the animals controlled cursor motion using arm movements, but eventually they learned to drive the cursor directly from cortical activity. Using a population vector (PV) based upon the relation between cortical activity and arm motion, the animals were able to control the cursor directly from the brain in a closed-loop environment, but with difficulty. We added a supervised learning method that modified the parameters of the PV according to task performance (adaptive PV), and found that animals were able to exert much finer control over the cursor motion from brain signals. Here we describe a maximum likelihood method (ML) to assess the information about target contained in neuronal ensemble activity. Using this method, we compared the information about target contained in the ensemble during arm control, during brain control early in the adaptive PV, and during brain control after the adaptive PV had settled and the animal could drive the cursor reliably and with fine gradations. During the arm-control task, the ML was able to determine the target of the movement in as few as 10% of the trials, and as many as 75% of the trials, with an average of 65%. This average dropped when the animals used a population vector to control motion of the cursor. On average we could determine the target in around 35% of the trials. This low percentage was also reflected in poor control of the cursor, so that the animal was unable to reach the target in a large percentage of trials. Supervised adjustment of the population vector parameters produced new weighting

  12. Parallel Optical Control of Spatiotemporal Neuronal Spike Activity Using High-Speed Digital Light Processing

    PubMed Central

    Jerome, Jason; Foehring, Robert C.; Armstrong, William E.; Spain, William J.; Heck, Detlef H.

    2011-01-01

    Neurons in the mammalian neocortex receive inputs from and communicate back to thousands of other neurons, creating complex spatiotemporal activity patterns. The experimental investigation of these parallel dynamic interactions has been limited due to the technical challenges of monitoring or manipulating neuronal activity at that level of complexity. Here we describe a new massively parallel photostimulation system that can be used to control action potential firing in in vitro brain slices with high spatial and temporal resolution while performing extracellular or intracellular electrophysiological measurements. The system uses digital light processing technology to generate 2-dimensional (2D) stimulus patterns with >780,000 independently controlled photostimulation sites that operate at high spatial (5.4 μm) and temporal (>13 kHz) resolution. Light is projected through the quartz–glass bottom of the perfusion chamber providing access to a large area (2.76 mm × 2.07 mm) of the slice preparation. This system has the unique capability to induce temporally precise action potential firing in large groups of neurons distributed over a wide area covering several cortical columns. Parallel photostimulation opens up new opportunities for the in vitro experimental investigation of spatiotemporal neuronal interactions at a broad range of anatomical scales. PMID:21904526

  13. Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice.

    PubMed

    Oishi, Yo; Xu, Qi; Wang, Lu; Zhang, Bin-Jia; Takahashi, Koji; Takata, Yohko; Luo, Yan-Jia; Cherasse, Yoan; Schiffmann, Serge N; de Kerchove d'Exaerde, Alban; Urade, Yoshihiro; Qu, Wei-Min; Huang, Zhi-Li; Lazarus, Michael

    2017-09-29

    Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep-wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.In addition to circadian and homoeostatic drives, motivational levels influence sleep-wake cycles. Here the authors demonstrate that adenosine receptor-expressing neurons in the nucleus accumbens core that project to the ventral pallidum are inhibited by motivational stimuli and are causally involved in the control of slow-wave sleep.

  14. Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve

    PubMed Central

    Machhada, Asif; Ang, Richard; Ackland, Gareth L.; Ninkina, Natalia; Buchman, Vladimir L.; Lythgoe, Mark F.; Trapp, Stefan; Tinker, Andrew; Marina, Nephtali; Gourine, Alexander V.

    2015-01-01

    Background The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial. Objective This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology. Methods In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein. Results In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation. Conclusion Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases. PMID:26051529

  15. Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission

    PubMed Central

    Bannerman, David M.

    2017-01-01

    The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10–20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output. SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders

  16. Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission.

    PubMed

    Sengupta, Ayesha; Bocchio, Marco; Bannerman, David M; Sharp, Trevor; Capogna, Marco

    2017-02-15

    The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output.SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders

  17. Motor control may support mirror neuron research with new hypotheses and methods. Reply to comments on "Grasping synergies: A motor-control approach to the mirror neuron mechanism"

    NASA Astrophysics Data System (ADS)

    D'Ausilio, Alessandro; Bartoli, Eleonora; Maffongelli, Laura

    2015-03-01

    We are grateful to all commentators for their insightful commentaries and observations that enrich our proposal. One of our aims was indeed to bridge the gap between fields of research that, progressing independently, are facing similar issues regarding the neural representation of motor knowledge. In this respect, we were pleased to receive feedback from eminent researchers on both the mirror neuron as well as the motor control fields. Their expertise covers animal and human neurophysiology, as well as the computational modeling of neural and behavioral processes. Given their heterogeneous cultural perspectives and research approaches, a number of important open questions were raised. For simplicity we separated these issues into four sections. In the first section we present methodological aspects regarding how synergies can be measured in paradigms investigating the human mirror system. The second section regards the fundamental definition of what exactly synergies might be. The third concerns how synergies can generate testable predictions in mirror neuron research. Finally, the fourth section deals with the ultimate question regarding the function of the mirror neuron system.

  18. The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis.

    PubMed

    Boekhoorn, Karin; van Dis, Vera; Goedknegt, Erika; Sobel, André; Lucassen, Paul J; Hoogenraad, Casper C

    2014-12-01

    The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT-stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT-destabilizing proteins. Stathmin is such a MT-destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki-67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA-NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons.

  19. Paramagnetism Paradoxes: Projectable Demonstrations

    ERIC Educational Resources Information Center

    Sauls, Frederick C.; Vitz, Ed

    2008-01-01

    Drops of oil in Mn(SO[subscript 4])(aq) and drops of the solution in oil show opposite effects when brought near a rare earth magnet. Oxygen, nitrogen, and air bubbles atop water show expected attraction, repulsion, and null behavior, respectively. Air bubbles atop aqueous Mn(SO[subscript 4]) show paradoxical behavior because the magnet's…

  20. Behind the Mpemba paradox

    PubMed Central

    Sun, Chang Qing

    2015-01-01

    Mpemba paradox results from hydrogen-bond anomalous relaxation. Heating stretches the O:H nonbond and shortens the H‒O bond via Coulomb coupling; cooling reverses this process to emit heat at a rate depending on its initial storage. Skin ultra-low mass density raises the thermal diffusivity and favors outward heat flow from the liquid. PMID:27227000

  1. Behind the Mpemba paradox.

    PubMed

    Sun, Chang Qing

    2015-01-01

    Mpemba paradox results from hydrogen-bond anomalous relaxation. Heating stretches the O:H nonbond and shortens the H-O bond via Coulomb coupling; cooling reverses this process to emit heat at a rate depending on its initial storage. Skin ultra-low mass density raises the thermal diffusivity and favors outward heat flow from the liquid.

  2. Adventures in Paradox

    ERIC Educational Resources Information Center

    Lynch, Pip; Moore, Kevin

    2004-01-01

    The popularity of adventure recreation and adventure education has arisen, in part, from an assumption that adventure experiences are radically different from those of everyday life in modern societies. A paradox previously pointed out is that those seeking adventurous experiences often make use of technical and technological prosthetics, thus…

  3. Resolving the biodiversity paradox

    Treesearch

    James S. Clark; Mike Dieta; Sukhendu Chakraborty; Pankaj K.Ibeanez Agarwal; Shannon LaDeau; Mike Wolosin

    2007-01-01

    The paradox of biodiversity involves three elements, (i) mathematical models predict that species must differ in specific ways in order to coexist as stable ecological communities, (ii) such differences are difficult to identify, yet (iii) there is widespread evidence of stability in natural communities.

  4. Paramagnetism Paradoxes: Projectable Demonstrations

    ERIC Educational Resources Information Center

    Sauls, Frederick C.; Vitz, Ed

    2008-01-01

    Drops of oil in Mn(SO[subscript 4])(aq) and drops of the solution in oil show opposite effects when brought near a rare earth magnet. Oxygen, nitrogen, and air bubbles atop water show expected attraction, repulsion, and null behavior, respectively. Air bubbles atop aqueous Mn(SO[subscript 4]) show paradoxical behavior because the magnet's…

  5. A Hydrostatic Paradox Revisited

    ERIC Educational Resources Information Center

    Ganci, Salvatore

    2012-01-01

    This paper revisits a well-known hydrostatic paradox, observed when turning upside down a glass partially filled with water and covered with a sheet of light material. The phenomenon is studied in its most general form by including the mass of the cover. A historical survey of this experiment shows that a common misunderstanding of the phenomenon…

  6. Postradiation hypertrichosis: a paradox.

    PubMed

    Agarwal, Jai Prakash; Upasani, Maheshkumar N; Ghadi, Yogesh; Munshi, Anusheel

    2014-01-01

    Alopecia due to radiation has remained a widely accepted aspect of radiotherapy. We present an unexpected clinical scenario, where a patient with left lung stage IIIB nonsmall cell adenocarcinoma, treated with radiochemotherapy achieved a complete response and developed an obscure late effect in terms of paradoxical hypertrichosis in the radiation portals. The paper presents plausible hypothesis for this unusual phenomenon.

  7. Adventures in Paradox

    ERIC Educational Resources Information Center

    Lynch, Pip; Moore, Kevin

    2004-01-01

    The popularity of adventure recreation and adventure education has arisen, in part, from an assumption that adventure experiences are radically different from those of everyday life in modern societies. A paradox previously pointed out is that those seeking adventurous experiences often make use of technical and technological prosthetics, thus…

  8. A Hydrostatic Paradox Revisited

    ERIC Educational Resources Information Center

    Ganci, Salvatore

    2012-01-01

    This paper revisits a well-known hydrostatic paradox, observed when turning upside down a glass partially filled with water and covered with a sheet of light material. The phenomenon is studied in its most general form by including the mass of the cover. A historical survey of this experiment shows that a common misunderstanding of the phenomenon…

  9. The Hydrostatic Paradox.

    ERIC Educational Resources Information Center

    Wilson, Alpha E.

    1995-01-01

    Presents an example demonstrating the quantitative resolution of the hydrostatic paradox which is the realization that the force due to fluid pressure on the bottom of a vessel can be considerably greater or considerably less than the weight of the fluid in the vessel. (JRH)

  10. The Paradox of Empowerment.

    ERIC Educational Resources Information Center

    Knott, Christine A.

    This personal narrative recounts the experiences of a group of adult learners six months after they completed a graduate diploma in adult education. They speak of their discovery that empowerment, in terms of enabling and energizing, involved a seeming contradictory sense of vulnerability in terms of "the paradox of empowerment." The…

  11. Prenatal programming by testosterone of hypothalamic metabolic control neurones in the ewe.

    PubMed

    Sheppard, K M; Padmanabhan, V; Coolen, L M; Lehman, M N

    2011-05-01

    Ewes treated prenatally with testosterone develop metabolic deficits, including insulin resistance, in addition to reproductive dysfunctions that collectively mimic polycystic ovarian syndrome (PCOS), a common endocrine disease in women. We hypothesised that metabolic deficits associated with prenatal testosterone excess involve alterations in arcuate nucleus (ARC) neurones that contain either agouti-related peptide (AgRP) or pro-opiomelanocortin (POMC). Characterisation of these neurones in the ewe showed that immunoreactive AgRP and POMC neurones were present in separate populations in the ARC, that AgRP and POMC neurones co-expressed either neuropeptide Y or cocaine- and amphetamine-regulated transcript, respectively, and that each population had a high degree of co-localisation with androgen receptors. Examination of the effect of prenatal testosterone exposure on the number of AgRP and POMC neurones in adult ewes showed that prenatal testosterone excess significantly increased the number of AgRP but not POMC neurones compared to controls; this increase was restricted to the middle division of the ARC, was mimicked by prenatal treatment with dihydrotestosterone, a non-aromatisable androgen, and was blocked by co-treatment of prenatal testosterone with the anti-androgen, flutamide. The density of AgRP fibre immunoreactivity in the preoptic area, paraventricular nucleus, lateral hypothalamus and dorsomedial hypothalamic nucleus was also increased by prenatal testosterone exposure. Thus, ewes that were exposed to androgens during foetal life showed alterations in the number of AgRP-immunoreactive neurones and the density of fibre immunoreactivity in their projection areas, suggestive of permanent prenatal programming of metabolic circuitry that may, in turn, contribute to insulin resistance and an increased risk of obesity in this model of PCOS. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

  12. Balance between excitation and inhibition controls the temporal organization of neuronal avalanches.

    PubMed

    Lombardi, F; Herrmann, H J; Perrone-Capano, C; Plenz, D; de Arcangelis, L

    2012-06-01

    Neuronal avalanches, measured in vitro and in vivo, exhibit a robust critical behavior. Their temporal organization hides the presence of correlations. Here we present experimental measurements of the waiting time distribution between successive avalanches in the rat cortex in vitro. This exhibits a nonmonotonic behavior not usually found in other natural processes. Numerical simulations provide evidence that this behavior is a consequence of the alternation between states of high and low activity, named up and down states, leading to a balance between excitation and inhibition controlled by a single parameter. During these periods, both the single neuron state and the network excitability level, keeping memory of past activity, are tuned by homeostatic mechanisms.

  13. Optical controling dynamic and fluctuation processes in ensemble of neurons at pulsed electrical excitation ex vivo

    NASA Astrophysics Data System (ADS)

    Akchurin, Garif G.; Seliverstov, George A.; Akchurin, Alexander G.; Akchurin, George G.

    2004-05-01

    Dynamic response of the somatic frog nerve on electrical pulsed excitation was investigated ex vivo. Strong fluctuation of consequence compound action potential in ensemble of neurons near-threshold was discovered. The nonlinear response of the Hodgkin-Huxley model neurons with external electrical pulsed was investigated and numeral results correlation with experiments. Complex dynamic of compound action potential was discovered when on-line time of stimulatory electrical pulses comparable with nerve refractory period. New techniques research nonlinear behavior using photodynamic reactions or UV-A radiation at somatic frog nerve was approved. This nonlinear dynamic regime was controlling laser induced inactivation of processes in membrane of nerve.

  14. Predictive models of glucose control: roles for glucose-sensing neurones.

    PubMed

    Kosse, C; Gonzalez, A; Burdakov, D

    2015-01-01

    The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure (e.g. sight, smell, taste, sound). This allows rapidly measurable sensory information (rather than slowly generated internal feedback signals, e.g. digested nutrients) to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely projecting hypothalamic neurones, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurones (i) are activated by sensory cues (e.g. taste, sound), (ii) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves, (iii) stimulate wakefulness and exploration via global brain projections and (iv) are glucose-inhibited. MCH neurones are (i) glucose-excited, (ii) innervate learning and reward centres to promote synaptic plasticity, learning and memory and (iii) are critical for learning associations useful for predictive control (e.g. using taste to predict nutrient value of food). This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurones may promote connections between the 'fast' senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurones may engage locomotion/exploration and coordinate the required fuel supply. Feedback inhibition of the latter neurones by glucose would ensure that glucose fluxes they stimulate

  15. Mechanisms and neuronal networks involved in reactive and proactive cognitive control of interference in working memory.

    PubMed

    Irlbacher, Kerstin; Kraft, Antje; Kehrer, Stefanie; Brandt, Stephan A

    2014-10-01

    Cognitive control can be reactive or proactive in nature. Reactive control mechanisms, which support the resolution of interference, start after its onset. Conversely, proactive control involves the anticipation and prevention of interference prior to its occurrence. The interrelation of both types of cognitive control is currently under debate: Are they mediated by different neuronal networks? Or are there neuronal structures that have the potential to act in a proactive as well as in a reactive manner? This review illustrates the way in which integrating knowledge gathered from behavioral studies, functional imaging, and human electroencephalography proves useful in answering these questions. We focus on studies that investigate interference resolution at the level of working memory representations. In summary, different mechanisms are instrumental in supporting reactive and proactive control. Distinct neuronal networks are involved, though some brain regions, especially pre-SMA, possess functions that are relevant to both control modes. Therefore, activation of these brain areas could be observed in reactive, as well as proactive control, but at different times during information processing.

  16. Control of basal ganglia output by direct and indirect pathway projection neurons.

    PubMed

    Freeze, Benjamin S; Kravitz, Alexxai V; Hammack, Nora; Berke, Joshua D; Kreitzer, Anatol C

    2013-11-20

    The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.

  17. Control of Basal Ganglia Output by Direct and Indirect Pathway Projection Neurons

    PubMed Central

    Freeze, Benjamin S.; Kravitz, Alexxai V.; Hammack, Nora; Berke, Joshua D.

    2013-01-01

    The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively. PMID:24259575

  18. The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.

    PubMed

    Nagy, Vanja; Cole, Tiffany; Van Campenhout, Claude; Khoung, Thang M; Leung, Calvin; Vermeiren, Simon; Novatchkova, Maria; Wenzel, Daniel; Cikes, Domagoj; Polyansky, Anton A; Kozieradzki, Ivona; Meixner, Arabella; Bellefroid, Eric J; Neely, G Gregory; Penninger, Josef M

    2015-01-01

    PR homology domain-containing member 12 (PRDM12) belongs to a family of conserved transcription factors implicated in cell fate decisions. Here we show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and autonomic neuropathy (HSAN) revealed remarkable conservation of the mutated residues in evolution. Expression of wild-type human PRDM12 in Xenopus induced the expression of sensory neuronal markers, which was reduced using various human PRDM12 mutants. In Drosophila, we identified Hamlet as the functional PRDM12 homolog that controls nociceptive behavior in sensory neurons. Furthermore, expression analysis of human patient fibroblasts with PRDM12 mutations uncovered possible downstream target genes. Knockdown of several of these target genes including thyrotropin-releasing hormone degrading enzyme (TRHDE) in Drosophila sensory neurons resulted in altered cellular morphology and impaired nociception. These data show that PRDM12 and its functional fly homolog Hamlet are evolutionary conserved master regulators of sensory neuronal specification and play a critical role in pain perception. Our data also uncover novel pathways in multiple species that regulate evolutionary conserved nociception.

  19. The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster

    PubMed Central

    Li, Xianghua; Overton, Ian M.; Baines, Richard A.; Keegan, Liam P.; O’Connell, Mary A.

    2014-01-01

    RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar5G1 null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar5G1 mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar5G1 null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability. PMID:24137011

  20. Ventrolateral prefrontal neuronal activity related to active controlled memory retrieval in nonhuman primates.

    PubMed

    Cadoret, Geneviève; Petrides, Michael

    2007-09-01

    It is controversial whether monkeys, like human subjects, can recall, upon instruction, specific information about an event in memory. We therefore tested macaque monkeys on a task that was originally developed to study such active controlled memory retrieval in human subjects and we were able to demonstrate that monkeys, like human subjects, can retrieve, upon command, specific components of previously encoded events. Furthermore, following earlier functional neuroimaging work with human subjects showing the mid-ventrolateral prefrontal cortex to be involved in such active controlled retrieval, we recorded single-neuron activity within this region of the monkey brain while the monkeys performed the active retrieval task. Neuronal responses were related to the retrieval and the decision whether the retrieved information was the instructed one. These findings demonstrate, for the first time, an impressive capacity by macaque monkeys for controlled memory retrieval and, in addition, provide neurophysiological evidence about the role of the mid-ventrolateral prefrontal cortex in such controlled retrieval.

  1. Motor neurons in Drosophila flight control: could b1 be the one?

    NASA Astrophysics Data System (ADS)

    Whitehead, Samuel; Shirangi, Troy; Cohen, Itai

    Similar to balancing a stick on one's fingertip, flapping flight is inherently unstable; maintaining stability is a delicate balancing act made possible only by near-constant, often-subtle corrective actions. For fruit flies, such corrective responses need not only be robust, but also fast: the Drosophila flight control reflex has a response latency time of ~5 ms, ranking it among the fastest reflexes in the animal kingdom. How is such rapid, robust control implemented physiologically? Here we present an analysis of a putatively crucial component of the Drosophila flight control circuit: the b1 motor neuron. Specifically, we apply mechanical perturbations to freely-flying Drosophila and analyze the differences in kinematics patterns between flies with manipulated and un-manipulated b1 motor neurons. Ultimately, we hope to identify the functional role of b1 in flight stabilization, with the aim of linking it to previously-proposed, reduced-order models for reflexive control.

  2. Charge-Tunable Silk-Tropoelastin Protein Alloys That Control Neuron Cell Responses

    PubMed Central

    Hu, Xiao; Tang-Schomer, Min D.; Huang, Wenwen; Xia, Xiao-Xia; Weiss, Anthony S.

    2014-01-01

    Tunable protein composites are important for constructing extracellular matrix mimics of human tissues with control of biochemical, structural, and mechanical properties. Molecular interaction mechanisms between silk fibroin protein and recombinant human tropoelastin, based on charge, are utilized to generate a new group of multifunctional protein alloys (mixtures of silk and tropoelastin) with different net charges. These new biomaterials are then utilized as a biomaterial platform to control neuron cell response. With a +38 net charge in water, tropoelastin molecules provide extraordinary elasticity and selective interactions with cell surface integrins. In contrast, negatively charged silk fibroin protein (net charge −36) provides remarkable toughness and stiffness with morphologic stability in material formats via autoclaving-induced beta-sheet crystal physical crosslinks. The combination of these properties in alloy format extends the versatility of both structural proteins, providing a new biomaterial platform. The alloys with weak positive charges (silk/tropoelastin mass ratio 75/25, net charge around +16) significantly improved the formation of neuronal networks and maintained cell viability of rat cortical neurons after 10 days in vitro. The data point to these protein alloys as an alternative to commonly used poly-L-lysine (PLL) coatings or other charged synthetic polymers, particularly with regard to the versatility of material formats (e.g., gels, sponges, films, fibers). The results also provide a practical example of physically designed protein materials with control of net charge to direct biological outcomes, in this case for neuronal tissue engineering. PMID:25093018

  3. Golden goal controls dendrite elongation and branching of multidendritic arborization neurons in Drosophila.

    PubMed

    Hakeda, Satoko; Suzuki, Takashi

    2013-11-01

    Precise refinement of axonal and dendritic patterns is essential for the maturation of functional neuronal circuits. Although several transmembrane molecules have been shown to control the development of both axons and dendrites, the molecular mechanisms that regulate these different processes are poorly understood. Golden Goal (Gogo) is one of the molecules that are known to control the development of axons in the Drosophila visual system. In this study, we analyzed Gogo function in dendritic field formation of dorsal multidendritic arborization (md-da) neurons of the Drosophila Peripheral Nervous System. We showed that Gogo is required to restrain the growth of ddaC dendrites toward the midline in the embryo. During larval stages, Gogo promotes dendritic branching of the complex classIV ddaC neurons. However, over-expression of Gogo restrained dendritic branch formation in ddaC neurons, and this phenotype was enhanced by co-over-expression with Flamingo (Fmi), a partner of Gogo in axon guidance. These results suggest Gogo plays important roles in maintaining homeostasis of dendritic branching. Like axons, the cytoplasmic part of Gogo is required for its function in dendritic tree formation, suggesting that Gogo conveys information from extracellular cues to intracellular molecules that control dendrite development.

  4. Remote control of neuronal activity with a light-gated glutamate receptor.

    PubMed

    Szobota, Stephanie; Gorostiza, Pau; Del Bene, Filippo; Wyart, Claire; Fortin, Doris L; Kolstad, Kathleen D; Tulyathan, Orapim; Volgraf, Matthew; Numano, Rika; Aaron, Holly L; Scott, Ethan K; Kramer, Richard H; Flannery, John; Baier, Herwig; Trauner, Dirk; Isacoff, Ehud Y

    2007-05-24

    The ability to stimulate select neurons in isolated tissue and in living animals is important for investigating their role in circuits and behavior. We show that the engineered light-gated ionotropic glutamate receptor (LiGluR), when introduced into neurons, enables remote control of their activity. Trains of action potentials are optimally evoked and extinguished by 380 nm and 500 nm light, respectively, while intermediate wavelengths provide graded control over the amplitude of depolarization. Light pulses of 1-5 ms in duration at approximately 380 nm trigger precisely timed action potentials and EPSP-like responses or can evoke sustained depolarizations that persist for minutes in the dark until extinguished by a short pulse of approximately 500 nm light. When introduced into sensory neurons in zebrafish larvae, activation of LiGluR reversibly blocks the escape response to touch. Our studies show that LiGluR provides robust control over neuronal activity, enabling the dissection and manipulation of neural circuitry in vivo.

  5. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons.

    PubMed

    Cristino, Luigia; Busetto, Giuseppe; Imperatore, Roberta; Ferrandino, Ida; Palomba, Letizia; Silvestri, Cristoforo; Petrosino, Stefania; Orlando, Pierangelo; Bentivoglio, Marina; Mackie, Kenneth; Di Marzo, Vincenzo

    2013-06-11

    Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity.

  6. Biphasic cholinergic synaptic transmission controls action potential activity in thalamic reticular nucleus neurons.

    PubMed

    Sun, Yan-Gang; Pita-Almenar, Juan D; Wu, Chia-Shan; Renger, John J; Uebele, Victor N; Lu, Hui-Chen; Beierlein, Michael

    2013-01-30

    Cholinergic neurons in the basal forebrain and the brainstem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic α4β2 nicotinic ACh receptors (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits.

  7. α-1 adrenergic input to solitary nucleus neurones: calcium oscillations, excitation and gastric reflex control

    PubMed Central

    Hermann, Gerlinda E; Nasse, Jason S; Rogers, Richard C

    2005-01-01

    The nucleus of the solitary tract (NST) processes substantial visceral afferent input and sends divergent projections to a wide array of CNS targets. The NST is essential to the maintenance of behavioural and autonomic homeostasis and is the source, as well as the recipient, of considerable noradrenergic (NE) projections. The significance of NE projections from the NST to other CNS regions has long been appreciated, but the nature of NE action on NST neurones themselves, especially on the α-1 receptor subtype, is controversial. We used a combination of methodologies to establish, systematically, the effects and cellular basis of action of the α-1 agonist, phenylephrine (PHE), to control NST neurones responsible for vago-vagal reflex regulation of the stomach. Immunocytochemical and retrograde tracing studies verified that the area postrema, A2, A5, ventrolateral medulla and locus coeruleus regions are sources of catecholaminergic input to the NST. In vivo electrophysiological recordings showed that PHE activates physiologically identified, second-order gastric sensory NST neurones. In vivo microinjection of PHE onto NST neurones caused a significant reduction in gastric tone. Finally, in vitro calcium imaging studies revealed that PHE caused dramatic cytosolic calcium oscillations in NST neurones. These oscillations are probably the result of an interplay between agonist-induced and inositol 1,4,5-trisphosphate (IP3)-mediated intracellular calcium release and Ca2+-ATPase control of intracellular calcium storage pumps. The oscillations persisted even in perfusions of zero calcium–EGTA Krebs solution suggesting that the calcium oscillation is mediated principally by intracellular calcium release–reuptake mechanisms. Cyclical activation of the NST may function to increase the responsiveness of these neurones to incoming afferent input (i.e., elevate the ‘gain’). An increase in gain of afferent input may cause an amplification of the response part of the

  8. Towards a neuronal network controller for vertical jumping from different initial squat depths.

    PubMed

    Bobbert, Maarten F

    2010-01-01

    In this study, a forward dynamic simulation model of the human musculoskeletal system was used to explore various strategies of generating muscle stimulation patterns for vertical squat jumping. It was shown that a simple mapping from joint angles to muscle stimulation onsets yielded successful control, albeit not optimal control, for jumps from different initial squat depths. Furthermore, it was shown that this mapping could be implemented in a straightforward way in a simple network of Hodgkin-Huxley type neurons.

  9. Control of feeding movements in the freshwater snail Planorbis corneus. II. Activity of isolated neurons of buccal ganglia.

    PubMed

    Arshavsky YuI; Deliagina, T G; Orlovsky, G N; Panchin YuV

    1988-01-01

    Isolated buccal ganglia of Planorbis corneus are capable of generating a feeding rhythm. In the present work, "rhythmic" neurons of different groups (see Arshavsky et al. 1988a) have been extracted, by means of an intracellular microelectrode, from the buccal ganglia. (1) After extraction, efferent neurons of groups 3, 5, 7, 9 and most group 4 neurons generated repeated spikes at a frequency controlled by a polarizing current. Any periodic oscillations, similar to those during feeding rhythm generation, were absent in these isolated neurons. It is concluded, therefore, that these neurons are "followers", that is, their rhythmic activity before extraction is determined by synaptic inputs from other neurons of the ganglia. (2) Isolated interneurons of groups 1 and 2 generated slow periodic oscillations similar to those observed in these neurons before their extraction. Subgroup 1e neurons generated smoothly growing depolarization accompanied by increasing spike activity; this depolarization was periodically interrupted by abrupt hyperpolarization, after which a new cycle started. Subgroup 1d neurons periodically generated short series of spikes. Group 2 neurons periodically generated a rectangular wave of depolarization with spike-like oscillations on its top. These results suggest that feeding rhythm generation in Planorbis is based on the endogenous rhythmic activity of group 1 and 2 neurons. (3) A pulse of hyperpolarizing current injected into an isolated neuron of subgroup 1e stopped the growth of depolarization in the neuron and reinitiated the process. This property as well as the character of the synaptic interactions of the interneurons (group 1 neurons excite those of group 2, while those of group 2 inhibit group 1 neurons; Arshavsky et al. 1988b) determine the alternating activity of groups 1 and 2.

  10. Managing the Paradox of Control: The Case of Ground-Up Implementation of Active Learning in Singapore's Primary Schools

    ERIC Educational Resources Information Center

    Lim-Ratnam, Christina; Atencio, Matthew; Lee, Christine Kim-Eng

    2016-01-01

    The Singaporean education system has recently shifted emphasis from being highly centralised and standardised towards one that aims to promote innovation and autonomy at the school level. Yet, the concomitant move towards a more decentralised and flexible curriculum enacted and controlled at the local level has not been straightforward.…

  11. Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior.

    PubMed

    Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

    2014-03-01

    Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(-) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(-) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per⁰¹ mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per⁰¹ flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output.

  12. Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior

    PubMed Central

    Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

    2014-01-01

    Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(−) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(−) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per01 mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per01 flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output. PMID:24643294

  13. Substance P Differentially Modulates Firing Rate of Solitary Complex (SC) Neurons from Control and Chronic Hypoxia-Adapted Adult Rats

    PubMed Central

    Nichols, Nicole L.; Powell, Frank L.; Dean, Jay B.; Putnam, Robert W.

    2014-01-01

    NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H+-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS). Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus) neurons from control and chronic hypoxia-adapted (CHx) adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats. PMID:24516602

  14. Controlled neuronal cell patterning and guided neurite growth on micropatterned nanofiber platforms

    NASA Astrophysics Data System (ADS)

    Malkoc, Veysi; Gallego-Perez, Daniel; Nelson, Tyler; Lannutti, John J.; Hansford, Derek J.

    2015-12-01

    Patterning neuronal cells and guiding neurite growth are important for applications such as prosthetics, cell based biosensors, and tissue engineering. In this paper, a microdevice is presented that provides neuronal cell patterning and guided neurite growth on a collagen coated gelatin/PCL nanofiber mat. The pattern consisted of a grid of polystyrene microwells/nodes to confine the cell bodies and orthogonal grooves to guide neurite growth from each node. Vacuum assisted cell seeding was used to localize cell bodies in the microwells and physically separate the cells during seeding. The electrospun nanofiber mats under the polystyrene microstructures were coated with collagen to enhance the cellular attachment and enhance differentiation. We evaluated the performance of our device using adhesion, viability, and differentiation assays of neuron-like PC12 cells compared to controls for vacuum seeding, spatial isolation and guidance, and collagen coating of the fibers. The device provided PC12 cell patterning with increased adhesion, differentiation, and guided neurite outgrowth compared to controls, demonstrating its potential for in vitro neuronal cell patterning studies.

  15. Automated analysis of sleep control via a single neuron active at sleep onset in C. elegans.

    PubMed

    Urmersbach, Birk; Besseling, Judith; Spies, Jan-Philipp; Bringmann, Henrik

    2016-04-01

    Longitudinal analyses are crucial for understanding long-term processes such as development and behavioral rhythms. For a complete understanding of such processes, both organism-level observations as well as single-cell observations are necessary. Sleep is an example for a long-term process that is under developmental control. This behavioral state is induced by conserved sleep-active neurons, but little is known about how sleep neurons control the physiology of an animal systemically. In the nematode C. elegans, sleep induction crucially requires the single RIS interneuron to actively induce a developmentally regulated sleep behavior. Here, we used RIS-induced sleep as an example of how longitudinal analyses can be automated. We developed methods to analyze both behavior and neural activity in larva across the sleep-wake cycle. To image behavior, we used an improved DIC contrast to extract the head and detect the nose. To image neural activity, we used GCaMP3 expression in a small number of neurons including RIS combined with a neuron discrimination algorithm. Thus, we present a comprehensive platform for automatically analyzing behavior and neural activity in C. elegans exemplified by using RIS-induced sleep during C. elegans development.

  16. Motor cortical control of cardiovascular bulbar neurones projecting to spinal autonomic areas.

    PubMed

    Viltart, Odile; Mullier, Olivia; Bernet, François; Poulain, Pierre; Ba-M'Hamed, Saadia; Sequeira, Henrique

    2003-07-01

    There is evidence that the motor cortex is involved in cardiovascular adjustments associated with somatic motor activity, as it has functional connections with the ventrolateral medulla, a brainstem region critically involved in the control of blood pressure and the regulation of plasma catecholamine levels. The ventrolateral medulla sends projections to the spinal intermediolateral nucleus, where preganglionic neurones controlling heart and blood vessels (T2 segment) and adrenal medulla (T8 segment) are found. The aim of the present study was to determine whether electrical stimulation of the rat motor cortex induces cardiovascular responses and Fos expression in ventrolateral medulla neurones projecting to the T2 and T8 segments. After a set of experiments designed to record cardiovascular parameters (blood pressure and plasma catecholamine levels), injections of retrograde tracer (Fluorogold) were performed in the intermediolateral nucleus of two groups of rats, at the T2 or at the T8 segmental levels. Five days later, the motor cortex was stimulated in order to induce Fos expression in the ventrolateral medulla. Stimulation of the motor cortex induced: (1). hypotension and a significant decrease in plasma noradrenaline levels, and (2). a significant increase in the number of the double-labelled neurones in the rostral ventrolateral medulla projecting to T2. These data demonstrate that cardiovascular adjustments, preparatory to, or concomitant with, motor activity may be initiated in the motor cortex and transmitted to cardiac and vasomotor spinal preganglionic neurones, via the ventrolateral medulla. Copyright 2003 Wiley-Liss, Inc.

  17. Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action.

    PubMed

    Shin, Andrew C; Filatova, Nika; Lindtner, Claudia; Chi, Tiffany; Degann, Seta; Oberlin, Douglas; Buettner, Christoph

    2017-06-01

    Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet-induced hepatic steatosis. © 2017 by the American Diabetes Association.

  18. Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

    PubMed Central

    Du, Xiaona; Hao, Han; Gigout, Sylvain; Huang, Dongyang; Yang, Yuehui; Li, Li; Wang, Caixue; Sundt, Danielle; Jaffe, David B.; Zhang, Hailin; Gamper, Nikita

    2014-01-01

    Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on Erest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on Erest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive KV channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na+, and T-type Ca2+ channels to a lesser extent also contributed to Erest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or KATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic Erest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron. PMID:25168672

  19. Adaptive synchronization control of coupled chaotic neurons in an external electrical stimulation

    NASA Astrophysics Data System (ADS)

    Yu, Hai-Tao; Wang, Jiang; Deng, Bin; Wei, Xi-Le; Chen, Ying-Yuan

    2013-05-01

    In this paper we present a combined algorithm for the synchronization control of two gap junction coupled chaotic FitzHugh—Nagumo (FHN) neurons in an external electrical stimulation. The controller consists of a combination of dynamical sliding mode control and adaptive backstepping control. The combined algorithm yields an adaptive dynamical sliding mode control law which has the advantage over static sliding mode-based controllers of being chattering-free, i.e., a sufficiently smooth control input signal is generated. It is shown that the proposed control scheme can not only compensate for the system uncertainty, but also guarantee the stability of the synchronized error system. In addition, numerical simulations are also performed to demonstrate the effectiveness of the proposed adaptive controller.

  20. The study of the Bithorax-complex genes in patterning CCAP neurons reveals a temporal control of neuronal differentiation by Abd-B

    PubMed Central

    Moris-Sanz, M.; Estacio-Gómez, A.; Sánchez-Herrero, E.; Díaz-Benjumea, F. J.

    2015-01-01

    ABSTRACT During development, HOX genes play critical roles in the establishment of segmental differences. In the Drosophila central nervous system, these differences are manifested in the number and type of neurons generated by each neuroblast in each segment. HOX genes can act either in neuroblasts or in postmitotic cells, and either early or late in a lineage. Additionally, they can be continuously required during development or just at a specific stage. Moreover, these features are generally segment-specific. Lately, it has been shown that contrary to what happens in other tissues, where HOX genes define domains of expression, these genes are expressed in individual cells as part of the combinatorial codes involved in cell type specification. In this report we analyse the role of the Bithorax-complex genes – Ultrabithorax, abdominal-A and Abdominal-B – in sculpting the pattern of crustacean cardioactive peptide (CCAP)-expressing neurons. These neurons are widespread in invertebrates, express CCAP, Bursicon and MIP neuropeptides and play major roles in controlling ecdysis. There are two types of CCAP neuron: interneurons and efferent neurons. Our results indicate that Ultrabithorax and Abdominal-A are not necessary for specification of the CCAP-interneurons, but are absolutely required to prevent the death by apoptosis of the CCAP-efferent neurons. Furthermore, Abdominal-B controls by repression the temporal onset of neuropeptide expression in a subset of CCAP-efferent neurons, and a peak of ecdysone hormone at the end of larval life counteracts this repression. Thus, Bithorax complex genes control the developmental appearance of these neuropeptides both temporally and spatially. PMID:26276099

  1. [Five paradoxes in health promotion].

    PubMed

    López-Dicastillo, Olga; Canga-Armayor, Navidad; Mujika, Agurtzane; Pardavila-Belio, Miren Idoia; Belintxon, Maider; Serrano-Monzó, Inmaculada; Pumar-Méndez, María J

    2017-02-17

    The World Health Organization states that health promotion is a key strategy to improve health, and it is conceived as a global process of enabling people to increase control over, and to improve, their health. Health promotion does not focus solely on empowering individuals dealing with their knowledge, attitudes and skills, but it also takes political, social, economic and environmental aspects influencing health and wellbeing into account. The complexity of applying these concepts is reflected in the five paradoxes in health promotion; these arise in between the rhetoric in health promotion and implementation. The detected paradoxes which are described herein involve the patient versus the person, the individual versus the group, disease professionals versus health professionals, disease indicators versus health indicators, and health as an expense versus health as an investment. Making these contradictions explicit can help determine why it is so complex to put the concepts related to health promotion into practice. It can also help to put forward aspects that need further work if health promotion is to put into practice.

  2. A paradox for air pollution controlling in China revealed by “APEC Blue” and “Parade Blue”

    PubMed Central

    Liu, Haoran; Liu, Cheng; Xie, Zhouqing; Li, Ying; Huang, Xin; Wang, Shanshan; Xu, Jin; Xie, Pinhua

    2016-01-01

    A series of strict emission control measures were implemented in Beijing and surrounding regions to ensure good air quality during the 2014 Asia-Pacific Economic Cooperation (APEC) summit and 2015 Grand Military Parade (Parade), which led to blue sky days during these two events commonly referred to as “APEC Blue” and “Parade Blue”. Here we calculated Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) and Ozone Monitoring Instrument (OMI) NO2 and HCHO results based on well known DOAS trace gas fitting algorithm and WRF-Chem model (with measured climatology parameter and newest emission inventor) simulated trace gases profiles. We found the NO2 columns abruptly decreased both Parade (43%) and APEC (21%) compared with the periods before these two events. The back-trajectory cluster analysis and the potential source contribution function (PSCF) proved regional transport from southern peripheral cities plays a key role in pollutants observed at Beijing. The diminishing transport contribution from southern air mass during Parade manifests the real effect of emission control measures on NO2 pollution. Based on the ratios of HCHO over NO2 we found there were not only limited the NO2 pollutant but also suppress the O3 contaminant during Parade, while O3 increased during the APEC. PMID:27680499

  3. A paradox for air pollution controlling in China revealed by “APEC Blue” and “Parade Blue”

    NASA Astrophysics Data System (ADS)

    Liu, Haoran; Liu, Cheng; Xie, Zhouqing; Li, Ying; Huang, Xin; Wang, Shanshan; Xu, Jin; Xie, Pinhua

    2016-09-01

    A series of strict emission control measures were implemented in Beijing and surrounding regions to ensure good air quality during the 2014 Asia-Pacific Economic Cooperation (APEC) summit and 2015 Grand Military Parade (Parade), which led to blue sky days during these two events commonly referred to as “APEC Blue” and “Parade Blue”. Here we calculated Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) and Ozone Monitoring Instrument (OMI) NO2 and HCHO results based on well known DOAS trace gas fitting algorithm and WRF-Chem model (with measured climatology parameter and newest emission inventor) simulated trace gases profiles. We found the NO2 columns abruptly decreased both Parade (43%) and APEC (21%) compared with the periods before these two events. The back-trajectory cluster analysis and the potential source contribution function (PSCF) proved regional transport from southern peripheral cities plays a key role in pollutants observed at Beijing. The diminishing transport contribution from southern air mass during Parade manifests the real effect of emission control measures on NO2 pollution. Based on the ratios of HCHO over NO2 we found there were not only limited the NO2 pollutant but also suppress the O3 contaminant during Parade, while O3 increased during the APEC.

  4. Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA.

    PubMed

    Ota, Haruko; Hikita, Takao; Sawada, Masato; Nishioka, Tomoki; Matsumoto, Mami; Komura, Masayuki; Ohno, Akihisa; Kamiya, Yukiyo; Miyamoto, Takuya; Asai, Naoya; Enomoto, Atsushi; Takahashi, Masahide; Kaibuchi, Kozo; Sobue, Kazuya; Sawamoto, Kazunobu

    2014-07-30

    Throughout life, new neurons generated in the ventricular-subventricular zone take the long journey to the olfactory bulb. The intracellular mechanisms that precisely control the neurons' migration speed, enabling their well-organized movement, remain unclear. Rho signalling is known to affect the morphology and movement of various cell types, including neurons. Here we identify Gem-interacting protein (Gmip), a RhoA-specific GTPase-activating protein, as a key factor in saltatory neuronal migration. RhoA is activated at the proximal leading process of migrating neurons, where Gmip is also localized and negatively regulates RhoA. Gmip controls the saltatory movement of neurons that regulate their migration speed and 'stop' positions in the olfactory bulb, thereby altering the neural circuitry. This study demonstrates that Gmip serves as a brake for the RhoA-mediated movement of neuronal somata, and highlights the significance of speed control in the well-organized neuronal migration and the maintenance of neuronal circuits in the postnatal brain.

  5. Paradoxes of measurement.

    PubMed

    Heelan, Patrick A

    2003-05-01

    Applying Husserl's Eidetic Phenomenology to the transcendental structure (or "phenomenological reduction") of scientific data "given" in measurement to a first-person individual observer (the experimenter, S(1)) and a related third-person individual observer (the observer of the measurement process, S(3)), and comparing the outcomes, two paradoxical theses, "paradoxes of measurement," are derived. Thesis I: classical science necessarily entails "complementarity," "uncertainty relations," and the "entanglement" of observers and the data they observe. This situation is analogous in structure to that of quantum physics. Thesis II: a quantum object is a physical object with footprints in the perceptual world, but lacking a space-time "body"; it exists ontologically before the constitution of the perceptual world of the laboratory.

  6. The Bohr paradox

    NASA Astrophysics Data System (ADS)

    Crease, Robert P.

    2008-05-01

    In his book Niels Bohr's Times, the physicist Abraham Pais captures a paradox in his subject's legacy by quoting three conflicting assessments. Pais cites Max Born, of the first generation of quantum physics, and Werner Heisenberg, of the second, as saying that Bohr had a greater influence on physics and physicists than any other scientist. Yet Pais also reports a distinguished younger colleague asking with puzzlement and scepticism "What did Bohr really do?".

  7. Pentagrams and Paradoxes

    NASA Astrophysics Data System (ADS)

    Badziaģ, Piotr; Bengtsson, Ingemar; Cabello, Adán; Granström, Helena; Larsson, Jan-Åke

    2011-03-01

    Klyachko and coworkers consider an orthogonality graph in the form of a pentagram, and in this way derive a Kochen-Specker inequality for spin 1 systems. In some low-dimensional situations Hilbert spaces are naturally organised, by a magical choice of basis, into SO( N) orbits. Combining these ideas some very elegant results emerge. We give a careful discussion of the pentagram operator, and then show how the pentagram underlies a number of other quantum "paradoxes", such as that of Hardy.

  8. Perisomatic GABAergic synapses of basket cells effectively control principal neuron activity in amygdala networks

    PubMed Central

    Veres, Judit M; Nagy, Gergő A; Hájos, Norbert

    2017-01-01

    Efficient control of principal neuron firing by basket cells is critical for information processing in cortical microcircuits, however, the relative contribution of their perisomatic and dendritic synapses to spike inhibition is still unknown. Using in vitro electrophysiological paired recordings we reveal that in the mouse basal amygdala cholecystokinin- and parvalbumin-containing basket cells provide equally potent control of principal neuron spiking. We performed pharmacological manipulations, light and electron microscopic investigations to show that, although basket cells innervate the entire somato-denditic membrane surface of principal neurons, the spike controlling effect is achieved primarily via the minority of synapses targeting the perisomatic region. As the innervation patterns of individual basket cells on their different postsynaptic partners show high variability, the impact of inhibitory control accomplished by single basket cells is also variable. Our results show that both basket cell types can powerfully regulate the activity in amygdala networks predominantly via their perisomatic synapses. DOI: http://dx.doi.org/10.7554/eLife.20721.001 PMID:28060701

  9. Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

    PubMed Central

    Tomassy, Giulio Srubek; De Leonibus, Elvira; Jabaudon, Denis; Lodato, Simona; Alfano, Christian; Mele, Andrea; Macklis, Jeffrey D.; Studer, Michèle

    2010-01-01

    Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise. PMID:20133588

  10. Sub-millisecond optogenetic control of neuronal firing with two-photon holographic photoactivation of Chronos.

    PubMed

    Ronzitti, E; Conti, R; Zampini, V; Tanese, D; Foust, A J; Klapoetke, N; Boyden, E S; Papagiakoumou, E; Emiliani, V

    2017-10-02

    Optogenetic neuronal network manipulation promises to unravel a long-standing mystery in neuroscience: how does microcircuit activity causally relate to behavioral and pathological states? The challenge to evoke spikes with high spatial and temporal complexity necessitates further joint development of light-delivery approaches and custom opsins. Two-photon light-targeting strategies demonstrated, in-depth generation of action potentials in photosensitive neurons both in-vitro and in-vivo, but thus far lack the temporal precision necessary to induce precisely timed spiking events. Here, we show that efficient current integration enabled by two-photon holographic amplified laser illumination of Chronos, a highly light-sensitive and fast opsin, can evoke spikes with submillisecond precision and repeated firing up to 100 Hz in brain slices from Swiss male mice. These results pave the way for optogenetic manipulation with the spatial and temporal sophistication necessary to mimic natural microcircuit activity.SIGNIFICANT STATEMENTTo reveal causal links between neuronal activity and behavior, it is necessary to develop experimental strategies to induce spatially and temporally sophisticated perturbation of network microcircuits. Two-photon computer generated holography (2P-CGH) recently demonstrated three-dimensional optogenetic control of selected pools of neurons with single-cell accuracy in-depth in the brain. Here we show that exciting the fast opsin Chronos with amplified laser 2P-CGH enables cellular-resolution targeting with unprecedented temporal control, driving spiking up to 100 Hz with submillisecond onset precision, using low laser power densities. This system achieves a unique combination of spatial flexibility and temporal precision needed to optogenetically pattern inputs that mimic natural neuronal network activity patterns. Copyright © 2017 the authors.

  11. The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase.

    PubMed

    De Mario, Agnese; Castellani, Angela; Peggion, Caterina; Massimino, Maria Lina; Lim, Dmitry; Hill, Andrew F; Sorgato, M Catia; Bertoli, Alessandro

    2015-01-01

    The prion protein (PrP(C)) is a cell surface glycoprotein mainly expressed in neurons, whose misfolded isoforms generate the prion responsible for incurable neurodegenerative disorders. Whereas PrP(C) involvement in prion propagation is well established, PrP(C) physiological function is still enigmatic despite suggestions that it could act in cell signal transduction by modulating phosphorylation cascades and Ca(2+) homeostasis. Because PrP(C) binds neurotoxic protein aggregates with high-affinity, it has also been proposed that PrP(C) acts as receptor for amyloid-β (Aβ) oligomers associated with Alzheimer's disease (AD), and that PrP(C)-Aβ binding mediates AD-related synaptic dysfunctions following activation of the tyrosine kinase Fyn. Here, use of gene-encoded Ca(2+) probes targeting different cell domains in primary cerebellar granule neurons (CGN) expressing, or not, PrP(C), allowed us to investigate whether PrP(C) regulates store-operated Ca(2+) entry (SOCE) and the implication of Fyn in this control. Our findings show that PrP(C) attenuates SOCE, and Ca(2+) accumulation in the cytosol and mitochondria, by constitutively restraining Fyn activation and tyrosine phosphorylation of STIM1, a key molecular component of SOCE. This data establishes the existence of a PrP(C)-Fyn-SOCE triad in neurons. We also demonstrate that treating cerebellar granule and cortical neurons with soluble Aβ(1-42) oligomers abrogates the control of PrP(C) over Fyn and SOCE, suggesting a PrP(C)-dependent mechanizm for Aβ-induced neuronal Ca(2+) dyshomeostasis.

  12. Expiratory muscle control during vomiting - Role of brain stem expiratory neurons

    NASA Technical Reports Server (NTRS)

    Miller, A. D.; Tan, L. K.

    1987-01-01

    The neural mechanisms controlling the muscles involved during vomiting were examined using decerebrated cats. In one experiment, the activity of the ventral respiratory group (VRG) expiratory (E) neurons was recorded during induced 'fictive vomiting' (i.e., a series of bursts of coactivation of abdominal and phrenic nerves that would be expected to produce expulsion in unparalyzed animals) and vomiting. In a second, abdominal muscle electromyographic and nerve activity were compared before and after sectioning the axons of descending VRG E neurons as they cross the midline between C1 and the obex (the procedure that is known to abolish expiratory modulation of internal intercostal muscle activity). The results of the study indicate that the abdominal muscles are controlled differently during respiration and vomiting.

  13. Desynchronization in an ensemble of globally coupled chaotic bursting neuronal oscillators by dynamic delayed feedback control

    NASA Astrophysics Data System (ADS)

    Che, Yanqiu; Yang, Tingting; Li, Ruixue; Li, Huiyan; Han, Chunxiao; Wang, Jiang; Wei, Xile

    2015-09-01

    In this paper, we propose a dynamic delayed feedback control approach or desynchronization of chaotic-bursting synchronous activities in an ensemble of globally coupled neuronal oscillators. We demonstrate that the difference signal between an ensemble's mean field and its time delayed state, filtered and fed back to the ensemble, can suppress the self-synchronization in the ensemble. These individual units are decoupled and stabilized at the desired desynchronized states while the stimulation signal reduces to the noise level. The effectiveness of the method is illustrated by examples of two different populations of globally coupled chaotic-bursting neurons. The proposed method has potential for mild, effective and demand-controlled therapy of neurological diseases characterized by pathological synchronization.

  14. Expiratory muscle control during vomiting - Role of brain stem expiratory neurons

    NASA Technical Reports Server (NTRS)

    Miller, A. D.; Tan, L. K.

    1987-01-01

    The neural mechanisms controlling the muscles involved during vomiting were examined using decerebrated cats. In one experiment, the activity of the ventral respiratory group (VRG) expiratory (E) neurons was recorded during induced 'fictive vomiting' (i.e., a series of bursts of coactivation of abdominal and phrenic nerves that would be expected to produce expulsion in unparalyzed animals) and vomiting. In a second, abdominal muscle electromyographic and nerve activity were compared before and after sectioning the axons of descending VRG E neurons as they cross the midline between C1 and the obex (the procedure that is known to abolish expiratory modulation of internal intercostal muscle activity). The results of the study indicate that the abdominal muscles are controlled differently during respiration and vomiting.

  15. AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons.

    PubMed

    Gorshkov, Kirill; Mehta, Sohum; Ramamurthy, Santosh; Ronnett, Gabriele V; Zhou, Feng-Quan; Zhang, Jin

    2017-04-01

    Cyclic AMP (cAMP) and protein kinase A (PKA), classical examples of spatially compartmentalized signaling molecules, are critical axon determinants that regulate neuronal polarity and axon formation, yet little is known about micro-compartmentalization of cAMP and PKA signaling and its role in developing neurons. Here, we revealed that cAMP forms a gradient in developing hippocampal neurons, with higher cAMP levels in more distal regions of the axon compared to other regions of the cell. Interestingly, this cAMP gradient changed according to the developmental stage and depended on proper anchoring of PKA by A-kinase anchoring proteins (AKAPs). Disrupting PKA anchoring to AKAPs increased the cAMP gradient in early-stage neurons and led to enhanced axon elongation. Our results provide new evidence for a local negative-feedback loop, assembled by AKAPs, for the precise control of a growth-stage-dependent cAMP gradient to ensure proper axon growth.

  16. AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons

    PubMed Central

    Gorshkov, Kirill; Mehta, Sohum; Ramamurthy, Santosh; Ronnett, Gabriele V.; Zhou, Feng-Quan; Zhang, Jin

    2017-01-01

    Cyclic AMP (cAMP) and protein kinase A (PKA), classical examples of spatially compartmentalized signaling molecules, are critical axon determinants that regulate neuronal polarity and axon formation, yet little is known about micro-compartmentalization of cAMP and PKA signaling and its role in developing neurons. Here, we revealed that cAMP forms a gradient in developing hippocampal neurons, with higher cAMP levels in more distal regions of the axon compared to other regions of the cell. Interestingly, this cAMP gradient changed according to the developmental stage and depended on proper anchoring of PKA by A-kinase anchoring proteins (AKAPs). Disrupting PKA anchoring to AKAPs increased the cAMP gradient in early-stage neurons and led to enhanced axon elongation. Our results provide new evidence for a local negative feedback loop, assembled by AKAPs, for the precise control of a growth-stage-dependent cAMP gradient to ensure proper axon growth. PMID:28192412

  17. Necdin controls Foxo1 acetylation in hypothalamic arcuate neurons to modulate the thyroid axis.

    PubMed

    Hasegawa, Koichi; Kawahara, Tomohiro; Fujiwara, Kazushiro; Shimpuku, Mayumi; Sasaki, Tsutomu; Kitamura, Tadahiro; Yoshikawa, Kazuaki

    2012-04-18

    The forkhead transcription factor Foxo1 regulates energy homeostasis by modulating gene expression in the hypothalamus. Foxo1 undergoes post-translational modifications such as phosphorylation and acetylation, which modulate its functional activities. Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, regulates the acetylation status of Foxo1 in mammalian cells. Necdin, a pleiotropic protein required for neuronal development and survival, interacts with both Sirt1 and p53 to facilitate p53 deacetylation. The necdin gene (Ndn), an imprinted gene transcribed only from the paternal allele, is strongly expressed in hypothalamic neurons. Here, we demonstrate that necdin controls the acetylation status of Foxo1 in vivo in hypothalamic arcuate neurons to modulate the thyroid function. Necdin forms a stable ternary complex with Sirt1 and Foxo1, diminishes Foxo1 acetylation, and suppresses the transcriptional activity of Foxo1 in vitro. Paternal Ndn mutant mice express high levels of acetylated Foxo1 and mRNAs encoding agouti-related protein and neuropeptide Y in the hypothalamus in vivo during the juvenile period. The mutant mice exhibit endocrine dysfunction characteristic of hypothalamic hypothyroidism. Chemically induced hyperthyroidism and hypothyroidism lead to hypothalamic responses similar to those under necdin-deficient and excessive conditions, respectively, suggesting that thyroid hormone serves as a negative regulator of this system. These results suggest that necdin regulates Foxo1 acetylation and neuropeptide gene expression in the arcuate neurons to modulate the hypothalamic-pituitary-thyroid axis during development.

  18. Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism.

    PubMed

    Koch, M; Horvath, T L

    2014-07-01

    The brain receives and integrates environmental and metabolic information, transforms these signals into adequate neuronal circuit activities, and generates physiological behaviors to promote energy homeostasis. The responsible neuronal circuitries show lifetime plasticity and guaranty metabolic health and survival. However, this highly evolved organization has become challenged nowadays by chronic overload with nutrients and reduced physical activity, which results in an ever-increasing number of obese individuals worldwide. Research within the last two decades has aimed to decipher the responsible molecular and cellular mechanisms for regulation of the hypothalamic melanocortin neurons, which have a key role in the control of food intake and energy metabolism. This review maps the central connections of the melanocortin system and highlights its global position and divergent character in physiological and pathological metabolic events. Moreover, recently uncovered molecular and cellular processes in hypothalamic neurons and glial cells that drive plastic morphological and physiological changes in these cells, and account for regulation of food intake and energy metabolism, are brought into focus. Finally, potential functional interactions between metabolic disorders and psychiatric diseases are discussed.

  19. Specific subgroups of FruM neurons control sexually dimorphic patterns of aggression in Drosophila melanogaster

    PubMed Central

    Chan, Yick-Bun; Kravitz, Edward A.

    2007-01-01

    A great challenge facing neuroscience is to understand how genes, molecules, cells, circuits, and systems interact to generate social behavior. Fruit flies (Drosophila melanogaster) offer a powerful model system to address questions of this magnitude. These animals display genetically specified, sexually dimorphic patterns of fighting behavior via sex-specific splicing of the fruitless gene. Here, we show that sexually dimorphic behavioral patterns displayed during aggression are controlled by specific subgroups of neurons expressing male forms of fruitless proteins (FruM). Using the GAL4/UAS system to manipulate transformer expression, we feminized or masculinized different populations of neurons in fly nervous systems. With a panneuronal elav-GAL4 driver, male patterns of fighting behavior were transferred into females and female patterns into males. We screened 60 Gal4 lines that express the yeast transcription factor in different patterns in fly central nervous systems and found five that showed abnormal same-sex courtship behavior. The sexually dimorphic fighting patterns, however, were completely switched only in one and partially switched in a second of these lines. In the other three lines, female patterns of aggression were seen despite a switch in courtship preference. A tight correspondence was seen between FruM expression and how flies fight in several subgroups of neurons usually expressing these proteins: Expression is absent when flies fight like females and present when flies fight like males, thereby beginning a separation between courtship and aggression among these neurons. PMID:18042702

  20. Control of abdominal and expiratory intercostal muscle activity during vomiting - Role of ventral respiratory group expiratory neurons

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.; Tan, L. K.; Suzuki, Ichiro

    1987-01-01

    The role of ventral respiratory group (VRG) expiratory (E) neurons in the control of abdominal and internal intercostal muscle activity during vomiting was investigated in cats. Two series of experiments were performed: in one, the activity of VRG E neurons was recorded during fictive vomiting in cats that were decerebrated, paralyzed, and artificially ventilated; in the second, the abdominal muscle activity during vomiting was compared before and after sectioning the axons of descending VRG E neurons in decerebrate spontaneously breathing cats. The results show that about two-thirds of VRG E neurons that project at least as far caudally as the lower thoracic cord contribute to internal intercostal muscle activity during vomiting. The remaining VRG E neurons contribute to abdominal muscle activation. As shown by severing the axons of the VRG E neurons, other, as yet unidenified, inputs (either descending from the brain stem or arising from spinal reflexes) can also produce abdominal muscle activation.

  1. Control of abdominal and expiratory intercostal muscle activity during vomiting - Role of ventral respiratory group expiratory neurons

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.; Tan, L. K.; Suzuki, Ichiro

    1987-01-01

    The role of ventral respiratory group (VRG) expiratory (E) neurons in the control of abdominal and internal intercostal muscle activity during vomiting was investigated in cats. Two series of experiments were performed: in one, the activity of VRG E neurons was recorded during fictive vomiting in cats that were decerebrated, paralyzed, and artificially ventilated; in the second, the abdominal muscle activity during vomiting was compared before and after sectioning the axons of descending VRG E neurons in decerebrate spontaneously breathing cats. The results show that about two-thirds of VRG E neurons that project at least as far caudally as the lower thoracic cord contribute to internal intercostal muscle activity during vomiting. The remaining VRG E neurons contribute to abdominal muscle activation. As shown by severing the axons of the VRG E neurons, other, as yet unidenified, inputs (either descending from the brain stem or arising from spinal reflexes) can also produce abdominal muscle activation.

  2. Fast two-photon neuronal imaging and control using a spatial light modulator and ruthenium compounds

    NASA Astrophysics Data System (ADS)

    Peterka, Darcy S.; Nikolenko, Volodymyr; Fino, Elodie; Araya, Roberto; Etchenique, Roberto; Yuste, Rafael

    2010-02-01

    We have developed a spatial light modulator (SLM) based microscope that uses diffraction to shape the incoming two-photon laser source to any arbitrary light pattern. This allows the simultaneous imaging or photostimulation of different regions of a sample with three-dimensional precision at high frame rates. Additionally, we have combined this microscope with a new class of two photon active neuromodulators with Ruthenium BiPyridine (RuBi) based cages that offer great flexibility for neuronal control.

  3. Mechanisms of Gain Control by Voltage-Gated Channels in Intrinsically-Firing Neurons

    PubMed Central

    Patel, Ameera X.; Burdakov, Denis

    2015-01-01

    Gain modulation is a key feature of neural information processing, but underlying mechanisms remain unclear. In single neurons, gain can be measured as the slope of the current-frequency (input-output) relationship over any given range of inputs. While much work has focused on the control of basal firing rates and spike rate adaptation, gain control has been relatively unstudied. Of the limited studies on gain control, some have examined the roles of synaptic noise and passive somatic currents, but the roles of voltage-gated channels present ubiquitously in neurons have been less explored. Here, we systematically examined the relationship between gain and voltage-gated ion channels in a conductance-based, tonically-active, model neuron. Changes in expression (conductance density) of voltage-gated channels increased (Ca2+ channel), reduced (K+ channels), or produced little effect (h-type channel) on gain. We found that the gain-controlling ability of channels increased exponentially with the steepness of their activation within the dynamic voltage window (voltage range associated with firing). For depolarization-activated channels, this produced a greater channel current per action potential at higher firing rates. This allowed these channels to modulate gain by contributing to firing preferentially at states of higher excitation. A finer analysis of the current-voltage relationship during tonic firing identified narrow voltage windows at which the gain-modulating channels exerted their effects. As a proof of concept, we show that h-type channels can be tuned to modulate gain by changing the steepness of their activation within the dynamic voltage window. These results show how the impact of an ion channel on gain can be predicted from the relationship between channel kinetics and the membrane potential during firing. This is potentially relevant to understanding input-output scaling in a wide class of neurons found throughout the brain and other nervous systems

  4. Frontoparietal Structural Connectivity Mediates the Top-Down Control of Neuronal Synchronization Associated with Selective Attention

    PubMed Central

    Marshall, Tom Rhys; Bergmann, Til Ole; Jensen, Ole

    2015-01-01

    Neuronal synchronization reflected by oscillatory brain activity has been strongly implicated in the mechanisms supporting selective gating. We here aimed at identifying the anatomical pathways in humans supporting the top-down control of neuronal synchronization. We first collected diffusion imaging data using magnetic resonance imaging to identify the medial branch of the superior longitudinal fasciculus (SLF), a white-matter tract connecting frontal control areas to parietal regions. We then quantified the modulations in oscillatory activity using magnetoencephalography in the same subjects performing a spatial attention task. We found that subjects with a stronger SLF volume in the right compared to the left hemisphere (or vice versa) also were the subjects who had a better ability to modulate right compared to left hemisphere alpha and gamma band synchronization, with the latter also predicting biases in reaction time. Our findings implicate the medial branch of the SLF in mediating top-down control of neuronal synchronization in sensory regions that support selective attention. PMID:26441286

  5. The oxygen paradox of neurovascular coupling

    PubMed Central

    Leithner, Christoph; Royl, Georg

    2014-01-01

    The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. PMID:24149931

  6. Comment on the extinct paradox

    NASA Technical Reports Server (NTRS)

    Levine, D. M.

    1983-01-01

    The extinction paradox is a contradiction between geometrical optics results which predict that at high frequencies the scattering cross section of an object should equal its geometrical cross section and rigorous scattering theory which shows that at high frequencies the scattering cross section approaches twice the geometrical cross section of the object. Confusion about the reason for this paradox persists today even though the nature of the paradox was correctly identified many years ago by Brillouin. The resolution of the paradox is restated and illustrated with an example, and then the implications to the interpretation of scattering cross sections are identified.

  7. The paradox of Schrodinger's cat

    NASA Astrophysics Data System (ADS)

    Villars, C. N.

    1986-07-01

    Erwin Schrodinger first described the thought-experiment which has since become known as 'the paradox of Schrodinger's cat' 51 years ago. In recent years, popular accounts of quantum mechanics have tended to adopt one or other of the philosophically most extreme solutions to this paradox, i.e. the consciousness hypothesis or the many worlds interpretation. The author attempts to redress the balance by describing what he takes to be the orthodox solution to the paradox which explains the paradox, without recourse to such counterintuitive notions as a cat simultaneously dead and alive or a universe continually splitting into multiple worlds, as being due to a misapplication of the quantum formalism.

  8. A Circuit Node that Integrates Convergent Input from Neuromodulatory and Social Behavior-Promoting Neurons to Control Aggression in Drosophila.

    PubMed

    Watanabe, Kiichi; Chiu, Hui; Pfeiffer, Barret D; Wong, Allan M; Hoopfer, Eric D; Rubin, Gerald M; Anderson, David J

    2017-08-30

    Diffuse neuromodulatory systems such as norepinephrine (NE) control brain-wide states such as arousal, but whether they control complex social behaviors more specifically is not clear. Octopamine (OA), the insect homolog of NE, is known to promote both arousal and aggression. We have performed a systematic, unbiased screen to identify OA receptor-expressing neurons (OARNs) that control aggression in Drosophila. Our results uncover a tiny population of male-specific aSP2 neurons that mediate a specific influence of OA on aggression, independent of any effect on arousal. Unexpectedly, these neurons receive convergent input from OA neurons and P1 neurons, a population of FruM(+) neurons that promotes male courtship behavior. Behavioral epistasis experiments suggest that aSP2 neurons may constitute an integration node at which OAergic neuromodulation can bias the output of P1 neurons to favor aggression over inter-male courtship. These results have potential implications for thinking about the role of related neuromodulatory systems in mammals. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Zermelo, Boltzmann, and the recurrence paradox

    NASA Astrophysics Data System (ADS)

    Steckline, Vincent S.

    1983-10-01

    The papers exchanged by Ludwig Boltzmann and Ernst Zermelo concerning the recurrence paradox are summarized. The historical context of the paradox, Zermelo's proof of the paradox, his opinions of its consequences, Boltzmann's reply, and the ensuing discussion are described.

  10. Cerebral emboli of paradoxical origin.

    PubMed

    Jones, H R; Caplan, L R; Come, P C; Swinton, N W; Breslin, D J

    1983-03-01

    A diagnosis of paradoxical cerebral embolus (PCE) was made in five patients aged 31 to 62 years who sustained eight cerebral ischemic events. No patient had evidence of primary carotid system or left heart disease. A probe-patent foramen ovale was the presumed mechanism in four patients, and an unsuspected congenital atrial septal defect was found in the fifth patient. Clinically apparent pulmonary emboli or venous thrombosis preceded the cerebral event in only one instance. Review of the literature reveals a high mortality with PCE. However, careful clinical search for this lesion may be rewarding: four of our five patients survived. One should consider PCE in any patient with cerebral embolus in whom there is no demonstrable left-sided circulatory source. This principle applies particularly if there is concomitant venous thrombosis, pulmonary embolism, or enhanced potential for venous thrombosis due to, for example, morbid obesity, use of hormonal birth control pills, prolonged bed rest (especially postoperatively), or systemic carcinoma.

  11. Post-translational Modifications and Protein Quality Control in Motor Neuron and Polyglutamine Diseases

    PubMed Central

    Sambataro, Fabio; Pennuto, Maria

    2017-01-01

    Neurodegenerative diseases, including motor neuron and polyglutamine (polyQ) diseases, are a broad class of neurological disorders. These diseases are characterized by neuronal dysfunction and death, and by the accumulation of toxic aggregation-prone proteins in the forms of inclusions and micro-aggregates. Protein quality control is a cellular mechanism to reduce the burden of accumulation of misfolded proteins, a function that results from the coordinated actions of chaperones and degradation systems, such as the ubiquitin-proteasome system (UPS) and autophagy-lysosomal degradation system. The rate of turnover, aggregation and degradation of the disease-causing proteins is modulated by post-translational modifications (PTMs), such as phosphorylation, arginine methylation, palmitoylation, acetylation, SUMOylation, ubiquitination, and proteolytic cleavage. Here, we describe how PTMs of proteins linked to motor neuron and polyQ diseases can either enhance or suppress protein quality control check and protein aggregation and degradation. The identification of molecular strategies targeting these modifications may offer novel avenues for the treatment of these yet incurable diseases. PMID:28408866

  12. Minimum energy control for a two-compartment neuron to extracellular electric fields

    NASA Astrophysics Data System (ADS)

    Yi, Guo-Sheng; Wang, Jiang; Li, Hui-Yan; Wei, Xi-Le; Deng, Bin

    2016-11-01

    The energy optimization of extracellular electric field (EF) stimulus for a neuron is considered in this paper. We employ the optimal control theory to design a low energy EF input for a reduced two-compartment model. It works by driving the neuron to closely track a prescriptive spike train. A cost function is introduced to balance the contradictory objectives, i.e., tracking errors and EF stimulus energy. By using the calculus of variations, we transform the minimization of cost function to a six-dimensional two-point boundary value problem (BVP). Through solving the obtained BVP in the cases of three fundamental bifurcations, it is shown that the control method is able to provide an optimal EF stimulus of reduced energy for the neuron to effectively track a prescriptive spike train. Further, the feasibility of the adopted method is interpreted from the point of view of the biophysical basis of spike initiation. These investigations are conducive to designing stimulating dose for extracellular neural stimulation, which are also helpful to interpret the effects of extracellular field on neural activity.

  13. Neuronal ensemble control of prosthetic devices by a human with tetraplegia

    NASA Astrophysics Data System (ADS)

    Hochberg, Leigh R.; Serruya, Mijail D.; Friehs, Gerhard M.; Mukand, Jon A.; Saleh, Maryam; Caplan, Abraham H.; Branner, Almut; Chen, David; Penn, Richard D.; Donoghue, John P.

    2006-07-01

    Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a `neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.

  14. The Easterlin paradox revisited.

    PubMed

    Frank, Robert H

    2012-12-01

    The traditional view that well-being depends on both absolute and relative income was challenged in a 1974 paper by Richard Easterlin (Does economic growth improve the human lot? In P. David and M. Reder (Eds.), Nations and households in economic growth: Essays in honor of Moses Abramovitz (pp. 89-125), New York: Academic Press). He noted that although individual well-being is strongly positively associated with income within any country at a given point in time, the average level of measured well-being for a country changes little over time, even in the face of substantial growth in average incomes. For decades, social scientists have struggled to explain this "Easterlin Paradox." In a 2008 paper, Betsey Stephenson and Justin Wolfers (Economic growth and subjective well-being: Reassessing the Easterlin Paradox, Brookings Papers on Economic Activity, Vol. 39, pp. 1-87) argued that the Easterlin Paradox was a statistical illusion. Using richer data sets that facilitate more precise estimates of the various links between income and well-being, they assert that average well-being in a country does, in fact, rise as average income rises over time, and that rich countries are happier than slightly poorer ones. They also suggest that the link between income and well-being may run through absolute income alone-that is, that individual well-being may be completely independent of relative income. In this article, I argue that there have always been good reasons to believe that well-being is positively linked to absolute income. I also argue, however, that there is no reason to believe that individual well-being is independent of relative income.

  15. Remote control of ion channels and neurons through magnetic-field heating of nanoparticles

    NASA Astrophysics Data System (ADS)

    Huang, Heng; Delikanli, Savas; Zeng, Hao; Ferkey, Denise M.; Pralle, Arnd

    2010-08-01

    Recently, optical stimulation has begun to unravel the neuronal processing that controls certain animal behaviours. However, optical approaches are limited by the inability of visible light to penetrate deep into tissues. Here, we show an approach based on radio-frequency magnetic-field heating of nanoparticles to remotely activate temperature-sensitive cation channels in cells. Superparamagnetic ferrite nanoparticles were targeted to specific proteins on the plasma membrane of cells expressing TRPV1, and heated by a radio-frequency magnetic field. Using fluorophores as molecular thermometers, we show that the induced temperature increase is highly localized. Thermal activation of the channels triggers action potentials in cultured neurons without observable toxic effects. This approach can be adapted to stimulate other cell types and, moreover, may be used to remotely manipulate other cellular machinery for novel therapeutics.

  16. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice.

    PubMed

    Bryson, J Barney; Machado, Carolina Barcellos; Crossley, Martin; Stevenson, Danielle; Bros-Facer, Virginie; Burrone, Juan; Greensmith, Linda; Lieberam, Ivo

    2014-04-04

    Damage to the central nervous system caused by traumatic injury or neurological disorders can lead to permanent loss of voluntary motor function and muscle paralysis. Here, we describe an approach that circumvents central motor circuit pathology to restore specific skeletal muscle function. We generated murine embryonic stem cell-derived motor neurons that express the light-sensitive ion channel channelrhodopsin-2, which we then engrafted into partially denervated branches of the sciatic nerve of adult mice. These engrafted motor neurons not only reinnervated lower hind-limb muscles but also enabled their function to be restored in a controllable manner using optogenetic stimulation. This synthesis of regenerative medicine and optogenetics may be a successful strategy to restore muscle function after traumatic injury or disease.

  17. Plexin A is a neuronal semaphorin receptor that controls axon guidance.

    PubMed

    Winberg, M L; Noordermeer, J N; Tamagnone, L; Comoglio, P M; Spriggs, M K; Tessier-Lavigne, M; Goodman, C S

    1998-12-23

    The Semaphorins comprise a large family of secreted and transmembrane proteins, some of which function as repellents during axon guidance. Semaphorins fall into seven subclasses. Neuropilins are neuronal receptors for class III Semaphorins. In the immune system, VESPR, a member of the Plexin family, is a receptor for a viral-encoded Semaphorin. Here, we identify two Drosophila Plexins, both of which are expressed in the developing nervous system. We present evidence that Plexin A is a neuronal receptor for class I Semaphorins (Sema 1a and Sema 1b) and show that Plexin A controls motor and CNS axon guidance. Plexins, which themselves contain complete Semaphorin domains, may be both the ancestors of classical Semaphorins and binding partners for Semaphorins.

  18. Opposing Dopaminergic and GABAergic Neurons Control the Duration and Persistence of Copulation in Drosophila

    PubMed Central

    Crickmore, Michael A.; Vosshall, Leslie B.

    2014-01-01

    SUMMARY Behavioral persistence is a major factor in determiningwhen and under which circumstances animals will terminate their current activity and transition into more profitable, appropriate, or urgent behavior. We show that, for the first 5 min of copulation in Drosophila, stressful stimuli do not interrupt mating, whereas 10 min later, even minor perturbations are sufficient to terminate copulation. This decline in persistence occurs as the probability of successful mating increases and is promoted by approximately eight sexually dimorphic, GABAergic interneurons of the male abdominal ganglion. When these interneurons were silenced, persistence increased and males copulated far longer than required for successful mating. When these interneurons were stimulated, persistence decreased and copulations were shortened. In contrast, dopaminergic neurons of the ventral nerve cord promote copulation persistence and extend copulation duration. Thus, copulation duration in Drosophila is a product of gradually declining persistence controlled by opposing neuronal populations using conserved neurotransmission systems. PMID:24209625

  19. The Teacher's Paradox

    NASA Astrophysics Data System (ADS)

    Lilyquist, J. Gary

    1998-06-01

    New findings suggest that the way in which schools conduct their business is blocking our educational system from improving at a rate required to meet society's needs. A ground theory developed by exploring six organizational dimensions: external and internal environment cultures, leadership, strategy, structure, and results, verified the existence of the teacher's paradox. Implications suggest educational reformers must rethink approaches to school improvement by work within cultural boundaries. The forth coming book, "Are schools really like this?" presents "The Balance Alignment Model and Theory" to improve our schools using system thinking.

  20. Control of alternative splicing by forskolin through hnRNP K during neuronal differentiation.

    PubMed

    Cao, Wenguang; Razanau, Aleh; Feng, Dairong; Lobo, Vincent G; Xie, Jiuyong

    2012-09-01

    The molecular basis of cell signal-regulated alternative splicing at the 3' splice site remains largely unknown. We isolated a protein kinase A-responsive ribonucleic acid (RNA) element from a 3' splice site of the synaptosomal-associated protein 25 (Snap25) gene for forskolin-inhibited splicing during neuronal differentiation of rat pheochromocytoma PC12 cells. The element binds specifically to heterogeneous nuclear ribonucleo protein (hnRNP) K in a phosphatase-sensitive way, which directly competes with the U2 auxiliary factor U2AF65, an essential component of early spliceosomes. Transcripts with similarly localized hnRNP K target motifs upstream of alternative exons are enriched in genes often associated with neurological diseases. We show that such motifs upstream of the Runx1 exon 6 also bind hnRNP K, and importantly, hnRNP K is required for forskolin-induced repression of the exon. Interestingly, this exon encodes the peptide domain that determines the switch of the transcriptional repressor/activator activity of Runx1, a change known to be critical in specifying neuron lineages. Consistent with an important role of the target genes in neurons, knocking down hnRNP K severely disrupts forskolin-induced neurite growth. Thus, through hnRNP K, the neuronal differentiation stimulus forskolin targets a critical 3' splice site component of the splicing machinery to control alternative splicing of crucial genes. This also provides a regulated direct competitor of U2AF65 for cell signal control of 3' splice site usage.

  1. Association Between Infliximab Trough Levels and the Occurrence of Paradoxical Manifestations in Patients with Inflammatory Bowel Disease: a Case-Control Study.

    PubMed

    Coutzac, C; Chapuis, J; Poullenot, F; Chabrun, E; Capdepont, M; Blanco, P; Laharie, D

    2015-11-01

    Anti-tumour necrosis factor [TNF] agents have dramatically improved the prognosis of inflammatory bowel disease [IBD]. However, despite their good safety profile, use of these agents may lead to paradoxical manifestations involving skin or joints. Pathogenesis of such side effects is poorly understood and may involve anti-TNF pharmacokinetics. The aim of the present study was to look for an association between infliximab trough levels [ITL] and cutaneous [CPM] or rheumatological [RPM] paradoxical manifestations. IBD patients receiving infliximab as maintenance therapy were included in a cross-sectional prospective monocentre study. At inclusion, patients had an ITL measurement [LISA-TRACKER®, Biomedical Diagnostics BMD] and were assessed for paradoxical manifestations: a CPM was defined by new onset or exacerbation of pre-existing psoriasis lesions during IFX therapy, and an RPM by new onset of severe poly-arthralgia during IFX therapy. Among the 121 patients included [69 female; median age: 38.9 years; 92 with Crohn's disease], 7% had CPM and 8% RPM. Median ITL values were 5.87 [range: 0.52-19.53] µg/ml in patients with CPM and 1.90 [0.00-13.5] µg/ml in those with RPM, as compared respectively with 5.12 [0.00-49.12] µg/ml in patients without CPM [p = 0.56] and 5.57 [0.00-49.12] µg/ml in those without RPM [p = 0.058]. No prognostic factor was associated with CPM. The single factor associated with RPM was elevated antinuclear antibodies. ITL were not elevated in IBD patients developing cutaneous or rheumatological paradoxical manifestations when receiving IFX as maintenance therapy. As suggested by the high level of antinuclear antibodies, RPM could be related to an induced autoimmune disorder. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Adaptive, fast walking in a biped robot under neuronal control and learning.

    PubMed

    Manoonpong, Poramate; Geng, Tao; Kulvicius, Tomas; Porr, Bernd; Wörgötter, Florentin

    2007-07-01

    Human walking is a dynamic, partly self-stabilizing process relying on the interaction of the biomechanical design with its neuronal control. The coordination of this process is a very difficult problem, and it has been suggested that it involves a hierarchy of levels, where the lower ones, e.g., interactions between muscles and the spinal cord, are largely autonomous, and where higher level control (e.g., cortical) arises only pointwise, as needed. This requires an architecture of several nested, sensori-motor loops where the walking process provides feedback signals to the walker's sensory systems, which can be used to coordinate its movements. To complicate the situation, at a maximal walking speed of more than four leg-lengths per second, the cycle period available to coordinate all these loops is rather short. In this study we present a planar biped robot, which uses the design principle of nested loops to combine the self-stabilizing properties of its biomechanical design with several levels of neuronal control. Specifically, we show how to adapt control by including online learning mechanisms based on simulated synaptic plasticity. This robot can walk with a high speed (>3.0 leg length/s), self-adapting to minor disturbances, and reacting in a robust way to abruptly induced gait changes. At the same time, it can learn walking on different terrains, requiring only few learning experiences. This study shows that the tight coupling of physical with neuronal control, guided by sensory feedback from the walking pattern itself, combined with synaptic learning may be a way forward to better understand and solve coordination problems in other complex motor tasks.

  3. Adaptive, Fast Walking in a Biped Robot under Neuronal Control and Learning

    PubMed Central

    Kulvicius, Tomas; Porr, Bernd; Wörgötter, Florentin

    2007-01-01

    Human walking is a dynamic, partly self-stabilizing process relying on the interaction of the biomechanical design with its neuronal control. The coordination of this process is a very difficult problem, and it has been suggested that it involves a hierarchy of levels, where the lower ones, e.g., interactions between muscles and the spinal cord, are largely autonomous, and where higher level control (e.g., cortical) arises only pointwise, as needed. This requires an architecture of several nested, sensori–motor loops where the walking process provides feedback signals to the walker's sensory systems, which can be used to coordinate its movements. To complicate the situation, at a maximal walking speed of more than four leg-lengths per second, the cycle period available to coordinate all these loops is rather short. In this study we present a planar biped robot, which uses the design principle of nested loops to combine the self-stabilizing properties of its biomechanical design with several levels of neuronal control. Specifically, we show how to adapt control by including online learning mechanisms based on simulated synaptic plasticity. This robot can walk with a high speed (>3.0 leg length/s), self-adapting to minor disturbances, and reacting in a robust way to abruptly induced gait changes. At the same time, it can learn walking on different terrains, requiring only few learning experiences. This study shows that the tight coupling of physical with neuronal control, guided by sensory feedback from the walking pattern itself, combined with synaptic learning may be a way forward to better understand and solve coordination problems in other complex motor tasks. PMID:17630828

  4. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning.

    PubMed

    Veyrac, Alexandra; Gros, Alexandra; Bruel-Jungerman, Elodie; Rochefort, Christelle; Kleine Borgmann, Felix B; Jessberger, Sebastian; Laroche, Serge

    2013-04-23

    New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.

  5. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning

    PubMed Central

    Veyrac, Alexandra; Gros, Alexandra; Bruel-Jungerman, Elodie; Rochefort, Christelle; Kleine Borgmann, Felix B.; Jessberger, Sebastian; Laroche, Serge

    2013-01-01

    New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2–3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory. PMID:23569253

  6. Ephrin-B1 controls the columnar distribution of cortical pyramidal neurons by restricting their tangential migration.

    PubMed

    Dimidschstein, Jordane; Passante, Lara; Dufour, Audrey; van den Ameele, Jelle; Tiberi, Luca; Hrechdakian, Tatyana; Adams, Ralf; Klein, Rüdiger; Lie, Dieter Chichung; Jossin, Yves; Vanderhaeghen, Pierre

    2013-09-18

    Neurons of the cerebral cortex are organized in layers and columns. Unlike laminar patterning, the mechanisms underlying columnar organization remain largely unexplored. Here, we show that ephrin-B1 plays a key role in this process through the control of nonradial steps of migration of pyramidal neurons. In vivo gain of function of ephrin-B1 resulted in a reduction of tangential motility of pyramidal neurons, leading to abnormal neuronal clustering. Conversely, following genetic disruption of ephrin-B1, cortical neurons displayed a wider lateral dispersion, resulting in enlarged ontogenic columns. Dynamic analyses revealed that ephrin-B1 controls the lateral spread of pyramidal neurons by limiting neurite extension and tangential migration during the multipolar phase. Furthermore, we identified P-Rex1, a guanine-exchange factor for Rac3, as a downstream ephrin-B1 effector required to control migration during the multipolar phase. Our results demonstrate that ephrin-B1 inhibits nonradial migration of pyramidal neurons, thereby controlling the pattern of cortical columns.

  7. Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain

    PubMed Central

    Prakash, Nilima; Puelles, Eduardo; Freude, Kristine; Trümbach, Dietrich; Omodei, Daniela; Di Salvio, Michela; Sussel, Lori; Ericson, Johan; Sander, Maike; Simeone, Antonio; Wurst, Wolfgang

    2009-01-01

    Summary Little is known about the cues controlling the generation of motoneuron populations in the mammalian ventral midbrain. We show that Otx2 provides the crucial anterior-posterior positional information for the generation of red nucleus neurons in the murine midbrain. Moreover, the homeodomain transcription factor Nkx6-1 controls the proper development of the red nucleus and of the oculomotor and trochlear nucleus neurons. Nkx6-1 is expressed in ventral midbrain progenitors and acts as a fate determinant of the Brn3a+ (also known as Pou4f1) red nucleus neurons. These progenitors are partially dorsalized in the absence of Nkx6-1, and a fraction of their postmitotic offspring adopts an alternative cell fate, as revealed by the activation of Dbx1 and Otx2 in these cells. Nkx6-1 is also expressed in postmitotic Isl1+ oculomotor and trochlear neurons. Similar to hindbrain visceral (branchio-) motoneurons, Nkx6-1 controls the proper migration and axon outgrowth of these neurons by regulating the expression of at least three axon guidance/neuronal migration molecules. Based on these findings, we provide additional evidence that the developmental mechanism of the oculomotor and trochlear neurons exhibits more similarity with that of special visceral motoneurons than with that controlling the generation of somatic motoneurons located in the murine caudal hindbrain and spinal cord. PMID:19592574

  8. Model-based iterative learning control of Parkinsonian state in thalamic relay neuron

    NASA Astrophysics Data System (ADS)

    Liu, Chen; Wang, Jiang; Li, Huiyan; Xue, Zhiqin; Deng, Bin; Wei, Xile

    2014-09-01

    Although the beneficial effects of chronic deep brain stimulation on Parkinson's disease motor symptoms are now largely confirmed, the underlying mechanisms behind deep brain stimulation remain unclear and under debate. Hence, the selection of stimulation parameters is full of challenges. Additionally, due to the complexity of neural system, together with omnipresent noises, the accurate model of thalamic relay neuron is unknown. Thus, the iterative learning control of the thalamic relay neuron's Parkinsonian state based on various variables is presented. Combining the iterative learning control with typical proportional-integral control algorithm, a novel and efficient control strategy is proposed, which does not require any particular knowledge on the detailed physiological characteristics of cortico-basal ganglia-thalamocortical loop and can automatically adjust the stimulation parameters. Simulation results demonstrate the feasibility of the proposed control strategy to restore the fidelity of thalamic relay in the Parkinsonian condition. Furthermore, through changing the important parameter—the maximum ionic conductance densities of low-threshold calcium current, the dominant characteristic of the proposed method which is independent of the accurate model can be further verified.

  9. Augmented neuronal death in CA3 hippocampus following hyperventilation early after controlled cortical impact.

    PubMed

    Forbes, M L; Clark, R S; Dixon, C E; Graham, S H; Marion, D W; DeKosky, S T; Schiding, J K; Kochanek, P M

    1998-03-01

    Minimizing secondary injury after severe traumatic brain injury (TBI) is the primary goal of cerebral resuscitation. For more than two decades, hyperventilation has been one of the most often used strategies in the management of TBI. Laboratory and clinical studies, however, have verified a post-TBI state of reduced cerebral perfusion that may increase the brain's vulnerability to secondary injury. In addition, it has been suggested in a clinical study that hyperventilation may worsen outcome after TBI. Using the controlled cortical impact model in rats, the authors tested the hypothesis that aggressive hyperventilation applied immediately after TBI would worsen functional outcome, expand the contusion, and promote neuronal death in selectively vulnerable hippocampal neurons. Twenty-six intubated, mechanically ventilated, isoflurane-anesthetized male Sprague-Dawley rats were subjected to controlled cortical impact (4 m/second, 2.5-mm depth of deformation) and randomized after 10 minutes to either hyperventilation (PaCO2 = 20.3 +/- 0.7 mm Hg) or normal ventilation groups (PaCO2 = 34.9 +/- 0.3 mm Hg) containing 13 rats apiece and were treated for 5 hours. Beam balance and Morris water maze (MWM) performance latencies were measured in eight rats from each group on Days 1 to 5 and 7 to 11, respectively, after controlled cortical impact. The rats were killed at 14 days postinjury, and serial coronal sections of their brains were studied for contusion volume and hippocampal neuron counting (CA1, CA3) by an observer who was blinded to their treatment group. Mortality rates were similar in both groups (two of 13 in the normal ventilation compared with three of 13 in the hyperventilation group, not significant [NS]). There were no differences between the groups in mean arterial blood pressure, brain temperature, and serum glucose concentration. There were no differences between groups in performance latencies for both beam balance and MWM or contusion volume (27.8 +/- 5

  10. Barn and Pole Paradox: Revisited

    ERIC Educational Resources Information Center

    Cacioppo, Robert; Gangopadhyaya, Asim

    2012-01-01

    Paradoxes have played great instructive roles in many cultures. They provide an excellent paradigm for teaching concepts that require deep reflection. In this article, the authors present two different paradoxes related to the length contraction in special relativity and explain their resolution. They hope that these two Gedanken experiments and…

  11. Barn and Pole Paradox: Revisited

    ERIC Educational Resources Information Center

    Cacioppo, Robert; Gangopadhyaya, Asim

    2012-01-01

    Paradoxes have played great instructive roles in many cultures. They provide an excellent paradigm for teaching concepts that require deep reflection. In this article, the authors present two different paradoxes related to the length contraction in special relativity and explain their resolution. They hope that these two Gedanken experiments and…

  12. Paradoxes of French accreditation.

    PubMed

    Pomey, M-P; François, P; Contandriopoulos, A-P; Tosh, A; Bertrand, D

    2005-02-01

    The accreditation system introduced into the French healthcare system in 1996 has five particular characteristics: (1) it is mandatory for all healthcare establishments; (2) it is performed by an independent government agency; (3) surveyors have to report all instances of non-compliance with safety regulations; (4) the accreditation report is delivered to regional administrative authorities and a summary is made available to the public; and (5) regional administrative authorities can use the information contained in the accreditation report to revise hospital budgets. These give rise to a number of paradoxes: (1) the fact that accreditation is mandatory lends itself to ambiguity and likens the process to an inspection; (2) the fact that decision makers can use the information contained in the accreditation report for resource allocation can incite establishments to adopt strategic behaviours aimed merely at complying with the accreditation manual; and (3) there is a tendency for establishments to reduce quality processes to nothing more than the completion of accreditation and to focus efforts on standardizing practices and resolving safety issues to the detriment of organizational development. All accreditation systems must be aware of these paradoxes and decide on the level of government involvement and the relationship between accreditation and resource allocation. With time, accreditation in France could benefit from both a professionally driven system and from the increased amount of freedom to focus on quality improvement which is necessary for organizational development.

  13. Paradoxes of French accreditation

    PubMed Central

    Pomey, M; Francois, P; Contandriopoulos, A; Tosh, A; Bertrand, D

    2005-01-01

    

 The accreditation system introduced into the French healthcare system in 1996 has five particular characteristics: (1) it is mandatory for all healthcare establishments; (2) it is performed by an independent government agency; (3) surveyors have to report all instances of non-compliance with safety regulations; (4) the accreditation report is delivered to regional administrative authorities and a summary is made available to the public; and (5) regional administrative authorities can use the information contained in the accreditation report to revise hospital budgets. These give rise to a number of paradoxes: (1) the fact that accreditation is mandatory lends itself to ambiguity and likens the process to an inspection; (2) the fact that decision makers can use the information contained in the accreditation report for resource allocation can incite establishments to adopt strategic behaviours aimed merely at complying with the accreditation manual; and (3) there is a tendency for establishments to reduce quality processes to nothing more than the completion of accreditation and to focus efforts on standardizing practices and resolving safety issues to the detriment of organizational development. All accreditation systems must be aware of these paradoxes and decide on the level of government involvement and the relationship between accreditation and resource allocation. With time, accreditation in France could benefit from both a professionally driven system and from the increased amount of freedom to focus on quality improvement which is necessary for organizational development. PMID:15692004

  14. The in vivo contribution of motor neuron TrkB receptors to mutant SOD1 motor neuron disease.

    PubMed

    Zhai, Jinbin; Zhou, Weiguo; Li, Jian; Hayworth, Christopher R; Zhang, Lei; Misawa, Hidemi; Klein, Rudiger; Scherer, Steven S; Balice-Gordon, Rita J; Kalb, Robert Gordon

    2011-11-01

    Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are widely expressed in the vertebrate nervous system and play a central role in mature neuronal function. In vitro BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults. Paradoxically, BDNF/TrkB signaling has also been shown, under certain in vitro circumstances, to render neurons vulnerable to insults. We show here that in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity. Mutant SOD1 mice lacking motor neuron TrkB live a month longer than controls and retain motor function for a longer period, particularly in the early phase of the disease. These effects are subserved by slowed motor neuron loss, persistence of neuromuscular junction integrity and reduced astrocytic and microglial reactivity within the spinal cord. These results suggest that manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases.

  15. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

    PubMed Central

    Bell, Robert D.; Winkler, Ethan A.; Sagare, Abhay P.; Singh, Itender; LaRue, Barb; Deane, Rashid; Zlokovic, Berislav V.

    2010-01-01

    SUMMARY Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow and cerebral blood flow responses to brain activation which ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericytes loss results in a progressive age-dependent vascular-mediated neurodegeneration. PMID:21040844

  16. A method for high fidelity optogenetic control of individual pyramidal neurons in vivo.

    PubMed

    Nakamura, Shinya; Baratta, Michael V; Cooper, Donald C

    2013-09-02

    Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales. We first demonstrate a simple approach for adeno-associated virus-mediated delivery of ChR2 and NpHR transgenes to the dorsal subiculum and prelimbic region of the prefrontal cortex in rat. Because ChR2 and NpHR are genetically targetable, we describe the use of this technology to control the electrical activity of specific populations of neurons (i.e., pyramidal neurons) embedded in heterogeneous tissue with high temporal precision. We describe herein the hardware, custom software user interface, and procedures that allow for simultaneous light delivery and electrical recording from transduced pyramidal neurons in an anesthetized in vivo preparation. These light-responsive tools provide the opportunity for identifying the causal contributions of different cell types to information processing and behavior.

  17. A Method for High Fidelity Optogenetic Control of Individual Pyramidal Neurons In vivo

    PubMed Central

    Cooper, Donald C.

    2013-01-01

    Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales. We first demonstrate a simple approach for adeno-associated virus-mediated delivery of ChR2 and NpHR transgenes to the dorsal subiculum and prelimbic region of the prefrontal cortex in rat. Because ChR2 and NpHR are genetically targetable, we describe the use of this technology to control the electrical activity of specific populations of neurons (i.e., pyramidal neurons) embedded in heterogeneous tissue with high temporal precision. We describe herein the hardware, custom software user interface, and procedures that allow for simultaneous light delivery and electrical recording from transduced pyramidal neurons in an anesthetized in vivo preparation. These light-responsive tools provide the opportunity for identifying the causal contributions of different cell types to information processing and behavior. PMID:24022017

  18. The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation

    PubMed Central

    Li, Qin; Zheng, Sika; Han, Areum; Lin, Chia-Ho; Stoilov, Peter; Fu, Xiang-Dong; Black, Douglas L

    2014-01-01

    We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2−/− neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron. DOI: http://dx.doi.org/10.7554/eLife.01201.001 PMID:24448406

  19. The splicing regulator PTBP1 controls the activity of the transcription factor Pbx1 during neuronal differentiation

    PubMed Central

    Linares, Anthony J; Lin, Chia-Ho; Damianov, Andrey; Adams, Katrina L; Novitch, Bennett G; Black, Douglas L

    2015-01-01

    The RNA-binding proteins PTBP1 and PTBP2 control programs of alternative splicing during neuronal development. PTBP2 was found to maintain embryonic splicing patterns of many synaptic and cytoskeletal proteins during differentiation of neuronal progenitor cells (NPCs) into early neurons. However, the role of the earlier PTBP1 program in embryonic stem cells (ESCs) and NPCs was not clear. We show that PTBP1 controls a program of neuronal gene expression that includes the transcription factor Pbx1. We identify exons specifically regulated by PTBP1 and not PTBP2 as mouse ESCs differentiate into NPCs. We find that PTBP1 represses Pbx1 exon 7 and the expression of the neuronal Pbx1a isoform in ESCs. Using CRISPR-Cas9 to delete regulatory elements for exon 7, we induce Pbx1a expression in ESCs, finding that this activates transcription of neuronal genes. Thus, PTBP1 controls the activity of Pbx1 to suppress its neuronal transcriptional program prior to induction of NPC development. DOI: http://dx.doi.org/10.7554/eLife.09268.001 PMID:26705333

  20. Optogenetic Stimulation of Frontal D1 Neurons Compensates for Impaired Temporal Control of Action in Dopamine-Depleted Mice.

    PubMed

    Kim, Young-Cho; Han, Sang-Woo; Alberico, Stephanie L; Ruggiero, Rafael N; De Corte, Benjamin; Chen, Kuan-Hua; Narayanan, Nandakumar S

    2017-01-09

    Disrupted mesocortical dopamine contributes to cognitive symptoms of Parkinson's disease (PD). Past work has implicated medial frontal neurons expressing D1 dopamine receptors (D1DRs) in temporal processing. Here, we investigated whether these neurons can compensate for behavioral deficits resulting from midbrain dopamine dysfunction. We report three main results. First, both PD patients and mice with ventral tegmental area (VTA) dopamine depletion had attenuated delta activity (1-4 Hz) in the medial frontal cortex (MFC) during interval timing. Second, we found that optogenetically stimulating MFC D1DR neurons could increase ramping activity among MFC neurons. Finally, stimulating MFC D1DR neurons specifically at delta frequencies (2 Hz) compensated for deficits in temporal control of action caused by VTA dopamine depletion. Our results suggest that cortical networks can be targeted by frequency-specific brain stimulation to improve dopamine-dependent cognitive processing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Kalman meets neuron: the emerging intersection of control theory with neuroscience.

    PubMed

    Schiff, Steven J

    2009-01-01

    Since the 1950s, we have developed mature theories of modern control theory and computational neuroscience with almost no interaction between these disciplines. With the advent of computationally efficient nonlinear Kalman filtering techniques, along with improved neuroscience models that provide increasingly accurate reconstruction of dynamics in a variety of important normal and disease states in the brain, the prospects for a synergistic interaction between these fields are now strong. I show recent examples of the use of nonlinear control theory for the assimilation and control of single neuron dynamics, the modulation of oscillatory wave dynamics in brain cortex, a control framework for Parkinsonian dynamics and seizures, and the use of optimized parameter model networks to assimilate complex network data - the 'consensus set'.

  2. DREADDs in Drosophila: A Pharmacogenetic Approach for Controlling Behavior, Neuronal Signaling, and Physiology in the Fly

    PubMed Central

    Becnel, Jaime; Johnson, Oralee; Majeed, Zana R.; Tran, Vi; Yu, Bangning; Roth, Bryan L.; Cooper, Robin L.; Kerut, Edmund K.; Nichols, Charles D.

    2013-01-01

    SUMMARY We have translated a powerful genetic tool, designer receptors exclusively activated by designer drugs (DREADDs), from mammalian systems to Drosophila melanogaster to selectively, rapidly, reversibly, and dose-dependently control behaviors and physiological processes in the fly. DREADDs are muscarinic acetylcholine G protein-coupled receptors evolved for loss of affinity to acetylcholine and for the ability to be fully activated by an otherwise biologically inert chemical, clozapine-N-oxide. We demonstrate its ability to control a variety of behaviors and processes in larvae and adults, including heart rate, sensory processing, diurnal behavior, learning and memory, and courtship. The advantages of this particular technology include the dose-responsive control of behaviors, the lack of a need for specialized equipment, and the capacity to remotely control signaling in essentially all neuronal and nonneuronal fly tissues. PMID:24012754

  3. High fidelity optogenetic control of individual prefrontal cortical pyramidal neurons in vivo

    PubMed Central

    Cooper, Donald C

    2012-01-01

    Precise spatial and temporal manipulation of neural activity in specific genetically defined cell populations is now possible with the advent of optogenetics. The emerging field of optogenetics consists of a set of naturally-occurring and engineered light-sensitive membrane proteins that are able to activate (e.g. channelrhodopsin-2, ChR2) or silence (e.g. halorhodopsin, NpHR) neural activity. Here we demonstrate the technique and the feasibility of using novel adeno-associated viral (AAV) tools to activate (AAV-CaMKllα-ChR2-eYFP) or silence (AAV-CaMKllα-eNpHR3.0-eYFP) neural activity of rat prefrontal cortical prelimbic (PL) pyramidal neurons  in vivo.  In vivo single unit extracellular recording of ChR2-transduced pyramidal neurons showed that delivery of brief (10 ms) blue (473 nm) light-pulse trains up to 20 Hz via a custom fiber optic-coupled recording electrode (optrode) induced spiking with high fidelity at 20 Hz for the duration of recording (up to two hours in some cases). To silence spontaneously active neurons, we transduced them with the NpHR construct and administered continuous green (532 nm) light to completely inhibit action potential activity for up to 10 seconds with 100% fidelity in most cases. These versatile photosensitive tools, combined with optrode recording methods, provide experimental control over activity of genetically defined neurons and can be used to investigate the functional relationship between neural activity and complex cognitive behavior. PMID:24555016

  4. EXERCISE-INDUCED NEURONAL PLASTICITY IN CENTRAL AUTONOMIC NETWORKS: ROLE IN CARDIOVASCULAR CONTROL

    PubMed Central

    Michelini, Lisete C.; Stern, Javier E.

    2010-01-01

    It is now well established that brain plasticity is an inherent property not only of the developing, but also of the adult brain. Numerous beneficial effects of exercise, including improved memory, cognitive function and neuroprotection, have been shown to involve an important neuroplastic component. However, whether major adaptive cardiovascular adjustments during exercise, needed to ensure proper blood perfusion of peripheral tissues, also require brain neuroplasticity, is presently unknown. This review will critically evaluate current knowledge on proposed mechanisms that likely underlie the continuous resetting of baroreflex control of heart rate during/after exercise and following exercise training. Accumulating evidence indicates that not only somatosensory afferents (conveyed by skeletal muscle receptors, baroreceptors and/or cardiopulmonary receptors), but also projections arising from central command neurons (in particular peptidergic hypothalamic preautonomic neurons) converge into the nucleus tractus solitarii (NTS) in the dorsal brainstem, to coordinate complex cardiovascular adaptations during dynamic exercise. This review focuses in particular on a reciprocally interconnected network between the NTS and the hypothalamic paraventricular nucleus (PVN), which is proposed to act as a pivotal anatomical and functional substrate underlying integrative feed-forward and feed-back cardiovascular adjustments during exercise. Recent findings supporting neuroplastic adaptive changes within the NTS-PVN reciprocal network (e.g., remodeling of afferent inputs, structural and functional neuronal plasticity, and changes in neurotransmitter content), will be discussed within the context of their role as important underlying cellular mechanisms supporting the tonic activation and improved efficacy of these central pathways in response to circulatory demand at rest and during exercise, both in sedentary and trained individuals. We hope this review will stimulate more

  5. Exercise-induced neuronal plasticity in central autonomic networks: role in cardiovascular control.

    PubMed

    Michelini, Lisete C; Stern, Javier E

    2009-09-01

    It is now well established that brain plasticity is an inherent property not only of the developing but also of the adult brain. Numerous beneficial effects of exercise, including improved memory, cognitive function and neuroprotection, have been shown to involve an important neuroplastic component. However, whether major adaptive cardiovascular adjustments during exercise, needed to ensure proper blood perfusion of peripheral tissues, also require brain neuroplasticity, is presently unknown. This review will critically evaluate current knowledge on proposed mechanisms that are likely to underlie the continuous resetting of baroreflex control of heart rate during/after exercise and following exercise training. Accumulating evidence indicates that not only somatosensory afferents (conveyed by skeletal muscle receptors, baroreceptors and/or cardiopulmonary receptors) but also projections arising from central command neurons (in particular, peptidergic hypothalamic pre-autonomic neurons) converge into the nucleus tractus solitarii (NTS) in the dorsal brainstem, to co-ordinate complex cardiovascular adaptations during dynamic exercise. This review focuses in particular on a reciprocally interconnected network between the NTS and the hypothalamic paraventricular nucleus (PVN), which is proposed to act as a pivotal anatomical and functional substrate underlying integrative feedforward and feedback cardiovascular adjustments during exercise. Recent findings supporting neuroplastic adaptive changes within the NTS-PVN reciprocal network (e.g. remodelling of afferent inputs, structural and functional neuronal plasticity and changes in neurotransmitter content) will be discussed within the context of their role as important underlying cellular mechanisms supporting the tonic activation and improved efficacy of these central pathways in response to circulatory demand at rest and during exercise, both in sedentary and in trained individuals. We hope this review will stimulate

  6. High fidelity optogenetic control of individual prefrontal cortical pyramidal neurons in vivo.

    PubMed

    Nakamura, Shinya; Baratta, Michael V; Pomrenze, Matthew B; Dolzani, Samuel D; Cooper, Donald C

    2012-01-01

    Precise spatial and temporal manipulation of neural activity in specific genetically defined cell populations is now possible with the advent of optogenetics. The emerging field of optogenetics consists of a set of naturally-occurring and engineered light-sensitive membrane proteins that are able to activate (e.g. channelrhodopsin-2, ChR2) or silence (e.g. halorhodopsin, NpHR) neural activity. Here we demonstrate the technique and the feasibility of using novel adeno-associated viral (AAV) tools to activate (AAV-CaMKllα-ChR2-eYFP) or silence (AAV-CaMKllα-eNpHR3.0-eYFP) neural activity of rat prefrontal cortical prelimbic (PL) pyramidal neurons  in vivo.  In vivo single unit extracellular recording of ChR2-transduced pyramidal neurons showed that delivery of brief (10 ms) blue (473 nm) light-pulse trains up to 20 Hz via a custom fiber optic-coupled recording electrode (optrode) induced spiking with high fidelity at 20 Hz for the duration of recording (up to two hours in some cases). To silence spontaneously active neurons, we transduced them with the NpHR construct and administered continuous green (532 nm) light to completely inhibit action potential activity for up to 10 seconds with 100% fidelity in most cases. These versatile photosensitive tools, combined with optrode recording methods, provide experimental control over activity of genetically defined neurons and can be used to investigate the functional relationship between neural activity and complex cognitive behavior.

  7. Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control.

    PubMed

    Ramírez, Sara; Gómez-Valadés, Alicia G; Schneeberger, Marc; Varela, Luis; Haddad-Tóvolli, Roberta; Altirriba, Jordi; Noguera, Eduard; Drougard, Anne; Flores-Martínez, Álvaro; Imbernón, Mónica; Chivite, Iñigo; Pozo, Macarena; Vidal-Itriago, Andrés; Garcia, Ainhoa; Cervantes, Sara; Gasa, Rosa; Nogueiras, Ruben; Gama-Pérez, Pau; Garcia-Roves, Pablo M; Cano, David A; Knauf, Claude; Servitja, Joan-Marc; Horvath, Tamas L; Gomis, Ramon; Zorzano, Antonio; Claret, Marc

    2017-06-06

    Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.

    PubMed

    Magee, J C; Johnston, D

    1997-01-10

    The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.

  9. Neuronal Correlates of Cognitive Control during Gaming Revealed by Near-Infrared Spectroscopy.

    PubMed

    Witte, Matthias; Ninaus, Manuel; Kober, Silvia Erika; Neuper, Christa; Wood, Guilherme

    2015-01-01

    In everyday life we quickly build and maintain associations between stimuli and behavioral responses. This is governed by rules of varying complexity and past studies have identified an underlying fronto-parietal network involved in cognitive control processes. However, there is only limited knowledge about the neuronal activations during more natural settings like game playing. We thus assessed whether near-infrared spectroscopy recordings can reflect different demands on cognitive control during a simple game playing task. Sixteen healthy participants had to catch falling objects by pressing computer keys. These objects either fell randomly (RANDOM task), according to a known stimulus-response mapping applied by players (APPLY task) or according to a stimulus-response mapping that had to be learned (LEARN task). We found an increased change of oxygenated and deoxygenated hemoglobin during LEARN covering broad areas over right frontal, central and parietal cortex. Opposed to this, hemoglobin changes were less pronounced for RANDOM and APPLY. Along with the findings that fewer objects were caught during LEARN but stimulus-response mappings were successfully identified, we attribute the higher activations to an increased cognitive load when extracting an unknown mapping. This study therefore demonstrates a neuronal marker of cognitive control during gaming revealed by near-infrared spectroscopy recordings.

  10. Neuronal Correlates of Cognitive Control during Gaming Revealed by Near-Infrared Spectroscopy

    PubMed Central

    Witte, Matthias; Ninaus, Manuel; Kober, Silvia Erika; Neuper, Christa; Wood, Guilherme

    2015-01-01

    In everyday life we quickly build and maintain associations between stimuli and behavioral responses. This is governed by rules of varying complexity and past studies have identified an underlying fronto-parietal network involved in cognitive control processes. However, there is only limited knowledge about the neuronal activations during more natural settings like game playing. We thus assessed whether near-infrared spectroscopy recordings can reflect different demands on cognitive control during a simple game playing task. Sixteen healthy participants had to catch falling objects by pressing computer keys. These objects either fell randomly (RANDOM task), according to a known stimulus-response mapping applied by players (APPLY task) or according to a stimulus-response mapping that had to be learned (LEARN task). We found an increased change of oxygenated and deoxygenated hemoglobin during LEARN covering broad areas over right frontal, central and parietal cortex. Opposed to this, hemoglobin changes were less pronounced for RANDOM and APPLY. Along with the findings that fewer objects were caught during LEARN but stimulus-response mappings were successfully identified, we attribute the higher activations to an increased cognitive load when extracting an unknown mapping. This study therefore demonstrates a neuronal marker of cognitive control during gaming revealed by near-infrared spectroscopy recordings. PMID:26244781

  11. Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets.

    PubMed

    Hong, Weizhe; Kim, Dong-Wook; Anderson, David J

    2014-09-11

    Animals display a range of innate social behaviors that play essential roles in survival and reproduction. While the medial amygdala (MeA) has been implicated in prototypic social behaviors such as aggression, the circuit-level mechanisms controlling such behaviors are not well understood. Using cell-type-specific functional manipulations, we find that distinct neuronal populations in the MeA control different social and asocial behaviors. A GABAergic subpopulation promotes aggression and two other social behaviors, while neighboring glutamatergic neurons promote repetitive self-grooming, an asocial behavior. Moreover, this glutamatergic subpopulation inhibits social interactions independently of its effect to promote self-grooming, while the GABAergic subpopulation inhibits self-grooming, even in a nonsocial context. These data suggest that social versus repetitive asocial behaviors are controlled in an antagonistic manner by inhibitory versus excitatory amygdala subpopulations, respectively. These findings provide a framework for understanding circuit-level mechanisms underlying opponency between innate behaviors, with implications for their perturbation in psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

    PubMed Central

    Pristerà, Alessandro; Lin, Wei; Kaufmann, Anna-Kristin; Brimblecombe, Katherine R.; Threlfell, Sarah; Dodson, Paul D.; Magill, Peter J.; Fernandes, Cathy; Cragg, Stephanie J.; Ang, Siew-Lan

    2015-01-01

    Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by l-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice. PMID:26283356

  13. High precision position control of voice coil motor based on single neuron PID

    NASA Astrophysics Data System (ADS)

    Li, Liyi; Chen, Qiming; Tan, Guangjun; Zhu, He

    2013-01-01

    Voice coil motor(VCM) is widely used in high-speed and high-precision positioning control system in recent years. However, there are system uncertainty, nonlinear, modeling error, and external disturbances in the high-precision positioning control system, traditional PID control method is difficult to achieve precise positioning control. In this paper, a new position control strategy with a single neuron controller which has the capability of self-studying and self-adapting composed with PID controller is put forward, and the feedforward compensator is added to improve the dynamic response of the system in the position loop. Moreover, the disturbance observer is designed to suppress model parameter uncertainty and external disturbance signal in the current loop. In addition, the problem of high precision position control of VCM under the influence of significant disturbances is addressed, which including the gas-lubricated damping, the spring, the back EMF and ripple forces, on the basis, the mathematical model of VCM is established accurately. The simulation results show that this kind of controller can improve the dynamic characteristic and strengthen the robustness of the system, and the current loop with disturbance observer can also restrain disturbance and high frequency.

  14. Euthanasia: the final paradox.

    PubMed

    Ellard, John

    2007-10-01

    The aim of this paper is to consider the history of human beings killing one another and reflect upon their reasons. Has it ever been altruistic? Important examples of large episodes of killing, such as wars, the Crusades, the Inquisition and genocides were examined. Reasons are always advanced for killing large numbers of people who did not want to die. They were not based on logic nor on altruism but on moralities constructed from religious and political beliefs. Those who wanted to die because of unrelievable pain involved in the process of dying from an incurable illness are always preserved against their wishes. Once more, the reasons were usually religious and/or politically supported. The belief that it is acceptable to kill those who do not want to die but unacceptable to kill those who want to die provides a curious paradox.

  15. The lunar apatite paradox.

    PubMed

    Boyce, J W; Tomlinson, S M; McCubbin, F M; Greenwood, J P; Treiman, A H

    2014-04-25

    Recent discoveries of water-rich lunar apatite are more consistent with the hydrous magmas of Earth than the otherwise volatile-depleted rocks of the Moon. Paradoxically, this requires H-rich minerals to form in rocks that are otherwise nearly anhydrous. We modeled existing data from the literature, finding that nominally anhydrous minerals do not sufficiently fractionate H from F and Cl to generate H-rich apatite. Hydrous apatites are explained as the products of apatite-induced low magmatic fluorine, which increases the H/F ratio in melt and apatite. Mare basalts may contain hydrogen-rich apatite, but lunar magmas were most likely poor in hydrogen, in agreement with the volatile depletion that is both observed in lunar rocks and required for canonical giant-impact models of the formation of the Moon.

  16. Paradoxes of neutrino oscillations

    SciTech Connect

    Akhmedov, E. Kh.; Smirnov, A. Yu.

    2009-08-15

    Despite the theory of neutrino oscillations being rather old, some of its basic issues are still being debated in the literature. We discuss a number of such issues, including the relevance of the 'same energy' and 'same momentum' assumptions, the role of quantum-mechanical uncertainty relations in neutrino oscillations, the dependence of the coherence and localization conditions that ensure the observability of neutrino oscillations on neutrino energy and momentum uncertainties, the question of (in)dependence of the oscillation probabilities on the neutrino production and detection processes, and the applicability limits of the stationary-source approximation. We also develop a novel approach to calculation of the oscillation probability in the wave-packet approach, based on the summation/integration conventions different from the standard one, which allows a new insight into the 'same energy' vs. 'same momentum' problem. We also discuss a number of apparently paradoxical features of the theory of neutrino oscillations.

  17. Resveratrol: French Paradox Revisited

    PubMed Central

    Catalgol, Betul; Batirel, Saime; Taga, Yavuz; Ozer, Nesrin Kartal

    2012-01-01

    Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the “French paradox,” which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed. PMID:22822401

  18. Oxygen, a paradoxical element?

    PubMed

    Greabu, Maria; Battino, M; Mohora, Maria; Olinescu, R; Totan, Alexandra; Didilescu, Andreea

    2008-01-01

    Oxygen is an essential element for life on earth. No life may exist without oxygen. But in the last forty years, conclusive evidence demonstrated the double-edge sword of this element. In certain conditions, oxygen may produce reactive species, even free radicals. More, the production of reactive oxygen species (ROS) takes place everywhere: in air, nature or inside human bodies. The paradox of oxygen atom is entirely due to its peculiar electronic structure. But life began on earth, only when nature found efficient weapons against ROS, these antioxidants, which all creatures are extensibly endowed with. The consequences of oxygen activation in human bodies are only partly known, in spite of extensive scientific research on theoretical, experimental and clinical domains.

  19. Peripheral competition in the control of sensory neuron numbers in Xenopus frogs reared with a single bilaterally innervated hindlimb.

    PubMed

    Lamb, A H; Ferns, M J; Klose, K

    1989-01-01

    Sensory neurons were counted in the hind-limb innervating spinal ganglia on both sides of juvenile Xenopus frogs which, as tadpoles, had had one hind limb bud amputated prior to innervation, and a channel made to allow innervation of the remaining limb bud from both sides. The total number of sensory neurons surviving on the two sides approximated the number on one side of normal frogs, the ipsilateral and contralateral numbers being negatively correlated. These effects differ markedly from the effects on motoneuron numbers, suggesting different control mechanisms of cell death in the two neuronal classes.

  20. Reconsideration of the Paradox of Inquiry

    ERIC Educational Resources Information Center

    Sato, Kunimasa

    2014-01-01

    It is well known that the Meno presents the argument called "the paradox of inquiry." This paper has two purposes. First, I analyze the paradox of inquiry and reformulate the argument as the "renewed paradox of inquiry." Second, I clarify that the problem of inquiry posed by this paradox concerns the necessary conditions for a…

  1. Muscarinic Receptor Subtypes Differentially Control Synaptic Input and Excitability of Cerebellum-Projecting Medial Vestibular Nucleus Neurons

    PubMed Central

    Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin

    2016-01-01

    Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it is unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory postsynaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory postsynaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant postsynaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Presynaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. PMID:26823384

  2. Paradoxical communication as interpersonal influence.

    PubMed

    Bogdan, J L

    1982-12-01

    This paper is concerned with the strategic uses of paradoxical communication in therapy. Eight more or less distinct uses of paradoxical communication are described, and the proposition is put forward that the paradoxical interventions associated with the Milan group differ from those described by Haley and the Palo Alto group only in that they appear to be designed to influence simultaneously the behavior of several family members. The currently popular idea that such interventions should, or even can, be based on a systemic hypothesis, if "hypothesis" is understood in its usual sense as a statement amenable to empirical testing, is explicitly questioned.

  3. The Island Wind-Buoyancy Paradox

    NASA Astrophysics Data System (ADS)

    de Boer, A. M.; Nof, D.

    2003-04-01

    In recent years, a variety of studies have suggested that the meridional overturning circulation is at least partially controlled by the Southern Ocean winds. However, the overturning requires transformation of water masses, a process driven by buoyancy fluxes. This seems paradoxical as the wind and buoyancy fluxes are generally thought to be independent. The paradox is resolved qualitatively, using salinity and temperature mixed dynamical-box models, and quantitatively, employing a numerical model. The salinity and temperature box models suggest that stronger southern winds will tend to weaken the vertical and horizontal salinity stratification so that it is easier for the conversion of deep to surface water (and vice versa) to take place. The (process-orientated) reduced-gravity numerical model is adapted to include a thermodynamic parameterization for the surface heat and freshwater fluxes. In response to stronger southern winds, the thermocline thickens in the north, releasing more heat to the atmosphere and, thereby, converting more surface to deep water.

  4. Control of Phasic Firing by a Background Leak Current in Avian Forebrain Auditory Neurons

    PubMed Central

    Dagostin, André A.; Lovell, Peter V.; Hilscher, Markus M.; Mello, Claudio V.; Leão, Ricardo M.

    2015-01-01

    Central neurons express a variety of neuronal types and ion channels that promote firing heterogeneity among their distinct neuronal populations. Action potential (AP) phasic firing, produced by low-threshold voltage-activated potassium currents (VAKCs), is commonly observed in mammalian brainstem neurons involved in the processing of temporal properties of the acoustic information. The avian caudomedial nidopallium (NCM) is an auditory area analogous to portions of the mammalian auditory cortex that is involved in the perceptual discrimination and memorization of birdsong and shows complex responses to auditory stimuli We performed in vitro whole-cell patch-clamp recordings in brain slices from adult zebra finches (Taeniopygia guttata) and observed that half of NCM neurons fire APs phasically in response to membrane depolarizations, while the rest fire transiently or tonically. Phasic neurons fired APs faster and with more temporal precision than tonic and transient neurons. These neurons had similar membrane resting potentials, but phasic neurons had lower membrane input resistance and time constant. Surprisingly phasic neurons did not express low-threshold VAKCs, which curtailed firing in phasic mammalian brainstem neurons, having similar VAKCs to other NCM neurons. The phasic firing was determined not by VAKCs, but by the potassium background leak conductances, which was more prominently expressed in phasic neurons, a result corroborated by pharmacological, dynamic-clamp, and modeling experiments. These results reveal a new role for leak currents in generating firing diversity in central neurons. PMID:26696830

  5. Tectal microcircuit generating visual selection commands on gaze-controlling neurons

    PubMed Central

    Kardamakis, Andreas A.; Saitoh, Kazuya; Grillner, Sten

    2015-01-01

    The optic tectum (called superior colliculus in mammals) is critical for eye–head gaze shifts as we navigate in the terrain and need to adapt our movements to the visual scene. The neuronal mechanisms underlying the tectal contribution to stimulus selection and gaze reorientation remains, however, unclear at the microcircuit level. To analyze this complex—yet phylogenetically conserved—sensorimotor system, we developed a novel in vitro preparation in the lamprey that maintains the eye and midbrain intact and allows for whole-cell recordings from prelabeled tectal gaze-controlling cells in the deep layer, while visual stimuli are delivered. We found that receptive field activation of these cells provide monosynaptic retinal excitation followed by local GABAergic inhibition (feedforward). The entire remaining retina, on the other hand, elicits only inhibition (surround inhibition). If two stimuli are delivered simultaneously, one inside and one outside the receptive field, the former excitatory response is suppressed. When local inhibition is pharmacologically blocked, the suppression induced by competing stimuli is canceled. We suggest that this rivalry between visual areas across the tectal map is triggered through long-range inhibitory tectal connections. Selection commands conveyed via gaze-controlling neurons in the optic tectum are, thus, formed through synaptic integration of local retinotopic excitation and global tectal inhibition. We anticipate that this mechanism not only exists in lamprey but is also conserved throughout vertebrate evolution. PMID:25825743

  6. Controlled and Impaired Mitochondrial Quality in Neurons: Molecular Physiology and Prospective Pharmacology.

    PubMed

    Matic, Ivana; Strobbe, Daniela; Frison, Michele; Campanella, Michelangelo

    2015-09-01

    Tuned mitochondrial physiology is fundamental for qualitative cellular function. This is particularly relevant for neurons, whose pathology is frequently associated with mitochondrial deficiencies. Defects in mitochondria are indeed key features in most neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). When mitochondrial coupling impairs, so does cell metabolism, trafficking and the signaling depending on the homeostasis of the mitochondrial network. Moreover, the quality control of mitochondria - via the process of mitochondrial autophagy - results biased in neurodegeneration stemming major interest on the molecular determinants of this process among neuroscientists. In this review, we highlight the most notable and acknowledged deficiencies of mitochondrial function and their relationship with diseases occurring in neurons and their transmission. The physiological aspects of mitochondrial biology in relation to bio-energy, dynamics and quality control will be discussed with the finality to form a comprehensive picture of the mitochondrial contribution to the pathophysiology of neurodegenerative syndromes. In this way we aim to set the scene to conceive novel strategies to better diagnose and target these debilitative conditions.

  7. AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons.

    PubMed

    Amadoro, G; Corsetti, V; Florenzano, F; Atlante, A; Ciotti, M T; Mongiardi, M P; Bussani, R; Nicolin, V; Nori, S L; Campanella, M; Calissano, P

    2014-02-01

    Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20-22kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau -but not the physiological full-length protein- interacts with Aβ at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clearance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin-mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autophagic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles. © 2013.

  8. Antecedent glycemic control reduces severe hypoglycemia-induced neuronal damage in diabetic rats.

    PubMed

    Reno, Candace M; Tanoli, Tariq; Bree, Adam; Daphna-Iken, Dorit; Cui, Chen; Maloney, Susan E; Wozniak, David F; Fisher, Simon J

    2013-06-15

    Brain damage due to severe hypoglycemia occurs in insulin-treated people with diabetes. This study tests the hypothesis that chronic insulin therapy that normalizes elevated blood glucose in diabetic rats would be neuroprotective against brain damage induced by an acute episode of severe hypoglycemia. Male Sprague-Dawley rats were split into three groups: 1) control, non-diabetic; 2) STZ-diabetic; and 3) insulin-treated STZ-diabetic. After 3 wk of chronic treatment, unrestrained awake rats underwent acute hyperinsulinemic severe hypoglycemic (10-15 mg/dl) clamps for 1 h. Rats were subsequently analyzed for brain damage and cognitive function. Severe hypoglycemia induced 15-fold more neuronal damage in STZ-diabetic rats compared with nondiabetic rats. Chronic insulin treatment of diabetic rats, which nearly normalized glucose levels, markedly reduced neuronal damage induced by severe hypoglycemia. Fortunately, no cognitive defects associated with the hypoglycemia-induced brain damage were observed in any group. In conclusion, antecedent blood glucose control represents a major modifiable therapeutic intervention that can afford diabetic subjects neuroprotection against severe hypoglycemia-induced brain damage.

  9. The Fermi Paradox Is Neither Fermi's Nor a Paradox

    NASA Astrophysics Data System (ADS)

    Gray, Robert H.

    2015-03-01

    The so-called Fermi paradox claims that if technological life existed anywhere else, we would see evidence of its visits to Earth-and since we do not, such life does not exist, or some special explanation is needed. Enrico Fermi, however, never published anything on this topic. On the one occasion he is known to have mentioned it, he asked 'where is everybody?'- apparently suggesting that we don't see extraterrestrials on Earth because interstellar travel may not be feasible, but not suggesting that intelligent extraterrestrial life does not exist, or suggesting its absence is paradoxical. The claim 'they are not here; therefore they do not exist' was first published by Michael Hart, claiming that interstellar travel and colonization of the galaxy would be inevitable if intelligent extraterrestrial life existed, and taking its absence here as proof that it does not exist anywhere. The Fermi paradox appears to originate in Hart's argument, not Fermi's question. Clarifying the origin of these ideas is important, because the Fermi paradox is seen by some as an authoritative objection to searching for evidence of extraterrestrial intelligence-cited in the U. S. Congress as a reason for killing NASA's SETI program on one occasion-but evidence indicates that it misrepresents Fermi's views, misappropriates his authority, deprives the actual authors of credit, and is not a valid paradox. Keywords: Astrobiology, SETI, Fermi paradox, extraterrestrial life

  10. Deciphering the Neuronal Circuitry Controlling Local Blood Flow in the Cerebral Cortex with Optogenetics in PV::Cre Transgenic Mice

    PubMed Central

    Urban, Alan; Rancillac, Armelle; Martinez, Lucie; Rossier, Jean

    2012-01-01

    Although it is know since more than a century that neuronal activity is coupled to blood supply regulation, the underlying pathways remains to be identified. In the brain, neuronal activation triggers a local increase of cerebral blood flow (CBF) that is controlled by the neurogliovascular unit composed of terminals of neurons, astrocytes, and blood vessel muscles. It is generally accepted that the regulation of the neurogliovascular unit is adjusted to local metabolic demand by local circuits. Today experimental data led us to realize that the regulatory mechanisms are more complex and that a neuronal system within the brain is devoted to the control of local brain-blood flow. Recent optogenetic experiments combined with functional magnetic resonance imaging have revealed that light stimulation of neurons expressing the calcium binding protein parvalbumin (PV) is associated with positive blood oxygen level-dependent (BOLD) signal in the corresponding barrel field but also with negative BOLD in the surrounding deeper area. Here, we demonstrate that in acute brain slices, channelrhodopsin-2 (ChR2) based photostimulation of PV containing neurons gives rise to an effective contraction of penetrating arterioles. These results support the neurogenic hypothesis of a complex distributed nervous system controlling the CBF. PMID:22715327

  11. Striatopallidal Neuron NMDA Receptors Control Synaptic Connectivity, Locomotor, and Goal-Directed Behaviors

    PubMed Central

    Lambot, Laurie; Chaves Rodriguez, Elena; Houtteman, Delphine; Li, Yuquing; Schiffmann, Serge N.; Gall, David

    2016-01-01

    The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goal-directed learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected. SIGNIFICANCE STATEMENT The striatum controls habits, locomotion, and goal-directed behaviors by coordinated activation of two antagonistic pathways. Insofar as NMDA receptors (NMDA-Rs) play a key role in synaptic

  12. Autonomic control network active in Aplysia during locomotion includes neurons that express splice variants of R15-neuropeptides.

    PubMed

    Romanova, Elena V; McKay, Natasha; Weiss, Klaudiusz R; Sweedler, Jonathan V; Koester, John

    2007-01-01

    Splice-variant products of the R15 neuropeptide gene are differentially expressed within the CNS of Aplysia. The goal of this study was to test whether the neurons in the abdominal ganglion that express the peptides encoded by this gene are part of a common circuit. Expression of R15 peptides had been demonstrated previously in neuron R15. Using a combination of immunocytochemical and analytical methods, this study demonstrated that R15 peptides are also expressed in heart exciter neuron RB(HE), the two L9(G) gill motoneurons, and L40--a newly identified interneuron. Mass spectrometric profiling of individual neurons that exhibit R15 peptide-like immunoreactivity confirmed the mutually exclusive expression of two splice-variant forms of R15 peptides in different neurons. The L9(G) cells were found to co-express pedal peptide in addition to the R15 peptides. The R15 peptide-expressing neurons examined here were shown to be part of an autonomic control circuit that is active during fictive locomotion. Activity in this circuit contributes to implementing a central command that may help to coordinate autonomic activity with escape locomotion. Chronic extracellular nerve recording was used to determine the activity patterns of a subset of neurons of this circuit in vivo. These results demonstrate the potential utility of using shared patterns of neuropeptide expression as a guide for neural circuit identification.

  13. Leptin Activates Oxytocin Neurons of the Hypothalamic Paraventricular Nucleus in Both Control and Diet-Induced Obese Rodents

    PubMed Central

    Perello, Mario; Raingo, Jesica

    2013-01-01

    The adipocyte-derived hormone leptin acts in the brain to reduce body weight and fat mass. Recent studies suggest that parvocellular oxytocin (OXT) neurons of the hypothalamic paraventricular nucleus (PVN) can mediate body weight reduction through inhibition of food intake and increased energy expenditure. However, the role of OXT neurons of the PVN as a primary target of leptin has not been investigated. Here, we studied the potential role of OXT neurons of the PVN in leptin-mediated effects on body weight regulation in fasted rats. We demonstrated that intracerebroventricular (ICV) leptin activates STAT3 phosphorylation in OXT neurons of the PVN, showed that this occurs in a subpopulation of OXT neurons that innervate the nucleus of the solitary tract (NTS), and provided further evidence suggesting a role of OXT to mediate leptin’s actions on body weight. In addition, our results indicated that OXT neurons are responsive to ICV leptin and mediate leptin effects on body weight in diet induced obese (DIO) rats, which are resistant to the anorectic effects of the hormone. Thus, we conclude that leptin targets a specific subpopulation of parvocellular OXT neurons of the PVN, and that this action may be important for leptin’s ability to reduce body weight in both control and obese rats. PMID:23527232

  14. Explaining the harmonic sequence paradox.

    PubMed

    Schmidt, Ulrich; Zimper, Alexander

    2012-05-01

    According to the harmonic sequence paradox, an expected utility decision maker's willingness to pay for a gamble whose expected payoffs evolve according to the harmonic series is finite if and only if his marginal utility of additional income becomes zero for rather low payoff levels. Since the assumption of zero marginal utility is implausible for finite payoff levels, expected utility theory - as well as its standard generalizations such as cumulative prospect theory - are apparently unable to explain a finite willingness to pay. This paper presents first an experimental study of the harmonic sequence paradox. Additionally, it demonstrates that the theoretical argument of the harmonic sequence paradox only applies to time-patient decision makers, whereas the paradox is easily avoided if time-impatience is introduced.

  15. A Codimension-2 Bifurcation Controlling Endogenous Bursting Activity and Pulse-Triggered Responses of a Neuron Model

    PubMed Central

    Barnett, William H.; Cymbalyuk, Gennady S.

    2014-01-01

    The dynamics of individual neurons are crucial for producing functional activity in neuronal networks. An open question is how temporal characteristics can be controlled in bursting activity and in transient neuronal responses to synaptic input. Bifurcation theory provides a framework to discover generic mechanisms addressing this question. We present a family of mechanisms organized around a global codimension-2 bifurcation. The cornerstone bifurcation is located at the intersection of the border between bursting and spiking and the border between bursting and silence. These borders correspond to the blue sky catastrophe bifurcation and the saddle-node bifurcation on an invariant circle (SNIC) curves, respectively. The cornerstone bifurcation satisfies the conditions for both the blue sky catastrophe and SNIC. The burst duration and interburst interval increase as the inverse of the square root of the difference between the corresponding bifurcation parameter and its bifurcation value. For a given set of burst duration and interburst interval, one can find the parameter values supporting these temporal characteristics. The cornerstone bifurcation also determines the responses of silent and spiking neurons. In a silent neuron with parameters close to the SNIC, a pulse of current triggers a single burst. In a spiking neuron with parameters close to the blue sky catastrophe, a pulse of current temporarily silences the neuron. These responses are stereotypical: the durations of the transient intervals–the duration of the burst and the duration of latency to spiking–are governed by the inverse-square-root laws. The mechanisms described here could be used to coordinate neuromuscular control in central pattern generators. As proof of principle, we construct small networks that control metachronal-wave motor pattern exhibited in locomotion. This pattern is determined by the phase relations of bursting neurons in a simple central pattern generator modeled by a chain of

  16. Multiple Notch signaling events control Drosophila CNS midline neurogenesis, gliogenesis and neuronal identity

    PubMed Central

    Wheeler, Scott R.; Stagg, Stephanie B.; Crews, Stephen T.

    2009-01-01

    The study of how transcriptional control and cell signaling influence neurons and glia to acquire their differentiated properties is fundamental to understanding CNS development and function. The Drosophila CNS midline cells are an excellent system for studying these issues because they consist of a small population of diverse cells with well-defined gene expression profiles. In this paper, the origins and differentiation of midline neurons and glia were analyzed. Midline precursor (MP) cells each divide once giving rise to two neurons; here, we use a combination of single-cell gene expression mapping and time-lapse imaging to identify individual MPs, their locations, movements and stereotyped patterns of division. The role of Notch signaling was investigated by analyzing 37 midline-expressed genes in Notch pathway mutant and misexpression embryos. Notch signaling had opposing functions: it inhibited neurogenesis in MP1,3,4 and promoted neurogenesis in MP5,6. Notch signaling also promoted midline glial and median neuroblast cell fate. This latter result suggests that the median neuroblast resembles brain neuroblasts that require Notch signaling, rather than nerve cord neuroblasts, the formation of which is inhibited by Notch signaling. Asymmetric MP daughter cell fates also depend on Notch signaling. One member of each pair of MP3–6 daughter cells was responsive to Notch signaling. By contrast, the other daughter cell asymmetrically acquired Numb, which inhibited Notch signaling, leading to a different fate choice. In summary, this paper describes the formation and division of MPs and multiple roles for Notch signaling in midline cell development, providing a foundation for comprehensive molecular analyses. PMID:18701546

  17. Muscarinic receptor subtypes differentially control synaptic input and excitability of cerebellum-projecting medial vestibular nucleus neurons.

    PubMed

    Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin

    2016-04-01

    Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it remains unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory post-synaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory post-synaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant post-synaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Pre-synaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. Medial vestibular nucleus (MVN) neurons projecting to the cerebellum are involved in balance control. We

  18. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

    PubMed Central

    Dragicevic, Elena; Poetschke, Christina; Duda, Johanna; Schlaudraff, Falk; Lammel, Stephan; Schiemann, Julia; Fauler, Michael; Hetzel, Andrea; Watanabe, Masahiko; Lujan, Rafael; Malenka, Robert C.; Striessnig, Joerg

    2014-01-01

    Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson’s disease. Their selective loss causes the major motor symptoms of Parkinson’s disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson’s disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ channel blockers protect SN DA neurons from degeneration in Parkinson’s disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson’s disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson’s disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson’s disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson’s disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological

  19. The Statistical Fermi Paradox

    NASA Astrophysics Data System (ADS)

    Maccone, C.

    In this paper is provided the statistical generalization of the Fermi paradox. The statistics of habitable planets may be based on a set of ten (and possibly more) astrobiological requirements first pointed out by Stephen H. Dole in his book Habitable planets for man (1964). The statistical generalization of the original and by now too simplistic Dole equation is provided by replacing a product of ten positive numbers by the product of ten positive random variables. This is denoted the SEH, an acronym standing for “Statistical Equation for Habitables”. The proof in this paper is based on the Central Limit Theorem (CLT) of Statistics, stating that the sum of any number of independent random variables, each of which may be ARBITRARILY distributed, approaches a Gaussian (i.e. normal) random variable (Lyapunov form of the CLT). It is then shown that: 1. The new random variable NHab, yielding the number of habitables (i.e. habitable planets) in the Galaxy, follows the log- normal distribution. By construction, the mean value of this log-normal distribution is the total number of habitable planets as given by the statistical Dole equation. 2. The ten (or more) astrobiological factors are now positive random variables. The probability distribution of each random variable may be arbitrary. The CLT in the so-called Lyapunov or Lindeberg forms (that both do not assume the factors to be identically distributed) allows for that. In other words, the CLT "translates" into the SEH by allowing an arbitrary probability distribution for each factor. This is both astrobiologically realistic and useful for any further investigations. 3. By applying the SEH it is shown that the (average) distance between any two nearby habitable planets in the Galaxy may be shown to be inversely proportional to the cubic root of NHab. This distance is denoted by new random variable D. The relevant probability density function is derived, which was named the "Maccone distribution" by Paul Davies in

  20. The abortion paradox.

    PubMed

    Bergin, J D

    1983-10-12

    of what has changed to make induced abortions increase markedly in Wellington and in the country. The 1st paradox of abortion is that the more science, the more technical advance, the more clinical skills, yet more induced abortions. There are other paradoxical aspects like the continued surfacing of mental health as a reason for induced abortion when so much psychiatric literature indicates that there are no neurotic or psychotic conditions for which abortion is beneficial. Whether or not the law has been subject to abuse, there has been a change in the handling of abortion by doctors.

  1. [Single and Network Neuron Activity of Subthalamic Nucleus at Impulsive and Delayed (Self-Control) Reactions in Choice Behavior].

    PubMed

    Sidorina, V V; Gerasimova, Yu A; Kuleshova, E P; Merzhanova, G Kh

    2015-01-01

    During our experiments on cats was investigated the subthalamic neuron activity at different types of behavior in case of reinforcement choice depending on its value and availability. In chronic experiences the multiunit activity in subthalamic nucleus (STN) and orbitofrontal cortex (FC) has been recorded. Multiunit activity was analyzed over frequency and network properties of spikes. It was shown, that STN neurons reaction to different reinforcements and conditional stimulus at short- or long-delay reactions was represented by increasing or decreasing of frequency of single neurons. However the same STN neu- rons responded with increasing of frequency of single neuron during expectation of mix-bread-meat and decreasing--during the meat expectation. It has been revealed, that the number of STN interneuron interactions was authentic more at impulsive behavior than at self-control choice of behavior. The number of interactions between FC and STN neurons within intervals of 0-30 Ms was authentic more at display impulsive than during self-control behavior. These results suppose that FC and STN neurons participate in integration of reinforcement estimation; and distinctions in a choice of behavior are defined by the local and distributed interneuron interactions of STN and FC.

  2. Sexually dimorphic control of gene expression in sensory neurons regulates decision-making behavior in C. elegans.

    PubMed

    Hilbert, Zoë A; Kim, Dennis H

    2017-01-24

    Animal behavior is directed by the integration of sensory information from internal states and the environment. Neuroendocrine regulation of diverse behaviors of Caenorhabditis elegans is under the control of the DAF-7/TGF-β ligand that is secreted from sensory neurons. Here, we show that C. elegans males exhibit an altered, male-specific expression pattern of daf-7 in the ASJ sensory neuron pair with the onset of reproductive maturity, which functions to promote male-specific mate-searching behavior. Molecular genetic analysis of the switch-like regulation of daf-7 expression in the ASJ neuron pair reveals a hierarchy of regulation among multiple inputs-sex, age, nutritional status, and microbial environment-which function in the modulation of behavior. Our results suggest that regulation of gene expression in sensory neurons can function in the integration of a wide array of sensory information and facilitate decision-making behaviors in C. elegans.

  3. Optimal control of directional deep brain stimulation in the parkinsonian neuronal network

    NASA Astrophysics Data System (ADS)

    Fan, Denggui; Wang, Zhihui; Wang, Qingyun

    2016-07-01

    The effect of conventional deep brain stimulation (DBS) on debilitating symptoms of Parkinson's disease can be limited because it can only yield the spherical field. And, some side effects are clearly induced with influencing their adjacent ganglia. Recent experimental evidence for patients with Parkinson's disease has shown that a novel DBS electrode with 32 independent stimulation source contacts can effectively optimize the clinical therapy by enlarging the therapeutic windows, when it is applied on the subthalamic nucleus (STN). This is due to the selective activation in clusters of various stimulation contacts which can be steered directionally and accurately on the targeted regions of interest. In addition, because of the serious damage to the neural tissues, the charge-unbalanced stimulation is not typically indicated and the real DBS utilizes charge-balanced bi-phasic (CBBP) pulses. Inspired by this, we computationally investigate the optimal control of directional CBBP-DBS from the proposed parkinsonian neuronal network of basal ganglia-thalamocortical circuit. By appropriately tuning stimulation for different neuronal populations, it can be found that directional steering CBBP-DBS paradigms are superior to the spherical case in improving parkinsonian dynamical properties including the synchronization of neuronal populations and the reliability of thalamus relaying the information from cortex, which is in a good agreement with the physiological experiments. Furthermore, it can be found that directional steering stimulations can increase the optimal stimulation intensity of desynchronization by more than 1 mA compared to the spherical case. This is consistent with the experimental result with showing that there exists at least one steering direction that can allow increasing the threshold of side effects by 1 mA. In addition, we also simulate the local field potential (LFP) and dominant frequency (DF) of the STN neuronal population induced by the activation

  4. Enjoying Sad Music: Paradox or Parallel Processes?

    PubMed Central

    Schubert, Emery

    2016-01-01

    Enjoyment of negative emotions in music is seen by many as a paradox. This article argues that the paradox exists because it is difficult to view the process that generates enjoyment as being part of the same system that also generates the subjective negative feeling. Compensation theories explain the paradox as the compensation of a negative emotion by the concomitant presence of one or more positive emotions. But compensation brings us no closer to explaining the paradox because it does not explain how experiencing sadness itself is enjoyed. The solution proposed is that an emotion is determined by three critical processes—labeled motivational action tendency (MAT), subjective feeling (SF) and Appraisal. For many emotions the MAT and SF processes are coupled in valence. For example, happiness has positive MAT and positive SF, annoyance has negative MAT and negative SF. However, it is argued that in an aesthetic context, such as listening to music, emotion processes can become decoupled. The decoupling is controlled by the Appraisal process, which can assess if the context of the sadness is real-life (where coupling occurs) or aesthetic (where decoupling can occur). In an aesthetic context sadness retains its negative SF but the aversive, negative MAT is inhibited, leaving sadness to still be experienced as a negative valanced emotion, while contributing to the overall positive MAT. Individual differences, mood and previous experiences mediate the degree to which the aversive aspects of MAT are inhibited according to this Parallel Processing Hypothesis (PPH). The reason for hesitancy in considering or testing PPH, as well as the preponderance of research on sadness at the exclusion of other negative emotions, are discussed. PMID:27445752

  5. Enjoying Sad Music: Paradox or Parallel Processes?

    PubMed

    Schubert, Emery

    2016-01-01

    Enjoyment of negative emotions in music is seen by many as a paradox. This article argues that the paradox exists because it is difficult to view the process that generates enjoyment as being part of the same system that also generates the subjective negative feeling. Compensation theories explain the paradox as the compensation of a negative emotion by the concomitant presence of one or more positive emotions. But compensation brings us no closer to explaining the paradox because it does not explain how experiencing sadness itself is enjoyed. The solution proposed is that an emotion is determined by three critical processes-labeled motivational action tendency (MAT), subjective feeling (SF) and Appraisal. For many emotions the MAT and SF processes are coupled in valence. For example, happiness has positive MAT and positive SF, annoyance has negative MAT and negative SF. However, it is argued that in an aesthetic context, such as listening to music, emotion processes can become decoupled. The decoupling is controlled by the Appraisal process, which can assess if the context of the sadness is real-life (where coupling occurs) or aesthetic (where decoupling can occur). In an aesthetic context sadness retains its negative SF but the aversive, negative MAT is inhibited, leaving sadness to still be experienced as a negative valanced emotion, while contributing to the overall positive MAT. Individual differences, mood and previous experiences mediate the degree to which the aversive aspects of MAT are inhibited according to this Parallel Processing Hypothesis (PPH). The reason for hesitancy in considering or testing PPH, as well as the preponderance of research on sadness at the exclusion of other negative emotions, are discussed.

  6. Lin28a regulates neuronal differentiation and controls miR-9 production

    PubMed Central

    Nowak, Jakub S.; Choudhury, Nila Roy; de Lima Alves, Flavia; Rappsilber, Juri; Michlewski, Gracjan

    2014-01-01

    microRNAs shape the identity and function of cells by regulating gene expression. It is known that brain-specific miR-9 is controlled transcriptionally; however, it is unknown whether post-transcriptional processes contribute to establishing its levels. Here, we show that miR-9 is regulated transcriptionally and post-transcriptionally during neuronal differentiation of the embryonic carcinoma cell line P19. We demonstrate that miR-9 is more efficiently processed in differentiated than undifferentiated cells. We reveal that Lin28a affects miR-9 by inducing the degradation of its precursor through a uridylation-independent mechanism. Furthermore, we show that constitutively expressed untagged but not GFP-tagged Lin28a decreases differentiation capacity of P19 cells, which coincides with reduced miR-9 levels. Finally, using an inducible system we demonstrate that Lin28a can also reduce miR-9 levels in differentiated P19 cells. Together, our results shed light on the role of Lin28a in neuronal differentiation and increase our understanding of the mechanisms regulating the level of brain-specific microRNAs. PMID:24722317

  7. Lin28a regulates neuronal differentiation and controls miR-9 production.

    PubMed

    Nowak, Jakub S; Choudhury, Nila Roy; de Lima Alves, Flavia; Rappsilber, Juri; Michlewski, Gracjan

    2014-04-11

    microRNAs shape the identity and function of cells by regulating gene expression. It is known that brain-specific miR-9 is controlled transcriptionally; however, it is unknown whether post-transcriptional processes contribute to establishing its levels. Here we show that miR-9 is regulated transcriptionally and post-transcriptionally during neuronal differentiation of the embryonic carcinoma cell line P19. We demonstrate that miR-9 is more efficiently processed in differentiated than in undifferentiated cells. We reveal that Lin28a affects miR-9 by inducing the degradation of its precursor through a uridylation-independent mechanism. Furthermore, we show that constitutively expressed untagged but not GFP-tagged Lin28a decreases differentiation capacity of P19 cells, which coincides with reduced miR-9 levels. Finally, using an inducible system we demonstrate that Lin28a can also reduce miR-9 levels in differentiated P19 cells. Together, our results shed light on the role of Lin28a in neuronal differentiation and increase our understanding of the mechanisms regulating the level of brain-specific microRNAs.

  8. Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons

    PubMed Central

    Sandberg, Magnus; Flandin, Pierre; Silberberg, Shanni; Su-Feher, Linda; Price, James D.; Hu, Jia Sheng; Kim, Carol; Visel, Axel; Nord, Alex S.; Rubenstein, John L.R.

    2017-01-01

    SUMMARY The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, NKX2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub-ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants. PMID:27657450

  9. Neuronal GPCR OCTR-1 regulates innate immunity by controlling protein synthesis in Caenorhabditis elegans

    PubMed Central

    Liu, Yiyong; Sellegounder, Durai; Sun, Jingru

    2016-01-01

    Upon pathogen infection, microbial killing pathways and cellular stress pathways are rapidly activated by the host innate immune system. These pathways must be tightly regulated because insufficient or excessive immune responses have deleterious consequences. Increasing evidence indicates that the nervous system regulates the immune system to confer coordinated protection to the host. However, the precise mechanisms of neural-immune communication remain unclear. Previously we have demonstrated that OCTR-1, a neuronal G protein-coupled receptor, functions in the sensory neurons ASH and ASI to suppress innate immune responses in non-neural tissues against Pseudomonas aeruginosa in Caenorhabditis elegans. In the current study, by using a mass spectrometry-based quantitative proteomics approach, we discovered that OCTR-1 regulates innate immunity by suppressing translation and the unfolded protein response (UPR) pathways at the protein level. Functional assays revealed that OCTR-1 inhibits specific protein synthesis factors such as ribosomal protein RPS-1 and translation initiation factor EIF-3.J to reduce infection-triggered protein synthesis and UPR. Translational inhibition by chemicals abolishes the OCTR-1-controlled innate immune responses, indicating that activation of the OCTR-1 pathway is dependent on translation upregulation such as that induced by pathogen infection. Because OCTR-1 downregulates protein translation activities, the OCTR-1 pathway could function to suppress excessive responses to infection or to restore protein homeostasis after infection. PMID:27833098

  10. Ongoing Spontaneous Activity Controls Access to Consciousness: A Neuronal Model for Inattentional Blindness

    PubMed Central

    Changeux, Jean-Pierre

    2005-01-01

    Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden “ignition” of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of “inattentional blindness,” in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness. PMID:15819609

  11. Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons.

    PubMed

    Sandberg, Magnus; Flandin, Pierre; Silberberg, Shanni; Su-Feher, Linda; Price, James D; Hu, Jia Sheng; Kim, Carol; Visel, Axel; Nord, Alex S; Rubenstein, John L R

    2016-09-21

    The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, NKX2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub-ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.

  12. SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease.

    PubMed

    Li, Darrick K; Tisdale, Sarah; Lotti, Francesco; Pellizzoni, Livio

    2014-08-01

    At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Ongoing spontaneous activity controls access to consciousness: a neuronal model for inattentional blindness.

    PubMed

    Dehaene, Stanislas; Changeux, Jean-Pierre

    2005-05-01

    Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden "ignition" of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of "inattentional blindness," in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness.

  14. A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease.

    PubMed

    Villaescusa, J Carlos; Li, Bingsi; Toledo, Enrique M; Rivetti di Val Cervo, Pia; Yang, Shanzheng; Stott, Simon Rw; Kaiser, Karol; Islam, Saiful; Gyllborg, Daniel; Laguna-Goya, Rocio; Landreh, Michael; Lönnerberg, Peter; Falk, Anna; Bergman, Tomas; Barker, Roger A; Linnarsson, Sten; Selleri, Licia; Arenas, Ernest

    2016-09-15

    Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.

  15. The obesity paradox: is it really a paradox? Hypertension.

    PubMed

    Lechi, Alessandro

    2017-03-01

    This article is a narrative overview of the role of hypertension on the relationships between obesity, morbidity, and mortality. We used as sources MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library, from inception to March 2016. Key words include overweight, obesity, visceral obesity, obesity paradox, and hypertension. In addition, we hand-searched references from the retrieved articles. This work is one of the works of the topical collection "Obesity Paradox". The positive association between overweight, obesity, and cardiovascular diseases is well established, though this relation is typically U shaped with an increased risk in low-weight subjects or even a beneficial effect of overweight and obesity, the so-called "obesity paradox". In addition, the relationship between obesity and arterial hypertension has been demonstrated in both children and adults by many epidemiological studies. Moreover, weight reduction is followed by a decrease in blood pressure in many patients and ameliorates the cardiovascular risk profile. Recent studies using more appropriate obesity indices raise some doubt about the real significance of obesity paradox and there are several studies that central obesity shows either no protective or even a worse effect. These observations raise the question: what kind of obesity is protective and what kind of obesity is harmful? The studies of obesity paradox suffer from several methodological limitations: most of these are retrospective analyses or were not specifically designed to study obesity paradox as a primary goal; a few studies have data on preceding unintentional weight loss and on some particular confounding variables. In conclusion, more prospective and accurate studies are necessary to better elucidate the clinical importance of obesity paradox. When weight loss is functional to reduce hypertension and cardiovascular risk, it should be encouraged, while an unintentional weight in a patient with chronic diseases may indicate an

  16. The Bicyclist's Paradox

    NASA Astrophysics Data System (ADS)

    Knight, Randy

    2008-05-01

    It's a situation every avid cyclist knows only too well. If you cycle up a hill and then back down with no net change in elevation, it seems as if your slower uphill speed and faster downhill speed should offset each other. But they don't. Your average speed is less than it would have been had you cycled the same distance on a level road. Similarly, cycling into a headwind for half your trip and returning home with a tailwind yields an average speed less than you would have achieved on a windless day. The faster part of the ride doesn't compensate for the slower part. It seems unjust. Most cyclists expect the uphill and downhill, or the headwind and tailwind, to more or less cancel and are surprised (and frustrated!) when they don't. The purpose of this paper is to resolve this paradox. Doing so involves some nice real-world applications of Newton's laws, numerical problem solving, and exercise physiology. There's a lot to learn from analyzing this problem, and it's readily accessible to introductory physics students.

  17. Cannabis and sex: multifaceted paradoxes.

    PubMed

    Cohen, S

    1982-01-01

    At the present level of ignorance about sexuality and cannabis, what rational position can be adopted? First, it must be recognized that even without cannabis, current involvement in sex-related activities may well have been called "promiscuous" by a preceding generation or two. The general loosening of morality, the erosion of family, church and other authoritarian controls, The Pill, antibiotics and other recent developments have contributed to current casual attitudes. Although one may not perceive it, counterculture beliefs have had their impact on the dominant culture. Marijuana has some enhancing effect upon sexual proceedings for some individuals. It may be sexually evocative and gratifying. Nonspecific factors play an important role in this matter. Opposite effects also occur, and an endocrinologic basis for actual diminution of drives and potency may exist. The final paradox is that cannabis' employment for sexual arousal is predominantly an activity of young adults. The older age groups most in need of sexual support and assistance are less frequently involved in its use. It is unclear why this dichotomy between need and utilization exists.

  18. Control of dendritic field formation in Drosophila: the roles of flamingo and competition between homologous neurons.

    PubMed

    Gao, F B; Kohwi, M; Brenman, J E; Jan, L Y; Jan, Y N

    2000-10-01

    Neurons elaborate dendrites with stereotypic branching patterns, thereby defining their receptive fields. These branching patterns may arise from properties intrinsic to the neurons or competition between neighboring neurons. Genetic and laser ablation studies reported here reveal that different multiple dendritic neurons in the same dorsal cluster in the Drosophila embryonic PNS do not compete with one another for dendritic fields. In contrast, when dendrites from homologous neurons in the two hemisegments meet at the dorsal midline in larval stages, they appear to repel each other. The formation of normal dendritic fields and the competition between dendrites of homologous neurons require the proper expression level of Flamingo, a G protein-coupled receptor-like protein, in embryonic neurons. Whereas Flamingo functions downstream of Frizzled in specifying planar polarity, Flamingo-dependent dendritic outgrowth is independent of Frizzled.

  19. The fermi paradox is neither Fermi's nor a paradox.

    PubMed

    Gray, Robert H

    2015-03-01

    The so-called Fermi paradox claims that if technological life existed anywhere else, we would see evidence of its visits to Earth--and since we do not, such life does not exist, or some special explanation is needed. Enrico Fermi, however, never published anything on this topic. On the one occasion he is known to have mentioned it, he asked "Where is everybody?"--apparently suggesting that we do not see extraterrestrials on Earth because interstellar travel may not be feasible, but not suggesting that intelligent extraterrestrial life does not exist or suggesting its absence is paradoxical. The claim "they are not here; therefore they do not exist" was first published by Michael Hart, claiming that interstellar travel and colonization of the Galaxy would be inevitable if intelligent extraterrestrial life existed, and taking its absence here as proof that it does not exist anywhere. The Fermi paradox appears to originate in Hart's argument, not Fermi's question. Clarifying the origin of these ideas is important, because the Fermi paradox is seen by some as an authoritative objection to searching for evidence of extraterrestrial intelligence--cited in the U.S. Congress as a reason for killing NASA's SETI program on one occasion. But evidence indicates that it misrepresents Fermi's views, misappropriates his authority, deprives the actual authors of credit, and is not a valid paradox.

  20. Temperature sensing by an olfactory neuron in a circuit controlling behavior of C. elegans.

    PubMed

    Kuhara, Atsushi; Okumura, Masatoshi; Kimata, Tsubasa; Tanizawa, Yoshinori; Takano, Ryo; Kimura, Koutarou D; Inada, Hitoshi; Matsumoto, Kunihiro; Mori, Ikue

    2008-05-09

    Temperature is an unavoidable environmental cue that affects the metabolism and behavior of any creature on Earth, yet how animals perceive temperature is poorly understood. The nematode Caenorhabditis elegans "memorizes" temperatures, and this stored information modifies its subsequent migration along a temperature gradient. We show that the olfactory neuron designated AWC senses temperature. Calcium imaging revealed that AWC responds to temperature changes and that response thresholds differ depending on the temperature to which the animal was previously exposed. In the mutant with impaired heterotrimeric guanine nucleotide-binding protein (G protein)-mediated signaling, AWC was hyperresponsive to temperature, whereas the AIY interneuron (which is postsynaptic to AWC) was hyporesponsive to temperature. Thus, temperature sensation exhibits a robust influence on a neural circuit controlling a memory-regulated behavior.

  1. Cannabinoid type 1 receptors located on single-minded 1-expressing neurons control emotional behaviors.

    PubMed

    Dubreucq, S; Kambire, S; Conforzi, M; Metna-Laurent, M; Cannich, A; Soria-Gomez, E; Richard, E; Marsicano, G; Chaouloff, F

    2012-03-01

    This study has investigated the role of hypothalamic and amygdalar type-1 cannabinoid (CB1) receptors in the emotional and neuroendocrine responses to stress. To do so, we used the Cre/loxP system to generate conditional mutant mice lacking the CB1 gene in neurons expressing the transcription factor single-minded 1 (Sim1). This choice was dictated by former evidence for Sim1-Cre transgenic mice bearing Cre activity in all areas expressing Sim1, which chiefly includes the hypothalamus (especially the paraventricular nucleus, the supraoptic nucleus, and the posterior hypothalamus) and the mediobasal amygdala. Genomic DNA analyses in Sim1-CB1(-/-) mice indicated that the CB1 allele was excised from the hypothalamus and the amygdala, but not from the cortex, the striatum, the thalamus, the nucleus accumbens, the brainstem, the hippocampus, the pituitary gland, and the spinal cord. Double-fluorescent in situ hybridization experiments further indicated that Sim1-CB1(-/-) mice displayed a weaker CB1 receptor mRNA expression in the paraventricular nucleus of the hypothalamus and the mediobasal part of the amygdala, compared to wild-type animals. Individually housed Sim1-CB1(-/-) mice and their Sim1-CB1(+/+) littermates were exposed to anxiety and fear memory tests under basal conditions as well as after acute/repeated social stress. A principal component analysis of the behaviors of Sim1-CB1(-/-) and Sim1-CB1(+/+) mice in anxiety tests (open field, elevated plus-maze, and light/dark box) revealed that CB1 receptors from Sim1-expressing neurons exert tonic, albeit opposite, controls of locomotor and anxiety reactivity to novel environments. No difference between genotypes was observed during the recall of contextual fear conditioning or during active avoidance learning. Sim1-CB1(-/-), but not Sim1-CB1(+/+), mice proved sensitive to an acute social stress as this procedure reverted the increased ambulation in the center of the open field. The stimulatory influence of

  2. A Scalable Weight-Free Learning Algorithm for Regulatory Control of Cell Activity in Spiking Neuronal Networks.

    PubMed

    Zhang, Xu; Foderaro, Greg; Henriquez, Craig; Ferrari, Silvia

    2016-12-22

    Recent developments in neural stimulation and recording technologies are providing scientists with the ability of recording and controlling the activity of individual neurons in vitro or in vivo, with very high spatial and temporal resolution. Tools such as optogenetics, for example, are having a significant impact in the neuroscience field by delivering optical firing control with the precision and spatiotemporal resolution required for investigating information processing and plasticity in biological brains. While a number of training algorithms have been developed to date for spiking neural network (SNN) models of biological neuronal circuits, exiting methods rely on learning rules that adjust the synaptic strengths (or weights) directly, in order to obtain the desired network-level (or functional-level) performance. As such, they are not applicable to modifying plasticity in biological neuronal circuits, in which synaptic strengths only change as a result of pre- and post-synaptic neuron firings or biological mechanisms beyond our control. This paper presents a weight-free training algorithm that relies solely on adjusting the spatiotemporal delivery of neuron firings in order to optimize the network performance. The proposed weight-free algorithm does not require any knowledge of the SNN model or its plasticity mechanisms. As a result, this training approach is potentially realizable in vitro or in vivo via neural stimulation and recording technologies, such as optogenetics and multielectrode arrays, and could be utilized to control plasticity at multiple scales of biological neuronal circuits. The approach is demonstrated by training SNNs with hundreds of units to control a virtual insect navigating in an unknown environment.

  3. Sexually Dimorphic Differentiation of a C. elegans Hub Neuron Is Cell Autonomously Controlled by a Conserved Transcription Factor.

    PubMed

    Serrano-Saiz, Esther; Oren-Suissa, Meital; Bayer, Emily A; Hobert, Oliver

    2017-01-23

    Functional and anatomical sexual dimorphisms in the brain are either the result of cells that are generated only in one sex or a manifestation of sex-specific differentiation of neurons present in both sexes. The PHC neuron pair of the nematode C. elegans differentiates in a strikingly sex-specific manner. In hermaphrodites the PHC neurons display a canonical pattern of synaptic connectivity similar to that of other sensory neurons, but in males PHC differentiates into a densely connected hub sensory neuron/interneuron, integrating a large number of male-specific synaptic inputs and conveying them to both male-specific and sex-shared circuitry. We show that the differentiation into such a hub neuron involves the sex-specific scaling of several components of the synaptic vesicle machinery, including the vesicular glutamate transporter eat-4/VGLUT, induction of neuropeptide expression, changes in axonal projection morphology, and a switch in neuronal function. We demonstrate that these molecular and anatomical remodeling events are controlled cell autonomously by the phylogenetically conserved Doublesex homolog dmd-3, which is both required and sufficient for sex-specific PHC differentiation. Cellular specificity of dmd-3 action is ensured by its collaboration with non-sex-specific terminal selector-type transcription factors, whereas the sex specificity of dmd-3 action is ensured by the hermaphrodite-specific transcriptional master regulator of hermaphroditic cell identity tra-1, which represses the transcription of dmd-3 in hermaphrodite PHC. Taken together, our studies provide mechanistic insights into how neurons are specified in a sexually dimorphic manner.

  4. The helium paradoxes.

    PubMed

    Anderson, D L

    1998-04-28

    The ratio 3He/4He (R) plays a central role in models of mantle evolution that propose an undegassed lower mantle, rich in the primordial isotope 3He. A large primordial volatile-rich reservoir, a feature of recent models, is inconsistent with high-temperature accretion and with estimates of crustal and bulk Earth chemistry. High R can alternatively reflect high integrated 3He/(U+Th) ratios or low 4He abundances, as expected in refractory portions of the upper mantle. I show that high R materials are gas-poor and are deficient in radiogenic 4He compared with midocean ridge basalts. The seemingly primitive (i.e., high R) signatures in "hotspot" magmas may be secondary, derived from CO2-rich gases, or residual peridotite, a result of differential partitioning of U and He into magmas. A shallow and low 3He source explains the spatial variability and the temporal trends of R in ocean islands and is consistent with a volatile-poor planet. A shallow origin for the "primitive" He signature in ocean island basalts, such as at Loihi, reconciles the paradoxical juxtaposition of crustal, seawater, and atmospheric signatures with inferred "primitive" characteristics. High 238U/204Pb components in ocean island basalts are generally attributed to recycled altered oceanic crust. The low 238U/3He component may be in the associated depleted refractory mantle. High 3He/4He ratios are due to low 4He, not excess 3He, and do not imply or require a deep or primordial or undegassed reservoir. 40Ar in the atmosphere also argues against such models.

  5. HIT paradigms and paradoxes.

    PubMed

    Warkentin, T E

    2011-07-01

    The current major problem with HIT is its overdiagnosis. This concept follows from the HIT central paradigm: HIT is caused by a subset of antibodies against platelet factor 4 (PF4)/heparin complexes that have strong platelet-activating properties. Prospective studies show that only a minority of sera containing such antibodies exhibit platelet-activating properties. Ironically, the earliest tests for HIT--platelet activation assays--remain today the most diagnostically useful, particularly the washed platelet assays. But the wider application of PF4-dependent immunoassays, and their much greater sensitivity for the larger subset of non-platelet-activating (and non-HIT-inducing) antibodies, has resulted in HIT overdiagnosis in many centres. Studies of anti-PF4/heparin immunization in diverse clinical situations have provided insights into the factors that influence the HIT immune response. Besides the conundrum of anticoagulant-induced thrombosis (including its potentiation of coumarin-induced microthrombosis), HIT evinces numerous other paradoxes: (i) it is a platelet-activating disorder with venous thrombosis as its predominant clinical manifestation; (ii) 'delayed-onset' (or 'autoimmune') HIT can lead to dramatic worsening of HIT-associated thrombosis despite cessation of heparin; (iii) partial thromboplastin time (PTT) monitoring of direct thrombin inhibitor treatment - and confounding of PTT monitoring by HIT-associated consumptive coagulopathy - infers that the worst subset of HIT patients may fail this therapeutic approach; (iv) the highly sulfated pentasaccharide anticoagulant, fondaparinux, can (rarely) cause HIT yet appears to be an effective treatment for this disorder; and (v) the transience of the HIT immune response means that many patients with previous HIT can safely receive future heparin. © 2011 International Society on Thrombosis and Haemostasis.

  6. [The paradox of motherhood].

    PubMed

    Ouaidou, N G

    1990-08-01

    All Sahelian countries are working to define their population policies. A population policy document avoids dispersion and duplication. It opens the path to efficiency. It makes it easier to achieve governmental socioeconomic objectives. Various recent population-related meetings have at least two points in common: they aim to overstep and improve a given situation and are at the same time some examples of implementing the Ndjamena action program, adopted in January 1989. All these population-centered actions return to the problem of adolescent fertility--a poignant problem. Adolescent pregnancy is a major source of family and social break-ups. This paradox of motherhood makes a violent storm burst in the skies ordinarily serene with joy and hope. It is an enemy perverse to economic development and social progress. Adolescent motherhood is a phenomenon which complicates and aggravates population problems and is taboo to the point it is still imperceptible, unknown. It is a problem of premier importance in the Sahel. Pregnancy strikes a woman so very unprepared for motherhood and its demands. It risks the life of a being which is preparing itself to enter the world. Adolescent pregnancy has equally tragic health effects: poorly performed underground abortions and maternal and infant deaths. Adolescent fertility is a burning problem regardless of the perspective (demographic, economic, social, or health). In Sahelian countries, one is beginning to be interested in and to speak about it. It will be necessary to search for solutions. Schools must be a top target for all activities aiming to check adolescent fertility. The emphasis must be on information, education, and responsibility of girls, boys, teachers, and parents. Education and training are of capital importance for socioeconomic development of the Sahel. All activities implemented in the education sector should include a large place for family life education in pregnancy prevention.

  7. Paradoxical and bidirectional drug effects.

    PubMed

    Smith, Silas W; Hauben, Manfred; Aronson, Jeffrey K

    2012-03-01

    A paradoxical drug reaction constitutes an outcome that is opposite from the outcome that would be expected from the drug's known actions. There are three types: 1. A paradoxical response in a condition for which the drug is being explicitly prescribed. 2. Paradoxical precipitation of a condition for which the drug is indicated, when the drug is being used for an alternative indication. 3. Effects that are paradoxical in relation to an aspect of the pharmacology of the drug but unrelated to the usual indication. In bidirectional drug reactions, a drug may produce opposite effects, either in the same or different individuals, the effects usually being different from the expected beneficial effect. Paradoxical and bidirectional drug effects can sometimes be harnessed for benefit; some may be adverse. Such reactions arise in a wide variety of drug classes. Some are common; others are reported in single case reports. Paradoxical effects are often adverse, since they are opposite the direction of the expected effect. They may complicate the assessment of adverse drug reactions, pharmacovigilance, and clinical management. Bidirectional effects may be clinically useful or adverse. From a clinical toxicological perspective, altered pharmacokinetics or pharmacodynamics in overdose may exacerbate paradoxical and bidirectional effects. Certain antidotes have paradoxical attributes, complicating management. Apparent clinical paradoxical or bidirectional effects and reactions ensue when conflicts arise at different levels in self-regulating biological systems, as complexity increases from subcellular components, such as receptors, to cells, tissues, organs, and the whole individual. These may be incompletely understood. Mechanisms of such effects include different actions at the same receptor, owing to changes with time and downstream effects; stereochemical effects; multiple receptor targets with or without associated temporal effects; antibody-mediated reactions; three

  8. Optogenetic Manipulation of Activity and Temporally Controlled Cell-Specific Ablation Reveal a Role for MCH Neurons in Sleep/Wake Regulation

    PubMed Central

    Tsunematsu, Tomomi; Ueno, Takafumi; Tabuchi, Sawako; Inutsuka, Ayumu; Tanaka, Kenji F.; Hasuwa, Hidetoshi; Kilduff, Thomas S.; Terao, Akira

    2014-01-01

    Melanin-concentrating hormone (MCH) is a neuropeptide produced in neurons sparsely distributed in the lateral hypothalamic area. Recent studies have reported that MCH neurons are active during rapid eye movement (REM) sleep, but their physiological role in the regulation of sleep/wakefulness is not fully understood. To determine the physiological role of MCH neurons, newly developed transgenic mouse strains that enable manipulation of the activity and fate of MCH neurons in vivo were generated using the recently developed knockin-mediated enhanced gene expression by improved tetracycline-controlled gene induction system. The activity of these cells was controlled by optogenetics by expressing channelrhodopsin2 (E123T/T159C) or archaerhodopsin-T in MCH neurons. Acute optogenetic activation of MCH neurons at 10 Hz induced transitions from non-REM (NREM) to REM sleep and increased REM sleep time in conjunction with decreased NREM sleep. Activation of MCH neurons while mice were in NREM sleep induced REM sleep, but activation during wakefulness was ineffective. Acute optogenetic silencing of MCH neurons using archaerhodopsin-T had no effect on any vigilance states. Temporally controlled ablation of MCH neurons by cell-specific expression of diphtheria toxin A increased wakefulness and decreased NREM sleep duration without affecting REM sleep. Together, these results indicate that acute activation of MCH neurons is sufficient, but not necessary, to trigger the transition from NREM to REM sleep and that MCH neurons also play a role in the initiation and maintenance of NREM sleep. PMID:24828644

  9. Electronic control of Ca2+ signalling in neuronal cells using an organic electronic ion pump.

    PubMed

    Isaksson, Joakim; Kjäll, Peter; Nilsson, David; Robinson, Nathaniel D; Berggren, Magnus; Richter-Dahlfors, Agneta

    2007-09-01

    Cells and tissues use finely regulated ion fluxes for their intra- and intercellular communication. Technologies providing spatial and temporal control for studies of such fluxes are however, limited. We have developed an electrophoretic ion pump made of poly(3,4-ethylenedioxythiophene) doped with poly(styrene sulphonate) (PEDOT:PSS) to mediate electronic control of the ion homeostasis in neurons. Ion delivery from a source reservoir to a receiving electrolyte via a PEDOT:PSS thin-film channel was achieved by electronic addressing. Ions are delivered in high quantities at an associated on/off ratio exceeding 300. This induces physiological signalling events that can be recorded at the single-cell level. Furthermore, miniaturization of the device to a 50-microm-wide channel allows for stimulation of individual cells. As this technology platform allows for electronic control of ion signalling in individual cells with proper spatial and temporal resolution, it will be useful in further studies of communication in biological systems.

  10. Adaptation as a mechanism for gain control in cockroach ON and OFF olfactory receptor neurons.

    PubMed

    Burgstaller, Maria; Tichy, Harald

    2012-02-01

    In many sensory systems adaptation acts as a gain control mechanism that optimizes sensory performance by trading increased sensitivity to low stimulus intensity for decreased sensitivity to high stimulus intensity. Adaptation of insect antennal olfactory receptor neurons (ORNs) has been studied for strong odour concentrations, either pulsed or constant. Here, we report that during slowly oscillating changes in the concentration of the odour of lemon oil, the ON and OFF ORNs on the antenna of the cockroach Periplaneta americana adapt to the actual odour concentration and the rate at which concentration changes. When odour concentration oscillates rapidly with brief periods, adaptation improves gain for instantaneous odour concentration and reduces gain for the rate of concentration change. Conversely, when odour concentration oscillates slowly with long periods, adaptation increases gain for the rate of change at the expense of instantaneous concentration. Without this gain control the ON and OFF ORNs would, at brief oscillation periods, soon reach their saturation level and become insensitive to further concentration increments and decrements. At long oscillation periods, on the other hand, the cue would simply be that the discharge begins to change. Because of the high gain for the rate of change, the cockroach will receive creeping changes in odour concentration, even if they persist in one direction. Gain control permits a high degree of precision at small rates when it counts most, without sacrificing the range of detection and without extending the measuring scale.

  11. Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1

    PubMed Central

    Cochella, Luisa; Tursun, Baris; Hsieh, Yi-Wen; Galindo, Samantha; Johnston, Robert J.; Chuang, Chiou-Fen; Hobert, Oliver

    2014-01-01

    Left/right asymmetric features of animals are either randomly distributed on either the left or right side within a population (“antisymmetries”) or found stereotypically on one particular side of an animal (“directional asymmetries”). Both types of asymmetries can be found in nervous systems, but whether the regulatory programs that establish these asymmetries share any mechanistic features is not known. We describe here an unprecedented molecular link between these two types of asymmetries in Caenorhabditis elegans. The zinc finger transcription factor die-1 is expressed in a directionally asymmetric manner in the gustatory neuron pair ASE left (ASEL) and ASE right (ASER), while it is expressed in an antisymmetric manner in the olfactory neuron pair AWC left (AWCL) and AWC right (AWCR). Asymmetric die-1 expression is controlled in a fundamentally distinct manner in these two neuron pairs. Importantly, asymmetric die-1 expression controls the directionally asymmetric expression of gustatory receptor proteins in the ASE neurons and the antisymmetric expression of olfactory receptor proteins in the AWC neurons. These asymmetries serve to increase the ability of the animal to discriminate distinct chemosensory inputs. PMID:24361693

  12. Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1.

    PubMed

    Cochella, Luisa; Tursun, Baris; Hsieh, Yi-Wen; Galindo, Samantha; Johnston, Robert J; Chuang, Chiou-Fen; Hobert, Oliver

    2014-01-01

    Left/right asymmetric features of animals are either randomly distributed on either the left or right side within a population ("antisymmetries") or found stereotypically on one particular side of an animal ("directional asymmetries"). Both types of asymmetries can be found in nervous systems, but whether the regulatory programs that establish these asymmetries share any mechanistic features is not known. We describe here an unprecedented molecular link between these two types of asymmetries in Caenorhabditis elegans. The zinc finger transcription factor die-1 is expressed in a directionally asymmetric manner in the gustatory neuron pair ASE left (ASEL) and ASE right (ASER), while it is expressed in an antisymmetric manner in the olfactory neuron pair AWC left (AWCL) and AWC right (AWCR). Asymmetric die-1 expression is controlled in a fundamentally distinct manner in these two neuron pairs. Importantly, asymmetric die-1 expression controls the directionally asymmetric expression of gustatory receptor proteins in the ASE neurons and the antisymmetric expression of olfactory receptor proteins in the AWC neurons. These asymmetries serve to increase the ability of the animal to discriminate distinct chemosensory inputs.

  13. The role of medullary serotonin (5-HT) neurons in respiratory control: contributions to eupneic ventilation, CO2 chemoreception, and thermoregulation.

    PubMed

    Hodges, Matthew R; Richerson, George B

    2010-05-01

    The functional roles of the medullary raphé, and specifically 5-HT neurons, are not well understood. It has previously been stated that the role of 5-HT has been so difficult to understand, because "it is implicated in virtually everything, but responsible for nothing"(Cowen PJ. Foreword. In: Serotonin and Sleep: Molecular, Functional and Clinical Aspects, edited by Monti JM, Prandi-Perumal SR, Jacobs BL, Nutt DJ. Switzerland: Birkhauser, 2008). Are 5-HT neurons important, and can we assign a general, or even specific, function to them given their diffuse projections? Recent data obtained from transgenic animals and other model systems indicate that the 5-HT system is not expendable, particularly during postnatal development, and likely plays specific roles in vital functions such as respiratory and thermoregulatory control. We recently provided a detailed and updated review of one specific function of 5-HT neurons, as central respiratory chemoreceptors contributing to the brain's ability to detect changes in pH/CO2 and stimulate adjustments to ventilation accordingly (9). Here, we turn our focus to recent data demonstrating that 5-HT neurons provide an essential excitatory drive to the respiratory network. We then further discuss their role in the CO2 chemoreflex, as well as other homeostatic functions that are closely related to ventilatory control. Last, we provide additional hypotheses/concepts that are worthy of further study, and how 5-HT neurons may be involved in human disease.

  14. Descending control of electroreception. I. Properties of nucleus praeeminentialis neurons projecting indirectly to the electrosensory lateral line lobe.

    PubMed

    Bastian, J; Bratton, B

    1990-04-01

    The first-order CNS processing region within the electrosensory system, the electrosensory lateral line lobe, receives massive descending inputs from the nucleus praeeminentialis as well as the primary afferent projection. The n. praeeminentialis receives its input from the electrosensory lateral line lobe as well as from higher centers; hence this nucleus occupies an important position in a feedback loop within the electrosensory system. This report describes the physiological properties of a category of n. praeeminentialis neurons characterized by very high spontaneous firing frequency, but relatively poor sensitivity to electrolocation targets as compared to neurons in the electrosensory lateral line lobe. These neurons are specialized to encode long-term changes in electric organ discharge amplitude with high resolution. Intracellular recording and Lucifer yellow staining of these neurons show that they are the previously described multipolar neurons of the n. praeeminentialis, and they project bilaterally to the posterior eminentia granularis. Posterior eminentia granularis efferents project to the electrosensory lateral line lobe forming its dorsal molecular layer. Hence, these multipolar cells influence the electrosensory lateral line lobe circuitry indirectly. The information that the multipolar cells encode regarding the electric organ discharge amplitude may be needed for a gain control mechanism operative within the electrosensory lateral line lobe. Previous studies have shown that the indirect projection from the n. praeeminentialis to the electrosensory lateral line lobe must be intact for this gain control mechanism to operate.

  15. Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly

    PubMed Central

    Scandaglia, Marilyn; Benito, Eva; Morenilla-Palao, Cruz; Fiorenza, Anna; del Blanco, Beatriz; Coca, Yaiza; Herrera, Eloísa; Barco, Angel

    2015-01-01

    The stimulus-regulated transcription factor Serum Response Factor (SRF) plays an important role in diverse neurodevelopmental processes related to structural plasticity and motile functions, although its precise mechanism of action has not yet been established. To further define the role of SRF in neural development and distinguish between cell-autonomous and non cell-autonomous effects, we bidirectionally manipulated SRF activity through gene transduction assays that allow the visualization of individual neurons and their comparison with neighboring control cells. In vitro assays showed that SRF promotes survival and filopodia formation and is required for normal asymmetric neurite outgrowth, indicating that its activation favors dendrite enlargement versus branching. In turn, in vivo experiments demonstrated that SRF-dependent regulation of neuronal morphology has important consequences in the developing cortex and retina, affecting neuronal migration, dendritic and axonal arborization and cell positioning in these laminated tissues. Overall, our results show that the controlled and timely activation of SRF is essential for the coordinated growth of neuronal processes, suggesting that this event regulates the switch between neuronal growth and branching during developmental processes. PMID:26638868

  16. Coordinate control of synaptic-layer specificity and rhodopsins in photoreceptor neurons

    PubMed Central

    Morey, Marta; Yee, Susan K.; Herman, Tory; Nern, Aljoscha; Blanco, Enrique; Zipursky, S. Lawrence

    2009-01-01

    How neurons make specific synaptic connections is a central question in neurobiology. The targeting of the Drosophila R7 and R8 photoreceptor axons to different synaptic layers in the brain provides a model with which to explore the genetic programs regulating target specificity. In principle this can be accomplished by cell-type-specific molecules mediating the recognition between synaptic partners1. Alternatively, specificity could also be achieved through cell-type-specific repression of particular targeting molecules. Here we show that a key step in the targeting of the R7 neuron is the active repression of the R8 targeting program. Repression is dependent on NF-YC, a subunit of the NF-Y (nuclear factor Y) transcription factor2. In the absence of NF-YC, R7 axons terminate in the same layer as R8 axons. Genetic experiments indicate that this is due solely to the derepression of the R8-specific transcription factor Senseless3 (Sens) late in R7 differentiation. Sens is sufficient to control R8 targeting specificity and we demonstrate that Sens directly binds to an evolutionarily conserved DNA sequence upstream of the start of transcription of an R8-specific cell-surface protein, Capricious (Caps) that regulates R8 target specificity. We show that R7 targeting requires the R7-specific transcription factor Prospero4,5 (Pros) in parallel to repression of the R8targetingpathway by NF-YC. Previous studies demonstrated that Sens6,7 and Pros8 directly regulate the expression of specific rhodopsins in R8 and R7. We propose that the use of the same transcription factors to promote the cell-type-specific expression of sensory receptors and cell-surface proteins regulating synaptic target specificity provides a simple and general mechanism for ensuring that transmission of sensory information is processed by the appropriate specialized neural circuits. PMID:18978774

  17. Obesity paradox in end-stage kidney disease patients.

    PubMed

    Park, Jongha; Ahmadi, Seyed-Foad; Streja, Elani; Molnar, Miklos Z; Flegal, Katherine M; Gillen, Daniel; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

    2014-01-01

    In the general population, obesity is associated with increased cardiovascular risk and decreased survival. In patients with end-stage renal disease (ESRD), however, an "obesity paradox" or "reverse epidemiology" (to include lipid and hypertension paradoxes) has been consistently reported, i.e. a higher body mass index (BMI) is paradoxically associated with better survival. This survival advantage of large body size is relatively consistent for hemodialysis patients across racial and regional differences, although published results are mixed for peritoneal dialysis patients. Recent data indicate that both higher skeletal muscle mass and increased total body fat are protective, although there are mixed data on visceral (intra-abdominal) fat. The obesity paradox in ESRD is unlikely to be due to residual confounding alone and has biologic plausibility. Possible causes of the obesity paradox include protein-energy wasting and inflammation, time discrepancy among competitive risk factors (undernutrition versus overnutrition), hemodynamic stability, alteration of circulatory cytokines, sequestration of uremic toxin in adipose tissue, and endotoxin-lipoprotein interaction. The obesity paradox may have significant clinical implications in the management of ESRD patients especially if obese dialysis patients are forced to lose weight upon transplant wait-listing. Well-designed studies exploring the causes and consequences of the reverse epidemiology of cardiovascular risk factors, including the obesity paradox, among ESRD patients could provide more information on mechanisms. These could include controlled trials of nutritional and pharmacologic interventions to examine whether gain in lean body mass or even body fat can improve survival and quality of life in these patients. © 2014.

  18. Amygdala Kisspeptin Neurons: Putative Mediators of Olfactory Control of the Gonadotropic Axis.

    PubMed

    Pineda, Rafael; Plaisier, Fabrice; Millar, Robert P; Ludwig, Mike

    2017-01-01

    Kisspeptins and their receptors are potent regulators of the gonadotropic axis. Kisspeptin neurons are found mainly in the hypothalamic arcuate nucleus and the anteroventral periventricular nucleus. However, there is also a third population of kisspeptin neurons, located in the amygdala. We used fluorescence immunohistochemistry to quantify and localize the amygdala kisspeptin neurons and to reveal close apposition and putative innervations by vasopressinergic and tyrosine hydroxylase-positive dopaminergic neurons. Using microinjections of retro- and anterograde tracers, and viral transfection systems in rats and transgenic mice, we showed reciprocal connectivity between the accessory olfactory bulb and the amygdala kisspeptin neurons. In vitro recordings indicate an inhibitory action of kisspeptin on mitral cells in the accessory olfactory bulb. Using viral specific-cell gene expression in transgenic mice in combination with double immunofluorescence histochemistry, we found that the amygdala kisspeptin neurons also project to gonadotropin-releasing hormone (GnRH) neurons in the preoptic area. Our neuroanatomical and electrophysiological data suggest that amygdala kisspeptin neurons integrate social behaviour and odour information into GnRH neurons in the preoptic area to coordinate the gonadotropic axis and the appropriate output behaviour to odour cues. © 2016 S. Karger AG, Basel.

  19. An Acid Hydrocarbon: A Chemical Paradox

    ERIC Educational Resources Information Center

    Burke, Jeffrey T.

    2004-01-01

    The chemical paradox of cyclopentadiene, a hydrocarbon, producing bubbles like a Bronsted acid is observed. The explanation that it is the comparative thermodynamic constancy of the fragrant cyclopentadienyl anion, which produces the powerful effect, resolves the paradox.

  20. An Acid Hydrocarbon: A Chemical Paradox

    ERIC Educational Resources Information Center

    Burke, Jeffrey T.

    2004-01-01

    The chemical paradox of cyclopentadiene, a hydrocarbon, producing bubbles like a Bronsted acid is observed. The explanation that it is the comparative thermodynamic constancy of the fragrant cyclopentadienyl anion, which produces the powerful effect, resolves the paradox.

  1. Continuous neuronal ensemble control of simulated arm reaching by a human with tetraplegia

    NASA Astrophysics Data System (ADS)

    Chadwick, E. K.; Blana, D.; Simeral, J. D.; Lambrecht, J.; Kim, S. P.; Cornwell, A. S.; Taylor, D. M.; Hochberg, L. R.; Donoghue, J. P.; Kirsch, R. F.

    2011-06-01

    Functional electrical stimulation (FES), the coordinated electrical activation of multiple muscles, has been used to restore arm and hand function in people with paralysis. User interfaces for such systems typically derive commands from mechanically unrelated parts of the body with retained volitional control, and are unnatural and unable to simultaneously command the various joints of the arm. Neural interface systems, based on spiking intracortical signals recorded from the arm area of motor cortex, have shown the ability to control computer cursors, robotic arms and individual muscles in intact non-human primates. Such neural interface systems may thus offer a more natural source of commands for restoring dexterous movements via FES. However, the ability to use decoded neural signals to control the complex mechanical dynamics of a reanimated human limb, rather than the kinematics of a computer mouse, has not been demonstrated. This study demonstrates the ability of an individual with long-standing tetraplegia to use cortical neuron recordings to command the real-time movements of a simulated dynamic arm. This virtual arm replicates the dynamics associated with arm mass and muscle contractile properties, as well as those of an FES feedback controller that converts user commands into the required muscle activation patterns. An individual with long-standing tetraplegia was thus able to control a virtual, two-joint, dynamic arm in real time using commands derived from an existing human intracortical interface technology. These results show the feasibility of combining such an intracortical interface with existing FES systems to provide a high-performance, natural system for restoring arm and hand function in individuals with extensive paralysis. This paper was originally submitted for the special issue containing contributions from the Fourth International Brain-Computer Interface Meeting.

  2. Continuous neuronal ensemble control of simulated arm reaching by a human with tetraplegia.

    PubMed

    Chadwick, E K; Blana, D; Simeral, J D; Lambrecht, J; Kim, S P; Cornwell, A S; Taylor, D M; Hochberg, L R; Donoghue, J P; Kirsch, R F

    2011-06-01

    Functional electrical stimulation (FES), the coordinated electrical activation of multiple muscles, has been used to restore arm and hand function in people with paralysis. User interfaces for such systems typically derive commands from mechanically unrelated parts of the body with retained volitional control, and are unnatural and unable to simultaneously command the various joints of the arm. Neural interface systems, based on spiking intracortical signals recorded from the arm area of motor cortex, have shown the ability to control computer cursors, robotic arms and individual muscles in intact non-human primates. Such neural interface systems may thus offer a more natural source of commands for restoring dexterous movements via FES. However, the ability to use decoded neural signals to control the complex mechanical dynamics of a reanimated human limb, rather than the kinematics of a computer mouse, has not been demonstrated. This study demonstrates the ability of an individual with long-standing tetraplegia to use cortical neuron recordings to command the real-time movements of a simulated dynamic arm. This virtual arm replicates the dynamics associated with arm mass and muscle contractile properties, as well as those of an FES feedback controller that converts user commands into the required muscle activation patterns. An individual with long-standing tetraplegia was thus able to control a virtual, two-joint, dynamic arm in real time using commands derived from an existing human intracortical interface technology. These results show the feasibility of combining such an intracortical interface with existing FES systems to provide a high-performance, natural system for restoring arm and hand function in individuals with extensive paralysis.

  3. Characterization of GABAergic neurons in rapid-eye-movement sleep controlling regions of the brainstem reticular formation in GAD67-green fluorescent protein knock-in mice.

    PubMed

    Brown, Ritchie E; McKenna, James T; Winston, Stuart; Basheer, Radhika; Yanagawa, Yuchio; Thakkar, Mahesh M; McCarley, Robert W

    2008-01-01

    Recent experiments suggest that brainstem GABAergic neurons may control rapid-eye-movement (REM) sleep. However, understanding their pharmacology/physiology has been hindered by difficulty in identification. Here we report that mice expressing green fluorescent protein (GFP) under the control of the GAD67 promoter (GAD67-GFP knock-in mice) exhibit numerous GFP-positive neurons in the central gray and reticular formation, allowing on-line identification in vitro. Small (10-15 microm) or medium-sized (15-25 microm) GFP-positive perikarya surrounded larger serotonergic, noradrenergic, cholinergic and reticular neurons, and > 96% of neurons were double-labeled for GFP and GABA, confirming that GFP-positive neurons are GABAergic. Whole-cell recordings in brainstem regions important for promoting REM sleep [subcoeruleus (SubC) or pontine nucleus oralis (PnO) regions] revealed that GFP-positive neurons were spontaneously active at 3-12 Hz, fired tonically, and possessed a medium-sized depolarizing sag during hyperpolarizing steps. Many neurons also exhibited a small, low-threshold calcium spike. GFP-positive neurons were tested with pharmacological agents known to promote (carbachol) or inhibit (orexin A) REM sleep. SubC GFP-positive neurons were excited by the cholinergic agonist carbachol, whereas those in the PnO were either inhibited or excited. GFP-positive neurons in both areas were excited by orexins/hypocretins. These data are congruent with the hypothesis that carbachol-inhibited GABAergic PnO neurons project to, and inhibit, REM-on SubC reticular neurons during waking, whereas carbachol-excited SubC and PnO GABAergic neurons are involved in silencing locus coeruleus and dorsal raphe aminergic neurons during REM sleep. Orexinergic suppression of REM during waking is probably mediated in part via excitation of acetylcholine-inhibited GABAergic neurons.

  4. Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control?

    PubMed

    Braegelmann, K M; Streeter, K A; Fields, D P; Baker, T L

    2017-01-01

    For most individuals, the respiratory control system produces a remarkably stable and coordinated motor output-recognizable as a breath-from birth until death. Very little is understood regarding the processes by which the respiratory control system maintains network stability in the presence of changing physiological demands and network properties that occur throughout life. An emerging principle of neuroscience is that neural activity is sensed and adjusted locally to assure that neurons continue to operate in an optimal range, yet to date, it is unknown whether such homeostatic plasticity is a feature of the neurons controlling breathing. Here, we review the evidence that local mechanisms sense and respond to perturbations in respiratory neural activity, with a focus on plasticity in respiratory motor neurons. We discuss whether these forms of plasticity represent homeostatic plasticity in respiratory control. We present new analyses demonstrating that reductions in synaptic inputs to phrenic motor neurons elicit a compensatory enhancement of phrenic inspiratory motor output, a form of plasticity termed inactivity-induced phrenic motor facilitation (iPMF), that is proportional to the magnitude of activity deprivation. Although the physiological role of iPMF is not understood, we hypothesize that it has an important role in protecting the drive to breathe during conditions of prolonged or intermittent reductions in respiratory neural activity, such as following spinal cord injury or during central sleep apnea.

  5. Allegre's Lead Paradox Revisited

    NASA Astrophysics Data System (ADS)

    Hofmann, A. W.; Goldstein, S. L.; Class, C.

    2007-12-01

    Allegre (1969), using a generalized Concordia plot, was first to note that in a 4.55 Ga old Earth, Pb has been removed from the mantle in preference to U, even though magmatism tends to do the opposite. He noted that this "contradiction" might require a separate reservoir where the missing lead is stored. This "contradiction", more commonly expressed by the conventional Holmes-Houtermans diagram, has become known as the "lead paradox." Several models have been proposed to resolve it, ranging from late "core pumping" of Pb (as suggested by Allègre) to Pb storage in the mantle transition zone (Murphy et al. 2003) or in ancient parts of the lower continental crust. The idea of late core pumping has recently been revived by Wood & Halliday (2005) who suggested that Pb was sequestered through late sulfide segregation into the core. Here we propose that crystallization of Ca-perovskite, accompanied by segregation of a dense silicate melt toward the core-mantle boundary, can account for the apparently elevated U/Pb ratio of the accessible silicate Earth, particularly if the partition coefficient for U and Th in Ca-perovskite is as high as 400 as suggested by Corgne and Wood (2005). Such a dense liquid is the inferred consequence of the measured crossover of melting temperatures of silicate perovskite and ferro-periclase at about 1200 km depth, and the predicted Fe-rich eutectic and low melting temperatures in the lowermost mantle (Boehler, 2000). In addition, lower-mantle melt segregation with residual Ca-perovskite will cause a decrease in Nb/Ta from the primitive (chondritic) value in the accessible mantle, another, more recently discovered puzzle of mantle geochemistry. Downward segregation of a dense melt fraction and final solidification of the lowermost mantle may have been a slow process requiring more than 100 Ma, and involving a substantial fraction of the mantle. We suggest that this process served to stabilize the D'' reservoir storing solar noble gases

  6. Selective activation of dorsal raphe nucleus-projecting neurons in the ventral medial prefrontal cortex by controllable stress

    PubMed Central

    Baratta, Michael V.; Zarza, Christina M.; Gomez, Devan M.; Campeau, Serge; Watkins, Linda R.; Maier, Steven F.

    2009-01-01

    Exposure to uncontrollable stressors produces a variety of behavioral consequences (e.g. exaggerated fear, reduced social exploration) that do not occur if the stressor is controllable. In addition, an initial experience with a controllable stressor can block the behavioral and neural responses to a later uncontrollable stressor. The serotonergic (5-HT) dorsal raphe nucleus (DRN) has come to be viewed as a critical structure in mediating the behavioral effects of uncontrollable stress. Recent work suggests that the buffering effects of behavioral control on the DRN-dependent behavioral outcomes of uncontrollable stress require ventral medial prefrontal cortex (mPFCv) activation at the time of behavioral control. The present studies were conducted to directly determine whether or not controllable stress selectively activates DRN-projecting neurons within the mPFCv. To examine this possibility in the rat, we combined retrograde tracing (fluorogold iontophoresed into the DRN) with Fos immunohistochemistry, a marker for neural activation. Exposure to controllable, relative to uncontrollable, stress increased Fos expression in fluorogold-labeled neurons in the prelimbic region (PL) of the mPFCv. Furthermore, in a separate experiment, a prior experience with controllable stress led to potentiation of Fos expression in retrogradely labeled PL neurons in response to an uncontrollable stressor one week later. These results suggest that the PL selectively responds to behavioral control and utilizes such information to regulate the brainstem response to ongoing and subsequent stressors. PMID:19686468

  7. Classical three-box 'paradox'

    NASA Astrophysics Data System (ADS)

    Kirkpatrick, K. A.

    2003-05-01

    A simple classical probabilistic system (a simple card game) classically exemplifies Aharonov and Vaidman's 'three-box 'paradox'' (1991 J. Phys. A: Math. Gen. 24 2315), implying that the three-box example is neither quantal nor a paradox and leaving one with less difficulty to busy the interpreters of quantum mechanics. An ambiguity in the usual expression of the retrodiction formula is shown to have misled Albert et al (1985 Phys. Rev. Lett. 54 5) to a result not, in fact, 'curious'; the discussion illustrates how to avoid this ambiguity.

  8. Reciprocal Control of Drinking Behavior by Median Preoptic Neurons in Mice

    PubMed Central

    Abbott, Stephen B. G.; Machado, Natalia L. S.; Geerling, Joel C.

    2016-01-01

    Stimulation of glutamatergic neurons in the subfornical organ drives drinking behavior, but the brain targets that mediate this response are not known. The densest target of subfornical axons is the anterior tip of the third ventricle, containing the median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a region that has also been implicated in fluid and electrolyte management. The neurochemical composition of this region is complex, containing both GABAergic and glutamatergic neurons, but the possible roles of these neurons in drinking responses have not been addressed. In mice, we show that optogenetic stimulation of glutamatergic neurons in MnPO/OVLT drives voracious water consumption, and that optogenetic stimulation of GABAergic neurons in the same region selectively reduces water consumption. Both populations of neurons have extensive projections to overlapping regions of the thalamus, hypothalamus, and hindbrain that are much more extensive than those from the subfornical organ, suggesting that the MnPO/OVLT serves as a key link in regulating drinking responses. SIGNIFICANCE STATEMENT Neurons in the median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT) are known to regulate fluid/electrolyte homeostasis, but few studies have examined this issue with an appreciation for the neurochemical heterogeneity of these nuclei. Using Cre-Lox genetic targeting of Channelrhodospin-2 in transgenic mice, we demonstrate that glutamate and GABA neurons in the MnPO/OVLT reciprocally regulate water consumption. Stimulating glutamatergic MnPO/OVLT neurons induced water consumption, whereas stimulating GABAergic MnPO neurons caused a sustained and specific reduction in water consumption in dehydrated mice, the latter highlighting a heretofore unappreciated role of GABAergic MnPO neurons in thirst regulation. These observations represent an important advance in our understanding of the neural circuits involved in

  9. Joining forces: Motor control meets mirror neurons. Comment on "Grasping synergies: A motor-control approach to the mirror neuron mechanism" by D'Ausilio, Bartoli, and Maffongelli

    NASA Astrophysics Data System (ADS)

    Casile, Antonino

    2015-03-01

    Several consistent and compelling experimental findings suggest that in primates the observation of actions or movements activates the observer's motor cortex (for a recent and very thorough review see [1]). One important piece of evidence was the discovery of mirror neurons, that are neurons in the macaque ventral pre-motor (area F5), motor and parietal cortices (area PFG) that respond both when the monkey executes a goal-directed motor act (e.g. breaking a peanut) or when it sees a similar action executed by others [2-5]. A similar system has been later reported also in humans ([6-8] but see also [9,10] for negative results).

  10. Controlled noxious chemical stimulation: responses of rat trigeminal brainstem neurones to CO2 pulses applied to the nasal mucosa.

    PubMed

    Anton, F; Peppel, P; Euchner, I; Handwerker, H O

    1991-02-25

    The nasal mucosa of halothane-anesthetized rats was stimulated with defined CO2 pulses. Recordings were performed from single trigeminal brainstem neurons to characterize their responses to this controlled chemical irritation. All cells examined with this stimulus displayed graded discharges to increasing concentrations of CO2. Enhanced responses were obtained in a group of neurons when the duration of the interstimulus interval was increased. The application of chemical irritants, notably mustard oil or acetic acid induced vigorous ongoing discharges in all cells tested. The CO2 stimulation method described here thus provides an ideal model for the quantitative physiological and pharmacological examination of chemically induced nociception.

  11. Nitric oxide control of cardiac function: is neuronal nitric oxide synthase a key component?

    PubMed Central

    Sears, Claire E; Ashley, Euan A; Casadei, Barbara

    2004-01-01

    Nitric oxide (NO) has been shown to regulate cardiac function, both in physiological conditions and in disease states. However, several aspects of NO signalling in the myocardium remain poorly understood. It is becoming increasingly apparent that the disparate functions ascribed to NO result from its generation by different isoforms of the NO synthase (NOS) enzyme, the varying subcellular localization and regulation of NOS isoforms and their effector proteins. Some apparently contrasting findings may have arisen from the use of non-isoform-specific inhibitors of NOS, and from the assumption that NO donors may be able to mimic the actions of endogenously produced NO. In recent years an at least partial explanation for some of the disagreements, although by no means all, may be found from studies that have focused on the role of the neuronal NOS (nNOS) isoform. These data have shown a key role for nNOS in the control of basal and adrenergically stimulated cardiac contractility and in the autonomic control of heart rate. Whether or not the role of nNOS carries implications for cardiovascular disease remains an intriguing possibility requiring future study. PMID:15306414

  12. Neuronal control of mammalian vocalization, with special reference to the squirrel monkey.

    PubMed

    Jürgens, U

    1998-08-01

    Squirrel monkey vocalization can be considered as a suitable model for the study in humans of the neurobiological basis of nonverbal emotional vocal utterances, such as laughing, crying, and groaning. Evaluation of electrical and chemical brain stimulation data, lesioning studies, single-neurone recordings, and neuroanatomical tracing work leads to the following conclusions: The periaqueductal gray and laterally bordering tegmentum of the midbrain represent a crucial area for the production of vocalization. This area collects the various vocalization-triggering stimuli, such as auditory, visual, and somatosensory input from diverse sensory-processing structures, motivation-controlling input from some limbic structures, and volitional impulses from the anterior cingulate cortex. Destruction of this area causes mutism. It is still under dispute whether the periaqueductal region harbors the vocal pattern generator or merely couples vocalization-triggering information to motor-coordinating structures further downward in the brainstem. The periaqueductal region is connected with the phonatory motoneuron pools indirectly via one or several interneurons. The nucleus retroambiguus represents a crucial relay station for the laryngeal and expiratory component of vocalization. The articulatory component reaches the orofacial motoneuron pools via the parvocellular reticular formation. Essential proprioceptive feedback from the larynx and lungs enter the vocal-controlling network via the solitary tract nucleus.

  13. Neuronal Control of Mammalian Vocalization, with Special Reference to the Squirrel Monkey

    NASA Astrophysics Data System (ADS)

    Jürgens, Uwe

    Squirrel monkey vocalization can be considered as a suitable model for the study in humans of the neurobiological basis of nonverbal emotional vocal utterances, such as laughing, crying, and groaning. Evaluation of electrical and chemical brain stimulation data, lesioning studies, single-neurone recordings, and neuroanatomical tracing work leads to the following conclusions: The periaqueductal gray and laterally bordering tegmentum of the midbrain represent a crucial area for the production of vocalization. This area collects the various vocalization-triggering stimuli, such as auditory, visual, and somatosensory input from diverse sensory-processing structures, motivation-controlling input from some limbic structures, and volitional impulses from the anterior cingulate cortex. Destruction of this area causes mutism. It is still under dispute whether the periaqueductal region harbors the vocal pattern generator or merely couples vocalization-triggering information to motor-coordinating structures further downward in the brainstem. The periaqueductal region is connected with the phonatory motoneuron pools indirectly via one or several interneurons. The nucleus retroambiguus represents a crucial relay station for the laryngeal and expiratory component of vocalization. The articulatory component reaches the orofacial motoneuron pools via the parvocellular reticular formation. Essential proprioceptive feedback from the larynx and lungs enter the vocal-controlling network via the solitary tract nucleus.

  14. Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells

    PubMed Central

    Ferretti, Elisabetta; De Smaele, Enrico; Miele, Evelina; Laneve, Pietro; Po, Agnese; Pelloni, Marianna; Paganelli, Arianna; Di Marcotullio, Lucia; Caffarelli, Elisa; Screpanti, Isabella; Bozzoni, Irene; Gulino, Alberto

    2008-01-01

    MicroRNAs (miRNA) are crucial post-transcriptional regulators of gene expression and control cell differentiation and proliferation. However, little is known about their targeting of specific developmental pathways. Hedgehog (Hh) signalling controls cerebellar granule cell progenitor development and a subversion of this pathway leads to neoplastic transformation into medulloblastoma (MB). Using a miRNA high-throughput profile screening, we identify here a downregulated miRNA signature in human MBs with high Hh signalling. Specifically, we identify miR-125b and miR-326 as suppressors of the pathway activator Smoothened together with miR-324-5p, which also targets the downstream transcription factor Gli1. Downregulation of these miRNAs allows high levels of Hh-dependent gene expression leading to tumour cell proliferation. Interestingly, the downregulation of miR-324-5p is genetically determined by MB-associated deletion of chromosome 17p. We also report that whereas miRNA expression is downregulated in cerebellar neuronal progenitors, it increases alongside differentiation, thereby allowing cell maturation and growth inhibition. These findings identify a novel regulatory circuitry of the Hh signalling and suggest that misregulation of specific miRNAs, leading to its aberrant activation, sustain cancer development. PMID:18756266

  15. Olfactory receptor neurons use gain control and complementary kinetics to encode intermittent odorant stimuli

    PubMed Central

    Gorur-Shandilya, Srinivas; Demir, Mahmut; Long, Junjiajia; Clark, Damon A; Emonet, Thierry

    2017-01-01

    Insects find food and mates by navigating odorant plumes that can be highly intermittent, with intensities and durations that vary rapidly over orders of magnitude. Much is known about olfactory responses to pulses and steps, but it remains unclear how olfactory receptor neurons (ORNs) detect the intensity and timing of natural stimuli, where the absence of scale in the signal makes detection a formidable olfactory task. By stimulating Drosophila ORNs in vivo with naturalistic and Gaussian stimuli, we show that ORNs adapt to stimulus mean and variance, and that adaptation and saturation contribute to naturalistic sensing. Mean-dependent gain control followed the Weber-Fechner relation and occurred primarily at odor transduction, while variance-dependent gain control occurred at both transduction and spiking. Transduction and spike generation possessed complementary kinetic properties, that together preserved the timing of odorant encounters in ORN spiking, regardless of intensity. Such scale-invariance could be critical during odor plume navigation. DOI: http://dx.doi.org/10.7554/eLife.27670.001 PMID:28653907

  16. Olfactory Sensory Neurons Control Dendritic Complexity of Mitral Cells via Notch Signaling

    PubMed Central

    Saito, Tetsuichiro

    2016-01-01

    Mitral cells (MCs) of the mammalian olfactory bulb have a single primary dendrite extending into a single glomerulus, where they receive odor information from olfactory sensory neurons (OSNs). Molecular mechanisms for controlling dendritic arbors of MCs, which dynamically change during development, are largely unknown. Here we found that MCs displayed more complex dendritic morphologies in mouse mutants of Maml1, a crucial gene in Notch signaling. Similar phenotypes were observed by conditionally misexpressing a dominant negative form of MAML1 (dnMAML1) in MCs after their migration. Conversely, conditional misexpression of a constitutively active form of Notch reduced their dendritic complexity. Furthermore, the intracellular domain of Notch1 (NICD1) was localized to nuclei of MCs. These findings suggest that Notch signaling at embryonic stages is involved in the dendritic complexity of MCs. After the embryonic misexpression of dnMAML1, many MCs aberrantly extended dendrites to more than one glomerulus at postnatal stages, suggesting that Notch signaling is essential for proper formation of olfactory circuits. Moreover, dendrites in cultured MCs were shortened by Jag1-expressing cells. Finally, blocking the activity of Notch ligands in OSNs led to an increase in dendritic complexity as well as a decrease in NICD1 signals in MCs. These results demonstrate that the dendritic complexity of MCs is controlled by their presynaptic partners, OSNs. PMID:28027303

  17. Neuronal systems and circuits involved in the control of food intake and adaptive thermogenesis.

    PubMed

    Caron, Alexandre; Richard, Denis

    2017-03-01

    With the still-growing prevalence of obesity worldwide, major efforts are made to understand the various behavioral, environmental, and genetic factors that promote excess fat gain. Obesity results from an imbalance between energy intake and energy expenditure, which emphasizes the importance of deciphering the mechanisms behind energy balance regulation to understand its physiopathology. The control of energy balance is assured by brain systems/circuits capable of generating adequate ingestive and thermogenic responses to maintain the stability of energy reserves, which implies a proper integration of the homeostatic signals that inform about the status of the energy stores. In this article, we overview the organization and functionality of key neuronal circuits or pathways involved in the control of food intake and energy expenditure. We review the role of the corticolimbic (executive and reward) and autonomic systems that integrate their activities to regulate energy balance. We also describe the mechanisms and pathways whereby homeostatic sensing is achieved in response to variations of homeostatic hormones, such as leptin, insulin, and ghrelin, while putting some emphasis on the prominent importance of the mechanistic target of the rapamycin signaling pathway in coordinating the homeostatic sensing process. © 2016 New York Academy of Sciences.

  18. Model-Based Analysis and Control of a Network of Basal Ganglia Spiking Neurons in the Normal and Parkinsonian States

    PubMed Central

    Liu, Jianbo; Khalil, Hassan K.; Oweiss, Karim G.

    2011-01-01

    Controlling the spatiotemporal firing pattern of an intricately connected network of neurons through microstimulation is highly desirable in many applications. We investigated in this paper the feasibility of using a model-based approach to the analysis and control of a Basal Ganglia (BG) network model of Hodgkin–Huxley (HH) spiking neurons through microstimulation. Detailed analysis of this network model suggests that it can reproduce the experimentally observed characteristics of BG neurons under a normal and a pathological Parkinsonian state. A simplified neuronal firing rate model, identified from the detailed HH network model, is shown to capture the essential network dynamics. Mathematical analysis of the simplified model reveals the presence of a systematic relationship between the network’s structure and its dynamic response to spatiotemporally patterned microstimulation. We show that both the network synaptic organization and the local mechanism of microstimulation can impose tight constraints on the possible spatiotemporal firing patterns that can be generated by the microstimulated network, which may hinder the effectiveness of microstimulation to achieve a desired objective under certain conditions. Finally, we demonstrate that the feedback control design aided by the mathematical analysis of the simplified model is indeed effective in driving the BG network in the normal and Parskinsonian states to follow a prescribed spatiotemporal firing pattern. We further show that the rhythmic/oscillatory patterns that characterize a dopamine-depleted BG network can be suppressed as a direct consequence of controlling the spatiotemporal pattern of a subpopulation of the output Globus Pallidus internalis (GPi) neurons in the network. This work may provide plausible explanations for the mechanisms underlying the therapeutic effects of Deep Brain Stimulation (DBS) in PD and pave the way towards a model-based, network level analysis and closed-loop control and

  19. Neuropeptide Secreted from a Pacemaker Activates Neurons to Control a Rhythmic Behavior

    PubMed Central

    Wang, Han; Girskis, Kelly; Janssen, Tom; Chan, Jason P.; Dasgupta, Krishnakali; Knowles, James A.; Schoofs, Liliane; Sieburth, Derek

    2013-01-01

    Summary Background Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 seconds, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown. Results Here we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G protein-coupled receptor on the GABAergic neurons, as the receptor of NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo. Conclusions Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors. PMID:23583549

  20. Analysis of connectivity map: Control to glutamate injured and phenobarbital treated neuronal network

    NASA Astrophysics Data System (ADS)

    Kamal, Hassan; Kanhirodan, Rajan; Srinivas, Kalyan V.; Sikdar, Sujit K.

    2010-04-01

    We study the responses of a cultured neural network when it is exposed to epileptogenesis glutamate injury causing epilepsy and subsequent treatment with phenobarbital by constructing connectivity map of neurons using correlation matrix. This study is particularly useful in understanding the pharmaceutical drug induced changes in the neuronal network properties with insights into changes at the systems biology level.

  1. Roles of oxytocin neurones in the control of stress, energy metabolism, and social behaviour.

    PubMed

    Onaka, T; Takayanagi, Y; Yoshida, M

    2012-04-01

    Oxytocin neurones are activated by stressful stimuli, food intake and social attachment. Activation of oxytocin neurones in response to stressful stimuli or food intake is mediated, at least in part, by noradrenaline/prolactin-releasing peptide (PrRP) neurones in the nucleus tractus solitarius, whereas oxytocin neurones are activated after social stimuli via medial amygdala neurones. Activation of oxytocin neurones induces the release of oxytocin not only from their axon terminals, but also from their dendrites. Oxytocin acts locally where released or diffuses and acts on remote oxytocin receptors widely distributed within the brain, resulting in anxiolytic, anorexic and pro-social actions. The action sites of oxytocin appear to be multiple. Oxytocin shows anxiolytic actions, at least in part, via serotoninergic neurones in the median raphe nucleus, has anorexic actions via pro-opiomelanocortin neurones in the nucleus tractus solitarius and facilitates social recognition via the medial amygdala. Stress, obesity and social isolation are major risk factors for mortality in humans. Thus, the oxytocin-oxytocin receptor system is a therapeutic target for the promotion of human health. © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.

  2. Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures.

    PubMed

    Lantoine, Joséphine; Grevesse, Thomas; Villers, Agnès; Delhaye, Geoffrey; Mestdagh, Camille; Versaevel, Marie; Mohammed, Danahe; Bruyère, Céline; Alaimo, Laura; Lacour, Stéphanie P; Ris, Laurence; Gabriele, Sylvain

    2016-05-01

    The ability to construct easily in vitro networks of primary neurons organized with imposed topologies is required for neural tissue engineering as well as for the development of neuronal interfaces with desirable characteristics. However, accumulating evidence suggests that the mechanical properties of the culture matrix can modulate important neuronal functions such as growth, extension, branching and activity. Here we designed robust and reproducible laminin-polylysine grid micropatterns on cell culture substrates that have similar biochemical properties but a 100-fold difference in Young's modulus to investigate the role of the matrix rigidity on the formation and activity of cortical neuronal networks. We found that cell bodies of primary cortical neurons gradually accumulate in circular islands, whereas axonal extensions spread on linear tracks to connect circular islands. Our findings indicate that migration of cortical neurons is enhanced on soft substrates, leading to a faster formation of neuronal networks. Furthermore, the pre-synaptic density was two times higher on stiff substrates and consistently the number of action potentials and miniature synaptic currents was enhanced on stiff substrates. Taken together, our results provide compelling evidence to indicate that matrix stiffness is a key parameter to modulate the growth dynamics, synaptic density and electrophysiological activity of cortical neuronal networks, thus providing useful information on scaffold design for neural tissue engineering.

  3. Controlling the spontaneous spiking regularity via channel blocking on Newman-Watts networks of Hodgkin-Huxley neurons

    NASA Astrophysics Data System (ADS)

    Ozer, Mahmut; Perc, Matjaž; Uzuntarla, Muhammet

    2009-05-01

    We investigate the regularity of spontaneous spiking activity on Newman-Watts small-world networks consisting of biophysically realistic Hodgkin-Huxley neurons with a tunable intensity of intrinsic noise and fraction of blocked voltage-gated sodium and potassium ion channels embedded in neuronal membranes. We show that there exists an optimal fraction of shortcut links between physically distant neurons, as well as an optimal intensity of intrinsic noise, which warrant an optimally ordered spontaneous spiking activity. This doubly coherence resonance-like phenomenon depends significantly on, and can be controlled via, the fraction of closed sodium and potassium ion channels, whereby the impacts can be understood via the analysis of the firing rate function as well as the deterministic system dynamics. Potential biological implications of our findings for information propagation across neural networks are also discussed.

  4. Speed and segmentation control mechanisms characterized in rhythmically-active circuits created from spinal neurons produced from genetically-tagged embryonic stem cells.

    PubMed

    Sternfeld, Matthew J; Hinckley, Christopher A; Moore, Niall J; Pankratz, Matthew T; Hilde, Kathryn L; Driscoll, Shawn P; Hayashi, Marito; Amin, Neal D; Bonanomi, Dario; Gifford, Wesley D; Sharma, Kamal; Goulding, Martyn; Pfaff, Samuel L

    2017-02-14

    Flexible neural networks, such as the interconnected spinal neurons that control distinct motor actions, can switch their activity to produce different behaviors. Both excitatory (E) and inhibitory (I) spinal neurons are necessary for motor behavior, but the influence of recruiting different ratios of E-to-I cells remains unclear. We constructed synthetic microphysical neural networks, called circuitoids, using precise combinations of spinal neuron subtypes derived from mouse stem cells. Circuitoids of purified excitatory interneurons were sufficient to generate oscillatory bursts with properties similar to in vivo central pattern generators. Inhibitory V1 neurons provided dual layers of regulation within excitatory rhythmogenic networks - they increased the rhythmic burst frequency of excitatory V3 neurons, and segmented excitatory motor neuron activity into sub-networks. Accordingly, the speed and pattern of spinal circuits that underlie complex motor behaviors may be regulated by quantitatively gating the intra-network cellular activity ratio of E-to-I neurons.

  5. Wnt-5a-regulated miR-101b controls COX2 expression in hippocampal neurons.

    PubMed

    Codocedo, Juan Francisco; Inestrosa, Nibaldo C

    2016-02-19

    Wnt-5a is a member of the WNT family of secreted lipoglycoproteins, whose expression increases during development; moreover, Wnt-5a plays a key role in synaptic structure and function in the adult nervous system. However, the mechanism underlying these effects is still elusive. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the gene expression of their targets through hybridization with complementary sequences in the 3' UTR, thereby inhibiting the translation of the target proteins. Several evidences indicate that the miRNAs are actively involved in the regulation of neuronal function. In the present study, we examined whether Wnt-5a modulates the levels of miRNAs in hippocampal neurons. Using PCR arrays, we identified a set of miRNAs that respond to Wnt-5a treatment. One of the most affected miRNAs was miR-101b, which targets cyclooxygenase-2 (COX2), an inducible enzyme that converts arachidonic acid to prostanoids, and has been involved in the injury/inflammatory response, and more recently in neuronal plasticity. Consistent with the Wnt-5a regulation of miR-101b, this Wnt ligand regulates COX2 expression in a time-dependent manner in cultured hippocampal neurons. The biological processes induced by Wnt-5a in hippocampal neurons, involve the regulation of several miRNAs including miR-101b, which has the capacity to regulate several targets, including COX-2 in the central nervous system.

  6. Cadherin-8 expression, synaptic localization and molecular control of neuronal form in prefrontal cortico-striatal circuits

    PubMed Central

    Friedman, Lauren G.; Riemslagh, Fréderike W.; Sullivan, Josefa M.; Mesias, Roxana; Williams, Frances M.; Huntley, George W.; Benson, Deanna L.

    2014-01-01

    Neocortical interactions with dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson’s disease, and Huntington’s disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of molecular mechanisms that control generation of prefrontal cortex-striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin 8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in medial prefrontal cortex and in striatal medium spiny neurons forming the direct- or indirect-pathways. Developmental analysis of quantitative RTPCR and Western blot data show that Cdh8 expression peaks in prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High-resolution immunoelectron-microscopy shows Cdh8 is concentrated at excitatory synapses in dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self-avoidance. Taken together our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses. PMID:25158904

  7. A screen for constituents of motor control and decision making in Drosophila reveals visual distance-estimation neurons

    PubMed Central

    Triphan, Tilman; Nern, Aljoscha; Roberts, Sonia F.; Korff, Wyatt; Naiman, Daniel Q.; Strauss, Roland

    2016-01-01

    Climbing over chasms larger than step size is vital to fruit flies, since foraging and mating are achieved while walking. Flies avoid futile climbing attempts by processing parallax-motion vision to estimate gap width. To identify neuronal substrates of climbing control, we screened a large collection of fly lines with temporarily inactivated neuronal populations in a novel high-throughput assay described here. The observed climbing phenotypes were classified; lines in each group are reported. Selected lines were further analysed by high-resolution video cinematography. One striking class of flies attempts to climb chasms of unsurmountable width; expression analysis guided us to C2 optic-lobe interneurons. Inactivation of C2 or the closely related C3 neurons with highly specific intersectional driver lines consistently reproduced hyperactive climbing whereas strong or weak artificial depolarization of C2/C3 neurons strongly or mildly decreased climbing frequency. Contrast-manipulation experiments support our conclusion that C2/C3 neurons are part of the distance-evaluation system. PMID:27255169

  8. A screen for constituents of motor control and decision making in Drosophila reveals visual distance-estimation neurons.

    PubMed

    Triphan, Tilman; Nern, Aljoscha; Roberts, Sonia F; Korff, Wyatt; Naiman, Daniel Q; Strauss, Roland

    2016-06-03

    Climbing over chasms larger than step size is vital to fruit flies, since foraging and mating are achieved while walking. Flies avoid futile climbing attempts by processing parallax-motion vision to estimate gap width. To identify neuronal substrates of climbing control, we screened a large collection of fly lines with temporarily inactivated neuronal populations in a novel high-throughput assay described here. The observed climbing phenotypes were classified; lines in each group are reported. Selected lines were further analysed by high-resolution video cinematography. One striking class of flies attempts to climb chasms of unsurmountable width; expression analysis guided us to C2 optic-lobe interneurons. Inactivation of C2 or the closely related C3 neurons with highly specific intersectional driver lines consistently reproduced hyperactive climbing whereas strong or weak artificial depolarization of C2/C3 neurons strongly or mildly decreased climbing frequency. Contrast-manipulation experiments support our conclusion that C2/C3 neurons are part of the distance-evaluation system.

  9. The Drosophila TRPA1 Channel and Neuronal Circuits Controlling Rhythmic Behaviours and Sleep in Response to Environmental Temperature.

    PubMed

    Roessingh, Sanne; Stanewsky, Ralf

    2017-10-03

    trpA1 encodes a thermosensitive transient receptor potential channel (TRP channel) that functions in selection of preferred temperatures and noxious heat avoidance. In this review, we discuss the evidence for a role of TRPA1 in the control of rhythmic behaviours in Drosophila melanogaster. Activity levels during the afternoon and rhythmic temperature preference are both regulated by TRPA1. In contrast, TRPA1 is dispensable for temperature synchronisation of circadian clocks. We discuss the neuronal basis of TRPA1-mediated temperature effects on rhythmic behaviours, and conclude that they are mediated by partly overlapping but distinct neuronal circuits. We have previously shown that TRPA1 is required to maintain siesta sleep under warm temperature cycles. Here, we present new data investigating the neuronal circuit responsible for this regulation. First, we discuss the difficulties that remain in identifying the responsible neurons. Second, we discuss the role of clock neurons (s-LNv/DN1 network) in temperature-driven regulation of siesta sleep, and highlight the role of TRPA1 therein. Finally, we discuss the sexual dimorphic nature of siesta sleep and propose that the s-LNv/DN1 clock network could play a role in the integration of environmental information, mating status and other internal drives, to appropriately drive adaptive sleep/wake behaviour.

  10. Neurons in the Cochlear Nuclei Controlling the Tensor Tympani Muscle in the Rat: a Study Using Pseudorabies Virus

    PubMed Central

    Billig, I.; Yeager, M.S.; Blikas, A.; Raz, Y.

    2010-01-01

    The middle ear muscle reflex has been implicated in modulation of auditory input and protection of the inner ear from acoustic trauma. However, the identification of neurons in the cochlear nuclei participating in this reflex has not been fully elucidated. In the present study, we injected the retrograde transynaptic tracer pseudorabies virus into single tensor tympani (TT) muscles, and identified transynaptically labeled cochlear nucleus neurons at multiple survival times. Motoneurons controlling TT were located ventral to the ipsilateral motor trigeminal nucleus and extended rostrally towards the medial aspect of the lateral lemniscus. Transynaptically-labeled neurons were observed bilaterally in the dorsal and dorso-medial parts of ventral cochlear nuclei as early as 48 h after virus injection, and had morphological features of radiate multipolar cells. After ≥ 69 h, labeled cells of different types were observed in all cochlear nuclei. At those times, labeling was also detected bilaterally in the medial nucleus of the trapezoid body and periolivary cell groups in the superior olivary complex. Based on the temporal course of viral replication, our data strongly suggest the presence of a direct projection of neurons from the ventral cochlear nuclei bilaterally to the TT motoneuron pool in rats. The influence of neurons in the cochlear nuclei upon TT activity through direct and indirect pathways may account for multifunctional roles of this muscle in auditory functions. PMID:17482147

  11. M-type potassium conductance controls the emergence of neural phase codes: a combined experimental and neuron modelling study.

    PubMed

    Kwag, Jeehyun; Jang, Hyun Jae; Kim, Mincheol; Lee, Sujeong

    2014-10-06

    Rate and phase codes are believed to be important in neural information processing. Hippocampal place cells provide a good example where both coding schemes coexist during spatial information processing. Spike rate increases in the place field, whereas spike phase precesses relative to the ongoing theta oscillation. However, what intrinsic mechanism allows for a single neuron to generate spike output patterns that contain both neural codes is unknown. Using dynamic clamp, we simulate an in vivo-like subthreshold dynamics of place cells to in vitro CA1 pyramidal neurons to establish an in vitro model of spike phase precession. Using this in vitro model, we show that membrane potential oscillation (MPO) dynamics is important in the emergence of spike phase codes: blocking the slowly activating, non-inactivating K+ current (IM), which is known to control subthreshold MPO, disrupts MPO and abolishes spike phase precession. We verify the importance of adaptive IM in the generation of phase codes using both an adaptive integrate-and-fire and a Hodgkin-Huxley (HH) neuron model. Especially, using the HH model, we further show that it is the perisomatically located IM with slow activation kinetics that is crucial for the generation of phase codes. These results suggest an important functional role of IM in single neuron computation, where IM serves as an intrinsic mechanism allowing for dual rate and phase coding in single neurons.

  12. Tcf4 Controls Neuronal Migration of the Cerebral Cortex through Regulation of Bmp7.

    PubMed

    Chen, Tianda; Wu, Qinwei; Zhang, Yang; Lu, Tianlan; Yue, Weihua; Zhang, Dai

    2016-01-01

    Background: Transcription factor 4 (TCF4) is found to be associated with schizophrenia. TCF4 mutations also cause Pitt-Hopkins Syndrome, a neurodevelopmental disorder associated with severe mental retardation. However, the function of TCF4 during brain development remains unclear. Results: Here, we report that Tcf4 is expressed in the developing cerebral cortex. In utero suppression of Tcf4 arrested neuronal migration, leading to accumulation of ectopic neurons in the intermediate zone. Knockdown of Tcf4 impaired leading process formation. Furthermore, Bone Morphogenetic Protein 7 (Bmp7) is upregulated in Tcf4-deficient neurons. In vivo gain of function and rescue experiments demonstrated that Bmp7 is the major downstream effector of Tcf4 required for neuronal migration. Conclusion: Thus, we have uncovered a new Tcf4/Bmp7-dependent mechanism underlying neuronal migration, and provide insights into the pathogenesis of neurodevelopmental disorders.

  13. Relative infertility: modeling clinical paradoxes.

    PubMed

    Jansen, R P

    1993-05-01

    To assume that a cause of relative infertility will decrease the monthly chance of conception (fecundability) in a dose-dependent manner and, by a mathematical model, to identify common clinical observations and paradoxes that are explainable within this hypothesis. An empirically based assumption of a population-mean fecundability of 0.2 and the accumulating probability of pregnancy equations and projections were used to examine over time the effects of diminishing such fecundability to one half, one fifth, and one twentieth of normal, and then reversing this effect with ideal treatment at points of 2 years and 5 years. [1] The duration of infertility is an important and powerful covariate in determining residual fecundability and the chance of pregnancy, with or without treatment. [2] The more substantial the pathology is, the greater should be the likelihood of pregnancy after its effective treatment. [3] Provided no harm is done by treatment, an increase in subsequent fecundability will result whatever the "dose" of the reproductive disturbance, but this will not always mean that pregnancy is probable. [4] The presence of a second infertility factor should compound dramatically the deleterious effects attributable to the first and make it more likely for either factor to be diagnosed. Duration of infertility is generally more important than the dose of an infertility factor as a covariate in clinical studies, and more emphasis should be placed on controlling for it. Discouraging clinical reports on the low success of treating certain conditions associated with infertility do not necessarily justify rejecting a hypothesis that such a condition decreases fertility in a dose-dependent manner.

  14. Law of the Minimum paradoxes.

    PubMed

    Gorban, Alexander N; Pokidysheva, Lyudmila I; Smirnova, Elena V; Tyukina, Tatiana A

    2011-09-01

    The "Law of the Minimum" states that growth is controlled by the scarcest resource (limiting factor). This concept was originally applied to plant or crop growth (Justus von Liebig, 1840, Salisbury, Plant physiology, 4th edn., Wadsworth, Belmont, 1992) and quantitatively supported by many experiments. Some generalizations based on more complicated "dose-response" curves were proposed. Violations of this law in natural and experimental ecosystems were also reported. We study models of adaptation in ensembles of similar organisms under load of environmental factors and prove that violation of Liebig's law follows from adaptation effects. If the fitness of an organism in a fixed environment satisfies the Law of the Minimum then adaptation equalizes the pressure of essential factors and, therefore, acts against the Liebig's law. This is the the Law of the Minimum paradox: if for a randomly chosen pair "organism-environment" the Law of the Minimum typically holds, then in a well-adapted system, we have to expect violations of this law.For the opposite interaction of factors (a synergistic system of factors which amplify each other), adaptation leads from factor equivalence to limitations by a smaller number of factors.For analysis of adaptation, we develop a system of models based on Selye's idea of the universal adaptation resource (adaptation energy). These models predict that under the load of an environmental factor a population separates into two groups (phases): a less correlated, well adapted group and a highly correlated group with a larger variance of attributes, which experiences problems with adaptation. Some empirical data are presented and evidences of interdisciplinary applications to econometrics are discussed.

  15. Catecholamines inhibit neuronal activity in the glossopharyngeal-vagal motor complex of the Japanese eel: significance for controlling swallowing water.

    PubMed

    Ito, Sunao; Mukuda, Takao; Ando, Masaaki

    2006-06-01

    To clarify neuronal networks controlling swallowing water, inhibitory neurotransmitters were searched on the glossopharyngeal-vagal motor complex (GVC) of the medulla oblongata (MO), which is proposed as a motor nucleus controlling swallowing. Spontaneous firing (20-30 Hz) in the GVC was inhibited by adrenaline (AD), noradrenaline (NA) and dopamine (DA). The inhibitory effects of these catecholamines (CAs) were dose-dependent, and the effects of AD and NA were completely blocked by phenoxybenzamine or yohimbine, indicating that at least these two CAs act on the same receptor, presumably on alpha(2)-adrenoceptor. Even after blocking the alpha(2)-adrenoceptor with yohimbine, the inhibitory effect of DA still remained, indicating separate action of DA from AD or NA. Although DA receptor type was not determined in the present study, these results suggest existence of CA receptors in the GVC neurons. Almost 70% GVC neurons were inhibited by CAs. The CA-sensitive neurons were specifically restricted in the middle part of the GVC area. There were many tyrosine hydroxylase (TH)-immunoreactive somata and fibers in the eel MO. Among these TH-immunoreactive nuclei, the area postrema (AP) and the commissural nucleus of Cajal (NCC) appeared to project to the GVC morphologically. Significance of the catecholaminergic inhibition in the GVC activity is discussed in relation to controlling swallowing water. (c) 2006 Wiley-Liss, Inc.

  16. Molecular control of the amount, subcellular location, and activity state of translation elongation factor 2 in neurons experiencing stress.

    PubMed

    Argüelles, Sandro; Camandola, Simonetta; Hutchison, Emmette R; Cutler, Roy G; Ayala, Antonio; Mattson, Mark P

    2013-08-01

    Eukaryotic elongation factor 2 (eEF-2) is an important regulator of the protein translation machinery whereby it controls the movement of the ribosome along the mRNA. The activity of eEF-2 is regulated by changes in cellular energy status and nutrient availability and by posttranslational modifications such as phosphorylation and mono-ADP-ribosylation. However, the mechanisms regulating protein translation under conditions of cellular stress in neurons are unknown. Here we show that when rat hippocampal neurons experience oxidative stress (lipid peroxidation induced by exposure to cumene hydroperoxide; CH), eEF-2 is hyperphosphorylated and ribosylated, resulting in reduced translational activity. The degradation of eEF-2 requires calpain proteolytic activity and is accompanied by accumulation of eEF-2 in the nuclear compartment. The subcellular localization of both native and phosphorylated forms of eEF-2 is influenced by CRM1 and 14.3.3, respectively. In hippocampal neurons p53 interacts with nonphosphorylated (active) eEF-2, but not with its phosphorylated form. The p53-eEF-2 complexes are present in cytoplasm and nucleus, and their abundance increases when neurons experience oxidative stress. The nuclear localization of active eEF-2 depends upon its interaction with p53, as cells lacking p53 contain less active eEF-2 in the nuclear compartment. Overexpression of eEF-2 in hippocampal neurons results in increased nuclear levels of eEF-2 and decreased cell death after exposure to CH. Our results reveal novel molecular mechanisms controlling the differential subcellular localization and activity state of eEF-2 that may influence the survival status of neurons during periods of elevated oxidative stress.

  17. A Hebbian learning rule gives rise to mirror neurons and links them to control theoretic inverse models.

    PubMed

    Hanuschkin, A; Ganguli, S; Hahnloser, R H R

    2013-01-01

    Mirror neurons are neurons whose responses to the observation of a motor act resemble responses measured during production of that act. Computationally, mirror neurons have been viewed as evidence for the existence of internal inverse models. Such models, rooted within control theory, map-desired sensory targets onto the motor commands required to generate those targets. To jointly explore both the formation of mirrored responses and their functional contribution to inverse models, we develop a correlation-based theory of interactions between a sensory and a motor area. We show that a simple eligibility-weighted Hebbian learning rule, operating within a sensorimotor loop during motor explorations and stabilized by heterosynaptic competition, naturally gives rise to mirror neurons as well as control theoretic inverse models encoded in the synaptic weights from sensory to motor neurons. Crucially, we find that the correlational structure or stereotypy of the neural code underlying motor explorations determines the nature of the learned inverse model: random motor codes lead to causal inverses that map sensory activity patterns to their motor causes; such inverses are maximally useful, by allowing the imitation of arbitrary sensory target sequences. By contrast, stereotyped motor codes lead to less useful predictive inverses that map sensory activity to future motor actions. Our theory generalizes previous work on inverse models by showing that such models can be learned in a simple Hebbian framework without the need for error signals or backpropagation, and it makes new conceptual connections between the causal nature of inverse models, the statistical structure of motor variability, and the time-lag between sensory and motor responses of mirror neurons. Applied to bird song learning, our theory can account for puzzling aspects of the song system, including necessity of sensorimotor gating and selectivity of auditory responses to bird's own song (BOS) stimuli.

  18. A Hebbian learning rule gives rise to mirror neurons and links them to control theoretic inverse models

    PubMed Central

    Hanuschkin, A.; Ganguli, S.; Hahnloser, R. H. R.

    2013-01-01

    Mirror neurons are neurons whose responses to the observation of a motor act resemble responses measured during production of that act. Computationally, mirror neurons have been viewed as evidence for the existence of internal inverse models. Such models, rooted within control theory, map-desired sensory targets onto the motor commands required to generate those targets. To jointly explore both the formation of mirrored responses and their functional contribution to inverse models, we develop a correlation-based theory of interactions between a sensory and a motor area. We show that a simple eligibility-weighted Hebbian learning rule, operating within a sensorimotor loop during motor explorations and stabilized by heterosynaptic competition, naturally gives rise to mirror neurons as well as control theoretic inverse models encoded in the synaptic weights from sensory to motor neurons. Crucially, we find that the correlational structure or stereotypy of the neural code underlying motor explorations determines the nature of the learned inverse model: random motor codes lead to causal inverses that map sensory activity patterns to their motor causes; such inverses are maximally useful, by allowing the imitation of arbitrary sensory target sequences. By contrast, stereotyped motor codes lead to less useful predictive inverses that map sensory activity to future motor actions. Our theory generalizes previous work on inverse models by showing that such models can be learned in a simple Hebbian framework without the need for error signals or backpropagation, and it makes new conceptual connections between the causal nature of inverse models, the statistical structure of motor variability, and the time-lag between sensory and motor responses of mirror neurons. Applied to bird song learning, our theory can account for puzzling aspects of the song system, including necessity of sensorimotor gating and selectivity of auditory responses to bird's own song (BOS) stimuli. PMID

  19. Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance.

    PubMed

    Stump, Madeliene; Guo, Deng-Fu; Lu, Ko-Ting; Mukohda, Masashi; Liu, Xuebo; Rahmouni, Kamal; Sigmund, Curt D

    2016-07-01

    Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NES(Cre)/PPARγ-P467L) or selectively in POMC neurons (POMC(Cre)/PPARγ-P467L). Whereas POMC(Cre)/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMC(Cre)/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMC(Cre)/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMC(Cre)/PPARγ-WT, but not POMC(Cre)/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

  20. The Paradox of Painful Art

    ERIC Educational Resources Information Center

    Smuts, Aaron

    2007-01-01

    Many of the most popular genres of narrative art are designed to elicit negative emotions: emotions that are experienced as painful or involving some degree of pain, which people generally avoid in their daily lives. Traditionally, the question of why people seek out such experiences of painful art has been presented as the paradox of tragedy, and…

  1. Gene networks and liar paradoxes.

    PubMed

    Isalan, Mark

    2009-10-01

    Network motifs are small patterns of connections, found over-represented in gene regulatory networks. An example is the negative feedback loop (e.g. factor A represses itself). This opposes its own state so that when 'on' it tends towards 'off' - and vice versa. Here, we argue that such self-opposition, if considered dimensionlessly, is analogous to the liar paradox: 'This statement is false'. When 'true' it implies 'false' - and vice versa. Such logical constructs have provided philosophical consternation for over 2000 years. Extending the analogy, other network topologies give strikingly varying outputs over different dimensions. For example, the motif 'A activates B and A. B inhibits A' can give switches or oscillators with time only, or can lead to Turing-type patterns with both space and time (spots, stripes or waves). It is argued here that the dimensionless form reduces to a variant of 'The following statement is true. The preceding statement is false'. Thus, merely having a static topological description of a gene network can lead to a liar paradox. Network diagrams are only snapshots of dynamic biological processes and apparent paradoxes can reveal important biological mechanisms that are far from paradoxical when considered explicitly in time and space.

  2. Gene networks and liar paradoxes

    PubMed Central

    Isalan, Mark

    2009-01-01

    Network motifs are small patterns of connections, found over-represented in gene regulatory networks. An example is the negative feedback loop (e.g. factor A represses itself). This opposes its own state so that when ‘on’ it tends towards ‘off’ – and vice versa. Here, we argue that such self-opposition, if considered dimensionlessly, is analogous to the liar paradox: ‘This statement is false’. When ‘true’ it implies ‘false’ – and vice versa. Such logical constructs have provided philosophical consternation for over 2000 years. Extending the analogy, other network topologies give strikingly varying outputs over different dimensions. For example, the motif ‘A activates B and A. B inhibits A’ can give switches or oscillators with time only, or can lead to Turing-type patterns with both space and time (spots, stripes or waves). It is argued here that the dimensionless form reduces to a variant of ‘The following statement is true. The preceding statement is false’. Thus, merely having a static topological description of a gene network can lead to a liar paradox. Network diagrams are only snapshots of dynamic biological processes and apparent paradoxes can reveal important biological mechanisms that are far from paradoxical when considered explicitly in time and space. PMID:19722183

  3. Mechanical Paradox: The Uphill Roller

    ERIC Educational Resources Information Center

    Cortes, Emilio; Cortes-Poza, D.

    2011-01-01

    We analyse in detail the dynamics of a mechanical system which is a rigid body with the geometry of a double cone. This double cone is apparently able to spontaneously roll uphill along inclined rails. The experiment has been known for some centuries, and because of its peculiar behaviour, it has been named "mechanical paradox". Although this…

  4. CCC and the Fermi paradox

    NASA Astrophysics Data System (ADS)

    Gurzadyan, V. G.; Penrose, R.

    2016-01-01

    Within the scheme of conformal cyclic cosmology (CCC), information can be transmitted from aeon to aeon. Accordingly, the "Fermi paradox" and the SETI programme --of communication by remote civilizations-- may be examined from a novel perspective: such information could, in principle, be encoded in the cosmic microwave background. The current empirical status of CCC is also discussed.

  5. Economics and the Fermi Paradox

    NASA Astrophysics Data System (ADS)

    Hosek, W. R.

    A resolution of the Fermi paradox is proposed using common economic assumptions that should apply to all intelligent, planet-bound civilizations. It is argued that seemingly rational decisions about resource allocation will lead all civilizations to forego the commitment to interstellar exploration and colonization. Consequently humans have not, and will not, be visited by them and humans will not visit other civilizations.

  6. The Paradox of Case Study.

    ERIC Educational Resources Information Center

    Simons, Helen

    1996-01-01

    Examines the paradox of case studies' abilities to understand the complexity in particular contexts while not being generalizable. Argues that the pressure for quantification and multisite case study design in policy research has weakened the original utility of the case study method for understanding complex educational phenomena. (DSK)

  7. Review Essay: Pondering Pedagogical Paradoxes

    ERIC Educational Resources Information Center

    Spencer, Leland G.

    2015-01-01

    Herein, Leland Spencer provides a review of four book selections while reflecting on paradoxes regularly faced by feminist teachers (and scholars, activists, and thinkers). The books include: (1) Bradley, Harriet. "Gender." Cambridge: Polity, 2012. Print; (2) Murphy, Michael J., and Elizabeth N. Ribarsky, eds. "Activities for…

  8. Paradoxical Results and Item Bundles

    ERIC Educational Resources Information Center

    Hooker, Giles; Finkelman, Matthew

    2010-01-01

    Hooker, Finkelman, and Schwartzman ("Psychometrika," 2009, in press) defined a paradoxical result as the attainment of a higher test score by changing answers from correct to incorrect and demonstrated that such results are unavoidable for maximum likelihood estimates in multidimensional item response theory. The potential for these results to…

  9. Teaching Quantum Physics without Paradoxes

    ERIC Educational Resources Information Center

    Hobson, Art

    2007-01-01

    Although the resolution to the wave-particle paradox has been known for 80 years, it is seldom presented. Briefly, the resolution is that material particles and photons are the quanta of extended spatially continuous but energetically quantized fields. But because the resolution resides in quantum field theory and is not usually spelled out in…

  10. Mechanical Paradox: The Uphill Roller

    ERIC Educational Resources Information Center

    Cortes, Emilio; Cortes-Poza, D.

    2011-01-01

    We analyse in detail the dynamics of a mechanical system which is a rigid body with the geometry of a double cone. This double cone is apparently able to spontaneously roll uphill along inclined rails. The experiment has been known for some centuries, and because of its peculiar behaviour, it has been named "mechanical paradox". Although this…

  11. Review Essay: Pondering Pedagogical Paradoxes

    ERIC Educational Resources Information Center

    Spencer, Leland G.

    2015-01-01

    Herein, Leland Spencer provides a review of four book selections while reflecting on paradoxes regularly faced by feminist teachers (and scholars, activists, and thinkers). The books include: (1) Bradley, Harriet. "Gender." Cambridge: Polity, 2012. Print; (2) Murphy, Michael J., and Elizabeth N. Ribarsky, eds. "Activities for…

  12. The Paradox of Painful Art

    ERIC Educational Resources Information Center

    Smuts, Aaron

    2007-01-01

    Many of the most popular genres of narrative art are designed to elicit negative emotions: emotions that are experienced as painful or involving some degree of pain, which people generally avoid in their daily lives. Traditionally, the question of why people seek out such experiences of painful art has been presented as the paradox of tragedy, and…

  13. Teaching Quantum Physics without Paradoxes

    ERIC Educational Resources Information Center

    Hobson, Art

    2007-01-01

    Although the resolution to the wave-particle paradox has been known for 80 years, it is seldom presented. Briefly, the resolution is that material particles and photons are the quanta of extended spatially continuous but energetically quantized fields. But because the resolution resides in quantum field theory and is not usually spelled out in…

  14. Paradoxical Results and Item Bundles

    ERIC Educational Resources Information Center

    Hooker, Giles; Finkelman, Matthew

    2010-01-01

    Hooker, Finkelman, and Schwartzman ("Psychometrika," 2009, in press) defined a paradoxical result as the attainment of a higher test score by changing answers from correct to incorrect and demonstrated that such results are unavoidable for maximum likelihood estimates in multidimensional item response theory. The potential for these results to…

  15. Development and application of an optogenetic platform for controlling and imaging a large number of individual neurons

    NASA Astrophysics Data System (ADS)

    Mohammed, Ali Ibrahim Ali

    The understanding and treatment of brain disorders as well as the development of intelligent machines is hampered by the lack of knowledge of how the brain fundamentally functions. Over the past century, we have learned much about how individual neurons and neural networks behave, however new tools are critically needed to interrogate how neural networks give rise to complex brain processes and disease conditions. Recent innovations in molecular techniques, such as optogenetics, have enabled neuroscientists unprecedented precision to excite, inhibit and record defined neurons. The impressive sensitivity of currently available optogenetic sensors and actuators has now enabled the possibility of analyzing a large number of individual neurons in the brains of behaving animals. To promote the use of these optogenetic tools, this thesis integrates cutting edge optogenetic molecular sensors which is ultrasensitive for imaging neuronal activity with custom wide field optical microscope to analyze a large number of individual neurons in living brains. Wide-field microscopy provides a large field of view and better spatial resolution approaching the Abbe diffraction limit of fluorescent microscope. To demonstrate the advantages of this optical platform, we imaged a deep brain structure, the Hippocampus, and tracked hundreds of neurons over time while mouse was performing a memory task to investigate how those individual neurons related to behavior. In addition, we tested our optical platform in investigating transient neural network changes upon mechanical perturbation related to blast injuries. In this experiment, all blasted mice show a consistent change in neural network. A small portion of neurons showed a sustained calcium increase for an extended period of time, whereas the majority lost their activities. Finally, using optogenetic silencer to control selective motor cortex neurons, we examined their contributions to the network pathology of basal ganglia related to

  16. Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: implications for peripheral vascular control.

    PubMed

    Copp, Steven W; Hirai, Daniel M; Sims, Gabrielle E; Fels, Richard J; Musch, Timothy I; Poole, David C; Kenney, Michael J

    2013-05-01

    Neuronal nitric oxide (NO) synthase (nNOS) inhibition with systemically administered S-methyl-l-thiocitrulline (SMTC) elevates mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle and renal blood flow. We tested the hypothesis that those SMTC-induced cardiovascular effects resulted, in part, from increased sympathetic nerve discharge (SND). MAP, HR, and lumbar and renal SND (direct nerve recordings) were measured in 9 baroreceptor (sino-aortic)-denervated rats for 20min each following both saline and SMTC (0.56mg/kg i.v.). SMTC increased MAP (peak ΔMAP: 50±8mmHg, p<0.01) compared to saline. Lumbar and renal SND were not different between saline and SMTC conditions at any time (p>0.05). The ΔSND between saline and SMTC conditions for the lumbar and renal nerves were not different from zero (peak ΔSND, lumbar: 2.0±6.8%; renal: 9.7±9.0%, p>0.05 versus zero for both). These data support that SMTC-induced reductions in skeletal muscle and renal blood flow reported previously reflect peripheral nNOS-derived NO vascular control as opposed to increased sympathetic vasoconstriction. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Developmental programming of hypothalamic neuronal circuits: impact on energy balance control